Jaberi-Elahi Syndrome

A number sign (#) is used with this entry because of evidence that Jaberi-Elahi syndrome (JABELS) is caused by homozygous mutation in the GTPBP2 gene (607434) on chromosome 6p21.

Description

JABELS is an autosomal recessive neurodevelopmental disorder characterized by developmental delay and intellectual disability with additional variable features. Patients have onset of symptoms in infancy, but the severity is highly variable. Some patients have social interaction and learn to walk but have an ataxic gait and abnormal movements, such as tremor or dystonia, whereas others do not achieve any motor control and are unable to speak. Additional features may include retinal anomalies, visual impairment, microcephaly, abnormal foot or hand posturing, and kyphoscoliosis; some patients have dysmorphic facial features or seizures. Brain imaging typically shows cerebellar atrophy and hypoplasia of the corpus callosum (summary by Jaberi et al., 2016 and Bertoli-Avella et al., 2018).

Clinical Features

Jaberi et al. (2016) reported a consanguineous Iranian family (DS-100) in which 4 adult sibs had a neurodevelopmental disorder with onset in infancy. All had delayed psychomotor development with mildly delayed walking, delayed speech, intellectual disability (IQ of 40 to 50), and behavioral abnormalities. One of the patients died at age 21 years. The patients were unable to attend school successfully, but the 3 living patients were oriented, cooperative, and able to perform common daily activities and participate in simple social interactions. The patients also had ataxia with a wide-based gait, mildly abnormal finger-nose test, dysmetria, and variable tremor and dystonia of the hands, feet, and face. Two patients had decreased distal muscle tone and strength, and all had hyporeflexia at the ankles and abnormal plantar reflexes. Electrophysiologic studies showed a chronic motor neuronopathy in the distal upper and lower extremities. More variable additional features included kyphoscoliosis, pectus carinatum, thin, sparse, brittle hair, and skin thickening and mottling, possibly reflecting autonomic dysfunction. One patient had cataracts and myopia, whereas the other 2 had retinal anomalies. Only 1 patient had 4 generalized seizures between 15 and 29 years of age. Brain imaging showed cerebellar atrophy and hypointensities in the globus pallidus and substantia nigra, suggestive of abnormal iron deposition. Laboratory studies were normal, although iron-related parameters were near the low end of normal.

Bertoli-Avella et al. (2018) reported 3 unrelated children, each born of consanguineous parents, with a severe neurodevelopmental disorder characterized by delayed psychomotor development apparent from infancy. One patient was in a wheelchair and the others were unable to sit or roll over. All had severe intellectual disability with poor or absent speech and no social smile or contact. The patients did not have ataxia or dystonia, but had variable motor abnormalities, including hypotonia, spasticity, and choreoathetosis, and all had seizures. All had microcephaly, and 1 had failure to thrive and poor overall growth. All had visual impairment, noted to be optic atrophy in 1 patient. Dysmorphic features were variable and included depressed nasal bridge, bitemporal narrowing, prominent ears, low-set ears, small nose, abnormal dentition, sparse thin hair and eyebrows, and kyphoscoliosis. One patient had stiffness of the interphalangeal joints and knees and equinovarus, another had clenched hands and talipes, and the third had mild joint hypermobility. Brain imaging showed agenesis or partial hypogenesis of the corpus callosum and cerebellar hypoplasia, but no evidence of iron deposition. One patient had a Dandy-Walker malformation. Bertoli-Avella et al. (2018) noted that the phenotype in these patients was much more severe than that reported by Jaberi et al. (2016). The disorder in both studies did not appear to be progressive, suggesting that it is a neurodevelopmental rather than a neurodegenerative disorder.

Inheritance

The transmission pattern of JABELS in the family reported by Jaberi et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 affected sibs from a consanguineous Iranian family (DS-100) with JABELS, Jaberi et al. (2016) identified a homozygous splice site mutation in the GTPBP2 gene (607434.0001). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed.

In 3 unrelated children, each born of consanguineous parents, with a severe form of JABELS, Bertoli-Avella et al. (2018) identified homozygous nonsense mutations in the GTPBP2 gene (607434.0002-607434.0004). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing, although parental DNA was only available for 1 proband, which showed segregation. Functional studies of the variants and studies of patient cells were not performed, but Bertoli-Avella et al. (2018) postulated that the mutations resulted in a complete loss of function.