Eyskens FJM 1 , Singh B 2 , Simons A 2 , Beckx K 2 1 Antwerp Univ Hospital, Div,Metab Dis, Antwerp, Belgium 2 ZNA-UKJA, Child psychiatry, Antwerp, Belgium Background: CTX is an autosomal recessive defect in bile acid biosynthesis with accumulation of cholestanol in most tissues and body fluids. The enzyme Sterol 27-hydroxilase is deficient and mutation analysis is possible of the CYP27A1gene The clinical picture of juvenile cataract, xanthomas and a progressive neurologic disorder is very suggestive. Patients: Two brothers were diagnosed at the age of 12 and 14 years with cataract, a cerebellar ataxia, a peripheral neuropathy, absence of xanthomas, and a chronic diarrhea from early childhood. They had a low IQ (range 60-78), speech disturbances and normal neuroimaging. Molecular studies established the diagnosis of CTX. Treatment objectives and results: They first received only chenodeoxycholic acid which resulted in an improvement of well being, strength, growth and speech and a spectacular disappearance of the steatorrhea. When a HMG-coA reductase inhibitor Atorvastatin was added to the treatment, the bile alcohols excretion in urine normalized which could not be achieved with Simvastatin. Follow-up under the combined therapy showed an improvement of several cognitive functions although the IQ remained in the same range. The peripheral neuropathy disappeared under treatment. Conclusion: Chenodeoxycholic acid and a HMG-coA reductase inhibitor, especially Atorvastatin, should be combined in the treatment of CTX patients. We present a case of a consanguineous child diagnosed on newborn screening with medium chain acyl-CoA dehydrogenase deficiency (MCADD) who went on to develop significant failure to thrive. His weight, height and head circumference were all below the 0.4th centile. Investigations revealed a low vitamin E but only marginally low apo-B, not consistent with either abetalipoproteinaemia or hypobetalipoproteinaemia. Attempts at nasogastric, lactose free and hydrolysed feeds failed to achieve weight gain. An endoscopy and small bowel biopsy demonstrated lipid laden enterocytes. Further investigation demonstrated he fulfilled the criteria for chylomicron retention disease (CRD). Mutation analysis showed him to be homozygous for the SAR1b gene (c.409 G>A) with a polymorphism in exon 7. This mutation has previously been seen in eight French-Canadian patients, but the polymorphism seen is novel. Management of CRD usually requires a medium chain triglyceride (MCT) based diet however this was impossible due to his MCADD. He has instead been treated with a non-MCT based, high carbohydrate diet and high dose vitamin E. He has made excellent progress in terms of growth. This case is of interest as it provides additional insight into intracellular trafficking and describes the unique challenges in its management due to co-morbidity with MCADD. Background: Primary disorders of exogenous lipoprotein metabolism can cause recurrent morbidity including pancreatitis. Currently, restriction of long chain fat intake is the only established management. Methods: A retrospective review of the clinical course and biochemistry of all children who presented with type 1 hyperlipoproteinaemia over a 15 year period. Results: Of the 14 patients, 8 were diagnosed before age 6 months (4 presented incidentally, 1 on family screening and 3 with rectal bleeding). Of those diagnosed after age 6 months, 2 presented with pancreatitis, 2 on family screening and 2 were fortuitous. No patient whose serial triglyceride levels remained <10 mmol/l (n=6) was symptomatic, but 7 of the 8 patients whose levels were recurrently >10 mmol/l had episodic abdominal pain and 5 had pancreatitis. There was no significant difference (p=0.524) in mean triglyceride levels between those with abdominal pain (17.93+/− 2.339) and those with pancreatitis (15.59 +/−2.766). No adverse effects on growth were seen. Conclusions: In over half of all patients adherence to a strict low long chain fat diet was not achievable and was associated with increased morbidity, especially pancreatitis. Background: Sjogren Larsson syndrome (SLS) that is a rare inherited disorder caused by mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase (FALDH) presents