Clinical Diagnosis

The diagnosis of MPV17-related hepatocerebral mitochondrial DNA (mtDNA) depletion syndrome should be suspected in infants with a combination of the following:

• Hepatic manifestations including elevated transaminases, jaundice, cholestasis, hepatomegaly, cirrhosis, and liver failure

• Neurologic manifestations including developmental delay, hypotonia, muscle weakness, ataxia, motor and sensory peripheral neuropathy, and leukoencephalopathy by brain MRI [Navarro-Sastre et al 2008, Spinazzola et al 2008]

• Failure to thrive

• Metabolic derangements including lactic acidosis and severe hypoglycemic crises in early infancy

Testing

Mitochondrial DNA (mtDNA) content (copy number) analysis

• MtDNA content is severely and consistently reduced in liver tissue (<20% of tissue- and age-matched controls).

• MtDNA content can also be reduced in muscle tissue (typically <30% of tissue- and age-matched controls).

Note: Mitochondrial DNA copy number values in blood cells are not a reliable indicator of mtDNA depletion [Dimmock et al 2010, El-Hattab et al 2010].

Electron transport chain (ETC) activity. ETC activity assays in liver and muscle tissue of affected individuals typically show decreased activity of multiple complexes with complex I or I+III being the most affected. Similar to the findings of mtDNA content, the liver ETC activities are usually more reduced than those of muscle tissue [El-Hattab et al 2010].

Molecular Genetic Testing

Gene. MPV17, which encodes for a mitochondrial inner membrane protein, is the only gene in which mutations cause MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. (See Table A. Genes and Databases for chromosome locus and protein encoded by this gene.)

Table 1. Summary of Molecular Genetic Testing Used in MPV17-Related Hepatocerebral Mitochondrial Depletion Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
MPV17	Sequence analysis	Sequence variants 2	28/31 (90%) 3	Clinical
	Deletion / duplication analysis 4	Exonic or whole-gene deletions	2/31 (6%) 5

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Sequencing of all coding exons and the flanking intronic regions identified homozygous or compound heterozygous mutations in 28 of 31 affected individuals [El-Hattab et al 2010, Merkle et al 2012].

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

5. A 1.57-kb deletion spanning exon 8 has been reported in two affected individuals [El-Hattab et al 2010].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. As a part of the workup of unexplained infantile liver dysfunction, the liver biopsy that is obtained for pathologic examination should also undergo mtDNA content analysis.

The identification of severely reduced mtDNA copy number should prompt further evaluation that includes molecular genetic testing of MPV17:

• If homozygous or compound heterozygous mutations are identified by sequence analysis, the diagnosis is confirmed. Molecular genetic testing of both parents is needed to confirm their carrier status and the phase of the mutations in the proband.

• If one or no mutations are detected by sequence analysis, or the parents’ carrier status cannot be confirmed, deletion/duplication analysis is recommended.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are associated with mutations in MPV17.

Natural History

MPV17-related hepatocerebral mtDNA depletion syndrome, an infantile-onset disorder, can present with a spectrum of combined hepatic, neurologic, and metabolic manifestations. To date, molecularly confirmed MPV17-related hepatocerebral mtDNA depletion syndrome has been reported in 31 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, Merkle et al 2012].

Of note, among the 31 confirmed cases are individuals with Navajo neurohepatopathy who were found to have homozygous p.Arg50Gln mutations in MPV17 [Karadimas et al 2006]. Navajo neurohepatopathy, a disorder prevalent in the Native American Navajo population, has the manifestations of MPV17-related hepatocerebral mtDNA depletion syndrome as well as painless fractures, acral mutilation, and corneal anesthesia, ulceration, and scarring.

The clinical manifestations of MPV17-related hepatocerebral mtDNA depletion syndrome discussed here are based on the phenotype observed in those 31 individuals and summarized in Table 2.

Liver dysfunction. All reported individuals with MPV17-related hepatocerebral mtDNA depletion syndrome came to medical attention in infancy with manifestations of liver dysfunction including jaundice, cholestasis, elevated transaminases and gamma-glutamyl transpeptidase (GGT), hyperbilirubinemia, and coagulopathy. Approximately half were reported to have hepatomegaly.

