Perrault Syndrome 5

A number sign (#) is used with this entry because of evidence that Perrault syndrome-5 (PRLTS5) is caused by compound heterozygous mutation in the C10ORF2 gene (TWNK; 606075) on chromosome 10q24.

Biallelic mutations in the C10ORF2 gene can also cause mitochondrial DNA depletion syndrome-7 (MTDPS7; 271245), which shares some features with PRLTS5 but is more severe.

For a general phenotypic description and a discussion of genetic heterogeneity of Perrault syndrome, see PRLTS1 (233400).

Clinical Features

Morino et al. (2014) reported 2 unrelated families in which 2 sisters in each family first presented as teenagers with primary amenorrhea, lack of secondary sexual characteristics, and gonadal dysgenesis; 2 sisters in 1 family showed streak ovaries. Three of the 4 girls had onset of sensorineural hearing loss at 7 to 8 years of age; the fourth had onset of hearing loss at age 13. Based on these features, all 4 patients were given a clinical diagnosis of Perrault syndrome. Laboratory studies of 2 sisters as adults showed elevated luteinizing hormone (see 152780) and follicle-stimulating hormone (see 136530) and low estradiol. Two sisters in 1 family had high-arched palate and pes cavus. All 4 patients developed neurologic involvement in the second or third decades, with features including ataxia, nystagmus, hyporeflexia, and sensory axonal neuropathy with distal sensory impairment. One girl had tonic-clonic seizures at age 7 years. In 1 family, 1 sister showed high levels of lactate and pyruvate at rest, which increased with aerobic exercise; her sister had normal levels at rest but also showed increased levels with exercise. These findings were suggestive of mitochondrial dysfunction, but mitochondrial DNA deletion/depletion studies were not performed. Brain imaging of 2 sisters showed hypoperfusion of the cerebellum, but none of the 4 girls had overt cerebellar atrophy.

Inheritance

The transmission pattern of Perrault syndrome in the families reported by Morino et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 women from 2 unrelated families with Perrault syndrome-5, Morino et al. (2014) identified compound heterozygous mutations in the C10ORF2 gene (606075.0016-606075.0019). The mutations, which were found by exome sequencing, segregated with the disorder in the families. All 4 mutations occurred in the helicase domain and were predicted to adversely affect enzyme activity based on structure, but functional studies of the variants were not performed. Morino et al. (2014) noted that the report expanded the phenotypic spectrum associated with recessive C10ORF2 mutations to include less severe neurologic involvement compared to mitochondrial DNA depletion syndrome-7 (MTDPS7; 271245) and a clinical presentation consistent with Perrault syndrome.