with mental retardation of variable severity, spastic or quadriplegia, and generalised ichthyosis at birth. FALDH catalyzes long-chain aldehydes derived from lipid metabolism. More than 80 mutations in ALDH3A2 have been reported worldwide. Here we report two novel mutations in Turkish patients with SLS. Case Report: Patient 1: 7 years old male patient born of consanguineous marriage had generalised ichthyosis at birth. Evaluation because of mental retardation, spastic quadriplegia and ichthyosis at the age of 6 years demonstrated profoundly low level of FALDH [0.02 nmol/(min.mg)] in skin fibroblasts. Molecular analysis confirmed the diagnosis of SLS and revealed a novel mutation (homozygous c.274_281del8ins1) in the ALDH3A2 gene. Patient 2: 10 years old male patient born of non-consanguineous marriage had generalised ichthyosis at birth. SLS was suspected with the findings of severe mental retardation, spastic quadriplegia and generalised ihthyosis at 9 years of age. Subsequent molecular analysis revealed homozygous c.153+5_385+ 361del3011ins19 mutation (full-length exon 2 deletion) in the ALDH3A2 gene. Conclusions: We predicts that described novel mutations in our patients with typical clinical features of SLS cause premature termination codon. 3 Tarbiat Modares Univ,Depart of Medi Gen, Tehran, Iran, Islamic Republic of Background: Cerebrotendinous xanthomatosis is a rare genetic disorder of cholesterol and bile acid metabolism that results in systemic and neurologic abnormalities. It was first described by Van Bogaert and has been characterized clinically, biochemically, and genetically (mutations in the gene CYP27A1). The disease begins in infancy with chronic diarrhea. Cataracts become evident in childhood or adolescence, and xanthomata develop in the second and third decades of life. Significant neurologic impairment includes seizures, dementia, and extra pyramidal dysfunction and begins in the third decade of life and progresses until death. The presentation and course widely varies, and treatment can dramatically alter, especially with early initiation. Case Report: We report an Iranian family with three affected child who are suffering from Cerebrotendinous Xanthomatosis. Cardinal features were: Motor dysfunction, ataxia, spastic paresis, Xanthomas of the Achilles tendon, Cataracts double. MRI of the brain show diffuse cerebral atrophy and increased signal intensity in the cerebellar white matter on T2weighted scans. In this report, we present 3 patients with Cerebrotendinous Xanthomatosis, who confirmed by Molecular Analysis. The patients are suffering from disease resulting from a homozygous splice-mutation in intron 2 of the CYP27A1 gene. Key word; Cerebrotendinous Xanthomatosis, Motor dysfunction, CYP27A1 gene. Background: Fabry disease (FD) is characterized by deficiency of alphagalactosidase A leading to accumulation of globotriaosylceramide (GL-3). Urine levels of GL-3 are elevated in males and females. Objectives: To develop a fully validated GLP assay to measure isoforms of GL-3 (C22:0 and C24:0) that are representative of GL-3 found in the kidney. This assay is designed to accurately quantify GL3 in urine from females with high residual enzyme activity resulting in lower levels of GL-3. Methods: Well characterized synthetic reference standards were used to validate for C22:0 and C24:0 isoforms of GL-3. The assay is validated as per the 2001 US FDA Bioanalytical Method Validation guidance. Results: The validated assay is able to accurately, specifically and reproducibly quantify C22:0 and C24:0 isoforms. Lower limit of quantitation for this assay is 1 ng/mL for both isoforms. Inter-assay precision and accuracy for six validation runs is as follows: C22:0 Precision (4.5 to 15.1%) Accuracy (−0.92 to −4.9%), C24:0 Precision (5.6 to 7.1 %) Accuracy (−3.5 to −11.6%). Normal GL-3 range was determined in 38 healthy males and females using the validated assay. Background: Retrospective studies report discordant rates of change of GFR (ΔeGFR) (−2.9-12.2 ml/min/year) in untreated males with FD. Most studies of ERT rely on historical controls, so prospective data not affected by ascertainment biases on ΔeGFR are needed. Objectives: Describe prospectively ΔeGFR in FD subjects Methods: CFDI subjects not meeting criteria for ERT (Cohort1c) and those who met treatment criteria and were started on ERT through the CFDI (Cohort1b) were included. Data on ΔeGFR were analyzed by gender and stratified by baseline proteinuria (using a threshold of 0.3 g/day). Results: 97 subjects (84 F, 13 M; median followup 35 months) did not meet criteria for ERT (Cohort 1c). 