Mitochondrial DNA depletion syndrome, hepatocerebral form
-Rare developmental defect during embryogenesis
-Rare eye disease
-Rare gastroenterologic disease
-Rare genetic disease
-Rare neurologic disease
Comment:
Navajo neurohepatopathy (NNH) is caused by mutations in the MPV17 (= MTDPS6) gene. It is an autosomal recessive disease that is prevalent among Navajo children in the southwestern United States. The major clinical features are hepatopathy, peripheral neuropathy, corneal anesthesia and scarring, acral mutilation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections. Infantile, childhood, and classic forms of NNH have been described. Mitochondrial DNA (mtDNA) depletion was detected in the livers of two patients, suggesting a primary defect in mtDNA maintenance (PMID:16909392; 20074988).
Mitochondrial DNA depletion syndrome-6 is an autosomal recessive disorder characterized by infantile onset of progressive liver failure, often leading to death in the first year of life. Those that survive develop progressive neurologic involvement, including ataxia, hypotonia, dystonia, ... Mitochondrial DNA depletion syndrome-6 is an autosomal recessive disorder characterized by infantile onset of progressive liver failure, often leading to death in the first year of life. Those that survive develop progressive neurologic involvement, including ataxia, hypotonia, dystonia, and psychomotor regression (Spinazzola et al., 2008). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).
Ebermann et al. (2008) reported an 11-year-old boy, born of Egyptian consanguineous parents, with a phenotype suggestive of Navajo neurohepatopathy, including short stature, frequent painless fractures, bruises, and cuts, hepatomegaly with elevated liver ... - Confounding Phenotypes Ebermann et al. (2008) reported an 11-year-old boy, born of Egyptian consanguineous parents, with a phenotype suggestive of Navajo neurohepatopathy, including short stature, frequent painless fractures, bruises, and cuts, hepatomegaly with elevated liver enzymes, corneal ulcerations, and mild hypotonia. His 22-month-old sister had short stature, hepatomegaly, increased liver enzymes, and hypotonia. A cousin had died at age 8 years from liver failure. After genetic analysis excluded a mutation in the MPV17 gene, Ebermann et al. (2008) postulated 2 recessive diseases. Genomewide linkage analysis and gene sequencing of the proband identified a homozygous mutation in the AGL gene (610860), consistent with glycogen storage disease III (GSD3; 232400), and a homozygous mutation in the SCN9A gene (603415), consistent with congenital insensitivity to pain (CIPA; 243000). His sister had the AGL mutation and GSD3 only. Ebermann et al. (2008) emphasized that consanguineous matings increase the risk of homozygous genotypes and recessive diseases, which may complicate genetic counseling.
Appenzeller et al. (1976) described 4 Navajo children with a mutilating neuropathy with severe motor involvement. The disorder appeared to be recessively inherited and was present from a very early age. Manifestations included severe anesthesia leading to corneal ... Appenzeller et al. (1976) described 4 Navajo children with a mutilating neuropathy with severe motor involvement. The disorder appeared to be recessively inherited and was present from a very early age. Manifestations included severe anesthesia leading to corneal ulceration, painless fractures, and acral mutilation; muscle weakness; absent or markedly decreased deep tendon reflexes; and normal IQ. Sural nerve biopsy showed nearly complete absence of myelinated fibers without evidence of regeneration, and degenerative unmyelinated fibers with evidence of regeneration. Snyder et al. (1988) reported 11 additional Navajo children with the syndrome and provided further details on the original 4 patients. Other features included systemic infections, macronodular cirrhosis, poor weight gain, and sexual infantilism. Singleton et al. (1990) performed a major epidemiologic survey of Navajo neuropathy, identifying 20 definite and 4 possible cases from a review of reservation hospital records and a questionnaire directed to all health providers on the Navajo reservation. The 24 cases identified came from 13 families, with 6 families having more than 1 affected child. Clinical features included sensorimotor neuropathy, corneal ulcerations, acral mutilation, poor weight gain, short stature, serious systemic infections, and liver disease. The liver disease presented as hepatomegaly, persistent neonatal jaundice, and even a Reye-like syndrome of acute hepatic failure. Brain imaging showed progressive CNS white matter lesions. Diagnosis was usually at the end of