Neurodevelopmental Disorder With Severe Motor Impairment And Absent Language

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL) is caused by heterozygous mutation in the DHX30 gene (DHX30; 616423) on chromosome 3p21.

Description

NEDMIAL is a neurodevelopmental disorder characterized by severely delayed psychomotor development and hypotonia apparent from early infancy, resulting in feeding difficulties, ataxic gait or inability to walk, minimal or absent speech development, and severe intellectual disability, often with behavioral abnormalities, such as hand-flapping. Additional common features may include sleep disorder, nonspecific dysmorphic facial features, and joint hyperlaxity (summary by Lessel et al., 2017).

Clinical Features

Lessel et al. (2017) reported 12 unrelated patients, ranging in age from 3 to 17 years, with a severe neurodevelopmental disorder apparent from early infancy. Most of the patients were Caucasian of European descent, although 2 were of Hispanic descent, 1 was Turkish, and 1 was of Yemenite/Tripolitan Jewish descent. The patients presented in infancy with delayed psychomotor development, hypotonia, and feeding difficulties. All had severe intellectual disability. Many had behavioral abnormalities, including autistic features, aggressive behavior, low frustration tolerance, and stereotypies, although some were described as pleasant or smiling. All but 2 patients were nonverbal and had very poor or absent communication skills, although a few had some nonverbal gestures and sounds. Six patients never achieved independent ambulation and 4 walked with an ataxic gait. Three patients had seizures and 1 had hearing loss. Brain imaging was normal in some patients, but showed nonspecific abnormalities in others, including cerebral atrophy, cerebellar atrophy, enlarged ventricles, and delayed myelination. Additional common features included sleep abnormalities, bruxism, joint hypermobility, persistent fingerpads, tapering fingers, flat feet, poor fine motor skills, and involuntary movements, such as dystonia or chorea. Many patients had variable dysmorphic facial features, such as small head, strabismus, epicanthal folds, synophrys, high palate, low-set ears, orofacial hypotonia, full eyelids, and eversion of the lower lip. The patients were severely disabled; none attended school, many had no purposeful hand movements and had impaired fine motor skills, and at least 1 patient was noted to be doubly incontinent at age 13 years. Two of the patients (probands F and G) had previously been reported by Eldomery et al. (2017) as part of a large study of patients who underwent exome sequencing.

Inheritance

The DHX30 mutations in all 12 patients with NEDMIAL reported by Lessel et al. (2017) occurred de novo.

Molecular Genetics

In 12 unrelated patients with NEDMIAL, Lessel et al. (2017) identified 6 different de novo heterozygous missense mutations in the DHX30 gene (616423.0001-616423.0006). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. All mutations occurred within the helicase core region, which is predicted to mediate either ATP binding/hydrolysis or RNA recognition. In vitro cellular expression studies showed that all 5 variants that occurred in the ATP binding motifs II or VI (616423.0002-616423.0006) showed markedly reduced ATPase activities compared to wildtype. The 1 remaining variant (R493H; 616423.0001), located in the putative RNA-binding motif Ia, did not alter RNA-dependent activity of DHX30, but did interfere with the binding capacity toward some target RNAs. Transfection of the mutations into a human cell line (U2OS) showed that the mutant proteins accumulated abnormally in cytoplasmic stress granules, which was associated with a global decrease in protein synthesis. Lessel et al. (2017) hypothesized that the DHX30 variants generate a chronic stress condition whereby pervasive and pronounced stress granule assembly induces impairments in the local regulation of translation, thus adversely affecting neurodevelopmental processes.