A number sign (#) is used with this entry because of evidence that mitochondrial DNA depletion syndrome-19 (MTDPS19) is caused by compound heterozygous mutation in the SLC25A10 gene (606794) on chromosome 17q25. One such patient has been reported.

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

Punzi et al. (2018) reported a 9-year-old boy, born of unrelated Italian parents, with a complex multisystem disorder. He presented at birth with hypospadias, bilateral hydrocele, and unilateral hearing loss. At age 3 months, he developed daily infantile spasms associated with multifocal epileptiform discharges and a suppression burst pattern on EEG. The seizures were refractory to treatment. He had severe hypotonia, absent eye tracking, and poor spontaneous movements that evolved to spastic quadriparesis and dyskinesias after the onset of seizures. MRI was initially normal, but later showed white matter abnormalities and thin corpus callosum. Growth parameters were normal, and neuropsychiatric evaluations revealed normal to high intellectual ability. Laboratory studies showed iron-deficient anemia, increased lactate, and reduced mitochondrial respiratory complex I activity (27% of controls) and decreased mtDNA content (40% lower than controls) in muscle.

The transmission pattern of MTDPS19 in the family reported by Punzi et al. (2018) was consistent with autosomal recessive inheritance.

In a 9-year-old boy with MTDPS19, Punzi et al. (2018) identified compound heterozygous loss-of-function mutations in the SLC25A10 gene (606794.0001 and 606794.0002). The mutations were found by trio-based whole-exome sequencing and segregated with the disorder in the family. Patient fibroblasts showed a 10-fold decrease in SLC25A10 transcripts compared to controls, and Western blot analysis did not detect the SLC25A10 protein. In vitro functional expression studies showed negligible, if any, transport activity for malate/phosphate exchange, consistent with a loss of function. In addition, patient cells showed a decrease in both the NADPH/NADP+ and GSH/GSSG ratios as well as a growth defect under stress conditions. Studies in yeast lacking the Slc25a10 ortholog showed impaired growth, impaired mitochondrial respiration, decreased mtDNA, and increased vulnerability to oxidative stress compared to controls. Punzi et al. (2018) postulated that the loss of SLC25A10 function causes disturbances in respiratory-demanding conditions and oxidative stress vulnerability, which may induce mitochondrial defects.