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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. the kidneys has occurred in persons taking large doses ("megadoses") of ascorbic acid (vitamin C) as well as in a number of persons who were "juicing" (extraction of juice from vegetables or fruit) with high oxalate-containing foods .Ingestion of ethylene glycol, an oxalate precursor, can lead to excess production and increased concentrations of oxalate in both the plasma and urine .Hyperoxaluria in association with total parenteral nutrition has been described in premature infants and adults .Hyperoxaluria has been documented in peroxisomal biogenesis disorders, Zellweger spectrum despite the apparent cytoplasmic stability of alanine:glyoxylate aminotransferase . The presence of hyperoxaluria was statistically correlated with the degree of neurologic involvement.ManagementEvaluations Following Initial DiagnosisThe following evaluations are recommended in part based on the guidelines and suggestions of the European hyperoxaluria consortium (OxalEurope) (see Table 3), and Hoppe .For those with preserved renal | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. been described in premature infants and adults .Hyperoxaluria has been documented in peroxisomal biogenesis disorders, Zellweger spectrum despite the apparent cytoplasmic stability of alanine:glyoxylate aminotransferase . The presence of hyperoxaluria was statistically correlated with the degree of neurologic involvement.ManagementEvaluations Following Initial DiagnosisThe following evaluations are recommended in part based on the guidelines and suggestions of the European hyperoxaluria consortium (OxalEurope) (see Table 3), and Hoppe .For those with preserved renal function (i.e., GFR >60 mL/min/1.73 m2):Renal ultrasound examination and fundoscopic eye examination to identify the presence/extent of oxalate depositionBaseline urinalysis and measurement of oxalate and creatinine, preferably in a 24-hour collectionFor those with a GFR <60 mL/min/1.73 m2, in addition to the above evaluations: measurement of plasma oxalateFor those with | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. and Hoppe .For those with preserved renal function (i.e., GFR >60 mL/min/1.73 m2):Renal ultrasound examination and fundoscopic eye examination to identify the presence/extent of oxalate depositionBaseline urinalysis and measurement of oxalate and creatinine, preferably in a 24-hour collectionFor those with a GFR <60 mL/min/1.73 m2, in addition to the above evaluations: measurement of plasma oxalateFor those with a GFR <30 mL/min/1.73 m2 or in whom there is a rapid deterioration in function, in addition to the above evaluations:Bone x-rays to evaluate for radiodense metaphyseal bands and diffuse demineralization or evidence of pathologic fracturesHemoglobin to evaluate for anemia associated with either renal dysfunction or marrow deposition of oxalate. Bone marrow examination may be needed.Electrocardiogram to evaluate for an associated atrioventricular blockEchocardiogram for evidence of | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. evaluations: measurement of plasma oxalateFor those with a GFR <30 mL/min/1.73 m2 or in whom there is a rapid deterioration in function, in addition to the above evaluations:Bone x-rays to evaluate for radiodense metaphyseal bands and diffuse demineralization or evidence of pathologic fracturesHemoglobin to evaluate for anemia associated with either renal dysfunction or marrow deposition of oxalate. Bone marrow examination may be needed.Electrocardiogram to evaluate for an associated atrioventricular blockEchocardiogram for evidence of oxalate cardiomyopathy which may show changes in refractile characteristics of myocardium and/or reduced ejection fractionUltrasound and/or CT scan of the heart and viscera for calcificationsHistory and physical examination to assess the risk of arterial insufficiency or ischemia based on vessel wall depositionThyroid function testingConsultation with a clinical geneticist and/or genetic counselor is recommended.Treatment of ManifestationsReduction of Urinary Calcium Oxalate SupersaturationThe general therapies for | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. associated atrioventricular blockEchocardiogram for evidence of oxalate cardiomyopathy which may show changes in refractile characteristics of myocardium and/or reduced ejection fractionUltrasound and/or CT scan of the heart and viscera for calcificationsHistory and physical examination to assess the risk of arterial insufficiency or ischemia based on vessel wall depositionThyroid function testingConsultation with a clinical geneticist and/or genetic counselor is recommended.Treatment of ManifestationsReduction of Urinary Calcium Oxalate SupersaturationThe general therapies for nephrolithiasis benefit all individuals with PH1. Early diagnosis and initiation of conservative therapy are critical in preserving adequate renal function for as long as possible .Drinking large volumes of fluid (2-3 L/m2/24 hours) at regular intervals over the entire day/night prevents calcium oxalate supersaturation. Small children may require a gastrostomy or nasogastric tube for feeds and fluid supplementation. Extreme care should be taken during any illness that could lead to hypovolemia | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. Urinary Calcium Oxalate SupersaturationThe general therapies for nephrolithiasis benefit all individuals with PH1. Early diagnosis and initiation of conservative therapy are critical in preserving adequate renal function for as long as possible .Drinking large volumes of fluid (2-3 L/m2/24 hours) at regular intervals over the entire day/night prevents calcium oxalate supersaturation. Small children may require a gastrostomy or nasogastric tube for feeds and fluid supplementation. Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention with initiation of intravenous fluids if needed to maintain urine volume.Alkalinzation of urine (pH 6.2-6.8) to inhibit calcium oxalate crystallization using oral potassium citrate at a dose of 0.1-0.15 mg/kg or 0.3-0.5 mmol/kg/day in 3-4 divided doses so long as the GFR is preserved | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention with initiation of intravenous fluids if needed to maintain urine volume.Alkalinzation of urine (pH 6.2-6.8) to inhibit calcium oxalate crystallization using oral potassium citrate at a dose of 0.1-0.15 mg/kg or 0.3-0.5 mmol/kg/day in 3-4 divided doses so long as the GFR is preserved. When the GFR is reduced or concerns about potassium levels ensue, alkalinization can be achieved with sodium citrate.Moderate doses of pyrophosphate-containing solutions may also inhibit crystal formation, and may be dosed as 20-30 mg/kg/day of phosphate in divided doses.Since the excess oxalate in PH1 is derived from endogenous metabolism and is not related to dietary oxalate intake, dietary restriction of oxalate is of little benefit. The principle of careful food | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. divided doses so long as the GFR is preserved. When the GFR is reduced or concerns about potassium levels ensue, alkalinization can be achieved with sodium citrate.Moderate doses of pyrophosphate-containing solutions may also inhibit crystal formation, and may be dosed as 20-30 mg/kg/day of phosphate in divided doses.Since the excess oxalate in PH1 is derived from endogenous metabolism and is not related to dietary oxalate intake, dietary restriction of oxalate is of little benefit. The principle of careful food choices (avoid high oxalate food and drink) is appropriate without strict limits.Some have advocated use of thiazide medications in PH1. However, urinary calcium is usually in the low normal range or below in individuals with PH1. There is also potential for intravascular volume depletion with thiazide medication. The benefits of thiazide diuretics have not been systematically studied in PH. For these reasons, the authors suggest that they be used on an individual basis only, when | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. of little benefit. The principle of careful food choices (avoid high oxalate food and drink) is appropriate without strict limits.Some have advocated use of thiazide medications in PH1. However, urinary calcium is usually in the low normal range or below in individuals with PH1. There is also potential for intravascular volume depletion with thiazide medication. The benefits of thiazide diuretics have not been systematically studied in PH. For these reasons, the authors suggest that they be used on an individual basis only, when specific clinical circumstances warrant.Treatment of Kidney StonesIndividuals with PH1 must be counseled regarding the different success rates of the following surgical modalities:Shockwave lithotripsy (SWL) is a viable first option, but has a lower success rate and higher rate of subsequent endoscopic surgery. Calcium oxalate monohydrate stones are among the hardest stones, and are thus more likely to be resistant to SWL . Stones in the lower pole of the kidney or | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. be used on an individual basis only, when specific clinical circumstances warrant.Treatment of Kidney StonesIndividuals with PH1 must be counseled regarding the different success rates of the following surgical modalities:Shockwave lithotripsy (SWL) is a viable first option, but has a lower success rate and higher rate of subsequent endoscopic surgery. Calcium oxalate monohydrate stones are among the hardest stones, and are thus more likely to be resistant to SWL . Stones in the lower pole of the kidney or parenchymal stones did not respond as well to SWL as stones in other locations . There is good evidence that any given stone should not be treated with more than two SWL sessions, particularly if no change is observed with treatment .Ureteroscopy holds a very good record for success of stone clearance with minimal complication rates and may be supplanting SWL as first-line therapy at many centers.• Percutaneous nephrolithotomy should be considered as first-line therapy for | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. Stones in the lower pole of the kidney or parenchymal stones did not respond as well to SWL as stones in other locations . There is good evidence that any given stone should not be treated with more than two SWL sessions, particularly if no change is observed with treatment .Ureteroscopy holds a very good record for success of stone clearance with minimal complication rates and may be supplanting SWL as first-line therapy at many centers.• Percutaneous nephrolithotomy should be considered as first-line therapy for larger, bulky stone burdens (>15 mm).Reduction of Oxalate BiosynthesisAlanine:glyoxylate aminotransferase (AGT) is a pyridoxal phosphate (PLP)-dependent enzyme. Approximately 30%-50% of individuals with PH1 respond to treatment with pyridoxine (vitamin B6, precursor to PLP) as defined by a greater than 30% reduction in urine oxalate concentration or normalization of urinary oxalate excretion after a minimum of three months of maximal therapy | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. should be considered as first-line therapy for larger, bulky stone burdens (>15 mm).Reduction of Oxalate BiosynthesisAlanine:glyoxylate aminotransferase (AGT) is a pyridoxal phosphate (PLP)-dependent enzyme. Approximately 30%-50% of individuals with PH1 respond to treatment with pyridoxine (vitamin B6, precursor to PLP) as defined by a greater than 30% reduction in urine oxalate concentration or normalization of urinary oxalate excretion after a minimum of three months of maximal therapy . Monico et al showed that the presence of the AGXT mistargeting pathogenic variant p.Gly170Arg was associated with pyridoxine responsiveness; homozygotes showed normalization or near-normalization of urine oxalate concentration (<0.5-0.7 mmol/1.73 m2/day) and compound heterozygotes demonstrated a partial reduction in urine oxalate concentration by at least 30% of prior documented levels. The same result has been seen in individuals with at | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. after a minimum of three months of maximal therapy . Monico et al showed that the presence of the AGXT mistargeting pathogenic variant p.Gly170Arg was associated with pyridoxine responsiveness; homozygotes showed normalization or near-normalization of urine oxalate concentration (<0.5-0.7 mmol/1.73 m2/day) and compound heterozygotes