Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency (ORPHA:279934)
A rare immune disease characterized by severely reduced mitochondrial DNA content due to DGUOK deficiency typically manifesting with early-onset liver dysfunction, psychomotor delay, hypotonia, rotary nystagmus that develops into opsoclonus, lactic acidosis and hypoglycemia.
Epidemiology
Prevalence of Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency (DGUOK-MDS) is unknown. However, more than 100 cases of MDS have been described, DGUOK deficiency being one of the most common causes of hepatocerebral form of mitochondrial DNA depletion syndromes.
Clinical description
In most cases, DGUOK-MDS presents as a multi-organ disease in the first week of life with hypoglycemia and lactic acidosis followed by development of hepatic and neuromuscular dysfunction within weeks of birth. Neuromuscular manifestations include hypotonia, psychomotor delay which progresses to developmental regression, typical rotary nystagmus developing into opsoclonus, and severe myopathy. Liver involvement includes jaundice, cholestasis (usually intrahepatic), hepatomegaly, and elevated serum transaminases, conjugated bilirubinemia and ferritin. Hepatic dysfunction frequently progresses to neonatal- or infantile-onset liver failure with coagulopathy, ascites, and edema. In a minority of cases, patients initially present isolated liver disease (with onset in infancy or early childhood). Development of mild hypotonia and renal involvement in these latter patients may be observed.
Etiology
DGUOK-MDS results from mitochondrial DNA depletion resulting from biallelic mutations in the DGUOK (2p13.1) gene, which codes for mitochondrial deoxyguanosine kinase involved in the mitochondrial nucleotide synthesis. The mitochondrial DNA deletion leads to insufficient production of key subunits of mitochondrial respiratory chain complexes causing insufient energy production. The reasons for tissue-specific clinical expression of the disease are not yet understood.
Diagnostic methods
Diagnosis is suggested by the clinicopathological correlation of hepatoencephalopathic signs and symptoms with the finding of reduced mitochondrial DNA copy numbers in liver or muscle (typically >20% of control in liver). It is confirmed by the presence of biallelic pathogenic mutations in the DGUOK gene. Elevated serum concentration of tyrosine or phenylalanine on newborn screening is suggestive of the disease and should prompt further examination. Respiratory chain enzyme assays in liver reveal a combined deﬁciency of complex I, III, and IV. Liver histology typically shows microvesicular cholestasis while electron microscopy usually reveals increased number of mitochondria with abnormal cristae.
Differential diagnosis
Differential diagnosis includes the other hepatocerebral mitochondrial depletion syndromes, namely due to mutations in the POLG, MPV17 or TWNK genes.
Antenatal diagnosis
Prenatal testing is possible if pathogenic variants have been previously identified in the family.
Genetic counseling
DGUOK-MDS is inherited in an autosomal recessive manner. Parents of an affected child should be informed of the 25% risk of disease recurrence among future offspring.
Management and treatment
Treatment is mostly directed towards providing symptomatic management, as currently no efficacious treatment exists. Diet modulation (e.g. fractional meals, nocturnal enteric nutrition, uncooked cornstarch and formulas with enriched medium-chain triglyceride content), as well as cofactor supplementation, may be beneficial. Liver transplantation is usually reserved for patients with isolated liver disease, as in patients with multi-organ involvement transplantation provides no survival benefit.
Prognosis
Prognosis is generally poor. Vital prognosis is typically engaged before four years of age.

                            Last update: 
                            November 2019


                            - Expert reviewer(s): 
                            Dr Ayman EL-HATTAB