Multiple Mitochondrial Dysfunctions Syndrome 6

A number sign (#) is used with this entry because of evidence that multiple mitochondrial dysfunctions syndrome-6 (MMDS6) is caused by homozygous or compound heterozygous mutation in the PMPCB gene (603131) on chromosome 7q22.

Description

Multiple mitochondrial dysfunctions syndrome-6 is an autosomal recessive severe neurodegenerative disorder with onset in early childhood. Affected individuals may have initial normal development, but show neurologic regression in the first year of life. They have hypotonia, inability to walk, poor speech, intellectual disability, and motor abnormalities, such as ataxia, dystonia, and spasticity. Some patients may die in childhood. Laboratory evidence indicates that the disorder results from mitochondrial dysfunction (summary by Vogtle et al., 2018).

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

Clinical Features

Vogtle et al. (2018) reported 5 children from 4 unrelated families with an early-onset neurodegenerative disorder. Two patients were alive at ages 5 and 6 years, and 3 died at ages 5 and 6 years. The patients presented in infancy with variable developmental delay and hypotonia. Four of the patients showed developmental regression in the first year of life, often associated with febrile illnesses or vaccination. None of the patients achieved independent ambulation or meaningful speech, and 4 patients had variable types of seizures, including 2 with refractory epileptic encephalopathy. More variable features included failure to thrive, poor feeding, poor head control, acquired microcephaly, optic atrophy, ataxia, dystonia, and spastic quadriplegia. Laboratory studies showed intermittently increased serum lactate in 3 patients, suggesting mitochondrial dysfunction. Tissue from 1 patient showed that mitochondrial respiratory enzyme activities were normal in fibroblasts and liver, although complex II activity was significantly reduced in muscle, suggesting tissue-specific manifestations, likely with significant effects in neurons and muscle. Brain imaging showed T2-weighted hyperintensities in the basal ganglia in all patients, consistent with a clinical diagnosis of Leigh syndrome (256000), as well as progressive cerebral and cerebellar atrophy.

Inheritance

The transmission pattern of MMDS6 in the families reported by Vogtle et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 patients from 4 unrelated families with MMDS6, Vogtle et al. (2018) identified compound heterozygous or homozygous missense mutations in the PMPCB gene (603131.0001-603131.0005). The mutations, which were found by whole-exome sequencing or sequencing of a mitochondrial disorder gene panel, were confirmed by Sanger sequencing and segregated with the disorder in the families from whom DNA was available. Expression of one of the variants in patient-derived pluripotent stem cells or patient's fibroblasts showed decreased PMPCB protein levels in the mitochondrial fraction, as well as an increase in the intermediate form of frataxin (iFXN; 606829) resulting from a decrease in MPP activity. Formation of intermediate iron-sulfur complexes was strongly increased. Analysis of biopsy materials from 1 patient showed decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes. Modeling of several of the mutations in yeast resulted in severe but variable growth defects with an MPP processing defect under stress conditions, consistent with an impairment in essential mitochondrial functions. These abnormalities were associated with accumulation of mitochondrial precursor proteins, early impairment of the biogenesis of iron-sulfur clusters, and decreased mitochondrial membrane potential. The findings indicated that biallelic mutations in PMPCB cause defects in MPP proteolytic activity, leading to dysregulation of iron-sulfur cluster biogenesis and mitochondrial dysfunction, triggering a complex neurologic phenotype of neurodegeneration.