Mitochondrial Dna Depletion Syndrome 17

A number sign (#) is used with this entry because of evidence that mitochondrial DNA depletion syndrome-17 (MTDPS17) is caused by homozygous mutation in the MRM2 gene (606906) on chromosome 7p22. One such patient has been reported.

Clinical Features

Garone et al. (2017) reported a 7-year-old Italian boy who presented at 8 months of life with developmental delay and a complex movement disorder characterized by generalized dyskinesia, featuring chorea and ballismus and also involving the cervical and oropharyngeal muscles, not responsive to levodopa and carbidopa treatment. CSF neurotransmitters and brain MRI (performed at 18 months of age) were unrevealing. No motor or language milestones were acquired. At 4 years of age, the boy exhibited an acute deterioration during a febrile respiratory infection. He was admitted to pediatric intensive care for recurrent episodes of convulsive status epilepticus that were associated with multiple stroke lesions on brain MRI. Epilepsy was refractory to combined anticonvulsant treatment and was further complicated by mixed acidosis. He required induction of pharmacologic coma, tracheostomy, and nasogastric tube feeding. Metabolic workup, including plasma amino acids, acylcarnitine and lactate, urinary organic acids, and orotic acid was unrevealing except for low levels of citrulline (9 micromol/l, normal range 17-53). Brain MRI on the second day after the first episode of status epilepticus showed a focal lesion in the left parietotemporal-occipital region with a ring of edema and restriction of diffusion. Cerebellar atrophy was also present. Magnetic resonance spectroscopy (MRS) showed a peak of lactate and reduction of N-acetyl aspartate/creatine (NAA/Cr) within the lesion. Follow-up MRI on day 10 confirmed the stroke-like lesion in the parietooccipital region and revealed additional lesions in the right parasagittal frontal and frontoinsular cortex. MRS showed normalization of the lactate peak. The patient survived the acute episode, but his neurologic condition was severely compromised, with spastic quadriparesis, a complex dyskinetic movement disorder, and epilepsia partialis continua resistant to multiple anticonvulsants. Repeat brain MRI at 1 year of follow-up showed severe cerebral and cerebellar atrophy. The clinical course was complicated by recurrent episodes of liver failure, hyperammonemia, and rhabdomyolysis triggered by infections. The patient died at 7 years of age after a febrile illness progressed to sepsis. Brain MRI, together with the clinical picture and the low level of plasma citrulline, was suggestive of MELAS (540000). Mitochondrial respiratory chain activities on muscle homogenate revealed multiple OXPHOS defects with complexes I and IV being severely affected, and other complexes at borderline level. Quantitative PCR with DNA extracted from muscle revealed 40% of residual mtDNA copy number.

Molecular Genetics

Using targeted exome sequencing of mitochondrial proteins and mitochondrial DNA, Garone et al. (2017) identified a homozygous missense mutation in the MRM2 gene (G189R; 606906.0001) in a boy with rapidly progressive encephalopathy and stroke-like episodes. The glycine at position 189 was conserved in 41 of 44 vertebrate species tested and in S. cerevisiae and E. coli as well. In a yeast model, defects in cellular respiration and modification of a human-equivalent uridine were rescued by complementation with wildtype yeast mrm2, but not by mrm2 carrying a mutation homologous to that carried by the patient.

Exclusion Studies

Because of phenotypic similarity in their patient to MELAS, Garone et al. (2017) investigated the MTTL1 gene for mutations and was able to exclude the common mutation resulting in that disorder (590050.0001).