GM1 Gangliosidosis Workup
- Author: David H Tegay, DO, FACMG; Chief Editor: Luis O Rohena, MD more...
Acid β -galactosidase activity: Diagnosis of G M1 gangliosidosis can be confirmed by measurement of acid β -galactosidase activity in peripheral blood leukocytes. Patients with the infantile form have almost no enzyme activity, whereas patients with the adult form may have residual activity of 5-10% of reference values. Overlap is often present between homozygotes without GM1 gangliosidosis and heterozygote carriers; therefore, screening for heterozygote carriers using enzyme analysis is not reliable.
Urine: Galactose-containing oligosaccharides are excreted in the urine. Their presence may be used as an ancillary diagnostic test, and the concentration of the metabolites is proportional to disease severity.
CBC count: Vacuolation of lymphocytes may be present in patients with GM1 gangliosidosis but is a nonspecific indicator seen in a variety of lysosomal storage disorders.
Dried blood spots: Diagnosis of GM1 gangliosidosis has been made based on dried blood spots from newborn screening filter paper, even after 15 months in storage.
Molecular analysis: Molecular analysis of the β -1 galactosidase gene (GLB1) is clinically available.[17, 2]
Radiography: Skeletal radiographs may reveal changes characteristic of dysostosis multiplex (as observed in mucopolysaccharidosis), including thickened calvaria, J-shaped enlarged sella turcica, wide spatula-shaped ribs, flared ilia, acetabular dysplasia and flat femoral heads, wide wedge-shaped metacarpals, shortened long bones with diaphyseal widening, and hypoplastic and anteriorly beaked thoracolumbar vertebrae. Delayed bone age also may be demonstrated. In the adult form, only mild vertebral changes may be observed.
CT and MRI: Neuroimaging using CT scan or MRI generally reveals diffuse atrophy and white matter demyelination with or without basal ganglia changes. Bilateral T2-weighted hyperintensities in the putamen are a frequently reported MRI finding in adult-onset disease. Mild cerebral atrophy may also be observed in the adult form. MR spectroscopy has demonstrated increased striatal myoinositol.
Ultrasound: An ultrasound of the abdomen may reveal organomegaly.
Echocardiography: Signs of cardiomyopathy or valvulopathy may be observed.
Electrocardiography: Signs of cardiomyopathy may be observed.
Electroencephalography: This test may reveal generalized dysrhythmia and epileptogenic foci.
Acid β -galactosidase genotyping: Molecular diagnosis by direct sequencing can be useful for detecting heterozygous carriers and affected patients.[19, 17]
Lumbar puncture: GM1 ganglioside levels can be increased in the cerebrospinal fluid (CSF) and may be useful for diagnosis and monitoring.
Bone marrow aspiration: Do not use this procedure as a diagnostic test. Nonspecific large foam cells, Gaucher cells, and ballooned cells have been reported in bone marrow but are typically reported in lower concentrations than in other lysosomal storage disorders. Sea-blue histiocytes have been reported.
Skin biopsy: Obtaining a skin biopsy may be useful to establish acid β -galactosidase activity in cultured fibroblasts.
Prenatal diagnosis: Prenatal diagnosis has been performed successfully by assay of β -galactosidase activity in cultured amniocytes or amniotic chorionic villi. Mutation identification allows prenatal or preimplantation genetic diagnosis.
Cytoplasmic distention is observed diffusely within neurons and glial cells (with numerous membranous cytoplasmic bodies) because of accumulated GM1 ganglioside.
Neuronal number is decreased, and cortical architecture is distorted.
Extraneural lipid-laden histiocytes are observed in the liver, spleen, lymph nodes, thymus, lung, intestine, interlobular septa of the pancreas, and bone marrow. Their distended cytoplasm leads to eccentrically placed small pyknotic nuclei.
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].