the first year of life or in the beginning of the second year, either because of neurologic symptoms or liver disease. The mean age of death was approximately 10 years, frequently due to liver disease. The incidence of this syndrome on the Western Navajo reservation was 5 times higher than on the Eastern reservations (38 compared to 7 cases per 100,000 births). Singleton et al. (1990) suggested an inborn error of metabolism, inherited in an autosomal recessive pattern. In a review of 20 children with Navajo neuropathy, Holve et al. (1999) found that all had liver disease. Three phenotypes were observed, based on age at presentation and disease course: 5 patients had onset before 6 months of age with jaundice and failure to thrive followed by progression to liver failure before 2 years of age; 6 children had onset between 1 and 5 years of age with liver dysfunction progressing to liver failure and death within 6 months; and 9 children had variable onset of liver disease, but progressive neurologic deterioration. Liver histologic findings included multinucleated giant cells, macrovesicular and microvesicular steatosis, pseudo-acini, inflammation, cholestasis, and bridging fibrosis and cirrhosis. Cases of all 3 phenotypes occurred within the same kindred. Holve et al. (1999) emphasized that liver disease is an important component of Navajo neuropathy and may be the predominant feature in infants and young children. They proposed changing the name of the disorder to Navajo neurohepatopathy. Erickson (1999) reviewed genetic diseases among the Navajo population. Spinazzola et al. (2006) studied 3 families with the hepatocerebral form of mtDNA depletion syndrome caused by MPV17 mutations. In a multigeneration family originating from southern Italy, 2 children died of liver failure during the first year of life, but liver transplantation at 1 year of age in another child and dietary control of hypoglycemia in a fourth were effective in maintaining relative metabolic compensation and long-term survival. However, growth in the surviving children, who were 4 and 9 years old at the time of report, remained below the fifth percentile and the older child had developed neurologic symptoms and multiple brain lesions documented by MRI. The probands of the other 2 families died of liver failure in the first months after birth. Spinazzola et al. (2008) reported 2 sisters, born of Iraqi consanguineous parents, with a hepatocerebral form of MTDPS confirmed by genetic analysis (137960.0005). The family history was positive for 2 miscarriages. At age 2 months, the older sister developed jaundice and hepatomegaly associated with clinical liver failure that progressed rapidly over the next few months. Initial MRI at age 3 months was normal but later showed edema of the white matter. She developed dystonic movements and deteriorating neurologic status and died from liver failure at age 11 months. The younger sister showed hypotonia and died of rapidly progressive liver failure at age 5 months. A third unrelated girl, conceived by artificial insemination because of a history of endometriosis in the mother, cried immediately after birth, fed poorly, and was jittery. At age 2 weeks, she was lethargic and had abnormal liver function tests. Brain MRI showed bilateral subdural hemorrhages with an area of periventricular leukomalacia in the right parietal region. Physical examination at age 5 months showed poor growth, hypotonia, roving eye movements, and nystagmus. She died of liver failure at 9 months of age. Genetic analysis showed compound heterozygosity for 2 mutations in the MPV17 gene (137960.0006; 137960.0007). Spinazzola et al. (2008) concluded that MPV17 mutations are associated with rapidly progressive infantile hepatic failure with subsequent neurologic involvement. - Navajo Familial Neurogenic Arthropathy Johnsen et al. (1993) reported 8 Navajo children with a disorder that they termed 'Navajo familial neurogenic arthropathy,' which was characterized by Charcot joints (neurogenic arthropathy) and unrecognized fractures, but with intact reflexes and normal strength. The sensory examination was variable: many had no discernible sensory deficit, whereas others had subtle deficiency in deep pain sensation, temperature discrimination, and corneal sensitivity. Nerve conduction velocities were normal, but sural nerve biopsy showed a marked reduction in small myelinated and unmyelinated nerve fibers. The 8 patients were distributed in 3 families in a pattern consistent with autosomal recessive inheritance. Johnsen et al. (1993) concluded that the disorder was distinct from that described by Appenzeller et al. (1976) as an acromutilating sensory neuropathy.