44 subjects (29 F, 15 M; median followup 38.5 months) were randomized to ERT through the CFDI (Cohort 1b). ΔeGFR rates were: Cohort 1b: M-3.96 ml/min/1.73 m2/year F +1.56 ml/min/1.73 m2/year Cohort 1c: M-2.16 ml/min/1.73 m2/year F 0.0 ml/min/1.73 m2/year. As expected, ΔeGFR tended to be higher in subjects above the proteinuric threshold then those below but these trends were not statistically significant due to limited numbers. Conclusions: ΔeGFR is lower than previously reported. ERT does not restore ΔeGFR to values seen in subjects with no clinically apparent renal disease. Conflict of Interest declared. Female carriers of Fabry disease have a high tendency of developing vital organ damage causing severe morbidity and mortality. According to our newborn screening study, we found most female carriers were not detected by enzyme assay. In this study, we developed a streamlined method for HRM analysis to screen the mutations of GLA gene using a single PCR programme and a single melting profile. A total of 299,007 (156,179 males) newborns were screened for Fabry disease at our newborn screening centers. From this screening, we identified 121 (106 males) newborns carrying Fabry mutations. A total of 20 different mutations were identified in these patients. Both male and female patients were enrolled in the HRM analysis study. Primer sets were designed to cover the 7 exons and the Chinese common intronic mutation, IVS4+919 G>A of GLA gene. PCR and HRM analyses were performed using a Roche LightCycler. 480. Both the heterozygous and hemizyous patients of these 20 mutations could be easily identified by HRM analysis. We also successfully used this method to test the dry bloodspots of the newborns with Fabry mutations without the need of determining DNA concentration before PCR amplification. Background: Fabry disease is an X-linked lysosomal disorder resulting from mutations in alpha-Galactosidase A (GalA) gene. Recent reports described that E66Q mutation in GalA gene is not a disease-causing mutation based on enzymatic studies. We carried out enzymatic and pathological studies on a patient with E66Q mutation in GalA gene. Case: A 34 years old male patients with end-stage renal failure and cardiomegaly who referred to our hospital for mutation analysis of GalA gene. He was diagnosed as gout in 15 years old and hemodialysis was started for gouty nephropathy from 31 years old. We carried out enzymatic and genetic analysis for GalA and cardiac biopsy. Result: He had E66Q mutation in GalA gene. GalA activity in leukocytes was 46.2% of average of normal controls and serum globotriaosylceramide (GL3) level was not elevated. The pathological study on cardiac biopsy sample showed no characteristic findings of Fabry disease. The immunostaining for GL3 of cardiac biopsy sample showed no positive cells. Conclusion: Although E66Q mutation reduced enzyme activity, the characteristic pathological findings of Fabry disease and the abnormal accumulation of GL3 were not detected. E66Q mutation of GalA gene was thought to be a functional polymorphism based on enzymatic and pathological studies. Conflict of Interest declared. We present PGD of Fabry disease (FD). Female in her thirties is FD carrier with positive family history. Her previous pregnancy was aborted. The risk 50% for offspring resulted in her informed decision for PGD in conjunction with genetic counseling. Our aim was to design specific-family test based on linkage analyses with GLA adjacent polymorphic markers avoiding the need to detect the mutation itself. Methods: Molecular analysis identified the pathogenic familial mutation c.1025 G>A (p.Arg342Gln) located in exon 7 of the GLA gene (GLA; EC 3.2.1.22), locus Xq22. In the IVF cycle we used genetic haplotyping technique by specific FD multiplex PCR on products of multiple displacement amplification (MDA) from one blastomere