Hypotonia, Infantile, With Psychomotor Retardation And Characteristic Facies 1

A number sign (#) is used with this entry because infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1) is caused by homozygous mutation in the NALCN gene (611549) on chromosome 13q33.

Description

Infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. Affected individuals show very poor, if any, normal cognitive development. Some patients are never learn to sit or walk independently (summary by Al-Sayed et al., 2013).

Genetic Heterogeneity of Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies

See also IHPRF2 (616801), caused by mutation in the UNC80 gene (612636) on chromosome 2q34; and IHPRF3 (616900), caused by mutation in the TBCK gene (616899) on chromosome 4q24.

Clinical Features

Seven et al. (2002) described a Turkish brother and sister, offspring of a first-cousin marriage, who were affected with severe neurodegeneration beginning in infancy. Both developed normally until about 6 months of age, and thereafter showed severe psychomotor regression and poor postnatal growth with microcephaly. They had lack of head control, inability to sit or walk, and no eye-to-eye contact or sense of vision or speech. Additional neurologic features included truncal hypotonia, widespread muscle atrophy, spastic tetraparesis with hyperreflexia, nystagmus, and optic atrophy. Facial dysmorphism was notable, with prominent forehead, strabismus, small nose, wide mouth (in the boy), micrognathia, and large, low-set ears. Both also had pectus carinatum and pes varus. One patient had a normal brain MRI at age 3 years, whereas the other showed cerebellar atrophy at age 5. EMG showed decreased motor nerve conduction velocities. Electron microscopy of sural nerve biopsy from 1 patient showed unmyelinated axons, spheroid formation, and edema, consistent with a clinical diagnosis of infantile neuroaxonal dystrophy. Seven et al. (2002) suggested that facial dysmorphism could permit diagnosis in the first months of life without any clinical or neurologic signs.

Koroglu et al. (2013) provided follow-up of the family reported by Seven et al. (2002). The patients were 21 and 18 years of age. Anthropomorphic measures later in childhood and as young adults showed severe growth impairment and microcephaly (-4 SD). Additional features included seizures and contractures. One of the patients had miscellaneous features, such as scoliosis and cryptorchidism.

Al-Sayed et al. (2013) reported 6 patients from 2 consanguineous Saudi Arabian families with IHPRF. The 3 patients in 1 family presented at birth with severe neonatal hypotonia and feeding difficulties, followed by severe psychomotor retardation with lack of speech development. None of the children could sit without support at 4 to 7 years of age. Other features included severe constipation, gastroesophageal reflux, and initial failure to thrive. One patient had white matter abnormalities on brain MRI; muscle biopsy of 1 patient was normal. The 3 patients in the second family had the same features, but were less severely affected. At ages 9 to 17 years, these patients were able to walk independently since 2 to 3 years of age, and they could speak a few words; IQ measured in the forties. All 3 members of this family had constipation, hyperactivity, and controlled seizures. Dysmorphic facial features present in all patients from both families included brachycephaly, broad forehead, triangular face, smooth philtrum, prominent slender nose, and thin upper lip. Patients in 1 family had large low-set ears. Sural nerve biopsies were not performed.

Inheritance

The transmission pattern of infantile hypotonia with psychomotor retardation and characteristic facies in the families reported by Seven et al. (2002) and Al-Sayed et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of related parents, with infantile hypotonia and developmental delay, originally reported by Seven et al. (2002), Koroglu et al. (2013) identified a homozygous truncating mutation in the NALCN gene (Q642X; 611549.0001). The mutation, which was found by homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the dbSNP or 1000 Genomes Project databases or in 110 Turkish controls.

In 6 patients from 2 consanguineous Saudi Arabian families with IHPRF, Al-Sayed et al. (2013) identified homozygous mutations in the NALCN gene (c.1489delT, 611549.0002 and W1287L, 611549.0003). The patients with the frameshift mutation were more severely affected than those with the missense mutation. The mutations in the first family were found by linkage analysis and candidate gene sequencing. Al-Sayed et al. (2013) speculated that loss of NALCN function due to the mutations may reduce the capacity of the permeability of the channel and cause accumulation of cations that would disturb neuronal conductance.