In affected members of an Italian and Moroccan family with the hepatocerebral form of mtDNA depletion syndrome, Spinazzola et al. (2006) identified homozygous mutations in the MPV17 gene (137960.0001-137960.0002). An affected proband from a Canadian family was found ... In affected members of an Italian and Moroccan family with the hepatocerebral form of mtDNA depletion syndrome, Spinazzola et al. (2006) identified homozygous mutations in the MPV17 gene (137960.0001-137960.0002). An affected proband from a Canadian family was found to be compound heterozygous for 2 MPV17 mutations (137960.0003 and 137960.0004). Karadimas et al. (2006) sequenced the MPV17 gene in 6 patients with Navajo neurohepatopathy from 5 families and found the homozygous arg50-to-gln mutation previously described in a southern Italian family (137960.0001) with hepatocerebral mtDNA depletion syndrome (Spinazzola et al., 2006). Identification of a single missense mutation in patients with NNH confirmed that the disease is probably due to a founder effect, and extended the phenotypic spectrum associated with MPV17 mutations.
The diagnosis of MPV17-related hepatocerebral mitochondrial DNA (mtDNA) depletion syndrome should be suspected in infants with a combination of the following:...
DiagnosisClinical 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 TestingMitochondrial DNA (mtDNA) content (copy number) analysisMtDNA 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 SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMPV17Sequence analysisSequence variants 228/31 (90%) 3ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletions2/31 (6%) 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.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.Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this GeneReview are associated with mutations in MPV17.
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]. ...
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. Table 2. Clinical Manifestations of MPV17-Related Hepatocerebral mtDNA Depletion Syndrome View in own windowClinical ManifestationsFrequencyHepatic • Liver dysfunction • Liver failure • Hepatomegaly • Liver cirrhosis • Hepatocellular cancer31/31 (100%)31/31 (100%) 28/31 (90%) 14/29 (48%) 7/29 (24%) 2/31 (6%)Neurologic • Developmental delay • Hypotonia, muscle weakness • White matter abnormalities in brain MRI • Peripheral neuropathy • Seizures • Microcephaly • Ataxia26/29 (90%)24/29 (83%) 19/29 (66%) 10/29 (34%) 8/29 (28%) 3/29 (10%) 2/29 (7%) 2/29 (7%)Failure to thrive26/29 (90%)Metabolic • Lactic acidosis • Hypoglycemia23/27 (85%)20/27 (74%) 13/27 (48%)Other manifestations • Renal tubulopathy • Gastroesophageal reflux • Vomiting and/or diarrhea • Corneal anesthesia and ulcers • Hypoparathyroidism3/29 (10%) 3/29 (10%) 3/29 (10%) 3/29 (10%) 2/29 (7%)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. Table 3. Outcome of Children with MPV17-Related Hepatocerebral mtDNA Depletion SyndromeView in own windowLiver Transplant?OutcomeFrequencyNo (21/31)DeathIn infancy or early childhood14/31 (45%)In the second decade3/31 (10%)Survival4/31 (13%)Yes (10/31)Death5/31 (16%)Survival5/31 (16%)
Mitochondrial disorders are caused by defects in mitochondrial DNA (mtDNA) or nuclear genes involved in mitochondrial biogenesis and function. Defects in nuclear genes involved in the maintenance of mtDNA integrity can be associated with large-scale rearrangements of mtDNA (mtDNA multiple deletion syndromes) (see Mitochondrial DNA Deletion Syndromes) or with reduction in the mtDNA content (mtDNA depletion syndromes) (see Table 4). ...