demonstrated a partial reduction in urine oxalate concentration by at least 30% of prior documented levels. The same result has been seen in individuals with at least one p.Phe152Ile pathogenic variant.Fargue et al demonstrated that pyridoxine increased peroxisomal import of AGT in individuals with PH1 with a p.Gly170Arg pathogenic variant; pyridoxine also increased expression and catalytic activity of the mutated AGT. These findings suggest potential beneficial effects in individuals with pathogenic variants that do not result in mistargeting of enzyme to the mitochondria. Accordingly, all individuals with PH1 should undergo a trial of | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. same result has been seen in individuals with at least one p.Phe152Ile pathogenic variant.Fargue et al demonstrated that pyridoxine increased peroxisomal import of AGT in individuals with PH1 with a p.Gly170Arg pathogenic variant; pyridoxine also increased expression and catalytic activity of the mutated AGT. These findings suggest potential beneficial effects in individuals with pathogenic variants that do not result in mistargeting of enzyme to the mitochondria. Accordingly, all individuals with PH1 should undergo a trial of pharmacologic-dose pyridoxine at the time of diagnosis to assess responsivenes – including individuals with ESRD requiring dialysis. Pyridoxine treatment is particularly important in pyridoxine-responsive individuals on dialysis since it is the only treatment currently available that can reduce hepatic oxalate production.Most pyridoxine-responsive individuals show maximum benefit at 5-8 mg/kg/day , though some have required a higher dose . A starting dose of 5 mg/kg/day is recommended. | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. individuals with PH1 should undergo a trial of pharmacologic-dose pyridoxine at the time of diagnosis to assess responsivenes – including individuals with ESRD requiring dialysis. Pyridoxine treatment is particularly important in pyridoxine-responsive individuals on dialysis since it is the only treatment currently available that can reduce hepatic oxalate production.Most pyridoxine-responsive individuals show maximum benefit at 5-8 mg/kg/day , though some have required a higher dose . A starting dose of 5 mg/kg/day is recommended. Response should be measured by comparison of the 24-hour urine oxalate excretion rate before treatment with the oxalate excretion rate after three to six months of pyridoxine treatment. It is important that pyridoxine be continued during the follow-up urine collection. Stepwise increases to a maximum of 10-20 mg/kg/day with assessments of response at each step is appropriate to determine effectiveness. If the individual is responsive, this approach also facilitates identification of lowest dose at which | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. 5 mg/kg/day is recommended. Response should be measured by comparison of the 24-hour urine oxalate excretion rate before treatment with the oxalate excretion rate after three to six months of pyridoxine treatment. It is important that pyridoxine be continued during the follow-up urine collection. Stepwise increases to a maximum of 10-20 mg/kg/day with assessments of response at each step is appropriate to determine effectiveness. If the individual is responsive, this approach also facilitates identification of lowest dose at which maximum response occurs. Several authors have noted little additional benefit at doses >10 mg/kg/day . Pyridoxine response can be difficult to ascertain in individuals with advanced CKD and ESRD since urinary oxalate excretion rates may be influenced by the low GFR. In individuals with GFR <30 mL/min/1.73 m2, changes in plasma oxalate may be valuable in assessing response.Individuals responsive to pyridoxine should continue this therapy indefini | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. approach also facilitates identification of lowest dose at which maximum response occurs. Several authors have noted little additional benefit at doses >10 mg/kg/day . Pyridoxine response can be difficult to ascertain in individuals with advanced CKD and ESRD since urinary oxalate excretion rates may be influenced by the low GFR. In individuals with GFR <30 mL/min/1.73 m2, changes in plasma oxalate may be valuable in assessing response.Individuals responsive to pyridoxine should continue this therapy indefinitely or until after orthotopic liver transplantation when normal enzyme has replaced deficient AGT. Blood levels of pyridoxine, measured as its metabolite pyridoxal phosphate, may be followed in individuals to ensure that adequate absorption is occurring , though correlation between blood levels and urine oxalate response was not observed in a recent study .Peripheral neuropathy has been reported in individuals who do not have PH1 who were receiving very large doses of pyridoxine (typically, adults receiving 1-2 g | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. pyridoxine should continue this therapy indefinitely or until after orthotopic liver transplantation when normal enzyme has replaced deficient AGT. Blood levels of pyridoxine, measured as its metabolite pyridoxal phosphate, may be followed in individuals to ensure that adequate absorption is occurring , though correlation between blood levels and urine oxalate response was not observed in a recent study .Peripheral neuropathy has been reported in individuals who do not have PH1 who were receiving very large doses of pyridoxine (typically, adults receiving 1-2 g/day). However, pyridoxine has demonstrated an excellent safety profile in individuals with PH1, even after decades of use. Paresthesias, a known complication of large doses of pyridoxine , have only been reported in one individual on a dose of 2.1 mg/kg/day and resolved following discontinuation of the drug.DialysisThe issues related to the removal of oxalate and current modalities of dialysis are complex. Interested readers are directed to papers outl | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. (typically, adults receiving 1-2 g/day). However, pyridoxine has demonstrated an excellent safety profile in individuals with PH1, even after decades of use. Paresthesias, a known complication of large doses of pyridoxine , have only been reported in one individual on a dose of 2.1 mg/kg/day and resolved following discontinuation of the drug.DialysisThe issues related to the removal of oxalate and current modalities of dialysis are complex. Interested readers are directed to papers outlining the specific details of extracorporeal removal of oxalate . Oxalate removal is much more effective with hemodialysis than peritoneal dialysis. For that reason, peritoneal dialysis should not be relied on as the primary dialysis modality in any individual with PH1.In brief, despite the small size of the oxalate molecule (90 daltons), the rate of oxalate production in persons with PH1-related ESRD (frequently 2-7 mmol/1.73 m2/day) vastly surpass | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. complex. Interested readers are directed to papers outlining the specific details of extracorporeal removal of oxalate . Oxalate removal is much more effective with hemodialysis than peritoneal dialysis. For that reason, peritoneal dialysis should not be relied on as the primary dialysis modality in any individual with PH1.In brief, despite the small size of the oxalate molecule (90 daltons), the rate of oxalate production in persons with PH1-related ESRD (frequently 2-7 mmol/1.73 m2/day) vastly surpasses the ability to remove it via conventional dialysis. The sequestration of oxalate in tissue compartments outside the vascular space makes it difficult to effectively remove it from the body. Current guidelines suggest that the intent of dialysis is to reduce and maintain the plasma oxalate level below 30-45 µmol/L (the calcium/oxalate supersaturation threshold at which tissue deposition occurs) as much of the time between dialysis sessions as possible.While more aggressive strategies using high-flux dialyz | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. .73 m2/day) vastly surpasses the ability to remove it via conventional dialysis. The sequestration of oxalate in tissue compartments outside the vascular space makes it difficult to effectively remove it from the body. Current guidelines suggest that the intent of dialysis is to reduce and maintain the plasma oxalate level below 30-45 µmol/L (the calcium/oxalate supersaturation threshold at which tissue deposition occurs) as much of the time between dialysis sessions as possible.While more aggressive strategies using high-flux dialyzers, daily hemodialysis, combined hemodialysis and peritoneal dialysis, hemodiafiltration, and even charcoal perfusion have all been reported , the end result is that while plasma removal rates of oxalate can be achieved in the range of greater than 60%, the total body store of oxalate rebounds to a level of 80% of the predialysis levels within 24 hours of the last hemodialysis session.A case report of one individual treated with aggressive hemodialysis (8-10 hrs | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. more aggressive strategies using high-flux dialyzers, daily hemodialysis, combined hemodialysis and peritoneal dialysis, hemodiafiltration, and even charcoal perfusion have all been reported , the end result is that while plasma removal rates of oxalate can be achieved in the range of greater than 60%, the total body store of oxalate rebounds to a level of 80% of the predialysis levels within 24 hours of the last hemodialysis session.A case report of one individual treated with aggressive hemodialysis (8-10 hrs, 7 nights/wk) does suggest that this level of intense dialysis allows for maintenance of the predialysis oxalate levels at or just below the tissue saturation point (30-45 µmol/L) . In most individuals with PH1, four or more dialysis sessions per week are needed to maintain predialysis plasma oxalate concentrations in a range to minimize risk of oxalosis . Since oxalate production varies significantly among individuals with PH1, it is important that dialysis prescriptions are | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. treated with aggressive hemodialysis (8-10 hrs, 7 nights/wk) does suggest that this level of intense dialysis allows for maintenance of the predialysis oxalate levels at or just below the tissue saturation point (30-45 µmol/L) . In most individuals with PH1, four or more dialysis sessions per week are needed to maintain predialysis plasma oxalate concentrations in a range to minimize risk of oxalosis . Since oxalate production varies significantly among individuals with PH1, it is important that dialysis prescriptions are individualized . In addition, continuous dialytic therapies such as continuous veno-venous hemodialysis can maintain plasma oxalate below 20 μmol/L for prolonged periods and may be useful in acute situations such as following transplantation in an individual with extensive oxalosis whose kidney allograft is functioning poorly.Though dialysis is most often used as a bridge to transplantation, it may also be needed as an adjunct therapy to decrease oxalate burden in the presence of delayed or poor renal function after liver/ | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. 