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GM2 Gangliosidoses

Introduction And Epidemiology

Background

The GM2 gangliosidoses are a group of lysosomal lipid storage disorders caused by mutations in at least 1 of 3 recessive genes: HEXA, HEXB, and GM2A. Normal products of all 3 genes are required for normal catabolism of the GM2 ganglioside substrate. Deficient activity of these enzymes leads to accumulation of the substrate inside neuronal lysosomes, leading to cell death. The products of the 3 genes are, respectively, the alpha subunits of b-hexosaminidase A (Hex A; EC 3.2.1.52), the beta subunits of Hex A (EC 3.2.1.52), and the GM2 activator protein. Hydrolysis of GM2 ganglioside requires a normal GM2 ganglioside–GM2 activator–Hex A complex.

Hex A is a dimer and has the structure alpha-beta. The alpha subunit is encoded by the HEXA gene at band 15q23-q24; the beta subunit is encoded by the HEXB gene at band 5q13. A site on the alpha subunit acts against negatively charged sulfated substrates, while a site on the beta subunit acts against neutral water-soluble substrates.

β-Hexosaminidase B (Hex B) is a dimer of beta chains. It hydrolyzes GM2 and its neutral asialo derivative GA2. Both subunit precursors acquire the mannose 6-phosphate marker for recognition by lysosomes.

Hexosaminidase S (Hex S) is a dimer of alpha chains; it is a normal constituent of plasma and degrades a wide range of glycoconjugates containing β-linked N -acetylhexosaminyl residues.

Lysosomal storage disorders (LSDs) are caused by a genetic deficiency in the enzymatic function of the hydrolases stored within lysosomes, causing an accumulation of materials meant for degradation. There are a few mechanisms by which a genetic defect can lead to an LSD. In the case of GM2 gangliosidosis, an activator protein is deficient, which leads to the accumulation of ganglioside GM2 and related glycolipids in neuronal cells.

Disease classification

Tay-Sachs disease (TSD) and its variants are caused by absence or defects of the alpha subunit of Hex A.

Type I GM2 gangliosidosis is also known as classic infantile acute TSD, B variant, pseudo-AB variant, or Hex A deficiency.

Type III GM2 gangliosidosis is also known as juvenile subacute TSD.

The B1 variant of GM2 gangliosidosis is also known as late infantile subacute-to-chronic TSD; it is characterized by a defect in formation and stabilization of the alpha subunit active site.

GM2 gangliosidosis, also known as adult chronic-type TSD is characterized by a pseudodeficiency mutation in one or both HEXA alleles.

Sandhoff disease (SD) and its variants are caused by absence or defects of the beta subunit of Hex A and the subunits of Hex B. Type II GM2 gangliosidosis is also known as SD (also including the juvenile subacute type); Hex A and Hex B deficiency; or GM2 gangliosidosis, O variant.

Hexosaminidase activator deficiency is caused by absence or defects of the hexosaminidase activator. Type AB GM2 gangliosidosis is also known as hexosaminidase activator deficiency.

Table 1. Genetic Characteristics of GM2 Gangliosidoses (Open Table in a new window)

Gene Features

HEXA

HEXB

GM2A

Chromosome location

Band 15q23-q24

Band 5q13

Band 5q31.3-q33.1

Product

Alpha subunit of Hex A; subunits of Hex S

Beta subunit of Hex A;

subunits of Hex B

GM2 activator

protein

Heat sensitivity, pH

Heat labile, acidic

Heat stabile, basic

Heat stabile, acidic

TSD-B variant

TSD-pseudo-AB variant

classic infantile acute TSD

Most severe phenotype; both alleles absent or mutated

(deficient Hex A; may

lead to increased

levels of Hex B)

Normal

Normal

B1 variant TSD

Mutated

(near-normal Hex A is inactive toward GM2)

Normal

Normal

Adult chronic-type TSD

Mutated, pseudodeficiency

mutation in at least 1 allele

Normal

Normal

SD, O variant

Normal

Both alleles absent or

mutated (deficient Hex B;

may lead to some

Hex S activity)

Normal

Hexosaminidase Paris (SD)

Normal

At least 1 mutated allele

(some normal Hex B activity)

Normal

AB variant (hexosaminidase

activator deficiency)

Normal (increased

amounts of product)

Normal (increased

amounts of product)

Absent or mutated

Known mutations

105

31

5

 

Pathophysiology

Clinical symptoms of progressive neurodegeneration and developmental delay are caused by accumulation of GM2 ganglioside in lysosomes, forming membranous cytoplasmic bodies (MCBs) in neuronal cells.
MCBs also contain cholesterol and phospholipid. Accumulation of storage material leads to unscheduled cell death. The classic infantile forms of the 3 subgroups of GM2 gangliosidosis (ie, TSD, SD, and hexosaminidase activator deficiency) have their onset in infancy and lead to death by age 4 years. The severity of the disease correlates inversely with the amount of residual Hex A activity in lysosomes. Usually, but not always, later disease onset corresponds with slower disease progression.

Patients with Hex A and Hex S deficiency (variant B) were found to have accumulated GM2 and minor amounts of GA2 in their brains. One patient without Hex deficiency (AB variant) had considerable GA2 levels and even higher GM2 levels. Patients with Hex A and Hex B deficiency (O variant) contained the highest GA2 levels and lowest GM2 levels.

