Hypotonia, Infantile, With Psychomotor Retardation

A number sign (#) is used with this entry because of evidence that infantile hypotonia with psychomotor retardation (IHPMR) is caused by homozygous mutation in the CCDC174 gene (616735) on chromosome 3p25.

Clinical Features

Volodarsky et al. (2015) reported 6 children from 2 unrelated families with a similar severe neurodevelopmental disorder. Two Egyptian sibs presented in the first month of life with severe generalized hypotonia requiring a feeding tube and artificial ventilation. The patients, aged 8 and 9 years at the time of the report, had mild psychomotor retardation with delayed speech acquisition. They still required continuous positive airway pressure (CPAP) and gastrostomy feeding. Brain imaging showed dilated lateral ventricles and thin corpus callosum. Four children from a consanguineous Israeli Arab Bedouin family had a similar, but more severe, disorder. Reduced fetal movements were apparent in some cases, and all had severe axial hypotonia and delayed psychomotor development. Brain imaging in 2 patients was normal. Three of the 4 died before 4 months of age, and 1 was alive at age 2 years. Muscle biopsy in the Egyptian sibs did not show evidence of necrosis or increased fibrosis, but electron microscopy showed destruction of myofibrils with no evidence of regeneration. Muscle biopsy in the Arab children showed moderate to severe myopathic changes, increased fibrosis, increased variation in fiber size, small atrophic fibers, and sporadic fibers with internal nuclei. Muscle biopsy of 1 patient showed depletion of RYR1 (180901). Additional features in both families included strabismus due to abducens nerve palsy, cardiac septal defects, and cryptorchidism in the males. Serum creatine kinase was normal in both families.

Inheritance

The transmission pattern of IHPMR in the families reported by Volodarsky et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 patients from 2 unrelated families with IHPMR, Volodarsky et al. (2015) identified a homozygous mutation in the CCDC164 gene (616735.0001) that was predicted to extend the protein by 6 additional residues (Ter468TrpextTer6). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in both families. Haplotype analysis suggested a founder effect for the 2 families. Expression of the mutation into ccdc174-null Xenopus oocytes was unable to rescue the neural defect, consistent with a loss of function. Mutant CCDC174 localized normally to the nucleus and was able to interact with EIF4A3 (608546), but overexpression of mutant CCDC174 resulted in rapid and massive apoptosis of cells and aggregation of the mutant protein in the nucleus.

Animal Model

Volodarsky et al. (2015) found that morpholino knockdown of the ccdc174 ortholog in Xenopus oocytes resulted in poor neural fold closure and a reduction in markers for differentiating primary neurons. Survival was also decreased at later embryonic stages. Knockdown embryos showed a sharp reduction in expression of n-tubulin, a marker for differentiating primary neurons, and of hindbrain markers krox20 (129010) and hoxb3 (142966), suggesting a disruption in early neural plate patterning and neuron formation.