A number sign (#) is used with this entry because of evidence that mitochondrial DNA depletion syndrome-17 (MTDPS18) is caused by homozygous mutation in the SLC25A21 gene (607571) on chromosome 14q11. One such patient has been reported.

Mitochondrial DNA depletion syndrome-18 (MTDPS18) is an autosomal recessive neuromuscular disorder characterized by early-onset progressive weakness and atrophy of the distal limb muscles, resulting in loss of ambulation as well as atrophy of the intrinsic hand muscles with clawed hands. Affected individuals may also develop scoliosis and have hypo- or hyperreflexia and decreased pulmonary vital capacity. Examination of skeletal muscle shows neurogenic atrophy and combined mitochondrial oxidative phosphorylation deficiency associated with mtDNA depletion. The clinical phenotype is reminiscent of spinal muscular atrophy (see SMA, 253300) and the metabolic profile is reminiscent of 2-aminoadipic 2-oxoadipic aciduria (AMOXAD; 204750), which is caused by mutation in the DHTKD1 gene (614984) (summary by Boczonadi et al., 2018).

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

Boczonadi et al. (2018) reported a 19-year-old woman, born of consanguineous Pakistani parents, with a progressive neurologic disorder. She achieved walking at 15 months of age, but showed progressive deterioration with frequent falls between 3 and 5 years. She developed distal muscle weakness and atrophy of the hands and feet with clenched hands and bilateral foot drop. The disorder was progressive, with the development of proximal weakness and intermittent relapses triggered by fever; she became wheelchair-bound at age 15. Other features included failure to thrive, scoliosis, hyporeflexia, brisk reflexes in the lower limbs with ankle clonus, and decreased forced vital capacity (56 to 65% normal values). Laboratory studies showed some lactic aciduria and urinary excretion of 3-hydroxyisovaleric and glutaric acid, with mildly increased lactate in the CSF. Brain and spinal cord imaging was normal. Neurophysiologic testing showed severe neurogenic changes consistent with an anterior horn cell process, and nerve biopsy showed an axonopathy with patchy loss of myelinated fibers. Skeletal muscle biopsy showed fiber type grouping suggesting neurogenic atrophy, as well as variably decreased activities and steady-state levels of mitochondrial complexes I, III, IV, and V, and significant mtDNA depletion (less than 10% of normal).

The transmission pattern of MTDPS18 in the family reported by Boczonadi et al. (2018) was consistent with autosomal recessive inheritance.

In a 19-year-old woman, born of consanguineous Pakistani parents, with MTDPS18, Boczonadi et al. (2018) identified a homozygous missense mutation in the SLC25A21 gene (K232R; 607571.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Immunoblot analysis of patient fibroblasts showed slightly reduced levels of SLC25A21, although expression of the mutation into the cytoplasmic membrane of Lactococcus lactis showed normal expression and membrane insertion of the mutant protein. In vitro functional expression studies in Lactococcus lactis showed completely impaired transport function for 2-oxoglutarate compared to controls, consistent with a loss of function. Targeted metabolic analysis in the patient showed increased urinary excretion of the intermediate metabolites 2-oxoadipate, quinolinic acid, and pipecolic acid, also consistent with impaired SLC25A21 (ODC) transporter function. Exposure of cultured neuronal cells to 2-oxoadipate and quinolinic acid resulted in mitochondrial respiratory dysfunction and increased cell death. These changes were not observed in fibroblasts, suggesting tissue-specific neurotoxic effects. Boczonadi et al. (2018) noted that the biochemical abnormalities and neuronal susceptibility were similar to those observed in patients with 2-aminoadipic 2-oxoadipic aciduria (AMOXAD; 204750), which is caused by mutation in the DHTKD1 gene (614984)