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Other entities represented in this entry:
SNOMEDCT: 18756002; ORPHA: 354, 79256; DO: 0080501;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p22.3 | GM1-gangliosidosis, type II | 230600 | Autosomal recessive | 3 | GLB1 | 611458 |
A number sign (#) is used with this entry because GM1-gangliosidosis type II (GM1G2) is caused by homozygous or compound heterozygous mutation in the gene encoding beta-galactosidase-1 (GLB1; 611458) on chromosome 3p22.
For a general discussion of the classification and phenotypic heterogeneity of GM1-gangliosidosis, see type I (230500).
GM1-gangliosidosis type II (GM1G2) is an autosomal recessive lysosomal storage disease characterized by slowly progressive generalized neurodegeneration and mild skeletal changes, with onset between 7 months and 3 years of age. Unlike the severe infantile type I, type II is usually not associated with macular cherry-red spots or organomegaly. Within type II, those with somewhat earlier onset and earlier death are considered to have the 'late-infantile' form, whereas those with slightly later onset and survival into late childhood are referred to as having the 'juvenile' form (Caciotti et al., 2003). However, there is no strict age marker to distinguish between these 2 type II forms. GLB1 enzyme activity in type II ranges from approximately 1 to 4% of control values (Nishimoto et al., 1991; Yoshida et al., 1991).
Derry et al. (1968) reported 2 sibs of French Canadian ancestry who developed normally until age 12 months when they showed psychomotor regression and loss of developmental skills. By age 2 years, they had spastic quadriplegia with extensor plantar responses and tonic neck reflex. Optic discs were pale, but cherry-red spots were not observed. Visceromegaly, facial dysmorphism, and skeletal changes were not present. Derry et al. (1968) suggested that this was a late-infantile form of GM1-gangliosidosis.
The patient reported by Kint et al. (1969) was likely affected with type II GM1-gangliosidosis. Wolfe et al. (1970) reported 2 sibs with the type II form. Onset occurred at 10 to 12 months of age with mental and motor retardation, seizures, spasticity, ataxia, and GM1-ganglioside accumulation in tissues.
O'Brien et al. (1972) reported 5 patients from 2 families with the juvenile type of GM1-gangliosidosis. Three sibs showed developmental regression beginning at about 15 to 18 months of age. Early symptoms included feeding difficulties, loss of ability to walk, unsteadiness, sleepiness, squinting, and loss of speech. Tonic-clonic seizures began at 23 to 30 months. A detailed report of 1 child noted lumbar kyphosis, muscle weakness and clumsiness, and hyperactive reflexes, hypoplasia of the vertebrae, coxa valga, and flaring of the wings of the iliac bones. Bone marrow biopsies showed histiocytic storage cells, and peripheral blood samples contained vacuolated lymphocytes. Two children had mild facial dysmorphism, including epicanthal folds, posteriorly rotated ears, flattened nasal bridge, mildly anteverted nostrils, and slightly prominent forehead. Two sibs from another family showed a similar phenotype. At age 5 years, 1 child exhibited decerebrate rigidity with generalized muscle weakness and spastic paraparesis. Brain biopsy of 1 child showed extensive cytoplasmic distention of most neurons and glial cells with storage material. Electron microscopy showed membranous cytoplasmic bodies containing material. Similar findings were observed in the liver. Biochemical analysis showed accumulation of GM1 gangliosides.
Singer and Schafer (1972) reported a child who showed normal development until 9 to 10 months of age. After this time, he showed psychomotor deterioration. At age 3 years, he showed severe spasticity and seizures. He had no organomegaly and normal maculae. Radiographic studies showed early beaking of the lumbar vertebrae. Laboratory studies showed vacuolated lymphocytes in peripheral blood smear and bone marrow, glycolipid-containing ganglion cells, and decreased beta-galactosidase activity. Detailed biochemical studies on beta-galactosidase obtained from liver tissue of this patient and a patient with type I disease suggested that they are related and likely allelic disorders.
Pinsky et al. (1974) described a milder variant of GM1-gangliosidosis with more beta-galactosidase activity than observed in types I or II. The patient developed seizures at age 5 months, followed by minimal hepatosplenomegaly, brisk reflexes, lower limb scissoring, and vacuolated cells on bone marrow biopsy. At age 8 months, her peripheral leukocyte GLB1 activity was one-tenth of normal values. She showed an unusual clinical course. There was no more seizure activity after age 5 months, she walked at age 22 months, and began to speak at age 3 years. Bone development was normal until age 3 when medullary cavities of the bones of the upper extremity and ribs widened. Given the residual enzyme activity and relatively milder phenotype, Pinsky et al. (1974) classified her as having a 'third' type of GM1-gangliosidosis. However, given the early age at onset of the first symptoms, she is noted here as having the juvenile type.
Caciotti et al. (2003) reported a child with late-infantile GM1-gangliosidosis with onset at 17 months and rapidly progressive psychomotor deterioration. At 12 months, he could stand and was on the verge of walking. During his third year of life, blindness, increasing pain, and spasticity were noted. By the age of 5 years, he had the onset of dramatic episodes of fever and hypertension of unknown etiology. At the age of 6 years, he developed renal failure and succumbed to the illness at the age of 6.5 years. He never showed a cherry-red spot of the macula. The clinical characterization of this patient as late-infantile GM1 gangliosidosis was in keeping with a clear-cut division between the 2 subforms of the type II phenotype.
