Hypotonia, Infantile, With Psychomotor Retardation And Characteristic Facies 3

A number sign (#) is used with this entry because of evidence that infantile hypotonia with psychomotor retardation and characteristic facies-3 (IHPRF3) is caused by homozygous or compound heterozygous mutation in the TBCK gene (616899) on chromosome 4q24.

Description

Infantile hypotonia with psychomotor retardation and characteristic facies-3 is a severe autosomal recessive neurodevelopmental disorder with onset at birth or in early infancy. Most affected individuals show very poor, if any, normal psychomotor development, poor speech, and inability to walk independently (summary by Bhoj et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of infantile hypotonia with psychomotor retardation and characteristic facies, see IHPRF1 (615419).

Clinical Features

Chong et al. (2016) reported 5 children from 4 unrelated families with profound developmental disability with little progression beyond infancy, and severe hypotonia resulting in respiratory insufficiency and feeding tube placement. The patients ranged from 2 to 14 years in age. Two patients were from a consanguineous Lebanese family, 1 was from a consanguineous Egyptian family and had a similarly affected deceased sib, and 2 were unrelated and of Puerto Rican descent. Common dysmorphic facial features included bitemporal narrowing, arched eyebrows, deep-set eyes, high nasal bridge with anteverted nares, and Cupid bow. Three patients had coarse facial features, 2 had macroglossia, and 2 had gingival hyperplasia. Other features included decreased or absent reflexes, seizures, and cortical visual impairment. Brain imaging showed ventriculomegaly and cerebral atrophy, decreased cortical gray and white matter volume, thinning of the corpus callosum, small basal ganglia, cerebellar hypoplasia, and periventricular white matter abnormalities. Two first cousins had evidence of an axonal neuropathy and 2 additional patients had decreased activities of mitochondrial respiratory chain enzymes in muscle.

Bhoj et al. (2016) reported 13 patients from 9 unrelated families with IHPRF. The patients ranged from 2 to 12 years in age; 2 sibs had previously been reported by Alazami et al. (2015). The patients presented at birth with severe hypotonia, mostly with reduced reflexes, and severely delayed psychomotor development; most did not achieve independent walking and had delayed speech acquisition. Three had respiratory insufficiency and 5 had seizures. Most had variable dysmorphic facial features, such as sloped forehead, macrocephaly, bulbous nose, tented upper lip, and coarse features with macroglossia. Brain imaging in most patients showed diffuse brain atrophy, enlarged ventricles, thin corpus callosum, and periventricular white matter abnormalities. However, 2 unrelated patients were slightly less affected and had mild cognitive impairment with normal or only mildly abnormal brain imaging findings.

Inheritance

The transmission pattern of IHPRF3 in the families reported by Chong et al. (2016) and Bhoj et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous Saudi parents (family 10DG1670), with IHPRF3, Alazami et al. (2015) identified a homozygous splice site mutation in the TBCK gene (616899.0001). The patients were part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing.

In 5 patients, including 2 sisters, with IHPRF3, Chong et al. (2016) identified homozygous mutations in the TBCK gene (616899.0002-616899.0004). The mutations were found by whole-exome sequencing. Two unrelated patients of Puerto Rican descent carried the same truncating mutation (R126X; 616899.0002). Cells from 1 of these patients showed near absence of the full-length TBCK 101-kD isoform and decreased levels of the 71-kD shorter isoform, consistent with a loss of function.

In 13 patients from 9 unrelated families with IHPRF3, Bhoj et al. (2016) identified homozygous or compound heterozygous mutations in the TBCK gene (see, e.g., 616899.0001-616899.0002; 616899.0005-616899.0008). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Studies of patient cells with a splice site mutation (616899.0001) showed undetectable levels of the TBCK protein. Studies of patient cells with a different frameshift mutation (616899.0005) showed significantly decreased phosphorylation of phosphoribosomal protein S6 (RPS6; 180460) compared to controls, suggesting downregulation of the mTOR signaling pathway. The addition of leucine to the culture media induced an upregulation of basal mTOR signaling as evidenced by increased levels of phosphorylated RPS6; these findings suggested a possible avenue for directed therapies for this disorder. Four patients from 3 families of Hispanic descent carried the R126X mutation, suggesting a founder effect in this population.