Mitochondrial Dna Depletion Syndrome 6 (Hepatocerebral Type)

A number sign (#) is used with this entry because mitochondrial DNA depletion syndrome-6 (MTDPS6), also known as Navajo neurohepatopathy (NNH), is caused by homozygous or compound heterozygous mutation in the MPV17 gene (137960) on chromosome 2p23.

Biallelic mutations in the MPV17 gene can also caused CMT2EE (618400), a much less severe disorder.

Description

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).

Clinical Features

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 4 children with Navajo neuropathy, including 1 previously reported by Appenzeller et al. (1976), and extended the clinical spectrum to include progressive central nervous system white matter abnormalities with spinal cord atrophy in older children and onset during early infancy.

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, sexual infantilism, 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.

El-Hattab et al. (2018) reviewed 75 individuals with biallelic MPV17 mutations and added 25 newly described patients. The vast majority of patients presented with an early-onset encephalohepatic disease consistent with MTDPS6. Patients had failure to thrive, lactic acidemia, and mtDNA depletion, mainly in liver tissue. Hepatic abnormalities included elevated liver enzymes, jaundice, hyperbilirubinemia, cholestasis, steatosis, hepatomegaly, and frank liver failure. Neurologic abnormalities included hypotonia, developmental delay, and neurologic deterioration later in childhood. Common, but not universal, features included feeding difficulties, seizures, microcephaly, and sensorimotor peripheral neuropathy. Less common features (in less than 10% of patients) included dystonia, ataxia, retinopathy, corneal ulcerations, nystagmus, renal tubulopathy, nephrocalcinosis, and hypoparathyroidism. Brain imaging showed diffuse white matter abnormalities consistent with leukodystrophy or hypomyelination, but many had normal scans. The prognosis was very poor: most patients (about 75%) died in the first decade of liver or multiorgan failure. Four of the 100 patients presented with later onset of a neuromyopathic disease with little or no liver involvement (see CMT2EE; 618400).

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.

Diagnosis

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.

Mapping

The clinical, pathologic, and biochemical features seen in patients with NNH resembles those in patients with mtDNA depletion syndrome, suggesting that abnormal regulation of mtDNA copy number may be the primary defect in NNH (Vu et al., 2001). Homozygosity mapping of 2 families with NNH suggested linkage to chromosome 2p24 (Karadimas et al., 2006). This locus includes the MPV17 gene, which, when mutated, was known to cause hepatocerebral mtDNA depletion syndrome.

Molecular Genetics

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.

Genotype/Phenotype Correlations

In a large review of 100 patients, El-Hattab et al. (2018) found that about half of the pathogenic MPV17 variants were missense, but other types of mutations (nonsense, frameshift, in-frame deletions, splice site) occurred throughout the gene. In general, those with biallelic missense mutations tended to have a less severe phenotype, in particular those with homozygous R50Q (137960.0001), P98L (137960.0008), or R41Q (137960.0009) mutations.

Animal Model

In an Mpv17-knockout mouse model, Viscomi et al. (2009) found severe mtDNA depletion in liver and skeletal muscle, whereas hardly any depletion was detected in brain and kidney. Mouse embryonic fibroblasts only showed mtDNA depletion after several culturing passages or in serum-free medium. In spite of severe mtDNA depletion, only moderate decreases in respiratory chain enzymatic activities and mild cytoarchitectural alterations were observed in Mpv17 -/- livers, but neither cirrhosis nor failure ever occurred. The mtDNA transcription rate was markedly increased in liver, which could contribute to compensation for the severe mtDNA depletion. This phenomenon was associated with specific downregulation of Mterf (602318), a negative modulator of mtDNA transcription. The most relevant clinical features involved skin, inner ear, and kidney. The coat of the Mpv17 -/- mice turned gray early in adulthood, and 18-month or older mice developed focal segmental glomerulosclerosis (FSGS) with massive proteinuria. Concomitant degeneration of cochlear sensory epithelia was reported as well. These symptoms were associated with significantly shorter life span. Coincidental with the onset of FSGS, minimal mtDNA was measurable in glomerular tufts.