In 4 Japanese patients with the juvenile form of GM1-gangliosidosis, Nishimoto et al. (1991) identified a mutation in the GLB1 gene (R201C; 611458.0003). One patient was homozygous for the mutation; the second mutant allele could not be identified in the 3 remaining patients. All had detectable GLB1 mRNA. Yoshida et al. (1991) identified a heterozygous R201C mutation in a Japanese patient with the late-infantile form of GM1-gangliosidosis. Beta-galactosidase activity was 3% of normal controls.
In a patient with the late-infantile form of GM1-gangliosidosis, Caciotti et al. (2003) identified compound heterozygosity for 2 mutations in the GLB1 gene (611458.0003; 611458.0022).
Holmes and O'Brien (1978) studied the feline disorder which is similar to type II generalized gangliosidosis. The residual enzyme was not only altered in its catalytic and physicochemical characteristics but was also different from normal antigenically.
Caciotti, A., Bardelli, T., Cunningham, J., D'Azzo, A., Zammarchi, E., Morrone, A. Modulating action of the new polymorphism L436F detected in the GLB1 gene of a type-II GM1 gangliosidosis patient. Hum. Genet. 113: 44-50, 2003. [PubMed: 12644936] [Full Text: https://doi.org/10.1007/s00439-003-0930-8]
Derry, D. M., Fawcett, J. S., Andermann, F., Wolfe, L. S. Late infantile systemic lipidosis (major monosialogangliosidosis; delineation of two types). Neurology 18: 340-347, 1968. [PubMed: 4173446] [Full Text: https://doi.org/10.1212/wnl.18.4.340]
Holmes, E. W., O'Brien, J. S. Feline Gm(1) gangliosidosis: characterization of the residual liver acid beta-galactosidase. Am. J. Hum. Genet. 30: 505-515, 1978. [PubMed: 83795]
Kint, J. A., Dacremont, G., Vlietinck, R. Type II Gm(1) gangliosidosis? Lancet 294: 108-109, 1969. Note: Originally Volume 2. [PubMed: 4182749] [Full Text: https://doi.org/10.1016/s0140-6736(69)92420-9]
Lowden, J. A., Callahan, J. W., Norman, M. G., Thain, M., Prichard, J. S. Juvenile Gm1-gangliosidosis: occurrence with absence of two beta-galactosidase components. Arch. Neurol. 31: 200-203, 1974. [PubMed: 4368854] [Full Text: https://doi.org/10.1001/archneur.1974.00490390082010]
Nishimoto, J., Nanba, E., Inui, K., Okada, S., Suzuki, K. GM1-gangliosidosis (genetic beta-galactosidase deficiency): identification of four mutations in different clinical phenotypes among Japanese patients. Am. J. Hum. Genet. 49: 566-574, 1991. [PubMed: 1909089]
O'Brien, J. S., Ho, M. W., Veath, M. L., Wilson, J. F., Myers, G., Opitz, J. M., ZuRhein, G. M., Spranger, J. W., Hartmann, H. A., Haneberg, B., Grosse, F. R. Juvenile Gm1 gangliosidosis: clinical, pathological, chemical and enzymatic studies. Clin. Genet. 3: 411-434, 1972. [PubMed: 4650864] [Full Text: https://doi.org/10.1111/j.1399-0004.1972.tb01476.x]
O'Brien, J. S. Five gangliosidoses. (Letter) Lancet 294: 805 only, 1969. Note: Originally Volume 2. [PubMed: 4186052] [Full Text: https://doi.org/10.1016/s0140-6736(69)90524-8]
Pinsky, L., Miller, J., Shanfield, B., Watters, G. V., Wolfe, L. S. Gm(1) gangliosidosis in skin fibroblast culture: enzymatic differences between types 1 and 2 and observation on a third variant. Am. J. Hum. Genet. 26: 563-577, 1974. [PubMed: 4420522]
Singer, H. S., Schafer, I. A. Clinical and enzymatic variations in Gm(1) generalized gangliosidosis. Am. J. Hum. Genet. 24: 454-463, 1972. [PubMed: 5031983]
Suzuki, K., Kamoshita, S. Chemical pathology of Gm(1)-gangliosidosis (generalized gangliosidosis). J. Neuropath. Exp. Neurol. 28: 25-73, 1969. [PubMed: 4237219] [Full Text: https://doi.org/10.1097/00005072-196901000-00003]
Wolfe, L. S., Callahan, J., Fawcett, J. S., Andermann, F., Scriver, C. R. Gm(1)-gangliosidosis without chondrodystrophy or visceromegaly. Neurology 20: 23-43, 1970. [PubMed: 4243740] [Full Text: https://doi.org/10.1212/wnl.20.1.23]
Yamamoto, A., Adachi, S., Kawamura, S., Takahashi, M., Kitani, T., Ohtori, T., Shinji, Y., Nishikawa, M. Localized beta-galactosidase deficiency: occurrence in cerebellar ataxia with myoclonus epilepsy and macular cherry-red spot--a new variant of Gm(1)-gangliosidosis. Arch. Intern. Med. 134: 627-634, 1974. [PubMed: 4278184] [Full Text: https://doi.org/10.1001/archinte.134.4.627]
Yoshida, K., Oshima, A., Shimmoto, M., Fukuhara, Y., Sakuraba, H., Yanagisawa, N., Suzuki, Y. Human beta-galactosidase gene mutations in G(M1)-gangliosidosis: a common mutation among Japanese adult/chronic cases. Am. J. Hum. Genet. 49: 435-442, 1991. [PubMed: 1907800]