Expert Reviewed By: Dr. Brandon Colby MD
GM2-gangliosidosis is a rare genetic disorder that affects the nervous system, leading to a range of symptoms including muscle weakness, loss of coordination, and intellectual disability. While the disease is typically diagnosed in infancy or childhood, adult-onset GM2-gangliosidosis is a less common and often underdiagnosed form of the disorder. This article aims to shed light on the understanding, diagnosis, and use of genetic testing for adult-onset GM2-gangliosidosis.
Understanding Adult-Onset GM2-Gangliosidosis
GM2-gangliosidosis is a lysosomal storage disorder caused by a deficiency of the enzyme beta-hexosaminidase A, which is responsible for breaking down a fatty substance called GM2 ganglioside. When this enzyme is deficient, GM2 ganglioside accumulates in the brain, leading to progressive neurological damage. The adult-onset form of the disease is characterized by a later onset of symptoms, typically in the second or third decade of life, and a slower progression compared to the infantile and juvenile forms of the disorder.
Recent case studies and research have helped to better understand the clinical presentation and disease course of adult-onset GM2-gangliosidosis. For example, a case study of a 71-year-old man with the disease reported ocular pendular nystagmus, palatal tremor, and progressive cerebellar ataxia as key symptoms. Another study described the first case of late-onset GM2-gangliosidosis AB variant in a 22-year-old male with spinocerebellar ataxia and lower limb motor deficiency. A multicenter cohort study further identified two distinct disease clusters with different clinical features and disease evolution.
Diagnosing Adult-Onset GM2-Gangliosidosis
Given the rarity and variable presentation of adult-onset GM2-gangliosidosis, diagnosis can be challenging. Clinical suspicion should be raised in individuals presenting with atypical neurological symptoms, particularly if there is a family history of the disease. A thorough neurological examination, imaging studies such as MRI, and enzyme analysis can help guide the diagnostic process.
Importantly, neuropsychiatric symptoms are also prevalent in adult-onset GM2-gangliosidosis, as highlighted in a review that emphasized the importance of accurate diagnosis and appropriate treatment. These symptoms may include psychosis, mood disorders, and cognitive impairment, further complicating the diagnostic process.
Genetic Testing for Adult-Onset GM2-Gangliosidosis
Confirming the Diagnosis
Genetic testing is a crucial tool in the diagnosis of adult-onset GM2-gangliosidosis. By analyzing the HEXA and HEXB genes, which encode the subunits of the beta-hexosaminidase A enzyme, genetic testing can identify pathogenic mutations responsible for the enzyme deficiency. Confirming the genetic diagnosis is essential to guide appropriate management and treatment strategies for affected individuals.
Prenatal and Carrier Screening
As GM2-gangliosidosis is an inherited disorder, genetic testing can also be used for prenatal and carrier screening. Couples with a family history of the disease or those at risk due to their ethnic background can undergo carrier testing to determine if they carry a mutation in the HEXA or HEXB gene. If both partners are carriers, prenatal testing can be performed to assess the risk of the fetus being affected by the disorder. This information can help couples make informed reproductive decisions and prepare for the potential challenges associated with raising a child with GM2-gangliosidosis.
Guiding Treatment and Management
While there is currently no cure for GM2-gangliosidosis, genetic testing can help guide treatment and management strategies. For example, the identification of specific gene mutations may allow for targeted therapies, such as enzyme replacement or gene therapy, in the future. Additionally, understanding the genetic basis of the disease can help clinicians monitor disease progression and provide appropriate symptomatic treatment and support for affected individuals and their families.
In conclusion, adult-onset GM2-gangliosidosis is a rare and often underdiagnosed form of the disorder. Increased awareness, improved diagnostic tools, and the use of genetic testing can help enhance our understanding of this complex disease, ultimately leading to better care and support for those affected.
About The Expert Reviewer
Dr. Brandon Colby MD is a US physician specializing in the personalized prevention of disease through the use of genomic technologies. He’s an expert in genetic testing, genetic analysis, and precision medicine. Dr. Colby is also the Founder of and the author of Outsmart Your Genes.
Dr. Colby holds an MD from the Mount Sinai School of Medicine, an MBA from Stanford University’s Graduate School of Business, and a degree in Genetics with Honors from the University of Michigan. He is an Affiliate Specialist of the American College of Medical Genetics and Genomics (ACMG), an Associate of the American College of Preventive Medicine (ACPM), and a member of the National Society of Genetic Counselors (NSGC)