Patients with nonclassic variants of GM2 gangliosidoses may present with other symptoms, such as ataxia, dystonia, psychosis, and/or muscle wasting. The various symptoms are not pathognomonic and may occur in many other conditions, including conditions caused by exposures to certain environmental agents.

Frequency

See the list below:

United States

TSD

Before community-based carrier screening programs were developed for the Ashkenazi Jewish population,
1 per 2500-3600 newborns of Ashkenazi Jewish descent was affected. Heterozygote screening and counseling programs led to a 90% reduction of the disease in the high-risk Jewish population.

One in 25-30 persons of Ashkenazi Jewish descent is a heterozygous unaffected carrier of a HEXA mutation.

In certain isolated populations, such as Louisiana Cajuns and Pennsylvania Dutch, the prevalence of TSD is as high as or higher than in individuals of Ashkenazi Jewish descent.

In the general population, 1 per 320,000 newborns is affected.

One in 283 individuals is a heterozygous unaffected carrier of a HEXA mutation.

SD

One per 309,000 non-Jewish newborns is affected.

One in 278 persons of non-Jewish descent is a heterozygous unaffected carrier of a HEXB mutation.

One in 7 persons of the Maronite community in Cyprus is a carrier.

Approximately 1 per 1 million Jewish newborns is affected.

Approximately 1 per 500 Jewish persons is a heterozygous unaffected carrier of a HEXB mutation.

Hexosaminidase activator deficiency: This condition is extremely rare.

Internationally

TSD

One per 360,000 newborns in the general population is affected.

One in 280 individuals is a heterozygous unaffected carrier of a HEXA mutation.

The incidence in French Canadians of the eastern St. Lawrence River Valley area of Quebec is similar to that in persons of Ashkenazi Jewish descent.

In the Cordoba region of Argentina, among Creole, Spanish, and native peoples, 1 in 26 individuals is a carrier.

Increased frequencies were reported in Moroccan Jews (1 in 110 is a carrier) as well as in some isolated populations in Switzerland and Japan.

One in 140 Iraqi Jews is a carrier.

In Saudi Arabia, the cause is private mutations, which prevents replicating the successful approach used with Ashkenazi Jewish population. Therefore, alternative solutions must be implemented for other autosomal recessive diseases.

SD

Approximately 1 per 310,000 non-Jewish newborns is affected.

Approximately 1 per 1 million Jewish newborns is affected.

Increased incidences were reported in Creoles of northern Argentina, Metis Indians of northern Saskatchewan, individuals of Lebanese heritage, and Hispanics of Mexican or Central American heritage. Four patients from different families were detected in Cyprus.

Hexosaminidase activator deficiency: This condition is extremely rare.

Mortality and morbidity

See the list below:

TSD

The classic infantile form is usually fatal by age 2-4 years.

In the late infantile subacute, B1 variant form, disease progression is particularly aggressive, leading to death within 2-4 years of disease onset.

In the juvenile subacute form, death occurs by age 10-15 years; it is usually due to infection and is preceded by several years in a vegetative state with decerebrate rigidity.

In the adult chronic form, most patients survive to age 60-80 years.

SD: Death generally occurs by age 4 years.

Hexosaminidase activator deficiency: The 5 cases reported involved the infantile acute form of TSD. All 5 infants known to be affected with hexosaminidase activator deficiency died in infancy.

Ethnicity

See the list below:

TSD

In the past, 99% of affected individuals were of Ashkenazi Jewish descent; yet, parental consanguinity was relatively infrequent. As a result of targeted community-based carrier screening, a relatively greater proportion of cases of TSD are now observed in non-Jewish individuals. Sephardic Jews have no increased risk.

In certain isolated populations, such as French Canadians of the eastern St Lawrence River Valley area of Quebec, Louisiana Cajuns, and Pennsylvania Dutch, the incidence of TSD is as high as or higher than in Ashkenazi Jews. Moroccan Jews appear to have an increased incidence. Among Creole, Spanish, and native peoples of the Cordoba region of Argentina, 1 in 26 individuals is a carrier. In non-Ashkenazi Jewish patients with TSD, parental consanguinity is frequent.

The disease has been found in blacks and in Asians. However, no cases have been reported in Eskimo, Gypsy, or Mongolian populations.

SD: Although the disease is panethnic, increased prevalences were reported in Creoles of northern Argentina, Metis Indians of northern Saskatchewan, individuals of Lebanese heritage, and Hispanic persons of Mexican or Central American heritage. Several affected were Maronites of Greek-Cypriot heritage.

Hexosaminidase activator deficiency: The 5 affected individuals reported were Indian, Saudi Arabian, Spanish, black, and Laotian.

Sex

See the list below:

In all GM2 gangliosidosis subgroups, males and females appear to be equally affected.

Age

See the list below:

TSD

Classic infantile acute form – Onset during age 4-8 months

Late infantile and juvenile subacute forms – Onset from age 2-10 years

Adult chronic form – Onset from childhood to adulthood

Late-onset form – Onset during adulthood

SD

Infantile acute form – Onset within the first 6 months of life

Late-onset subacute form – Onset during age 2-10 years

Adult chronic form – Onset in adulthood

Hexosaminidase activator deficiency: All 5 reported individuals exhibited symptoms in infancy.

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