1, it is important that dialysis prescriptions are individualized . In addition, continuous dialytic therapies such as continuous veno-venous hemodialysis can maintain plasma oxalate below 20 μmol/L for prolonged periods and may be useful in acute situations such as following transplantation in an individual with extensive oxalosis whose kidney allograft is functioning poorly.Though dialysis is most often used as a bridge to transplantation, it may also be needed as an adjunct therapy to decrease oxalate burden in the presence of delayed or poor renal function after liver/kidney transplantation, in older individuals if liver/kidney transplantation is not deemed an option, and in countries with no access to organ transplantation.Organ TransplantationAs dialysis cannot prevent systemic oxalosis in an individual with a GFR <25-30 mL/min/1.73 m2, organ transplantation is the preferred option for treatment. The reader is encouraged to review the best practice recommendations on organ transplant of non-pyridoxine-sensitive individuals with PH1 | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. of delayed or poor renal function after liver/kidney transplantation, in older individuals if liver/kidney transplantation is not deemed an option, and in countries with no access to organ transplantation.Organ TransplantationAs dialysis cannot prevent systemic oxalosis in an individual with a GFR <25-30 mL/min/1.73 m2, organ transplantation is the preferred option for treatment. The reader is encouraged to review the best practice recommendations on organ transplant of non-pyridoxine-sensitive individuals with PH1 . These guidelines take into consideration the individual's age, residual GFR, and evidence of systemic oxalate deposition in extrarenal organs.The percentage of survivors after liver-kidney transplant surpasses the percentage of survivors after isolated kidney transplant: adult five-year survival percentage for individuals after kidney vs dual transplant are 45% vs 67% ; those for children are 14% vs 76% .Isolated liver transplant may be considered in an individual with significant residual renal function | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. -pyridoxine-sensitive individuals with PH1 . These guidelines take into consideration the individual's age, residual GFR, and evidence of systemic oxalate deposition in extrarenal organs.The percentage of survivors after liver-kidney transplant surpasses the percentage of survivors after isolated kidney transplant: adult five-year survival percentage for individuals after kidney vs dual transplant are 45% vs 67% ; those for children are 14% vs 76% .Isolated liver transplant may be considered in an individual with significant residual renal function (e.g., GFR >60 mL/min/1.73 m2), with the presumption that decline in renal function will be arrested and only a single organ transplant required. However, the concerns regarding the risks of liver transplant, the uncertain and often slow rate of decline in renal function, and emerging novel treatments for PH1 are such that most experts defer the decision to proceed until dual transplantation is required.Most of the published | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. considered in an individual with significant residual renal function (e.g., GFR >60 mL/min/1.73 m2), with the presumption that decline in renal function will be arrested and only a single organ transplant required. However, the concerns regarding the risks of liver transplant, the uncertain and often slow rate of decline in renal function, and emerging novel treatments for PH1 are such that most experts defer the decision to proceed until dual transplantation is required.Most of the published literature includes reports of transplants using organs from deceased donors; however, living/living related donation of a split liver graft (if the recipient is small enough) and/or living donor kidney or liver allografts are viable alternatives in some situations. It is important to note that the appropriateness of using a parent or sib who is heterozygous for an AGXT pathogenic variant as a donor remains unclear. Heterozygotes can have reduced AGT enzyme activity in the liver, though they typically | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. dual transplantation is required.Most of the published literature includes reports of transplants using organs from deceased donors; however, living/living related donation of a split liver graft (if the recipient is small enough) and/or living donor kidney or liver allografts are viable alternatives in some situations. It is important to note that the appropriateness of using a parent or sib who is heterozygous for an AGXT pathogenic variant as a donor remains unclear. Heterozygotes can have reduced AGT enzyme activity in the liver, though they typically have normal urine oxalate excretion and remain free of stones or oxalate-related CKD.It is believed that simultaneous liver/kidney transplant is the most logical for any adult or child with CKD Category 4 or below, given the need for renal function to excrete the body burden of oxalate. However, if the wait for a suitable liver graft will significantly delay transplantation, simultaneous liver/kidney transplant may not be the best option for individuals with CKD Category 5 or on dialysis | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. enzyme activity in the liver, though they typically have normal urine oxalate excretion and remain free of stones or oxalate-related CKD.It is believed that simultaneous liver/kidney transplant is the most logical for any adult or child with CKD Category 4 or below, given the need for renal function to excrete the body burden of oxalate. However, if the wait for a suitable liver graft will significantly delay transplantation, simultaneous liver/kidney transplant may not be the best option for individuals with CKD Category 5 or on dialysis, as they often face severe oxalate burden that can overwhelm a new renal graft and lead to graft failure caused by oxalate stones/deposition. The choice in such individuals, most often small children/infants where anatomy may preclude a simultaneous approach, is to proceed with sequential (i.e., liver followed by kidney) transplantation.It is also important to note that in all forms of transplantation, mobilization of systemic oxalate places the renal allograft at risk until tissue | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. for individuals with CKD Category 5 or on dialysis, as they often face severe oxalate burden that can overwhelm a new renal graft and lead to graft failure caused by oxalate stones/deposition. The choice in such individuals, most often small children/infants where anatomy may preclude a simultaneous approach, is to proceed with sequential (i.e., liver followed by kidney) transplantation.It is also important to note that in all forms of transplantation, mobilization of systemic oxalate places the renal allograft at risk until tissue oxalate stores are completely cleared. For this reason, both liver and kidney transplant recipients must be monitored closely following transplantation with maintenance of high urine volume and crystal inhibitor medication, and even dialyzed following surgery if delayed or otherwise compromised kidney allograft function results in high plasma oxalate levels. In the post-kidney- and/or liver-transplant period, daily hemodialysis should be maintained until the renal clearance of oxalate maintains plasma oxalate well below 30 μmol/L, in order | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. oxalate places the renal allograft at risk until tissue oxalate stores are completely cleared. For this reason, both liver and kidney transplant recipients must be monitored closely following transplantation with maintenance of high urine volume and crystal inhibitor medication, and even dialyzed following surgery if delayed or otherwise compromised kidney allograft function results in high plasma oxalate levels. In the post-kidney- and/or liver-transplant period, daily hemodialysis should be maintained until the renal clearance of oxalate maintains plasma oxalate well below 30 μmol/L, in order to minimize risk of oxalate nephropathy. It is important to note that complete clearance of tissue oxalate stores by a well-functioning renal allograft requires several months to more than five years following successful liver transplantation and is confirmed by sustained normalization of urine oxalate excretion. Pyridoxine supplementation can be discontinued at the time of liver transplantation, since normal AGT activity will have been restored.Prevention of Primary ManifestationsRecommendations can all be found in Treatment of Manifestations, specifically | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. well below 30 μmol/L, in order to minimize risk of oxalate nephropathy. It is important to note that complete clearance of tissue oxalate stores by a well-functioning renal allograft requires several months to more than five years following successful liver transplantation and is confirmed by sustained normalization of urine oxalate excretion. Pyridoxine supplementation can be discontinued at the time of liver transplantation, since normal AGT activity will have been restored.Prevention of Primary ManifestationsRecommendations can all be found in Treatment of Manifestations, specifically in the subsections on Reduction of Calcium Oxalate Supersaturation and Reduction of Oxalate Biosynthesis.Prevention of Secondary ComplicationsSecondary complications arising as a result of systemic oxalosis are an increasing risk as GFR declines. Thus, careful monitoring of kidney function is essential. Recommendations for prevention of secondary complications can be found in the sections on Surveillance and Treatment of Manifestations (Dialysis and Organ Transplantation). See Clinical Description, Oxalosis, for a description of the broad range | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. all be found in Treatment of Manifestations, specifically in the subsections on Reduction of Calcium Oxalate Supersaturation and Reduction of Oxalate Biosynthesis.Prevention of Secondary ComplicationsSecondary complications arising as a result of systemic oxalosis are an increasing risk as GFR declines. Thus, careful monitoring of kidney function is essential. Recommendations for prevention of secondary complications can be found in the sections on Surveillance and Treatment of Manifestations (Dialysis and Organ Transplantation). See Clinical Description, Oxalosis, for a description of the broad range of tissues and organs that suffer consequences of oxalosis. Regular dental care and ophthalmologic follow up should be part of management in individuals with reduced GFR.SurveillanceIndividuals with PH type 1 require lifelong surveillance, the frequency of which is related to kidney function .Individuals with preserved renal function (i.e., measured or estimated GFR >60 mL/min/1.73 m2) require the following to evaluate/ensure treatment efficacy:Regular monitoring | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. osis, for a description of the broad range of tissues and organs that suffer consequences of oxalosis. Regular dental care and ophthalmologic follow up should be part of management in individuals with reduced GFR.SurveillanceIndividuals with PH type 1 require lifelong surveillance, the frequency of which is related to kidney function .Individuals with preserved renal function (i.e., measured or estimated GFR >60 mL/min/1.73 m2) require the following to evaluate/ensure treatment efficacy:Regular monitoring of kidney function. Serum creatinine for determination of eGFR should be performed at least annually and more frequently in children and adolescents and in individuals with changing kidney function or clinically active stone disease.Regular renal ultrasound examinations to monitor and manage stone forming activityUrinalysis and measurements of urine oxalate excretion, urine volume, and calcium oxalate saturation (spot and 24-hour collections)Periodic fundoscopic eye examination to identify the extent of any oxalate depositionWhen GFR is known to | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. to evaluate/ensure treatment efficacy:Regular monitoring of kidney function. Serum creatinine for determination of eGFR should be performed at least annually and more frequently in children and adolescents and in individuals with changing kidney function or clinically active stone disease.Regular renal ultrasound examinations to monitor and manage stone forming activityUrinalysis and measurements of urine oxalate excretion, urine volume, and calcium oxalate saturation (spot and 24-hour collections)Periodic fundoscopic eye examination to identify the extent of any oxalate depositionWhen GFR is known to be reduced to <60 mL/min/1.73 m2 plasma oxalate concentration should be measured and monitored regularly (at least annually or more often as indicated by the clinical course) in addition to the above evaluations. More frequent monitoring of kidney function is indicated.Individuals with a GFR <30 mL/min/1.73 m2 or a rapid deterioration in function should have the above evaluations as well as the following testing (performed prior to | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. any oxalate depositionWhen GFR is known to be reduced to <60 mL/min/1.73 m2 plasma oxalate concentration should be measured and monitored regularly (at least annually or more often as indicated by the clinical course) in addition to the above evaluations. More frequent monitoring of kidney function is indicated.Individuals with a GFR <30 mL/min/1.73 m2 or a rapid deterioration in function should have the above evaluations as