Infantile Cataract, Skin Abnormalities, Glutamate Excess, And Impaired Intellectual Development

A number sign (#) is used with this entry because of evidence that a syndrome of infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development (CASGID) is caused by heterozygous mutation in the glutaminase gene (GLS; 138280) on chromosome 2q32. One such patient has been reported.

Description

Aside from the clinical features of infantile cataract, skin abnormalities, and impaired intellectual development, CASGID is characterized by strikingly high intracerebral and urinary glutamate excess with almost undetectable glutamine. A gain-of-function mutation in the GLS gene was found (see MOLECULAR GENETICS). GLS loss of function is implicated in a form of neonatal epileptic encephalopathy (EIEE71; 618328) and a syndrome of global developmental delay and progressive ataxia (GDPAG; 618412).

Clinical Features

Rumping et al. (2019) reported a female diagnosed with bilateral cataract at age 3 months who was the product of an uncomplicated full-term gestation to nonconsanguineous Dutch parents. After lens extraction and replacement, eye contact remained absent. By the age of 8 months developmental delay was noted, and head circumference had fallen from 0 standard deviations (SD) to -2 SD. She developed recurrent dermatologic abnormalities on her extremities, cheeks, and ears without pruritus, characterized as erythematic subcutaneous nodules of approximately 1 cm. Histopathologic analysis of these lesions showed deep perivascular and periglandular lymphohistiocytic infiltrates and pronounced leukocytoclasia at the surface of the dermis, and focal vacuolar alterations, hyperkeratosis, and parakeratosis of the epidermis. Over time, the girl lost the ability to make meaningful sounds and to sit. She developed profound axial hypotonia leading to kyphoscoliosis. Upon arousal she exhibited uncontrolled motoric agitation and self-injurious behavior. At the age of 11 years, she was able to use gestures for communication, to understand verbal single component instructions, and to steer her own wheelchair. Extensive diagnostic evaluation revealed extremely low glutamine levels and high glutamate levels in both cortex and white matter, detected consistently with quantitative brain proton magnetic resonance spectroscopy and magnetic resonance spectroscopic imaging. Cerebrospinal fluid and plasma levels of glutamate and glutamine were unaffected. Brain MRI at the age of 16 months showed delayed myelination. Analyses of stored urine samples similarly showed low concentrations of glutamine and high concentrations of glutamate.

Molecular Genetics

By trio-based whole-exome sequencing, Rumping et al. (2019) identified a heterozygous de novo missense variant in the GLS gene (S482C; 138280.0004) in a girl with infantile cataract, skin abnormalities, glutamate excess, and intellectual developmental impairment. Patient fibroblasts showed increased intracellular glutamate-to-glutamine ratio. Transfection of mutant protein into HEK293 cells strongly increased the glutamate-to-glutamine ratio, while introduction of wildtype GLS had no effect. Alignment of the GLS sequence in more than 1,000 genera revealed that ser482, near the catalytic site of GLS, is extremely highly evolutionarily conserved, along with residues directly involved in the catalytic process. Rumping et al. (2019) stated that the substitution by cys for ser482 changes the electrostatic environment of tyr466, one of the catalytic residues that protonates glutamine and thereby accelerates deamination into glutamate. This change is likely to enhance the propensity for proton donation and thereby to increase the speed of the reaction. Injection of zebrafish embryos at the 1-cell stage with S482C-GLS cDNA resulted in structural lens opacities in 34 (72%) of 47 embryos, with no opacities observed in control embryos.