In 90% of affected individuals liver disease progressed to liver failure typically during infancy or early childhood. About a quarter were reported to have liver cirrhosis typically in early childhood; two developed hepatocellular carcinoma at ages seven and 11 years [Karadimas et al 2006, El-Hattab et al 2010].

Liver biopsy may show cholestasis and cirrhosis.

Neurologic manifestations. The vast majority of affected individuals exhibited neurologic manifestations, including developmental delay (~85%), hypotonia and muscle weakness (~65%), and motor and sensory peripheral neuropathy (~30%). Very few affected individuals were reported to have normal psychomotor development; the majority was reported to have a variable degree of developmental delay. Some affected individuals presented with psychomotor delays during early infancy while others had normal development early in life followed by loss of motor and cognitive abilities later in infancy or early childhood. Peripheral neuropathy typically manifests in early childhood with muscle weakness and wasting, decreased reflexes, and loss of sensation in the hands and feet [Karadimas et al 2006, Wong et al 2007, Navarro-Sastre et al 2008, Spinazzola et al 2008, Kaji et al 2009, Parini et al 2009].

Less frequent neurologic manifestations include epilepsy, ataxia, dystonia, microcephaly, cerebrovascular infarction, and subdural hematoma.

Brain MRI abnormalities were reported in approximately one third of affected individuals, with white matter abnormalities (leukoencephalopathy) being the most common. Two individuals have been reported with T₂ hyperintensities within the reticular formation of the lower dorsal brain stem and the reticulospinal tracts of the cervicomedullary junction [Merkle et al 2012].

Failure to thrive is one of the common manifestations, although some children have normal growth, especially early in the course of the disease.

Metabolic derangements occur in the vast majority with lactic acidosis occurring in approximately 75% and early-onset hypoglycemia in approximately 50%. Hypoglycemia typically presents during the first six months of life and can be associated with lethargy, apnea, and/or seizures. Lactic acidosis is a biochemical finding with mild to moderate elevation of lactate (3-9 mmol/L) [Karadimas et al 2006, Wong et al 2007, Navarro-Sastre et al 2008, Spinazzola et al 2008, Kaji et al 2009, Parini et al 2009].

Less frequent manifestations include renal tubulopathy, hypoparathyroidism, and gastrointestinal dysmotility manifest as gastroesophageal reflux, cyclic vomiting, and/or diarrhea.

Corneal anesthesia and ulcers were reported in three individuals considered to have Navajo neurohepatopathy who were homozygous for the mutation p.Arg50Gln.

Prognosis. Liver disease typically progresses to liver failure in affected children. Liver transplantation, the only treatment option for liver failure, has been performed in about one third of affected children. The outcome has not been satisfactory: half of the children undergoing transplantation died during the post-transplantation period because of multiorgan failure and/or sepsis.

Approximately half of affected children reported did not undergo liver transplantation and died because of progressive liver failure, the majority during infancy or early childhood. Three affected individuals homozygous for p.Arg50Gln died in their second decade.

Only four children were reported to survive without liver transplantation, the oldest of whom is age 13 years. Two of the four (including the 13-year old) are homozygous for the p.Arg50Gln mutation, indicating a better prognosis associated with p.Arg50Gln homozygosity (see Genotype-Phenotype Correlations; Table 3)

Two affected individuals developed hepatocellular carcinoma.

Genotype-Phenotype Correlations

To date, the p.Arg50Gln mutation has only been reported in the homozygous state in Navajo neurohepatopathy, which has the manifestations of MPV17-related hepatocerebral mtDNA depletion syndrome as well as corneal anesthesia, ulceration, and scarring.

In contrast to most MPV17 mutations that are associated with death in infancy or early childhood, the p.Arg50Gln mutation is associated with longer survival, suggesting that this is a hypomorphic mutation.

Homozygosity for p.Arg50Gln has been reported in ten children, five of whom died, typically in the second decade of life. Liver failure and death were reported in an infant homozygous for the p.Arg50Gln mutation whose mtDNA copy number in liver was very low (3%) [Spinazzola et al 2006], whereas children homozygous for the p.Arg50Gln mutation who survived longer have a relatively higher mtDNA copy number (10%-20%), suggesting that the degree of mtDNA depletion in the liver correlates with outcome in children homozygous for the p.Arg50Gln mutation [El-Hattab et al 2010].