well as the following testing (performed prior to initiation of dialysis if possible, and repeated as needed):Frequent assessment of serum creatinine and plasma oxalate, typically at least monthly or more often depending on clinical circumstancesX-ray examination of the long bones to evaluate for radiodense metaphyseal bands and diffuse demineralization. Bone marrow examination may also be required.Electrocardiogram to evaluate for an associated atrioventricular block or other oxalate related conduction abnormalitiesEchocardiogram for evidence of oxalate cardiomyopathyHemoglobin to evaluate for anemia associated with | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. well as the following testing (performed prior to initiation of dialysis if possible, and repeated as needed):Frequent assessment of serum creatinine and plasma oxalate, typically at least monthly or more often depending on clinical circumstancesX-ray examination of the long bones to evaluate for radiodense metaphyseal bands and diffuse demineralization. Bone marrow examination may also be required.Electrocardiogram to evaluate for an associated atrioventricular block or other oxalate related conduction abnormalitiesEchocardiogram for evidence of oxalate cardiomyopathyHemoglobin to evaluate for anemia associated with either renal dysfunction or marrow deposition of oxalateHistory and physical examination to assess the risk of arterial insufficiency or ischemia based on vessel wall depositionThyroid function testingFrequent clinical evaluation to monitor for additional complications of oxalosis (see Clinical Description, Oxalosis) – noting that at GFR <30 mL/min/1.73 m2 the ongoing deposition of tissue oxalate (oxalosis) will predispose all individuals to multiorgan involvement, and this | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. oxalate cardiomyopathyHemoglobin to evaluate for anemia associated with either renal dysfunction or marrow deposition of oxalateHistory and physical examination to assess the risk of arterial insufficiency or ischemia based on vessel wall depositionThyroid function testingFrequent clinical evaluation to monitor for additional complications of oxalosis (see Clinical Description, Oxalosis) – noting that at GFR <30 mL/min/1.73 m2 the ongoing deposition of tissue oxalate (oxalosis) will predispose all individuals to multiorgan involvement, and this will worsen/accelerate as the person enters ESRD and initiates dialysis.Note: Investigations should occur more often in newly diagnosed symptomatic individuals or in children younger than age two to three years.Agents/Circumstances to AvoidAvoid the following:Intravascular volume depletion. The importance of maintaining dilute urine cannot be overemphasized.Intake of vitamin C that exceeds the recommended daily allowanceLoop diuretics to maintain dilute urine, as they can lead to hypercalci | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. all individuals to multiorgan involvement, and this will worsen/accelerate as the person enters ESRD and initiates dialysis.Note: Investigations should occur more often in newly diagnosed symptomatic individuals or in children younger than age two to three years.Agents/Circumstances to AvoidAvoid the following:Intravascular volume depletion. The importance of maintaining dilute urine cannot be overemphasized.Intake of vitamin C that exceeds the recommended daily allowanceLoop diuretics to maintain dilute urine, as they can lead to hypercalciuria and increase the production of calcium oxalate stonesHigh doses of nonsteroidal anti-inflammatory medications or any pharmacologic agent that can compromise kidney functionLarge intake of foods high in oxalate (e.g., chocolate, rhubarb, starfruit)Evaluation of Relatives at RiskIt is appropriate to evaluate all at-risk family members, whether or not they are symptomatic, in order to identify those individuals who would benefit from early treatment | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. urine, as they can lead to hypercalciuria and increase the production of calcium oxalate stonesHigh doses of nonsteroidal anti-inflammatory medications or any pharmacologic agent that can compromise kidney functionLarge intake of foods high in oxalate (e.g., chocolate, rhubarb, starfruit)Evaluation of Relatives at RiskIt is appropriate to evaluate all at-risk family members, whether or not they are symptomatic, in order to identify those individuals who would benefit from early treatment, monitoring, and preventive intervention . If the AGXT pathogenic variants in the family are known, the genetic status of at-risk family members can be clarified by molecular genetic testing. The benefits of early initiation of conservative measures cannot be ignored .Asymptomatic individuals found to have biallelic AGXT pathogenic variants are at risk for stones and kidney damage and should be managed according to the same guidelines as those who present with symptoms.See Genetic Counseling for issues related | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. identify those individuals who would benefit from early treatment, monitoring, and preventive intervention . If the AGXT pathogenic variants in the family are known, the genetic status of at-risk family members can be clarified by molecular genetic testing. The benefits of early initiation of conservative measures cannot be ignored .Asymptomatic individuals found to have biallelic AGXT pathogenic variants are at risk for stones and kidney damage and should be managed according to the same guidelines as those who present with symptoms.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementPregnancy does not appear to be an important risk factor for the development of ESRD in the majority of women with PH1 ; however, women in whom renal function deteriorated during the pregnancy and remained abnormal post delivery have been reported . Maintenance of adequate fluid intake throughout pregnancy can be challenging, especially during the first trimester, and in some with hyperemesis gravidarum intravenous fluid administration may be | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. with symptoms.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementPregnancy does not appear to be an important risk factor for the development of ESRD in the majority of women with PH1 ; however, women in whom renal function deteriorated during the pregnancy and remained abnormal post delivery have been reported . Maintenance of adequate fluid intake throughout pregnancy can be challenging, especially during the first trimester, and in some with hyperemesis gravidarum intravenous fluid administration may be required. Continuation of pyridoxine (for pyridoxine-sensitive individuals) and careful monitoring of kidney function and stones throughout pregnancy and the early postpartum period are important to good outcomes.Women with PH1 have had successful pregnancies following liver/kidney transplantation. In one woman liver function was apparently preserved, but renal graft function declined transiently after the birth of her first child and permanently after the birth of her second child .Of particular note, pregnant women with PH1 warrant | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. sis gravidarum intravenous fluid administration may be required. Continuation of pyridoxine (for pyridoxine-sensitive individuals) and careful monitoring of kidney function and stones throughout pregnancy and the early postpartum period are important to good outcomes.Women with PH1 have had successful pregnancies following liver/kidney transplantation. In one woman liver function was apparently preserved, but renal graft function declined transiently after the birth of her first child and permanently after the birth of her second child .Of particular note, pregnant women with PH1 warrant close monitoring during pregnancy and the postpartum period by both an obstetrician and nephrologist.Generally, the offspring of women with PH1 have done well .Therapies Under InvestigationSeveral novel therapies are under investigation.Oxalate-Degrading BacteriaOral administration of bacteria such as Oxalobacter formigenes (O. formigenes) or lactic acid bacteria to degrade oxalate and reduce the amount of oxalate available for intestinal absorption is being investigated. O. formigenes shows the most promise as | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. particular note, pregnant women with PH1 warrant close monitoring during pregnancy and the postpartum period by both an obstetrician and nephrologist.Generally, the offspring of women with PH1 have done well .Therapies Under InvestigationSeveral novel therapies are under investigation.Oxalate-Degrading BacteriaOral administration of bacteria such as Oxalobacter formigenes (O. formigenes) or lactic acid bacteria to degrade oxalate and reduce the amount of oxalate available for intestinal absorption is being investigated. O. formigenes shows the most promise as a potential therapy for the hyperoxalurias. Although it is a normal component of the intestinal flora, many individuals do not maintain colonization. O. formigenes is also thought to stimulate secretion of endogenous oxalate into the intestine for its own metabolic use . A human strain of O. formigenes (HC-1) has been shown to promote oxalate secretion into the intestine of a mouse model of primary hyperoxaluria . Administration of the HC-1 strain reduced | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. O. formigenes shows the most promise as a potential therapy for the hyperoxalurias. Although it is a normal component of the intestinal flora, many individuals do not maintain colonization. O. formigenes is also thought to stimulate secretion of endogenous oxalate into the intestine for its own metabolic use . A human strain of O. formigenes (HC-1) has been shown to promote oxalate secretion into the intestine of a mouse model of primary hyperoxaluria . Administration of the HC-1 strain reduced the amount of oxalate excreted via the kidney. Despite these findings in animal studies, and promising early findings in pilot studies in individuals with PH , three double-blind, placebo-controlled trials of O. formigenes administered orally to individuals with PH have failed to show benefit In a different approach, a crystalline-stabilized oxalate-degrading enzyme administered orally has been used successfully in an Agxt knockout mouse model system of PH1. Urinary oxalate was reduced and in the | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. . Administration of the HC-1 strain reduced the amount of oxalate excreted via the kidney. Despite these findings in animal studies, and promising early findings in pilot studies in individuals with PH , three double-blind, placebo-controlled trials of O. formigenes administered orally to individuals with PH have failed to show benefit In a different approach, a crystalline-stabilized oxalate-degrading enzyme administered orally has been used successfully in an Agxt knockout mouse model system of PH1. Urinary oxalate was reduced and in the mice receiving the highest dose, there was complete protection against urolithiasis and nephrocalcinosis . To date, there have been no clinical studies of oxalate-degrading enzyme in individuals with PH.Gene ModificationA variety of strategies are currently being explored.Salido et al have demonstrated successful replacement of AGT enzyme activity in the livers of a knockout mouse model of PH1 utilizing a somatic gene transfer via two adeno-associated viral vectors. However, applicability of | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. 