The spectrum of neurological manifestations and genotype–phenotype correlation in Indian children with Gaucher disease

Abstract

Gaucher disease (GD), one of the most frequent autosomal recessive lysosomal storage disorders, occurs due to bi‐allelic pathogenic variants in the GBA1. Worldwide, the c.1448T>C (L483P) homozygous pathogenic variant is reported to be associated with neurological GD phenotype. Clinical distinction between GD1 and GD3 may be challenging due to subtle neurological features. Objective methods to evaluate neurological signs and saccades may help in early diagnosis. This study was conducted to assess the neurological phenotype, and its severity using a modified severity scoring tool (mSST), and the genotype–phenotype correlation. A total of 45 children aged 2 years 6 months to 15 years with a confirmed enzymatic and molecular diagnosis of GD with or without therapy were recruited. mSST tool was used to assess the severity of the neurological phenotype. A digital eye movement tracker (View Point Tracker) was used to assess eye movements. Clinical and genetic findings were analyzed. Out of 45 patients, 39 (86.7%) had at least one neurological phenotype detected using the mSST tool, with impairment of cognitive function (68.8%, 31/45) being the commonest feature. Thirty‐two of 45 (71%) were assessed for saccadic eye movements using the eye tracker. Of these, 62.5% (20/32) had absent saccades. Four children (8.9%, 4/32) without clinical oculomotor apraxia had absent saccades on the viewpoint eye tracker. Overall, 77.7% (35/45), had homozygosity for c.1448T>C in GBA1 of which 91.4% (32/35) had neurological manifestations. Other alleles associated with neurological phenotype included c.1603C>T(p.R535C), c.1184C>T (p.S395F), c.115+1G>A (g.4234G>A), c.260G>A (p.R87Q) and c.1352A>G (p.Y451C). To conclude, in India, the c.1448T>C pathogenic variant in GBA1 is the commonest and is associated with neurological phenotype of GD. Therefore, every patient of GD should be assessed using the mSST scoring tool for an early pick up of neurological features. The routine use of a viewpoint eye tracker in children with GD would be useful for early recognition of saccadic abnormalities.

Neurological symptoms in adults with Gaucher disease: a systematic review

“…Oculomotor abnormalities were not described with the N370S/N370S genotype, except in two cases associated with Parkinsonism [ 32 , 33 ]; these disturbances were frequently reported with the L444P variant, especially in homozygosis. Accordingly, the data emphasizes the need for further insight into the genotype–phenotype correlations and the pathophysiological mechanisms underlying these neurological symptoms [ 12 , 14 , 23 , 34 , 35 ].…”

Long‐term follow‐up of a patient with neonatal form of Gaucher disease

“…The accumulation of glucosylceramide in cells of the monocyte–macrophage system (Gaucher cells) leads to multisystemic disease. There is a wide phenotypic continuum, in which it is possible to distinguish: a type 1 form with visceral involvement, type 2 acute neuropathic early‐infantile form and type 3 subacute neuronopathic form (Alaei et al, 2019; Venkatachari et al, 2023). The neonatal form with onset in utero or in the neonatal period is at the most severe end (Daykin, Ryan, & Sidransky, 2021).…”