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:

• Hepatic manifestations (liver dysfunction that typically progresses to liver failure, cholestasis, hepatomegaly, and steatosis);
• Neurologic involvement (developmental delay, hypotonia, microcephaly, and motor and sensory peripheral neuropathy);
• Gastrointestinal manifestations (gastrointestinal dysmotility, feeding difficulties, and failure to thrive); and
• 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:

• Liver function to assess progression of liver disease;
• Serum alpha fetoprotein (AFP) concentration and hepatic ultrasound examination for evidence of hepatocellular carcinoma;
• 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.

Suggestive Findings

MPV17-related mitochondrial DNA (mtDNA) maintenance defect should be suspected in individuals with the following clinical features, brain MRI findings, and supportive laboratory findings.

Clinical features

• Hepatic
  • Liver dysfunction or failure
  • Cholestasis and steatosis
  • Hepatomegaly
• Neurologic
  • Developmental delay
  • Hypotonia
  • Microcephaly
  • Motor and sensory peripheral neuropathy
• Gastrointestinal
  • Gastrointestinal dysmotility
  • Feeding difficulties
  • Failure to thrive

Brain MRI findings

• White matter abnormalities
• Brain stem signal abnormalities
• Basal ganglia signal abnormalities

Supportive laboratory findings

• Serum testing
  • Elevated hepatic transaminases and hyperbilirubinemia
  • Lactic acidosis
  • Hypoglycemia
• Liver histology
  • Steatosis
  • Cirrhosis
• Mitochondrial DNA analysis in liver and muscle [El-Hattab et al 2018]
  • Mitochondrial DNA content:
    • Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
    • Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
  • Multiple mtDNA deletions have been occasionally described in muscle and liver.
• Electron transport chain (ETC) assays in liver and muscle tissue of affected individuals typically show decreased activity of multiple complexes with complex I having reduced activity in 80% of affected individuals [El-Hattab et al 2018].
  Note: Neither mtDNA analysis nor ETC assays are required to make the diagnosis of MPV17-related mtDNA maintenance defect.

Establishing the Diagnosis

The diagnosis of MPV17-related mtDNA maintenance defect is established in a proband with biallelic pathogenic variants in MPV17 by molecular genetic testing (see Table 1).

Because the phenotype of MPV17-related mtDNA maintenance defect is indistinguishable from many other inherited disorders with encephalohepatopathy, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of MPV17, followed by gene-targeted deletion/duplication analysis) is rarely useful.

• A multigene panel that includes MPV17 and other genes of interest (see Differential Diagnosis) 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. Note: (1) 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. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) 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. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible.
  Exome array (when clinically available) may be considered if exome sequencing is not diagnostic, particularly when evidence supports autosomal dominant inheritance.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

MPV17-related mtDNA maintenance defect has been reported in 100 individuals [Karadimas et al 2006, Spinazzola et al 2006, Wong et al 2007, Navarro-Sastre et al 2008, Spinazzola et al 2008, Kaji et al 2009, Parini et al 2009, El-Hattab et al 2010, Al-Jasmi et al 2011, AlSaman et al 2012, Blakely et al 2012, Garone et al 2012, Merkle et al 2012, Nogueira et al 2012, Al-Hussaini et al 2014, Bijarnia-Mahay et al 2014, Mendelsohn et al 2014, Piekutowska-Abramczuk et al 2014, Sarkhy et al 2014, Uusimaa et al 2014, Vilarinho et al 2014, Choi et al 2015, Bitting & Hanson 2016, Kim et al 2016, McKiernan et al 2016, El-Hattab et al 2018].

The vast majority of affected individuals (96/100) presented with an early-onset encephalohepatopathic (hepatocerebral) disease affecting mainly the nervous system and liver; mtDNA depletion is typically identified, particularly in liver. A later-onset neuromyopathic disease characterized by myopathy and neuropathy and associated with multiple mtDNA deletions in muscles has also rarely been described (4/100 affected individuals) [El-Hattab et al 2018].

MPV17-related mtDNA maintenance defect, encephalohepatopathy form is typically an early-onset disease that presents during the neonatal period (36 out of 96; 38%) or infancy (56 out of 96; 58%). Childhood onset (2-18 years) has been reported on rare occasions (4 out of 96; 4%) [El-Hattab et al 2018].

Clinical manifestations include hepatic and neurologic findings summarized in Table 2.

Prognosis. MPV17-related encephalohepatopathy typically has a poor prognosis due to early liver failure. Liver transplantation has been performed in some affected individuals, with high rates of post-transplantation death.

MPV17-related mtDNA maintenance defect, neuromyopathy form is a rare emerging phenotype described in four out of 100 (4%) affected individuals. Onset of symptoms is typically later and characterized by myopathy and neuropathy.

• One individual presented during childhood, two during adolescence, and one during adulthood.
• All four individuals had myopathy and peripheral neuropathy.
• Liver manifestations were absent in two individuals, while the other two had milder liver involvement but without liver failure.
• Development was normal in all affected individuals.
• One individual had ptosis and ophthalmoplegia.
• Mitochondrial DNA was assessed in muscle tissue in two individuals and showed normal mtDNA content with multiple mtDNA deletions [Blakely et al 2012, Garone et al 2012, Choi et al 2015].

Genotype-Phenotype Correlations

No clear genotype-phenotype correlation exists. However, a trend for longer survival can be observed in individuals with biallelic pathogenic missense variants compared to individuals with biallelic null (nonsense, frameshift, deletions, and splice site) variants or individuals compound heterozygous for missense and null variants. In particular, individuals homozygous for p.Arg50Gln, p.Pro98Leu, or p.Arg41Gln may carry a relatively better prognosis [El-Hattab et al 2018].

Nomenclature

Navajo neurohepatopathy (NNH) was originally described as a distinct condition among Navajo children in the southwestern United States, but it is now clear that NNH is part of the MPV17-related mtDNA maintenance defect spectrum, falling under the encephalohepatopathy phenotype.

Encephalohepatopathic MPV17-related mtDNA maintenance defect may also be referred to as infantile hepatocerebral mtDNA depletion syndrome.

Prevalence

The prevalence of MPV17-related mtDNA maintenance defect is unknown but likely to be very low; only 100 affected individuals have been reported to date.