1. Urinary oxalate was reduced and in the mice receiving the highest dose, there was complete protection against urolithiasis and nephrocalcinosis . To date, there have been no clinical studies of oxalate-degrading enzyme in individuals with PH.Gene ModificationA variety of strategies are currently being explored.Salido et al have demonstrated successful replacement of AGT enzyme activity in the livers of a knockout mouse model of PH1 utilizing a somatic gene transfer via two adeno-associated viral vectors. However, applicability of these approaches to treatment of individuals with PH1 will be challenging. Limitations include transduction efficiency (due to the need to modify a significant proportion of liver cells), loss of target expression over time, and potential adverse effects of viral vectors. An alternative strategy is coupling of functional AGT to a PEG-PGA polymer which will target the enzyme to the peroxisomes of hepatic cells . This approach is currently in early stages of exploration.Pluripotent cells induced from leukocytes or fibroblasts | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. -associated viral vectors. However, applicability of these approaches to treatment of individuals with PH1 will be challenging. Limitations include transduction efficiency (due to the need to modify a significant proportion of liver cells), loss of target expression over time, and potential adverse effects of viral vectors. An alternative strategy is coupling of functional AGT to a PEG-PGA polymer which will target the enzyme to the peroxisomes of hepatic cells . This approach is currently in early stages of exploration.Pluripotent cells induced from leukocytes or fibroblasts from individuals with PH1 could potentially be genetically modified to contain normal AGXT. If the genetically modified cells were then differentiated in vitro into hepatocytes, they could theoretically be used for autotransplantation to repopulate the liver of the cell donor with AGT-competent cells. Zapata-Linares and colleagues recently described an early step in this process in which they were able to generate pluripotent stem cells from an individual with PH1 with the p.Ile | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. exploration.Pluripotent cells induced from leukocytes or fibroblasts from individuals with PH1 could potentially be genetically modified to contain normal AGXT. If the genetically modified cells were then differentiated in vitro into hepatocytes, they could theoretically be used for autotransplantation to repopulate the liver of the cell donor with AGT-competent cells. Zapata-Linares and colleagues recently described an early step in this process in which they were able to generate pluripotent stem cells from an individual with PH1 with the p.Ile244Thr pathogenic variant . While autotransplantation of cells could bypass the immune barrier of hepatocyte transplantation, considerable work remains to establish this as viable treatment.Small Molecule TherapiesChemical chaperones facilitate folding of newly translated proteins offering protection from cellular quality-control degradative processes. Stabilization of AGT with a missense pathogenic variant may permit the protein to achieve a folded state with some degree of enzymatic activity . In PH1 specifically, this type of effect has been demonstrated in vitro | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. individual with PH1 with the p.Ile244Thr pathogenic variant . While autotransplantation of cells could bypass the immune barrier of hepatocyte transplantation, considerable work remains to establish this as viable treatment.Small Molecule TherapiesChemical chaperones facilitate folding of newly translated proteins offering protection from cellular quality-control degradative processes. Stabilization of AGT with a missense pathogenic variant may permit the protein to achieve a folded state with some degree of enzymatic activity . In PH1 specifically, this type of effect has been demonstrated in vitro for both mistargeting variants and AGT variants that induce aggregation/accelerated degradation . Chemical chaperones may have general stabilizing functions or they may be designed to target proteins with specific pathogenic variants. Missense pathogenic variants that do not cause loss of protein stability are not suitable candidates for this pharmacogenetic approach; nor are insertions, deletions, nonsense variants, or splice junction changes, which usually do not produce a protein product.Pyridoxine, commonly used in treatment of PH1, has | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. this type of effect has been demonstrated in vitro for both mistargeting variants and AGT variants that induce aggregation/accelerated degradation . Chemical chaperones may have general stabilizing functions or they may be designed to target proteins with specific pathogenic variants. Missense pathogenic variants that do not cause loss of protein stability are not suitable candidates for this pharmacogenetic approach; nor are insertions, deletions, nonsense variants, or splice junction changes, which usually do not produce a protein product.Pyridoxine, commonly used in treatment of PH1, has been shown in vitro to act as a chemical chaperone increasing AGT expression and correcting peroxisomal targeting in cells with three common pathogenic variants p.Gly170Arg, p.Phe152Ile, and p.Ile244Thr .Dequalinium chloride has been shown in vitro to rescue AGT mistargeting defects caused by the pathogenic variant p.Gly170Arg by blocking import into mitochondria. No clinical trials of this agent have been reported. High throughput | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. commonly used in treatment of PH1, has been shown in vitro to act as a chemical chaperone increasing AGT expression and correcting peroxisomal targeting in cells with three common pathogenic variants p.Gly170Arg, p.Phe152Ile, and p.Ile244Thr .Dequalinium chloride has been shown in vitro to rescue AGT mistargeting defects caused by the pathogenic variant p.Gly170Arg by blocking import into mitochondria. No clinical trials of this agent have been reported. High throughput methods are now being used to screen for other compounds with AGT chaperone effects.Pyridoxamine, a drug explored as therapy for human diabetic nephropathy, has been shown in a CHO cell model for PH1 to be more effective than pyridoxine in rescuing folding-defective variants of human AGT causing PH1 . In addition, pyridoxamine has been hypothesized to trap metabolic precursors of oxalate, glycoaldehyde, and glyoxylate . Animal studies have shown 50 | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. of this agent have been reported. High throughput methods are now being used to screen for other compounds with AGT chaperone effects.Pyridoxamine, a drug explored as therapy for human diabetic nephropathy, has been shown in a CHO cell model for PH1 to be more effective than pyridoxine in rescuing folding-defective variants of human AGT causing PH1 . In addition, pyridoxamine has been hypothesized to trap metabolic precursors of oxalate, glycoaldehyde, and glyoxylate . Animal studies have shown 50% reduction of urinary oxalate excretion in an ethylene glycol model of hyperoxaluria . A proposed clinical trial in hyperoxaluric stone formers and individuals with PH was withdrawn prior to enrollment (ClinicalTrials.gov).Manipulation of the Metabolic PathwaySubstrate reduction targets precursors in the metabolic pathway, reducing them and thus preventing their eventual metabolism to oxalate. Hydroxyproline is found in the diet as well as derived from normal bone turnover. Intravenous infusion of hydroxyproline labeled with a stable | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. glyoxylate . Animal studies have shown 50% reduction of urinary oxalate excretion in an ethylene glycol model of hyperoxaluria . A proposed clinical trial in hyperoxaluric stone formers and individuals with PH was withdrawn prior to enrollment (ClinicalTrials.gov).Manipulation of the Metabolic PathwaySubstrate reduction targets precursors in the metabolic pathway, reducing them and thus preventing their eventual metabolism to oxalate. Hydroxyproline is found in the diet as well as derived from normal bone turnover. Intravenous infusion of hydroxyproline labeled with a stable isotope demonstrated that its metabolism contributes 17% of the oxalate in urine in individuals with PH1, while it contributes 46% and 33% in individuals with PH2 and PH3, respectively. Thus hydroxyproline reduction would appear more valuable in forms of PH other than PH1 .L-2-oxothiazolindine-4-carboxylate (OTZ) is converted in tissues to cysteine, forms an adduct with glyoxylate, and has been shown to reduce | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. . Intravenous infusion of hydroxyproline labeled with a stable isotope demonstrated that its metabolism contributes 17% of the oxalate in urine in individuals with PH1, while it contributes 46% and 33% in individuals with PH2 and PH3, respectively. Thus hydroxyproline reduction would appear more valuable in forms of PH other than PH1 .L-2-oxothiazolindine-4-carboxylate (OTZ) is converted in tissues to cysteine, forms an adduct with glyoxylate, and has been shown to reduce urine oxalate in healthy subjects. Though its administration to two individuals with PH1 led to a slight reduction in plasma oxalate, there was no change in urine oxalate in these individuals .An Agxt knockout mouse model has been developed to explore the effects of substrate depletion and to clarify the various adjustments in the metabolic pathway that result from absence of AGT . A model system developed in CHO cells uses stable transfection with all combinations of recombinant genes that encode glycolate oxidase, | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. oxylate, and has been shown to reduce urine oxalate in healthy subjects. Though its administration to two individuals with PH1 led to a slight reduction in plasma oxalate, there was no change in urine oxalate in these individuals .An Agxt knockout mouse model has been developed to explore the effects of substrate depletion and to clarify the various adjustments in the metabolic pathway that result from absence of AGT . A model system developed in CHO cells uses stable transfection with all combinations of recombinant genes that encode glycolate oxidase, glyoxylate reductase, and AGT, allowing investigation of the interaction of these enzymes and the effects of deficiencies of one or more enzymes .Glycolate is converted to glyoxylate by glycolate oxidase. The glycolate oxidase inhibitor CPPST has been shown to significantly reduce oxalate production in Agxt1-/- hepatocytes; when administered orally, Agxt1-/- knockout mice reduced urine oxalate by 30%-50% . RNA inhibition (Dic | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. of recombinant genes that encode glycolate oxidase, glyoxylate reductase, and AGT, allowing investigation of the interaction of these enzymes and the effects of deficiencies of one or more enzymes .Glycolate is converted to glyoxylate by glycolate oxidase. The glycolate oxidase inhibitor CPPST has been shown to significantly reduce oxalate production in Agxt1-/- hepatocytes; when administered orally, Agxt1-/- knockout mice reduced urine oxalate by 30%-50% . RNA inhibition (Dicer-siRNA) targeting hydroxyacid oxidase 1 (HAO1) messenger RNA, which encodes glycolate oxidase, normalized oxalate production in hepatocytes of AGXT knockout mice . siRNA inhibition of GO is now in Phase I/II clinical trials in individuals with PH1. Implications of the expected increase in glycolate in individuals with PH1 treated with this agent remain to be evaluated .Inhibition of LDH activity is another logical target since formation of oxalate from glyoxylate could | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. %-50% . RNA inhibition (Dicer-siRNA) targeting hydroxyacid oxidase 1 (HAO1) messenger RNA, which encodes glycolate oxidase, normalized oxalate production in hepatocytes of AGXT knockout mice . siRNA inhibition of GO is now in Phase I/II clinical trials in individuals with PH1. Implications of the expected increase in glycolate in individuals with PH1 treated with this agent remain to be evaluated .Inhibition of LDH activity is another logical target since formation of oxalate from glyoxylate could potentially be prevented. Therapeutic reduction of LDH activity through technologies such as siRNA are in early stages of exploration.Hepatocyte TransplantationRepopulation of the liver of an individual with PH1 with normal or genetically corrected hepatocytes is less invasive than liver transplantation. However, host cells must be ablated as they would continue to produce oxalate and the donor hepatocytes would then require a growth advantage to achieve repopulation. This approach has been explored in a mouse model of PH1 . Koul | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. since formation of oxalate from glyoxylate could potentially be prevented. Therapeutic reduction of LDH activity through technologies such as siRNA are in early stages of exploration.Hepatocyte TransplantationRepopulation of the liver of an individual with PH1 with normal or genetically corrected hepatocytes is less invasive than liver transplantation. However, host cells must be ablated as they would continue to produce oxalate and the donor hepatocytes would then require a growth advantage to achieve repopulation. This approach has been explored in a mouse model of PH1 . Koul et al transfected AGXT (genetically engineered for selective peroxisomal delivery) into cultured human hepatocytes by amplifying the cDNA and using liposomal transfection techniques. They demonstrated high efficiency of transfection and appropriate intracellular localization to peroxisomes .Liver cell transplantation was reported in a girl age 15 months with PH1 as a potential bridge to orthotopic liver transplant . The child tolerated both the cellular infusions and the immunosuppression. Initially no significant change was seen in plasma oxalate levels post infusion; however, the | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. a mouse model of PH1 . Koul et al transfected AGXT (genetically engineered for selective peroxisomal delivery) into cultured human hepatocytes by amplifying the cDNA and using liposomal transfection techniques. They demonstrated high efficiency of transfection and appropriate intracellular localization to peroxisomes .Liver cell transplantation was reported in a girl age 15 months with PH1 as a potential bridge to orthotopic liver transplant . The child tolerated both the cellular infusions and the immunosuppression. Initially no significant change was seen in plasma oxalate levels post infusion; however, the plasma oxalate levels slowly decreased over the ensuing two weeks. Long-term follow up (2-11 months) demonstrated levels of plasma oxalate that were significantly elevated (mean 80 μmol/L), though improved over baseline. Donor chimerism was not demonstrated during the protocol biopsy at five months nor at the time of liver harvest prior to the eventual orthotopic liver transplant.Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. plasma oxalate levels post infusion; however, the plasma oxalate levels slowly decreased over the ensuing two weeks. Long-term follow up (2-11 months) demonstrated levels of plasma oxalate that were significantly elevated (mean 80 μmol/L), though improved over baseline. Donor chimerism was not demonstrated during the protocol biopsy at five months nor at the time of liver harvest prior to the eventual orthotopic liver transplant.Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.OtherAuxiliary liver transplant. Oxalate is an end product of metabolism that cannot be degraded by humans. Accordingly, elimination of all or a substantial portion of the native liver that is overproducting oxalate – in addition to replacement of functional AGT enzyme – is required . Simply adding normal liver cells cannot reduce the oxalate overproduction of the AGT-deficient liver that remains. Though it is possible for some | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.OtherAuxiliary liver transplant. Oxalate is an end product of metabolism that cannot be degraded by humans. Accordingly, elimination of all or a substantial portion of the native liver that is overproducting oxalate – in addition to replacement of functional AGT enzyme – is required . Simply adding normal liver cells cannot reduce the oxalate overproduction of the AGT-deficient liver that remains. Though it is possible for some degree of hyperoxaluria caused by remaining native liver to be adequately tolerated, it increases long-term risk to the renal allograft and is further complicated in most circumstances by the hyperoxaluria that follows liver transplantation for months or years due to gradual mobilization of oxalate from tissue stores. For these reasons, the authors cannot recommend auxiliary liver transplantation in individuals with PH1. | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1283/ | j4Rg9gA | Primary Hyperoxaluria Type 1 | C0268164 | 18 | primary hyperoxaluria type 1. that remains. Though it is possible for some degree of hyperoxaluria caused by remaining native liver to be adequately tolerated, it increases long-term risk to the renal allograft and is further complicated in most circumstances by the hyperoxaluria that follows liver transplantation for months or years due to gradual mobilization of oxalate from tissue stores. For these reasons, the authors cannot recommend auxiliary liver transplantation in individuals with PH1. | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. SummaryClinical characteristics.Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.Diagnosis/testing.The diagnosis of primary CoQ10 deficiency in a proband is established by identification of biallelic pathogenic variants in one of the nine genes encoding proteins directly involved in the synthesis | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.Diagnosis/testing.The diagnosis of primary CoQ10 deficiency in a proband is established by identification of biallelic pathogenic variants in one of the nine genes encoding proteins directly involved in the synthesis of coenzyme Q10 or by detection of reduced levels of CoQ10 (ubiquinone) in skeletal muscle or reduced activities of complex I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates.Management.Treatment of manifestations: In individuals with primary CoQ10 deficiency early treatment with high-dose oral CoQ10 supplementation (ranging from 5 to 50 mg/kg/day) can limit disease progression and reverse some manifestations; however, established severe neurologic and | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. genes encoding proteins directly involved in the synthesis of coenzyme Q10 or by detection of reduced levels of CoQ10 (ubiquinone) in skeletal muscle or reduced activities of complex I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates.Management.Treatment of manifestations: In individuals with primary CoQ10 deficiency early treatment with high-dose oral CoQ10 supplementation (ranging from 5 to 50 mg/kg/day) can limit disease progression and reverse some manifestations; however, established severe neurologic and/or renal damage cannot be reversed. ACE inhibitors may be used in combination with CoQ10 supplementation in persons with proteinuria; renal transplantation is an option for those with ESRD. Treatment of hypertrophic cardiomyopathy, retinopathy, and sensorineural hearing loss is per usual practice.Prevention of primary manifestations: Supplementation with high-dose oral CoQ10 can prevent progression of the renal disease and onset of neurologic manifestations.Surveillance: Periodic neurologic evaluation, urine analysis (for proteinuria) and renal function | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. manifestations; however, established severe neurologic and/or renal damage cannot be reversed. ACE inhibitors may be used in combination with CoQ10 supplementation in persons with proteinuria; renal transplantation is an option for those with ESRD. Treatment of hypertrophic cardiomyopathy, retinopathy, and sensorineural hearing loss is per usual practice.Prevention of primary manifestations: Supplementation with high-dose oral CoQ10 can prevent progression of the renal disease and onset of neurologic manifestations.Surveillance: Periodic neurologic evaluation, urine analysis (for proteinuria) and renal function tests, ophthalmologic evaluation, and audiometry.Evaluation of relatives at risk: Presymptomatic diagnosis for the purpose of early treatment with CoQ10 supplementation is warranted for relatives at risk.Genetic counseling.Primary coenzyme Q10 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. analysis (for proteinuria) and renal function tests, ophthalmologic evaluation, and audiometry.Evaluation of relatives at risk: Presymptomatic diagnosis for the purpose of early treatment with CoQ10 supplementation is warranted for relatives at risk.Genetic counseling.Primary coenzyme Q10 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in a family are known.DiagnosisPrimary deficiency of coenzyme Q10, a lipid component of the mitochondrial respiratory chain, is classified as a mitochondrial respiratory chain disorder .For this GeneReview the term "primary coenzyme Q10 deficiency" refers to the group of conditions characterized by a reduction of coenzyme Q10 ( | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. % chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in a family are known.DiagnosisPrimary deficiency of coenzyme Q10, a lipid component of the mitochondrial respiratory chain, is classified as a mitochondrial respiratory chain disorder .For this GeneReview the term "primary coenzyme Q10 deficiency" refers to the group of conditions characterized by a reduction of coenzyme Q10 (CoQ10) levels in tissues or cultured cells associated with mutation of the nine genes involved in the biosynthesis of coenzyme Q10 (collectively called "COQ genes").There are no formal diagnostic criteria for primary coenzyme Q10 deficiency.Suggestive FindingsPrimary coenzyme Q10 deficiency, which is associated with an extremely heterogeneous group of clinical manifestations, should be suspected in individuals with the following clinical findings (Table 1).Clinical findingsSteroid-resistant nephrotic syndrome | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. by a reduction of coenzyme Q10 (CoQ10) levels in tissues or cultured cells associated with mutation of the nine genes involved in the biosynthesis of coenzyme Q10 (collectively called "COQ genes").There are no formal diagnostic criteria for primary coenzyme Q10 deficiency.Suggestive FindingsPrimary coenzyme Q10 deficiency, which is associated with an extremely heterogeneous group of clinical manifestations, should be suspected in individuals with the following clinical findings (Table 1).Clinical findingsSteroid-resistant nephrotic syndrome (SRNS) without mutation of NPHS1 (encoding nephrin) or NPHS2 (encoding podocin), especially when accompanied by deafness, retinopathy, and/or other CNS manifestations Clinical features of a mitochondrial encephalomyopathy, including neurologic findings (hypotonia, seizures, dystonia, nystagmus, cerebellar ataxia or pyramidal dysfunction, spasticity, peripheral neuropathy, and intellectual disability), myopathy, retinopathy, or optic atrophy, sensorineural hearing loss, and/or hypertrophic cardiomyopathy | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. findingsSteroid-resistant nephrotic syndrome (SRNS) without mutation of NPHS1 (encoding nephrin) or NPHS2 (encoding podocin), especially when accompanied by deafness, retinopathy, and/or other CNS manifestations Clinical features of a mitochondrial encephalomyopathy, including neurologic findings (hypotonia, seizures, dystonia, nystagmus, cerebellar ataxia or pyramidal dysfunction, spasticity, peripheral neuropathy, and intellectual disability), myopathy, retinopathy, or optic atrophy, sensorineural hearing loss, and/or hypertrophic cardiomyopathy (Table 1).Unexplained ataxia (especially if family history suggests autosomal recessive inheritance) Subacute exercise intolerance (with onset usually between ages 6 and 33 years) with proximal muscle weakness and elevated CK (≤20 times upper limit of the control range) Table 1. Clinical Manifestations Associated with Mutation of Genes Encoding Proteins Directly Involved in the Synthesis of Coenzyme Q10View in own windowGeneClinical ManifestationsRenalHeartEyeHearingNeurologicMuscle | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. hearing loss, and/or hypertrophic cardiomyopathy (Table 1).Unexplained ataxia (especially if family history suggests autosomal recessive inheritance) Subacute exercise intolerance (with onset usually between ages 6 and 33 years) with proximal muscle weakness and elevated CK (≤20 times upper limit of the control range) Table 1. Clinical Manifestations Associated with Mutation of Genes Encoding Proteins Directly Involved in the Synthesis of Coenzyme Q10View in own windowGeneClinical ManifestationsRenalHeartEyeHearingNeurologicMuscleCOQ2SRNSHCMRetinopathySNHLEncephalopathy 1; seizures; other 2MyopathyCOQ4Heart failure; HCMEncephalopathy; seizures; other 3MyopathyCOQ6SRNS 4SNHLEncephalopathy; seizuresCOQ7Encephalopathy; ID; peripheral neuropathyMuscle weaknessCOQ8AEncephalopathy; cerebellar ataxia; dystonia; spasticity; seizuresExercise intoleranceCOQ8BSRNS 4ID | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. HearingNeurologicMuscleCOQ2SRNSHCMRetinopathySNHLEncephalopathy 1; seizures; other 2MyopathyCOQ4Heart failure; HCMEncephalopathy; seizures; other 3MyopathyCOQ6SRNS 4SNHLEncephalopathy; seizuresCOQ7Encephalopathy; ID; peripheral neuropathyMuscle weaknessCOQ8AEncephalopathy; cerebellar ataxia; dystonia; spasticity; seizuresExercise intoleranceCOQ8BSRNS 