Gangliosidosis (GM2) Type II

Heritable lysosomal storage disorder with ganglioside accumulation leading to severe neurologic impairment with premature death. Tay-Sachs disease (TSD) and its variants are caused by absence or defects of the alpha subunit of hexosaminidase A.

• GM2 Gangliosidosis B Variant: Tay-Sachs Disease (TSD; Hexosaminidase A Deficiency [Hex A deficiency]; Pseudo AB variant): Three types of TSD are described (infantile, juvenile, and adult, which is characterized by a pseudodeficiency mutation in one or both HEXA alleles).
• GM2 Gangliosidosis B1 variant.
• GM2 Gangliosidosis AB Variant (Hexosaminidase Activator Deficiency) is caused by absence or defects of the hexosaminidase activator. It represents a deficiency of sphingolipid activator protein GM2 required for in vivo degradation of GM2 ganglioside by beta-hexosaminidase A.
• GM2 Gangliosidosis O Variant: Sandhoff disease and its variants are caused by absence or defects of the beta subunit of hexosaminidase A and the subunits of hexosaminidase B. It is also known as SD (Sandhoff Disease), Hex A and Hex B deficiency, or GM2 gangliosidosis, O variant, and it includes the juvenile subacute type.

Incidence in the general US population is 1:320,000 live births, and only 1 in 283 persons is a heterozygous unaffected carrier of a HEXA mutation. However, in the Ashkenazi Jewish population, the incidence of affected individuals is 1:2500-3600 newborns. The carrier of the HEXA mutations in this subgroup of population is 1 in 30 individuals. In certain isolated populations, such as Louisiana Cajuns and Pennsylvania Dutch, the incidence of this disease appears even higher than in individuals of Ashkenazi Jewish descent. The incidence of Sandhoff disease in the United States is estimated to be 1:309,000 non-Jewish newborns. One in 278 persons of non-Jewish descent is a heterozygous unaffected carrier of a HEXB mutation. Approximately 1:1,000,000 Jewish newborns is affected. Individuals affected with the hexosaminidase activator deficiency are very rare. Internationally, the incidence for TSD is estimated at 1:360,000 live births in the general population, and 1:300 individuals is a carrier of the HEXA mutation. Increased frequencies have been reported in Moroccan Jews and some isolated populations in Switzerland and Japan. The incidence in French Canadians living along the border of the eastern St. Lawrence River in the Province of Quebec is similar to the incidence reported for those of Ashkenazi Jewish descent. The international incidence for Sandhoff disease is approximately 1:310,000 non-Jewish newborns. Increased incidences have been suggested in Creoles of northern Argentina, Metis Indians of northern Saskatchewan in Canada, Lebanese, and Hispanics of Mexican or Central American heritage. The mortality associated with this medical condition depends on the type. The classic infantile form usually is fatal by 2 to 4 years of age. In the late infantile subacute, B1 variant form, disease progression is particularly aggressive, leading to death within 2 to 4 years of disease onset. In the juvenile subacute form, death occurs by 10 to 15 years of age. It usually is caused by infection and most often is preceded by several years of vegetative state with decerebrate rigidity. In the adult chronic form, most patients survive to 60 to 80 years of age. Death in Sandhoff disease occurs by approximately 4 years of age.

Autosomal recessive inheritance. The gene for HEXA has been mapped to 15q23, while HEXB is located on 5q13.

As mentioned earlier, GM2 gangliosidosis comprises a group of lysosomal lipid storage disorders caused by mutations affecting at least three enzymes: the alpha subunit of β-hexosaminidase A (HEXA), the beta subunit of hexosaminidase A (HEXB), and the GM2 activator protein (GM2A). A normal catabolism of GM2 ganglioside requires all three enzymes to function properly. A deficient activity of one or more of these enzymes leads to accumulation of the substrate inside neuronal lysosomes. This accumulation of GM2 ganglioside in lysosomes results in the formation of so-called membranous cytoplasmic bodies in neuronal cells and ultimately cell death, which is responsible for the clinical symptoms of developmental delay and progressive neurodegeneration.

Clinically evocated in patients with progressive developmental retardation, followed by paralysis, dementia, and blindness.

Features can include hearing loss, optic disc atrophy with visual loss, neurologic regression with dementia, mental retardation, seizures, and hyperreflexia. Quadriparesis, myotonia, hypotonia or hypertonia, and spasticity are frequent.

Three variants have been described according to age of onset: In type I (classic infantile acute form with hexosaminidase A extremely low or absent), onset is between 2 and 6 months of age and death occurs in a few months. In type II (juvenile subacute form, hexosaminidase A is decreased but not absent), onset is between 2 and 6 years. Type III is an adult or chronic form with diagnosis generally at the adult age.

Evaluate neurologic function (clinical, EEG, CT) and seizure activities.

Aspiration risk can exist as a consequence of neurologic dysfunction and may require rapid-sequence induction. Visual and neurologic impairment may make cooperation of the patient difficult. Postoperative mechanical ventilation must be planned in children with severe neurologic dysfunction (e.g., quadriparesis).

Consider interaction between antiepileptic treatment and anesthetic drugs. Avoid medications that might precipitate seizures (e.g. ketamine, enflurane, methohexital). Succinylcholine should be avoided because of the potential risk of hyperkalemia.

Alpers Disease: Very rare and progressive neurologic disorder, predominantly involving the gray matter, characterized by spasticity, myoclonus, and dementia in combination with hepatic cirrhosis. Poor prognosis with death usually within a few months after onset.

Neuronal Ceroid Lipofuscinoses: Hereditary progressive neurodegenerative disorders with mental retardation, visual loss, and seizures. The neuronal ceroid lipofuscinoses probably are the most common class of neurodegenerative disease in children.

Leigh Syndrome: Severe progressive necrotizing encephalopathy caused by a mitochondrial disorder impeding oxidative phosphorylation.