biopsied from the cleavage-stage embryo. Results: There was at least one unaffected embryo available for transfer on day 3, resulting in ongoing pregnancy after first attempt. Conclusion: The karyotype was denoted 46,XX from amniocentesis. Direct DNA analysis of the GLA gene did not confirmed causal mutation. The pregnancy is followed till delivery. Fabry disease is an X-linked disorder of alpha-galactocidase A which causes the accumulation of glycolipids in lysosomes. The incidence of the classical type of the disease is approximately 1 in 40,000 males. Recent studies have revealed the late-onset type of the disease to have a higher frequency than previously known. To determine the disease incidence in Japan, we screened newborns to measure alpha-galactosidase A activity in dried blood spots from Japanese neonates. Enzyme-deficient infants were retested, and infants who were double-screening positive were diagnostically confirmed by enzymatic activity and mutation analyses. Thirty eight neonates had a deficiency in alpha-galactosidase A activities and specific mutations, including 5 neonates with classical mutations identified previously. Based on our newborn screening in Japan, the incidence of alpha-galactosidase A deficiency was 1 in 5,600 male. Based on enzymatic activities, the incidence was 1 in 6,000 male. These results suggest that the late-onset phenotype of Fabry disease is underdiagnosed among both males and females in Japan. The recognition of the existence of these patients suggests the need for both early diagnosis and therapeutic intervention. However, ethical issues need to be taken into consideration in terms of when and whom the screening should be performed. Introduction: Fabry disease(FD) is a lysosomal disorder caused by the deficiency of a-galactosidase A, which leads to storage of globotriaosylceramide(Gb3) and endothelial disease with involvement of kidney, heart and the nervous system. Presentation in female patients can be very late in life and usually is suspected from family history. We report a female patient(20yo) with an unusually presentation of FD. Case report: Patient was admitted to the ER with purpuric rash in buttocks and lower extremities. After seven days she started with joint and abdominal pain. Lab exams showed proteinuria and hematuria and the diagnosis of Henoch-Schonlein Purpura was made; metilprednisolone 1 mg/kg IVand anti-hypertensive were started. Skin biopsy was performed and showed neutrophilic vasculitis with storage of IgM and granular C3. A kidney biopsy showed vacuolated podocites, suggesting FD. The assay of α-galA showed normal enzyme activity in leukocytes. Molecular analysis has shown one heterozygous mutation in exon 5(c.644A>Gp.N215S). Discussion:The patient has no other signs or symptoms of FD, and has no family history of FD. The clue to the diagnosis was a kidney biopsy, performed as she did not improve of the proteinuria with the standard treatment. Although unusual, Fabry disease may be considered in the evaluation of Henoch-Schönlein purpura. Methods: A 28-item measure of symptoms, Fabry Outcome Survey (FOS) Paediatric Health and Pain Questionnaire was developed. FOS is a registry for all patients with Fabry disease who are treatment naïve or receiving enzyme replacement therapy (ERT) with agalsidase alfa. A battery of psychometric analyses was performed to assess the measurement properties of this new instrument. Results: 87 children (age 4-18 years) completed the questionnaire. 23 items in three subscales emerged: Pain associated with heat or exertion; pain associated with cold; abdominal pain and fatigue. Internal consistency reliability for all three subscales was good (α≥0.84) and was high for all age groups (4-7, 8-12, 13-18 years) . Test-retest reliability was high (intraclass correlation coefficient≥0.74). Construct validity showed that each subscale measured unique patient symptom experiences. Conclusions: Psychometric analyses indicate that the measurement properties of the three subscales are valid and reliable for measuring patient-reported symptoms of FD. The questionnaire could be a useful tool for clinicians to understand the progression of disease and monitor treatment effects. Conflict of Interest declared.