- Author: David H Tegay, DO, FACMG; Chief Editor: Luis O Rohena, MD more...
GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder characterized by the generalized accumulation of GM1 ganglioside, oligosaccharides, and the mucopolysaccharide keratan sulfate (and their derivatives). Deficiency of the lysosomal hydrolase, acid β -galactosidase, causes GM1 gangliosidosis and Morquio disease type B (ie, mucopolysaccharidosis type IVB). Three clinical subtypes of GM1 gangliosidosis are recognized, classified by age of onset, as follows:
Infantile (type 1): The classic infantile subtype combines the features of a neurolipidosis (ie, neurodegeneration, macular cherry-red spots) with those of a mucopolysaccharidosis (ie, visceromegaly, dysostosis multiplex, coarsened facial features). This form of G M1 gangliosidosis most frequently presents in early infancy and may be evident at birth. 
Juvenile (type 2): The juvenile subtype is marked by a slightly later age of onset and clinical variability in the classic physical features.
Adult (type 3): The adult subtype is marked by normal early neurologic development with no physical stigmata and subsequent development of a slowly progressive dementia with parkinsonian features, extrapyramidal disease, and dystonia. [3, 4, 5]
Acid β -galactosidase is a lysosomal hydrolase that catalyzes the removal of the terminal β -linked galactose from glycoconjugates (eg, GM1 ganglioside), generating GM2 ganglioside. It also functions to degrade other β -galactose–containing glycoconjugates, such as keratan sulfate.
Enzyme activity is markedly reduced in patients with GM1 gangliosidosis. Deficiency of acid β -galactosidase results in the accumulation of glycoconjugates in body tissues and their excretion in urine. GM1 ganglioside and its derivative asialo-GM1 ganglioside (GA1), glycoprotein-derived oligosaccharides, and keratan sulfate are found at elevated intracellular concentrations.[1, 6, 7, 8, 9]
Gangliosides are normal components of cell membranes, particularly neurons, and GM1 is the major ganglioside in the vertebrate brain. Accumulation of toxic asialo-compound and lyso-compound GM1 ganglioside derivatives is believed to be neuropathic.
GM1 gangliosidosis is a rare disorder, and data concerning incidence are not widely available. The estimated incidence is 1:100,000-200,000 live births.
An unusually high incidence of 1 case per 3700 live births has been reported in the population of Malta.
The infantile form (type 1) typically presents between birth and age 6 months with progressive organomegaly, dysostosis multiplex, facial coarsening, and rapid neurologic deterioration within the first year of life. Death usually occurs during the second year of life because of infection (usually due to pneumonia that results from recurrent aspiration) and cardiopulmonary failure.
The juvenile form (type 2) typically presents at age 1-2 years with progressive psychomotor retardation. Little visceromegaly and milder skeletal disease are present compared to the infantile form. Death usually occurs before the second decade of life.
The adult form (type 3) typically presents during childhood or adolescence as a slowly progressive dementia with prominent parkinsonian features and extrapyramidal disease, particularly dystonia. Marked phenotypic variability may occur. Age at death may widely vary.
GM1 gangliosidosis is found in all races, although specific alleles can be identified in certain ethnic groups. A high frequency of GM1 gangliosidosis has been reported from Southern Brazil, and a large number of Japanese patients with the adult form have been reported.[11, 1]
All 3 types of GM1 gangliosidosis are inherited as autosomal recessive traits and have equal sex distributions.
The infantile form (type 1) typically presents from birth to age 6 months, the juvenile form (type 2) typically presents in children aged 1-3 years, and the adult form (type 3) typically presents during childhood or adolescence.
Suzuki Y, Oshima A, Nanba E. B-Galactosidase deficiency (B-Galactosidosis): GM1 gangliosidosis and Morquio B disease. Scriver CR, Sly WS, Valle D, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill Professional; 2001. 3775-810.
Brunetti-Pierri N, Scaglia F. GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab. 2008 Aug. 94(4):391-6. [Medline].
Suzuki K. Neuropathology of late onset gangliosidoses. A review. Dev Neurosci. 1991. 13(4-5):205-10. [Medline].
