A number sign (#) is used with this entry because of evidence that muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (MDHLO) is caused by homozygous or compound heterozygous mutation in the GGPS1 gene (606982) on chromosome 1q42.

Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (MDHLO) is an autosomal recessive systemic disorder characterized by progressive muscle weakness, sensorineural hearing loss, and endocrine abnormalities, mainly primary amenorrhea due to ovarian insufficiency. Features of the disorder appear soon after birth, although endocrine anomalies are not noted until puberty. The severity of the phenotype is variable: some patients may lose ambulation and have significant respiratory insufficiency, whereas others retain the ability to walk (Foley et al., 2020).

Foley et al. (2020) reported 11 patients, ranging in age from 8 to 46 years, from 6 families with a similar syndromic disorder. Two of the families were consanguineous. Some pregnancies were complicated by decreased fetal movements, and some had weak cry and poor suck noted soon after birth. The patients had delayed motor milestones and delayed walking due to progressive muscle weakness. Five patients became wheelchair-bound by the second decade, whereas others had a milder phenotype and maintained independent ambulation into adulthood. Most patients had respiratory insufficiency with decreased forced vital capacity, sometimes necessitating tracheostomy and feeding tubes. More variable features included scoliosis and joint contractures. All except 1 had congenital sensorineural hearing loss. Affected females who had reached puberty age had amenorrhea with primary ovarian failure, and none of the affected men had children. In addition, 8 patients had failure to thrive and/or short stature, suggesting possible additional endocrine disturbances. Skeletal muscle biopsy showed dystrophic changes with degenerative and regenerative fibers, internal nuclei, occasional rimmed vacuoles, and enlarged mitochondria with evidence of excess autophagic material. Laboratory studies showed increased serum creatine kinase, which the authors noted is a sign of muscle cell membrane leakage. Cardiac function and cognitive development were normal.

Kaiyrzhanov et al. (2022) reported 13 patients with MDHLO from 5 families, including 2 sisters from a Pakistani family previously reported as patients P6 and P7 by Tucker et al. (2020) as possible cases of Perrault syndrome (see 233400). Eleven patients were still alive at a mean age of 10 years (range, 4-24 years); 2 patients had died at the age of 11 months and 30 years from respiratory insufficiency and choking, respectively. Decreased fetal movements were noted in 3 patients. Disease onset ranged from prenatal to preschool age, with delayed motor milestones, weak cry, and muscle weakness as the first presenting symptoms. Proximal or generalized muscle weakness was noted in 12 of 13 patients, with respiratory insufficiency in 8 of 13 and joint contractures in 7 of 12. Loss of ambulation occurred at a mean age of 8.1 years. Congenital or infantile-onset hearing loss was seen in 6 of 13. Disease progression was slow in 92% of patients. Only one of the females had reached puberty, and at age 30 years she did not have signs of primary ovarian insufficiency. Older patients had a more severe phenotype, consistent with the progressive nature of disease in most cases. Creatine kinase levels were elevated in all 10 patients in whom it was assessed. Based on their patients, Kaiyrzhanov et al. (2022) suggested that hearing loss and ovarian insufficiency may be variable features of the disorder.

The transmission pattern of MDHLO in the families reported by Foley et al. (2020) was consistent with autosomal recessive inheritance.

In 11 patients from 6 unrelated families with MDHLO, Foley et al. (2020) identified homozygous or compound heterozygous mutations in the GGPS1 gene (606982.0001-606982.0005). The mutations, which were found by exome sequencing or direct sequencing and confirmed by Sanger sequencing, were either absent from or present at a low frequency in the heterozygous state in gnomAD. All but 1 of the mutated residues occurred within a specific 5-amino acid region toward the C terminus around the start of helix 11. Whereas the catalytic domain of GGPPS1 is conserved across animals and plants, the mutated residues are conserved in all animals down to Drosophila, but not in plants, suggesting a specific role for this domain in animal cells. In vitro functional expression studies of patient-derived myoblasts showed about 50% decreased GGPPS1 enzymatic activity compared to controls. Decreased enzyme activity was noted for all the variants in the 5-residue region, but not for P15S, which was present in compound heterozygosity with another mutation. Additional studies in patient-derived myotubes showed impaired cell membrane repair after focal injury compared to controls. Foley et al. (2020) concluded that the mutations disrupt GGPSS1 enzymatic function enough to impair the generation of small GTPases involved in autophagy, mitochondrial dynamics, actin filament dynamics, and membrane shuttling. The mutations may also interfere with binding partners.

In 11 patients from 4 families with MDHLO, Kaiyrzhanov et al. (2022) identified homozygous or compound heterozygous mutations in the GGPSS1 gene (see, e.g., 606982.0005).

In mice, Foley et al. (2020) found that homozygosity for the Y259C mutation (606982.0002) was embryonic lethal.