Case reports of juvenile GM1 gangliosidosisis type II caused by mutation in GLB1 gene

Abstract

Background: Type II or juvenile GM1-gangliosidosis is an autosomal recessive lysosomal storage disorder, which is clinically distinct from infantile form of the disease by the lack of characteristic cherry-red spot and hepatosplenomegaly. The disease is characterized by slowly progressive neurodegeneration and mild skeletal changes. Due to the later age of onset and uncharacteristic presentation, diagnosis is frequently puzzled with other ataxic and purely neurological disorders. Up to now, 3-4 types of GM1-gangliosidosis have been reported and among them type I is the most common phenotype with the age of onset around 6 months. Various forms of GM1-gangliosidosis are caused by GLB1 gene mutations but severity of the disease and age of onset are directly related to the position and the nature of deleterious mutations. However, due to its unique genetic cause and overlapping clinical features, some researchers believe that GM1 gangliosidosis represents an overlapped disease spectrum instead of four distinct types.

Case presentation: Here, we report a less frequent type of autosomal recessive GM1 gangliosidosis with perplexing clinical presentation in three families in the southwest part of Iran, who are unrelated but all from "Lurs" ethnic background. To identify disease-causing mutations, Whole Exome Sequencing (WES) utilizing next generation sequencing was performed. Four patients from three families were investigated with the age of onset around 3 years old. Clinical presentations were ataxia, gate disturbances and dystonia leading to wheelchair-dependent disability, regression of intellectual abilities, and general developmental regression. They all were born in consanguineous families with no previous documented similar disease in their parents. A homozygote missense mutation in GLB1 gene (c. 601 G > A, p.R201C) was found in all patients. Using Sanger sequencing this identified mutation was confirmed in the proband, their parents, grandparents, and extended family members, confirming its autosomal recessive pattern of inheritance.

Conclusions: Our study identified a rare pathogenic missense mutation in GLB1 gene in patients with complex neurodevelopmental findings, which can extend the list of differential diagnoses for childhood ataxia in Iranian patients.

Keywords: Case report; GLB1; GM1 gangliosidosis.

Figures

Fig. 1

MRI report of patient I. a mild abnormal signal changes in periventricular white matter, b mild abnormal signal changes in periventricular white matter in T1 sequence

Fig. 2

MRI image of Patient II. It indicates mild cerebellar atrophy in an axial Image of brain MRI

Fig. 3

Pedigree and sanger sequencing details of Family I. Using Sanger sequencing, the inheritance mode of autosomal recessive was confirmed in this family based on identified heterozygote mutation in parents and homozygote in the proband. Sanger sequencing was performed on other patients, parents and their extended family members (data not shown)