Clinical characteristics: Acute infantile GM2 activator deficiency is a neurodegenerative disorder in which infants, who are generally normal at birth, have progressive weakness and slowing of developmental progress between ages four and 12 months. An ensuing developmental plateau is followed by progressively rapid developmental regression. By the second year of life decerebrate posturing, difficulty in swallowing, and worsening seizures lead to an unresponsive vegetative state. Death usually occurs between ages two and three years.
Diagnosis/testing: The diagnosis of GM2 activator deficiency is established in a proband with suggestive findings of GM2 gangliosidosis, normal beta-hexosaminidase A (HEX A) enzyme activity levels, and biallelic pathogenic (or likely pathogenic) variants in GM2A identified by molecular genetic testing.
Management: Treatment of manifestations: There is no cure for GM2 activator deficiency. Supportive care to provide adequate nutrition and hydration, manage infectious disease, protect the airway, and control seizures involves multidisciplinary care by specialists in relevant fields.
Surveillance: Periodic multidisciplinary evaluations to monitor existing disease manifestations and identify new manifestations requiring modification of supportive care.
Agents/circumstances to avoid: Positioning that increases aspiration risk during feedings and seizure medication dosages that result in excessive sedation.
Genetic counseling: GM2 activator deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GM2A pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the GM2A pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.
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