4IDCOQ9TubulopathyHCMEncephalopathyMyopathyPDSS1Optic atrophyEncephalopathy; peripheral neuropathyPDSS2SRNSRetinopathySNHLLeigh syndrome; ataxiaTable contents are ordered by gene.HCM = hypertrophic cardiomyopathy; ID = intellectual disability; SNHL = sensorineural hearing loss; SRNS = steroid-resistant nephrotic syndrome1. Encephalopathy comprises a wide spectrum of brain involvement with different clinical and neuroradiologic features, often not | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. COQ8BSRNS 4IDCOQ9TubulopathyHCMEncephalopathyMyopathyPDSS1Optic atrophyEncephalopathy; peripheral neuropathyPDSS2SRNSRetinopathySNHLLeigh syndrome; ataxiaTable contents are ordered by gene.HCM = hypertrophic cardiomyopathy; ID = intellectual disability; SNHL = sensorineural hearing loss; SRNS = steroid-resistant nephrotic syndrome1. Encephalopathy comprises a wide spectrum of brain involvement with different clinical and neuroradiologic features, often not further explicated by the reporting authors.2. Adult-onset multisystem atrophy-like phenotype 3. Severe hypotonia, respiratory insufficiency, cerebellar hypoplasia, slowly progressive neurologic deterioration4. Because individuals with COQ6- and COQ8B- related coenzyme Q10 deficiency were ascertained by the presence of SRNS, the authors cannot exclude the possibility that biallelic pathogenic variants in these two genes could also cause a broader phenotype.Laboratory findings. Serum or plasma | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. clinical and neuroradiologic features, often not further explicated by the reporting authors.2. Adult-onset multisystem atrophy-like phenotype 3. Severe hypotonia, respiratory insufficiency, cerebellar hypoplasia, slowly progressive neurologic deterioration4. Because individuals with COQ6- and COQ8B- related coenzyme Q10 deficiency were ascertained by the presence of SRNS, the authors cannot exclude the possibility that biallelic pathogenic variants in these two genes could also cause a broader phenotype.Laboratory findings. Serum or plasma lactate concentration may be high in those individuals with severe neonatal onset. Of note, normal lactate levels do not exclude the possibility of coenzyme Q10 deficiency .CSF lactate concentration may be more sensitive than serum/plasma levels, but can be normal.Establishing the DiagnosisThe diagnosis of primary coenzyme Q10 deficiency in a proband is established by identification of biallelic pathogenic variants in one of the nine genes encoding proteins directly involved in the synthesis of coenzyme Q10 (Table 2 | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. phenotype.Laboratory findings. Serum or plasma lactate concentration may be high in those individuals with severe neonatal onset. Of note, normal lactate levels do not exclude the possibility of coenzyme Q10 deficiency .CSF lactate concentration may be more sensitive than serum/plasma levels, but can be normal.Establishing the DiagnosisThe diagnosis of primary coenzyme Q10 deficiency in a proband is established by identification of biallelic pathogenic variants in one of the nine genes encoding proteins directly involved in the synthesis of coenzyme Q10 (Table 2).Note: If a diagnosis of primary coenzyme Q10 deficiency cannot be established by molecular genetic testing, biochemical testing may be considered.Molecular Genetic TestingMolecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive
genomic testing.Serial single-gene testing based on clinical findings (see Table 1). Sequence analysis is performed first, followed by deletion/duplication analysis if only one or no pathogenic variant | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. synthesis of coenzyme Q10 (Table 2).Note: If a diagnosis of primary coenzyme Q10 deficiency cannot be established by molecular genetic testing, biochemical testing may be considered.Molecular Genetic TestingMolecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive
genomic testing.Serial single-gene testing based on clinical findings (see Table 1). Sequence analysis is performed first, followed by deletion/duplication analysis if only one or no pathogenic variant is identified.Use of a multigene panel that includes the nine genes in Table 2 and some or all of the other genes of interest may be considered; for example, genes:Known (or suspected) to be required for CoQ10 biosynthesis but not identified to date as a cause of primary CoQ10 deficiency (i.e., ADCK1, ADCK2, ADCK5, COQ3, COQ10a, COQ10b, FDXR, and | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. analysis if only one or no pathogenic variant is identified.Use of a multigene panel that includes the nine genes in Table 2 and some or all of the other genes of interest may be considered; for example, genes:Known (or suspected) to be required for CoQ10 biosynthesis but not identified to date as a cause of primary CoQ10 deficiency (i.e., ADCK1, ADCK2, ADCK5, COQ3, COQ10a, COQ10b, FDXR, and FDX2 (FDX1L) )Associated with secondary deficiencies of coenzyme Q10 (APTX, BRAF, ETFDH) (see Differential Diagnosis)Associated with a specific phenotype (e.g., steroid-resistant nephrotic syndrome, ataxia)Note: (1) The choice of the specific panel depends on the phenotype observed in the patient. (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. COQ10b, FDXR, and FDX2 (FDX1L) )Associated with secondary deficiencies of coenzyme Q10 (APTX, BRAF, ETFDH) (see Differential Diagnosis)Associated with a specific phenotype (e.g., steroid-resistant nephrotic syndrome, ataxia)Note: (1) The choice of the specific panel depends on the phenotype observed in the patient. (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (3) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (4) In some laboratories, panel options may include a custom | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. the testing used for each gene vary by laboratory and are likely to change over time. (3) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (4) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (5) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based testsFor an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.More comprehensive genomic testing. Because of the large (and still growing) number of genes involved, the | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (5) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based testsFor an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.More comprehensive genomic testing. Because of the large (and still growing) number of genes involved, the rarity of primary coenzyme Q10 deficiency, the incomplete knowledge of the coenzyme Q10 biosynthetic pathway, and the continuous reduction in the cost of genomic testing, exome sequencing is an alternative to the use of single-gene testing and specific multigene panels . In fact, exome sequencing may also be able to detect all possible genetic causes of both primary and secondary coenzyme Q10 deficiency (see Differential Diagnosis).For an introduction to comprehensive genomic testing click here. More detailed information | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. growing) number of genes involved, the rarity of primary coenzyme Q10 deficiency, the incomplete knowledge of the coenzyme Q10 biosynthetic pathway, and the continuous reduction in the cost of genomic testing, exome sequencing is an alternative to the use of single-gene testing and specific multigene panels . In fact, exome sequencing may also be able to detect all possible genetic causes of both primary and secondary coenzyme Q10 deficiency (see Differential Diagnosis).For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.Table 2. Molecular Genetic Testing Used in Primary Coenzyme Q10 DeficiencyView in own windowGene 1Number of Familieswith Coenzyme Q10Deficiency Attributedto Mutation of GeneProportion of Pathogenic Variants 2 Detected byMethodSequence analysis 3Gene-targeteddeletion/duplicationanalysis 4COQ210 5All pathogenic variants reported to dateUnknownCOQ49 6All pathogenic variants | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.Table 2. Molecular Genetic Testing Used in Primary Coenzyme Q10 DeficiencyView in own windowGene 1Number of Familieswith Coenzyme Q10Deficiency Attributedto Mutation of GeneProportion of Pathogenic Variants 2 Detected byMethodSequence analysis 3Gene-targeteddeletion/duplicationanalysis 4COQ210 5All pathogenic variants reported to dateUnknownCOQ49 6All pathogenic variants reported to dateUnknown 7COQ65 8All pathogenic variants reported to dateUnknownCOQ71 9All pathogenic variants reported to dateUnknownCOQ8A14 10All pathogenic variants reported to dateUnknown 11COQ8B34 12Most pathogenic variants reported to dateUnknownCOQ92 13All pathogenic variants reported to dateUnknownPDSS12 14All pathogenic variants reported to | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. nCOQ49 6All pathogenic variants reported to dateUnknown 7COQ65 8All pathogenic variants reported to dateUnknownCOQ71 9All pathogenic variants reported to dateUnknownCOQ8A14 10All pathogenic variants reported to dateUnknown 11COQ8B34 12Most pathogenic variants reported to dateUnknownCOQ92 13All pathogenic variants reported to dateUnknownPDSS12 14All pathogenic variants reported to dateUnknownPDSS22 15All pathogenic variants reported to dateUnknownUnknown 16NANA1. See Table A. Genes and Databases for chromosome locus and protein.2. See Molecular Genetics for information on allelic variants detected in this gene.3. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. S12 14All pathogenic variants reported to dateUnknownPDSS22 15All pathogenic variants reported to dateUnknownUnknown 16NANA1. See Table A. Genes and Databases for chromosome locus and protein.2. See Molecular Genetics for information on allelic variants detected in this gene.3. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.4. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.5. Quin | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. enic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.4. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.5. Quinzii et al , Diomedi-Camassei et al , Mollet et al , Dinwiddie et al , Jakobs et al , McCarthy et al , Mitsui et al , Scalais et al , Desbats et al , Desbats et al 6. Salviati et al , Brea-Calvo et al , Chung et al 7. To date only one individual has had a heterozygous deletion | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. exon deletions or duplications.5. Quinzii et al , Diomedi-Camassei et al , Mollet et al , Dinwiddie et al , Jakobs et al , McCarthy et al , Mitsui et al , Scalais et al , Desbats et al , Desbats et al 6. Salviati et al , Brea-Calvo et al , Chung et al 7. To date only one individual has had a heterozygous deletion encompassing COQ4 .8. Heeringa et al , Doimo et al 9. Freyer et al 10. Lagier-Tourenne et al , Mollet et al , Anheim et al , Gerards et al , Horvath et al , Terracciano et al , Mignot et al , Blumkin et al , Liu et al 11. A deletion from exon 3 to exon 15 has been described .12 | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. only one individual has had a heterozygous deletion encompassing COQ4 .8. Heeringa et al , Doimo et al 9. Freyer et al 10. Lagier-Tourenne et al , Mollet et al , Anheim et al , Gerards et al , Horvath et al , Terracciano et al , Mignot et al , Blumkin et al , Liu et al 11. A deletion from exon 3 to exon 15 has been described .12. Ashraf et al , Korkmaz et al 13. Duncan et al , Rahman et al , Danhauser et al 14. Mollet et al , Vasta et al 15. Rötig et al , Rahman et al 16. To date many individuals with reduced CoQ10 in cells or tissues lack a clear genetic diagnosis, making it impossible to distinguish between primary and secondary CoQ10 deficiency .Biochemical Testing | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. to exon 15 has been described .12. Ashraf et al , Korkmaz et al 13. Duncan et al , Rahman et al , Danhauser et al 14. Mollet et al , Vasta et al 15. Rötig et al , Rahman et al 16. To date many individuals with reduced CoQ10 in cells or tissues lack a clear genetic diagnosis, making it impossible to distinguish between primary and secondary CoQ10 deficiency .Biochemical TestingThe following findings on biochemical testing can differentiate coenzyme Q10 deficiency from other mitochondrial disorders with similar clinical findings, but cannot differentiate primary from secondary coenzyme Q10 deficiency (see Differential Diagnosis).Reduced levels of CoQ10 in skeletal muscle . Note: While coenzyme Q10 measurements may be performed