Differential DiagnosisMitochondrial disorders are caused by defects in mitochondrial DNA (mtDNA) or nuclear genes involved in mitochondrial biogenesis and function. Defects in nuclear genes involved in the maintenance of mtDNA integrity can be associated with large-scale rearrangements of mtDNA (mtDNA multiple deletion syndromes) (see Mitochondrial DNA Deletion Syndromes) or with reduction in the mtDNA content (mtDNA depletion syndromes) (see Table 4). Mitochondrial DNA depletion syndromes are phenotypically heterogeneous and may affect either a specific organ or a combination of organs, including muscle, liver, brain, and kidney. Clinically, mtDNA depletion syndromes are classified as:Neurogastrointestinal encephalopathy associated with mutations in TYMP (encoding thymidine phosphorylase) or POLG (encoding DNA polymerase gamma); Myopathy associated with mutations in TK2 (encoding thymidine kinase 2);Encephalomyopathy associated with mutations in SUCLA2 (encoding ATP-dependent succinyl CoA synthase), SUCLG1 (encoding GTP-dependent succinyl CoA synthase), or RRM2B (encoding p53-induced ribonucleotide reductase B subunit); Hepatocerebral form associated with mutations in C10orf2 (encoding Twinkle), POLG (encoding DNA polymerase gamma), DGUOK (encoding deoxyguanosine kinase), or MPV17. Table 4. Mitochondrial DNA Depletion Syndrome: OMIM Phenotypic SeriesView in own windowPhenotypePhenotype MIM NumberGene / LocusGene/Locus MIM NumberMitochondrial DNA depletion syndrome 1 (MNGIE type) 603041 TYMP131222 Mitochondrial DNA depletion syndrome 2 (myopathic type) 609560 TK2188250 Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)251880 DGUOK 601465 Mitochondrial DNA depletion syndrome 4A (Alpers type) 203700 POLG 174763 Mitochondrial DNA depletion syndrome 4B (MNGIE type)613662 POLG174763 Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with methylmalonic aciduria)612073 SUCLA2603921 Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) 256810 MPV17 137960 Mitochondrial DNA depletion syndrome 7 (hepatocerebral type) 271245 C10orf2606075 Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) 612075 RRM2B604712 Mitochondrial DNA depletion syndrome 8B (MNGIE type) 612075 RRM2B604712 Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) 245400 SUCLG1611224 Data from Online Mendelian Inheritance in ManMPV17-related hepatocerebral mtDNA depletion syndrome needs to be differentiated from other types of hepatocerebral mtDNA depletion syndromes associated with biallelic mutations in DGUOK, C10orf2, or POLG. In addition, mutations in BCS1L (encoding a mitochondrial protein involved in complex III assembly) and SCO1 (encoding a mitochondrial protein involved in complex IV assembly) have been associated with encephalopathy and hepatic dysfunction [Valnot et al 2000, Visapää et al 2002]. In MPV17-related hepatocerebral mtDNA depletion syndrome, liver involvement appears early in the course of the disease, unlike most of the other multisystem mitochondrial disorders with prominent neuromuscular involvement, in which liver complications are more commonly a late feature. In contrast to other mtDNA depletion syndromes, neurologic involvement in MPV17-related hepatocerebral mtDNA depletion syndrome is generally mild at the onset of disease [Wong et al 2007, El-Hattab et al 2010]. However, DGUOK-related hepatocerebral mtDNA depletion syndrome may also present as isolated liver disease without neuromuscular involvement [Dimmock et al 2008, Freisinger et al 2006]. Infantile liver failure is also a feature of the disorders caused by mutations in TRMU (encoding mitochondria tRNA-specific 2-thiouridylase 1) and GFM1 (encoding mitochondrial elongation factor G); mtDNA depletion is not a feature in these disorders [Coenen et al 2004, Zeharia et al 2009]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an nteractive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with MPV17-related hepatocerebral mtDNA depletion syndrome, the following evaluations are recommended. ...
