MPV17- Related Mitochondrial DNA Maintenance Defect

Clinical characteristics: MPV17-related mitochondrial DNA (mtDNA) maintenance defect presents in the vast majority of affected individuals as an early-onset encephalohepatopathic (hepatocerebral) disease that is typically associated with mtDNA depletion, particularly in the liver. A later-onset neuromyopathic disease characterized by myopathy and neuropathy, and associated with multiple mtDNA deletions in muscle, has also rarely been described. MPV17-related mtDNA maintenance defect, encephalohepatopathic form is characterized by:

1. Hepatic manifestations (liver dysfunction that typically progresses to liver failure, cholestasis, hepatomegaly, and steatosis);

2. Neurologic involvement (developmental delay, hypotonia, microcephaly, and motor and sensory peripheral neuropathy);

3. Gastrointestinal manifestations (gastrointestinal dysmotility, feeding difficulties, and failure to thrive); and

4. Metabolic derangements (lactic acidosis and hypoglycemia).

Less frequent manifestations include renal tubulopathy, nephrocalcinosis, and hypoparathyroidism. Progressive liver disease often leads to death in infancy or early childhood. Hepatocellular carcinoma has been reported.

Diagnosis/testing: The diagnosis of MPV17-related mtDNA maintenance defect is established in a proband by the identification of biallelic pathogenic variants in MPV17 by molecular genetic testing.

Management: Treatment of manifestations: Ideally management is by a multidisciplinary team including specialists in hepatology, neurology, nutrition, clinical genetics, and child development. Nutritional support should be provided by a dietitian experienced in managing children with liver diseases; prevention of hypoglycemia requires frequent feeds and uncooked cornstarch (1-2 g/kg/dose). Although liver transplantation remains the only treatment option for liver failure, it is controversial because of the multisystem involvement in this disorder.

Prevention of secondary complications: Prevent nutritional deficiencies (e.g., of fat-soluble vitamins) by ensuring adequate intake.

Surveillance: Monitor:

1. Liver function to assess progression of liver disease;

2. Serum alpha fetoprotein (AFP) concentration and hepatic ultrasound examination for evidence of hepatocellular carcinoma;

3. Development, neurologic status, and nutritional status.

Agents/circumstances to avoid: Prolonged fasting.

Genetic counseling: MPV17-related mtDNA maintenance defect is inherited in an autosomal recessive manner. 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 and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family are known.