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

Abstract

BackgroundType 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 presentationHere, 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.ConclusionsOur 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.

Clinical and Laboratory Profile of Gangliosidosis from Southern Part of India

“…These features and high index of suspicion, especially in the presence of contributory family history and consanguineous parentage, helps in early diagnosis. 12 GM2 gangliosidosis includes TSD and SD. The TSD is due to HEXA gene mutation which encodes the β subunit of hexosaminidase A enzyme.…”

Genetic Analysis of Undiagnosed Juvenile GM1-Gangliosidosis by Microarray and Exome Sequencing

“…Our patients had generalized refractory seizures complicating feverish episodes. In the reported cases of the literature, seizures were described shortly and the common character was the refraction to antiepileptic drugs [7].…”

“…Patients with GM1 type II (juvenile form) start a normal neurological development until their late childhood [7]. This particularity gives the patients the chance to be treated with enzyme replacement therapy, bone marrow transplantation, and even cell therapy, if the diagnosis is made in early stage.…”

“…Among them, there were nine functional mutations, and only the p.R201C in GLB1 was known to be damaging, confirming the diagnosis of the GM1-gangliosidosis in the studied family. The p.R201C mutation is very common and was particularly reported in the juvenile form of GM1-gangliosidosis [7, 20–22]. Another amino acid substitution affecting the same codon (p.R201H) has been identified in both GM1 and MBD patients [23–25].…”

“…It is a rapidly progressive form as it leads to death by 1 to 2 years of age [5]. The type II is juvenile or late infantile form that starts between 7 months and 3 years of age [6, 7]. It is characterized by slower progression, delay in motor and cognitive development, muscle weakness, and seizures associated with cerebellar and extrapyramidal signs [5–8].…”