on cultured skin fibroblasts or blood mononuclear cells, these tissues may not be reliable in detecting secondary coenzyme Q10 defects .Reduced activities of complex I+III and II+III of | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. and secondary CoQ10 deficiency .Biochemical TestingThe following findings on biochemical testing can differentiate coenzyme Q10 deficiency from other mitochondrial disorders with similar clinical findings, but cannot differentiate primary from secondary coenzyme Q10 deficiency (see Differential Diagnosis).Reduced levels of CoQ10 in skeletal muscle . Note: While coenzyme Q10 measurements may be performed on cultured skin fibroblasts or blood mononuclear cells, these tissues may not be reliable in detecting secondary coenzyme Q10 defects .Reduced activities of complex I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates. These enzymatic activities, which depend on endogenous coenzyme Q10, are reduced in persons with a defect in CoQ10 even when isolated complex II and III respiratory chain activities are normal .Clinical CharacteristicsClinical DescriptionThe manifestations of primary coenzyme Q10 deficiency vary (Table 1). Traditionally, clinical presentations have been classified into five distinct phenotypes: encephalomyopathy, cerebellar ataxia, severe infantile multisystem disease, steroid-resistant nephrotic | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates. These enzymatic activities, which depend on endogenous coenzyme Q10, are reduced in persons with a defect in CoQ10 even when isolated complex II and III respiratory chain activities are normal .Clinical CharacteristicsClinical DescriptionThe manifestations of primary coenzyme Q10 deficiency vary (Table 1). Traditionally, clinical presentations have been classified into five distinct phenotypes: encephalomyopathy, cerebellar ataxia, severe infantile multisystem disease, steroid-resistant nephrotic syndrome, and isolated myopathy . This classification is probably now outdated because the range of clinical phenotypes is much wider, and different combinations of findings with significant overlap have been identified. Furthermore, no individuals with molecularly confirmed primary CoQ10 deficiency with isolated myopathy have been reported , since most individuals reported with predominantly muscle disease have secondary coenzyme Q10 deficiency (see Differential Diagnosis).The broad age of onset of primary coenzyme Q10 deficiency is exemplified by COQ2-related coenzyme | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. multisystem disease, steroid-resistant nephrotic syndrome, and isolated myopathy . This classification is probably now outdated because the range of clinical phenotypes is much wider, and different combinations of findings with significant overlap have been identified. Furthermore, no individuals with molecularly confirmed primary CoQ10 deficiency with isolated myopathy have been reported , since most individuals reported with predominantly muscle disease have secondary coenzyme Q10 deficiency (see Differential Diagnosis).The broad age of onset of primary coenzyme Q10 deficiency is exemplified by COQ2-related coenzyme Q10 deficiency, in which onset ranges from birth to the seventh decade.The principal clinical manifestations of primary CoQ10 deficiency (regardless of genetic cause) are summarized below , and followed by a summary of the phenotypes of COQ2-, COQ8A-, and COQ8B-related CoQ10 deficiencies, the three most common causes of primary coenzyme Q10 deficiency.Principal Clinical ManifestationsNeurologic. Central nervous system (CNS) manifestations include encephalopathy ( | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. is exemplified by COQ2-related coenzyme Q10 deficiency, in which onset ranges from birth to the seventh decade.The principal clinical manifestations of primary CoQ10 deficiency (regardless of genetic cause) are summarized below , and followed by a summary of the phenotypes of COQ2-, COQ8A-, and COQ8B-related CoQ10 deficiencies, the three most common causes of primary coenzyme Q10 deficiency.Principal Clinical ManifestationsNeurologic. Central nervous system (CNS) manifestations include encephalopathy (a wide spectrum of brain involvement with different clinical and neuroradiologic features often not further specified). In some individuals encephalopathy is associated with findings on neuroimaging resembling Leigh syndrome or MELAS (with stroke-like episodes) . CNS manifestations often include seizures, dystonia, spasticity, and/or intellectual disability .The age of onset and clinical severity range from fatal neonatal encephalopathy with hypotonia to a late-onset slowly progressive multiple-system atrophy (MSA)-like phenotype | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. system (CNS) manifestations include encephalopathy (a wide spectrum of brain involvement with different clinical and neuroradiologic features often not further specified). In some individuals encephalopathy is associated with findings on neuroimaging resembling Leigh syndrome or MELAS (with stroke-like episodes) . CNS manifestations often include seizures, dystonia, spasticity, and/or intellectual disability .The age of onset and clinical severity range from fatal neonatal encephalopathy with hypotonia to a late-onset slowly progressive multiple-system atrophy (MSA)-like phenotype, a neurodegenerative disorder characterized by autonomic failure associated with various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. This clinical picture resembling MSA with onset in the seventh decade was reported in two multiplex families with COQ2-related coenzyme Q10 deficiency .Individuals with COQ8A-related coenzyme Q10 deficiency display progressive cerebellar atrophy and ataxia with intellectual disability and seizures .Peripheral neuropathy with absent deep tendon reflexes has been reported in the two sibs with PDSS1-related | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. system atrophy (MSA)-like phenotype, a neurodegenerative disorder characterized by autonomic failure associated with various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. This clinical picture resembling MSA with onset in the seventh decade was reported in two multiplex families with COQ2-related coenzyme Q10 deficiency .Individuals with COQ8A-related coenzyme Q10 deficiency display progressive cerebellar atrophy and ataxia with intellectual disability and seizures .Peripheral neuropathy with absent deep tendon reflexes has been reported in the two sibs with PDSS1-related coenzyme Q10 deficiency; the age at onset and frequency of this manifestation are not known.Given the small number of affected individuals described to date, clinical data are insufficient to make any generalizations about other neurologic manifestations (e.g., dystonia, spasticity, seizures, intellectual disability).Renal. Steroid-resistant nephrotic syndrome (SRNS), an unusual feature of mitochondrial disorders, is a hallmark of primary CoQ10 deficiency. If not treated with coenzyme Q | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. two sibs with PDSS1-related coenzyme Q10 deficiency; the age at onset and frequency of this manifestation are not known.Given the small number of affected individuals described to date, clinical data are insufficient to make any generalizations about other neurologic manifestations (e.g., dystonia, spasticity, seizures, intellectual disability).Renal. Steroid-resistant nephrotic syndrome (SRNS), an unusual feature of mitochondrial disorders, is a hallmark of primary CoQ10 deficiency. If not treated with coenzyme Q10 (see Management), SRNS usually progresses to end-stage renal disease (ESRD).Renal involvement usually manifests as proteinuria in infancy. Affected individuals often present initially with SRNS that leads to ESRD, followed by an encephalomyopathy with seizures and stroke-like episodes resulting in severe neurologic impairment and ultimately death .Some affected individuals manifest only SRNS with onset in the first or second decade of life and slow progression to ESRD without extrarenal manifestations. | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. deficiency. If not treated with coenzyme Q10 (see Management), SRNS usually progresses to end-stage renal disease (ESRD).Renal involvement usually manifests as proteinuria in infancy. Affected individuals often present initially with SRNS that leads to ESRD, followed by an encephalomyopathy with seizures and stroke-like episodes resulting in severe neurologic impairment and ultimately death .Some affected individuals manifest only SRNS with onset in the first or second decade of life and slow progression to ESRD without extrarenal manifestations.One of the two individuals in a family with COQ9-related coenzyme Q10 deficiency manifested tubulopathy within a few hours after birth.Cardiac. Hypertrophic cardiomyopathy (HCM) has been reported in:Neonatal-onset COQ2-related coenzyme Q10 deficiency ;COQ4-related coenzyme Q10 deficiency manifesting as prenatal-onset HCM ;COQ9-related coenzyme Q10 deficiency manifesting as neonatal-onset lactic acidosis followed by a multisystem disease that included HCM . The | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. to ESRD without extrarenal manifestations.One of the two individuals in a family with COQ9-related coenzyme Q10 deficiency manifested tubulopathy within a few hours after birth.Cardiac. Hypertrophic cardiomyopathy (HCM) has been reported in:Neonatal-onset COQ2-related coenzyme Q10 deficiency ;COQ4-related coenzyme Q10 deficiency manifesting as prenatal-onset HCM ;COQ9-related coenzyme Q10 deficiency manifesting as neonatal-onset lactic acidosis followed by a multisystem disease that included HCM . The cardiac disease worsened despite treatment with CoQ10.Ocular. Retinopathy is observed in some persons with COQ2-related coenzyme Q10 deficiency .Optic atrophy is present in some individuals with PDSS1-related coenzyme Q10 deficiency and PDSS2-related coenzyme Q10 deficiency . Data regarding age of onset and course of the eye manifestations are not available.Hearing. Sensorineural hearing loss, which is common in individuals with COQ6-related coenzyme Q10 deficiency, is also observed | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. multisystem disease that included HCM . The cardiac disease worsened despite treatment with CoQ10.Ocular. Retinopathy is observed in some persons with COQ2-related coenzyme Q10 deficiency .Optic atrophy is present in some individuals with PDSS1-related coenzyme Q10 deficiency and PDSS2-related coenzyme Q10 deficiency . Data regarding age of onset and course of the eye manifestations are not available.Hearing. Sensorineural hearing loss, which is common in individuals with COQ6-related coenzyme Q10 deficiency, is also observed in some individuals with COQ2-related coenzyme Q10 deficiency .Muscle findings include weakness and exercise intolerance. Muscle biopsy may show nonspecific signs of lipid accumulation and mitochondrial proliferation .Prognosis. Data on the prognosis of primary CoQ10 deficiency are limited due to the small number of affected individuals reported to date. It is a progressive disorder, with variable rates of progression and tissue involvement depending on the gene that is mutated and the severity of the CoQ10 deficiency.Children with severe | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. coenzyme Q10 deficiency, is also observed in some individuals with COQ2-related coenzyme Q10 deficiency .Muscle findings include weakness and exercise intolerance. Muscle biopsy may show nonspecific signs of lipid accumulation and mitochondrial proliferation .Prognosis. Data on the prognosis of primary CoQ10 deficiency are limited due to the small number of affected individuals reported to date. It is a progressive disorder, with variable rates of progression and tissue involvement depending on the gene that is mutated and the severity of the CoQ10 deficiency.Children with severe multisystem CoQ10 deficiency generally die within the neonatal period or in the first year of life.The only child reported with COQ9-related coenzyme Q10 deficiency died before age two years of a progressive multisystem disorder .Of note, supplementation with high-dose oral CoQ10 can change the natural history of the disease by blocking progression of the renal disease and preventing the onset of neurologic manifestations in persons with biallelic pathogenic variants in COQ2, COQ6, | [
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