The other MPV17 mutations have been associated with a lower mtDNA copy number than those associated with the p.Arg50Gln mutation and death in infancy or early childhood if not treated by liver transplantation [El-Hattab et al 2010].

Liver transplantation was performed in ten children, five of whom survived the post-transplant period. Of the five survivors, three are homozygous for p.Arg50Gln mutation, indicating a relatively better response to liver transplantation with this genotype [El-Hattab et al 2010].

Prevalence

The prevalence of MPV17-related hepatocerebral mtDNA depletion syndrome is unknown but likely to be very rare, with only 31 affected individuals being reported to date. Seven of the 31 are of Navajo ancestry.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with MPV17-related hepatocerebral mtDNA depletion syndrome, the following evaluations are recommended.

• Hepatic

  • Liver function including liver transaminases (ALT and AST), GGT, albumin, total and direct bilirubin, and coagulation profile (PT and PTT)

  • Ultrasound examination to assess liver size and texture, and for the presence of masses

  • Alpha fetoprotein (AFP) to screen for hepatocellular carcinoma

  • Hepatology/liver transplantation consultation

• Neurologic

  • Developmental evaluation

  • Neurologic consultation and comprehensive neurologic examination

  • Brain MRI to assess white matter and other abnormalities. The brain MRI findings can establish the degree of central nervous system involvement and serve as a baseline for monitoring the progression of the neurologic disease.

  • Nerve conduction velocity (NCV) to assess peripheral neuropathy. NCV can establish the degree of the peripheral nervous system involvement and serve as a baseline for monitoring the progression of the neurologic disease.

  • EEG if seizures are suspected

• Nutritional evaluation

• Plasma lactate and glucose concentration

• Urinalysis and amino acids to assess for renal tubulopathy

• Gastrointestinal consultation if gastrointestinal dysmotility is present

• Ophthalmologic examination to assess corneal sensation and possible corneal ulcers/scaring

• Medical genetics consultation

Treatment of Manifestations

Management should involve a multidisciplinary team including specialists in hepatology, neurology, nutrition, medical genetics, and child development. Treatment of MPV17-related hepatocerebral mtDNA depletion syndrome remains unsatisfactory with a mortality rate higher than 50% (see Clinical Description, Prognosis).

Nutritional support should be provided by a dietitian experienced in managing children with liver diseases.

Prevention of hypoglycemia requires frequent feeds and avoidance of fasting. Uncooked cornstarch (1-2 grams/kg/dose) can be used to manage hypoglycemia, and it may slow but not stop the progression of the liver disease [Spinazzola et al 2008, Parini et al 2009].

Liver transplantation. Although liver transplantation remains the only treatment option for liver failure, liver transplantation in mitochondrial hepatopathy is controversial, largely because of the multisystemic involvement. Liver transplantation has been performed in about one third of affected children; the outcome has not been satisfactory, with half of the transplanted children dying in the post-transplantation period because of multiorgan failure and/or sepsis (see Clinical Description, Prognosis).

Hepatocellular carcinoma. The two children reported with hepatocellular carcinoma (HCC) were treated by liver transplantation. Screening for HCC using periodic hepatic ultrasound examination and serum alpha fetoprotein concentration potentially could result in earlier diagnosis, enabling liver transplantation before metastasis or local invasion occurs.

Prevention of Secondary Complications

Nutritional deficiencies, for example of fat-soluble vitamins, can be prevented by ensuring adequate intake and frequent assessment by a dietitian experienced in managing children with liver diseases.

Surveillance

No clinical guidelines for surveillance are available.

The following evaluations are suggested, with frequency varying according to the severity of the condition:

• Liver function tests including liver transaminases (ALT and AST), GGT, albumin, total and direct bilirubin, and coagulation profile (PT and PTT)

• Hepatic ultrasound examination to screen for liver masses that might suggest HCC

• Serum alpha fetoprotein (AFP) concentration

• Developmental evaluation

• Neurologic assessment

• Nutritional assessment

• Urinalysis and urine amino acids to assess for renal tubulopathy

• Ophthalmologic examination

Agents/Circumstances to Avoid

Prolonged fasting can lead to hypoglycemia and should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

MPV17-related hepatocerebral mtDNA depletion syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• 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.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. To date no affected individuals have reproduced; therefore, fertility is not yet known.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Revision History

• 17 May 2012 (me) Review posted live

• 27 February 2012 (aeh) Original submission