Muthane U, Chickabasaviah Y, Kaneski C, et al. Clinical features of adult GM1 gangliosidosis: report of three Indian patients and review of 40 cases. Mov Disord. 2004 Nov. 19(11):1334-41. [Medline].
Roze E, Paschke E, Lopez N, et al. Dystonia and parkinsonism in GM1 type 3 gangliosidosis. Mov Disord. 2005 Oct. 20(10):1366-9. [Medline].
Celtikçi B, Aydin HI, Sivri S, Sönmez M, Topçu M, Ozkara HA. Four novel mutations in the ß-galactosidase gene identified in infantile type of GM1 gangliosidosis. Clin Biochem. 2012 Jan 3. [Medline].
Ohto U, Usui K, Ochi T, Yuki K, Satow Y, Shimizu T. Crystal structure of human ß-galactosidase: structural basis of Gm1 gangliosidosis and morquio B diseases. J Biol Chem. 2012 Jan 13. 287(3):1801-12. [Medline]. [Full Text].
King JE, Dexter A, Gadi I, Zvereff V, Martin M, Bloom M, et al. Maternal uniparental isodisomy causing autosomal recessive GM1 gangliosidosis: a clinical report. J Genet Couns. 2014 Oct. 23(5):734-41. [Medline].
Zhong L, Zhang Z, Lu X, Liu S, Chen CY, Chen ZW. NSOM/QD-based visualization of GM1 serving as platforms for TCR/CD3 mediated T-cell activation. Biomed Res Int. 2013. 2013:276498. [Medline]. [Full Text].
Lenicker HM, Vassallo Agius P, Young EP, Attard Montalto SP. Infantile generalized GM1 gangliosidosis: high incidence in the Maltese Islands. J Inherit Metab Dis. 1997 Sep. 20(5):723-4. [Medline].
Severini MH, Silva CD, Sopelsa A, et al. High frequency of type 1 GM1 gangliosidosis in southern Brazil. Clin Genet. 1999 Aug. 56(2):168-9. [Medline].
Dweikat I, Libdeh BA, Murrar H, Khalil S, Maraqa N. Gm1 gangliosidosis associated with neonatal-onset of diffuse ecchymoses and mongolian spots. Indian J Dermatol. 2011 Jan. 56(1):98-100. [Medline]. [Full Text].
Takenouchi T, Kosaki R, Nakabayashi K, Hata K, Takahashi T, Kosaki K. Paramagnetic Signals in the Globus Pallidus as Late Radiographic Sign of Juvenile-Onset GM1 Gangliosidosis. Pediatr Neurol. 2014 Oct 16. [Medline].
Hanson M, Lupski JR, Hicks J, Metry D. Association of dermal melanocytosis with lysosomal storage disease: clinical features and hypotheses regarding pathogenesis. Arch Dermatol. 2003 Jul. 139(7):916-20. [Medline].
Snow TM. Mongolian spots in the newborn: do they mean anything?. Neonatal Netw. 2005 Jan-Feb. 24(1):31-3. [Medline].
Suzuki Y, Sakuraba H, Oshima A, et al. Clinical and molecular heterogeneity in hereditary beta-galactosidase deficiency. Dev Neurosci. 1991. 13(4-5):299-303. [Medline].
Morrone A, Bardelli T, Donati MA, et al. Beta-galactosidase gene mutations affecting the lysosomal enzyme and the elastin-binding protein in GM1-gangliosidosis patients with cardiac involvement. Hum Mutat. 2000. 15(4):354-66. [Medline].
Shield JP, Stone J, Steward CG. Bone marrow transplantation correcting beta-galactosidase activity does not influence neurological outcome in juvenile GM1-gangliosidosis. J Inherit Metab Dis. 2005. 28(5):797-8. [Medline].
Wynn RF, Wraith JE, Mercer J, et al. Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy. J Pediatr. 2009 Apr. 154(4):609-11. [Medline].
[Guideline] Cunningham M, Cox EO. Hearing assessment in infants and children: recommendations beyond neonatal screening. Pediatrics. 2003 Feb. 111(2):436-40. [Medline].