A number sign (#) is used with this entry because mitochondrial DNA depletion syndromes 8A (MTDPS8A) and 8B (MTDPS8B) are caused by homozygous or compound heterozygous mutation in the RRM2B gene (604712) on chromosome 8q22.

See also autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA (mtDNA) deletions-5 (PEOA5; 613077) and rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (RCDFRD; 268315), allelic disorders caused by heterozygous and homozygous mutations, respectively, in the RRM2B gene.

Mitochondrial DNA depletion syndrome-8A is a severe autosomal recessive disorder characterized by neonatal hypotonia, lactic acidosis, and neurologic deterioration. Renal tubular involvement may also occur (Bourdon et al., 2007).

Mitochondrial DNA depletion syndrome-8B is characterized by ophthalmoplegia, ptosis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and brain MRI changes, known as the MNGIE phenotype (Shaibani et al., 2009).

For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (603041).

Bourdon et al. (2007) reported 3 sibs, born of consanguineous Moroccan parents, with severe mtDNA depletion syndrome with less than 1% mtDNA in skeletal muscle. All had neonatal hypotonia, lactic acidosis, and neurologic deterioration with death in the first months of life. One patient developed a proximal renal tubulopathy. Four additional patients from 3 unrelated families had a similar disorder with early death.

Kollberg et al. (2009) reported 2 Sudanese brothers, born of consanguineous parents, with a severe form of fatal autosomal recessive encephalomyopathic mtDNA depletion syndrome. The older brother presented at age 2 months with feeding difficulties, failure to thrive, hypotonia, lactic acidosis, and massive aminoaciduria consistent with a renal proximal tubulopathy. He also had poor visual contact and developed seizures. The disorder progressed rapidly, and he died of respiratory insufficiency at the age of 3 months. His younger brother presented at 2 months of age with tonic-clonic seizures. He later had feeding difficulties with failure to thrive, progressive muscle weakness, hypotonia, lactic acidosis, and poor visual contact. He continued to deteriorate and died at 5 months of age. There was no aminoaciduria, but urinary organic acids showed combined keto- and lactic acidosis. Skeletal muscle biopsy of both patients showed cytochrome c oxidase deficiency and pathologic accumulation of fat in many muscle fibers without abnormal mitochondrial proliferation. There was also severe deficiency of mitochondrial respiratory chain complexes. Southern blot analysis of patient cells showed severe mtDNA depletion (1-4% of normal controls).

Penque et al. (2019) reported a male infant, born of consanguineous Latino parents, who had poor weight gain at 1 month of age and a weak cry and delayed development at 2 months of age. He was found to have elevated ammonia and creatine kinase as well as lactic acidosis, and he was admitted to the hospital. Initial brain MRI was normal. He developed emesis and feeding intolerance, and he was intubated due to labored breathing and hypoxia. Blood cultures grew E. coli. He developed a depressed neurologic status and respiratory failure, and repeat brain MRI with spectroscopy showed restricted diffusion and elevated lactate. The parents elected for palliative care, and he was extubated and died soon after.

Clinical Variability

Shaibani et al. (2009) reported a 42-year-old woman of mixed African American and Latin American descent referred for ophthalmoplegia, ptosis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and brain MRI changes. At age 30 years, she developed recurrent and severe episodes of nausea and vomiting due to gastrointestinal dysmotility and associated with severe weight loss. She also had gentamicin-induced sensorineural hearing loss. Since age 37, she had progressive restriction of eye movements, ptosis, micronystagmus, dysarthria, unsteady gait, generalized muscle weakness, and areflexia. There was no family history of a similar disorder. Laboratory studies showed mildly increased serum lactate, demyelinating polyneuropathy, increased T2-weighted signals in the basal ganglia, and muscle biopsy with ragged-red fibers and mtDNA depletion (12% of controls). All these findings were consistent with a mitochondrial disorder, although studies of respiratory chain enzymes in skeletal muscle were normal. Genetic analysis identified compound heterozygosity for 2 mutations in the RRM2B gene (R110H, 604712.0008; R121H, 604712.0009). Shaibani et al. (2009) noted that this was the oldest reported patient with RRM2B mutations and that her clinical course was different from that reported previously in patients with MNGIE. The findings also broadened the phenotype associated with RRM2B mutations to include an MNGIE (603041)-like picture.

In 3 Moroccan sibs with severe autosomal recessive mtDNA depletion syndrome-8A, Bourdon et al. (2007) identified homozygous or compound heterozygous mutations in the RRM2B gene (604712.0001-604712.0005).

Kollberg et al. (2009) reported 2 Sudanese brothers, born of consanguineous parents, with a severe form of fatal autosomal recessive encephalomyopathic mtDNA depletion syndrome-8B caused by a homozygous mutation in the RRM2B gene (G229V; 604712.0007).

In a male infant, born to consanguineous Latino parents, with MTDPS8A, Penque et al. (2019) identified a homozygous missense mutation in the RRM2B gene (N221S; 604712.0015). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Molecular modeling suggested that the mutation disrupts a conserved alpha helix region of the protein by altering intramolecular interactions.