GM2 gangliosidosis: the prototype of lysosomal storage disorders

While working as a surgeon, ophthalmologist, and dermatologist in the late nineteenth century, Warren Tay was the first to report in great detail a ‘brownish red fairly circular spot’ in the fovea of a 12-month infant with rapid progressive neurodegeneration.1 Following this report, Bernard Sachs, an academic neurologist in New York City, described several other infants with the same disorder, pointing out the familial nature of the autosomal recessive condition and its occurrence in children of Eastern European Jewish ancestry.2 Named after these two astute clinicians, Tay-Sachs disease is known as a severe, early infantile clinical variant of GM2 gangliosidosis, which is characterized by accumulation of an acidic glycosphingolipid (GM2 ganglioside) in lysosomes of neuronal cells. The classic eye finding is now known as ‘cherry red spot’, which represents a prominent fovea surrounded by abnormal retina with glycosphingolipid storage. The term GM2 gangliosidosis comprises not only Tay-Sachs disease but also other biochemical variants, Sandhoff disease and GM2 activator deficiency, which are clinically indistinguishable. Over 80 years after the initial clinical reports, intracytoplasmic membranous bodies were identified and reported in the autopsy of children affected with Tay-Sachs disease. In histochemical studies, these ultra-structures were lately shown to contain acid phosphatase activity, suggesting their lysosomal origin.3 Several other diseases were described with very similar clinical and pathological findings, forming a separate group of organelle diseases called lysosomal storage diseases. With the identification of the β-hexosaminidase A (Hex A) deficiency in patients with Tay-Sachs disease and Sandhoff disease,4,5 and the development of feasible and inexpensive biochemical assays, the diagnosis of affected children and carriers (heterozygous) has become possible.6 In parallel to these advances, older children with gait and speech problems along with adolescents, and even adults, with behavior or psychiatric disturbances have been diagnosed with GM2 gangliosidosis. These late onset cases allowed a better appreciation of the broad clinical spectrum of this progressive inherited neurological condition. From historical, clinical, genetic, and biochemical perspectives, GM2 gangliosidosis can be considered a prototype for most lysosomal storage diseases. Even today, however, the diagnosis of this inborn lysosomal disease can be very difficult in a regular clinical practice, especially in often busy and diverse pediatric and neurology offices. The first symptoms of the infantile form of GM2 gangliosidosis are usually subtle and non-specific, such as general hypotonia and poor feeding, which were well documented by Smith et al.7 Despite the absence of standard and specific treatment, which is the case for the majority of lysosomal storage diseases, the delayed diagnosis has substantial implications in the appropriate management of the affected patients and families. Based on current knowledge of the natural history of GM2 gangliosidosis, surveillance of potential complications, parental counselling, and preventive management may improve significantly the quality of life of the affected children. Additionally, only with the diagnosis of the affected child, genetic counseling with prenatal diagnosis in subsequent pregnancies can be offered to parents. These parents nowadays no longer belong to high-risk ethnic groups that usually have already prenatal carrier screening. Interestingly, the later the onset of the symptoms, such as those observed in juvenile and adult forms, the longer the time for the diagnosis.7 It is worthwhile to highlight that several research therapeutic interventions are currently been investigated for GM2 gangliosidosis, including stem cell and small molecules therapies.8 In this setting, the early diagnosis may bring a potential hope for these affected children and adults and their families. The closer to the onset of an lysosomal storage disease, the higher is the likelihood to determine measurable clinical endpoints which are valuable when testing a specific therapeutic modality. Furthermore, if the research treatment is efficacious, enrolled patients who are diagnosed at early stages of the disease course will certainly obtain the greatest benefit of the study treatment. Amongst our medical community only the increased awareness and up-to-date knowledge of GM2 gangliosidosis and, consequently, other lysosomal storage diseases and similar inherited neurological conditions, will promote comprehensive and efficacious clinical care needed by the patients and families afflicted with these devastating disorders.