A number sign (#) is used with this entry because of evidence that multiple mitochondrial dysfunctions syndrome-5 (MMDS5) is caused by homozygous mutation in the ISCA1 gene (611006) on chromosome 9q21.

Multiple mitochondrial dysfunctions syndrome-5 (MMDS5) is an autosomal recessive disorder characterized mainly by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Death usually occurs in early childhood (summary by Shukla et al., 2017).

For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711).

Shukla et al. (2017) reported 4 children from 2 unrelated families of Indian descent with a severe and progressive neurologic disease resulting in death in the first 5 years of life; all 4 patients were deceased at the time of the report. One of the families was known to be consanguineous. The affected sibs in the first family presented in the newborn period with crying and feeding difficulties and did not achieve any developmental milestones other than partial head control in 1. Brain imaging of both children showed pachygyria, extensive cerebral and cerebellar white matter disease, dilated ventricles, and myelination defects. In the second family, the patients were reportedly asymptomatic in the first 2 months of life, although they had no developmental progress. One patient had lactic acidosis, and both had extensive leukodystrophy involving the cerebral and cerebellar white matter with dilated ventricles. All patients developed seizures in the first months of life, followed by progressive neurologic deterioration and spasticity with hyperreflexia. More variable features included pigmentary retinopathy and increased serum creatine kinase, suggesting involvement of other systems. MR spectroscopy showed increased lactate in the probands from both families.

Torraco et al. (2018) described an Italian boy who had loss of head control, nystagmus, and a poor suck at 3 months of age. Serial MRIs at the ages of 11 months and 4 years showed vacuolating leukodystrophy. At age 6 years, he had dysarthria but was able to speak in sentences and to sit with some support. He had a severe spastic ataxic syndrome, persistent nystagmus, and a neurogenic bladder. At age 7, he developed worsening of swallowing difficulties and received a Nissen fundoplication gastrostomy. At age 8, laboratory testing showed metabolic acidosis and mild elevation of lactate in plasma. The patient died at age 11 during an episode of pneumonia.

The transmission pattern of MMDS5 in the families reported by Shukla et al. (2017) was consistent with autosomal recessive inheritance.

In 2 unrelated, deceased probands of Indian descent with MMDS5, Shukla et al. (2017) identified a homozygous missense mutation in the ISCA1 gene (E87K; 611006.0001). Molecular modeling predicted that the mutation would lead to destabilization of the protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Both probands had a similarly affected sib, although biologic material was not available from the sibs. Functional studies of the variant and studies of patient cells were not performed. Haplotype analysis suggested a founder effect.

In an Italian boy with MMDS5, Torraco et al. (2018) identified a homozygous missense mutation (V10G; 611006.0002) in the ISCA1 gene. The mutation was detected by next-generation sequencing of a mitochondrial-targeted gene panel and confirmed by Sanger sequencing. Both parents and an unaffected sib were heterozygous for the mutation.