ManagementEvaluations 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 massesAlpha fetoprotein (AFP) to screen for hepatocellular carcinoma Hepatology/liver transplantation consultation NeurologicDevelopmental evaluation Neurologic consultation and comprehensive neurologic examinationBrain 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 evaluationPlasma lactate and glucose concentration Urinalysis and amino acids to assess for renal tubulopathyGastrointestinal consultation if gastrointestinal dysmotility is present Ophthalmologic examination to assess corneal sensation and possible corneal ulcers/scaringMedical genetics consultationTreatment of ManifestationsManagement 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 ComplicationsNutritional 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. SurveillanceNo 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 assessmentNutritional assessmentUrinalysis and urine amino acids to assess for renal tubulopathyOphthalmologic examination Agents/Circumstances to Avoid Prolonged fasting can lead to hypoglycemia and should be avoided. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. MPV17-Related Hepatocerebral Mitochondrial DNA Depletion Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMPV172p23.3Protein Mpv17MPV17 homepage - Mendelian genesMPV17Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for MPV17-Related Hepatocerebral Mitochondrial DNA Depletion Syndrome (View All in OMIM) View in own window 137960MPV17, MOUSE, HOMOLOG OF; MPV17 256810MITOCHONDRIAL DNA DEPLETION SYNDROME 6 (HEPATOCEREBRAL TYPE); MTDPS6Normal allelic variants. MPV17 spans 13.6 kb and comprises eight exons. Pathologic allelic variants. To date, 20 different MPV17 mutations have been reported in children with hepatocerebral mtDNA depletion (Table 5). About half of those mutations are missense and the remaining half includes nonsense and splice site mutations and small deletions and insertions. A large deletion spanning exon 8 has also been reported. The most common mutation, p.Arg50Gln, has been identified in seven families.Each of four mutations (p.Arg50Trp, p.Lys88del, p.Leu91del, and the 1.57-kb deletion spanning the last exon) has been observed in two families. All other mutations are private [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]. Table 5. MPV17 Pathologic Allelic Variants Discussed in This GeneReview View in own windowType of MutationDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesMissensec.70G>Tp.Gly24TrpNM_002437.4 NP_002428.1 c.148C>Tp.Arg50Trpc.149G>Ap.Arg50Glnc.262A>Gp.Lys88Gluc.280G>Cp.Gly94Argc.293C>Tp.Pro98Leuc.485C>Ap.Ala162Aspc.498C>Ap.Asn166Lysc.509C>Tp.Ser170PheNonsensec.206G>Ap.Trp69Xc.359G>Ap.Trp120XIn-frame deletionc.234_242del9p.Gly79_Thr81delc.263_265del3p.Lys88delc.271_273del3p.Leu91delFrame shift deletionc.116-141del26p.Arg41Profs*63Insertionc.22_23insCp.Gln8Profs*24c.451_452insC p.Leu151Profs*39Splicing sitec.70+5G>Ac.186+2T>CLarge deletion1.57-kb deletion spanning exon 8See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). Normal gene product. MPV17 encodes the MPV17 protein, an inner mitochondrial membrane protein that is predicted to contain four transmembrane segments (pir.uniprot.org). The function of the MPV17 protein and its role in the pathogenesis of mtDNA depletion syndrome are as yet unknown. It has been suggested that MPV17 plays a role in controlling mtDNA maintenance and oxidative phosphorylation activity in mammals and yeast [Karadimas et al 2006, Dallabona et al 2010]. Abnormal gene product. MPV17 mutations result in dysfunctional MPV17 protein resulting in impaired mtDNA maintenance leading to mtDNA depletion. Individuals with biallelic MPV17 mutations have a severe decrease in mtDNA content, leading to insufficient production of respiratory chain components, resulting in impaired energy production and organ dysfunction [Spinazzola et al 2006].