GM1 Gangliosidosis Clinical Presentation

  • Author: David H Tegay, DO, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 29, 2012
 

History

  • Infantile G M1 gangliosidosis: In the most common infantile form, coarse facial features, hepatosplenomegaly, generalized skeletal dysplasia (dysostosis multiplex), macular cherry-red spots, and developmental delay/arrest (followed by progressive neurologic deterioration) usually occur within the first 6 months of life. Nonimmune hydrops has been reported. An increased incidence of Mongolian spots has also been reported. A wide spectrum of variability is observed in the appearance and progression of the typical dysmorphic features. As many as 50% of affected infants have a macular cherry-red spot.[1, 2, 10]
  • Juvenile: The juvenile form is characterized by a later age of onset, less hepatosplenomegaly (if any), fewer cherry-red spots (if any), dysmorphic features, or skeletal changes (vertebral dysplasia may be detected radiographically).[1, 2]
  • Adult: The adult form is characterized by normal early neurologic development, with variable age of clinical presentation. Slowly progressing dementia with parkinsonian features and extrapyramidal disease is common. Intellectual impairment may be initially absent or mild but progresses with time. Generalized dystonia with speech and gait disturbance is the most frequently reported early feature. Typically, no hepatosplenomegaly, cherry-red spots, dysmorphic features, or skeletal changes are present aside from scoliosis (mild vertebral changes may be revealed with radiography), but short stature is common.[4, 5]
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Physical

  • Neurologic findings
    • Developmental delay, arrest, and regression
    • Generalized hypotonia initially, developing into spasticity
    • Exaggerated startle response
    • Hyperreflexia
    • Seizures
    • Extrapyramidal disease (adult subtype)
    • Generalized dystonia (adult subtype)[5]
    • Ataxia (adult subtype)
    • Dementia (adult subtype)
    • Speech and swallowing disturbance (adult subtype)[4]
  • Ophthalmologic findings
  • Dysmorphic features
    • Frontal bossing
    • Depressed nasal bridge and broad nasal tip
    • Large low-set ears
    • Long philtrum
    • Gingival hypertrophy and macroglossia[1]
  • Coarse skin
  • Hirsutism
  • Cardiovascular - Dilated and/or hypertrophic cardiomyopathy, valvulopathy
  • Abdomen
    • Hepatosplenomegaly
    • Inguinal hernia
  • Skeletal abnormalities
    • Lumbar gibbus deformity and kyphoscoliosis
    • Dysostosis multiplex
    • Broad hands and feet
    • Brachydactyly
    • Joint contractures
  • Angiokeratoma corporis diffusum (reported infrequently)
  • Hydrops fetalis (has been reported)
  • Prominent dermal melanocytosis (Mongolian spots)[11, 12]
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Causes

  • All 3 forms of GM1 gangliosidosis are caused by deficiency in acid β -galactosidase activity.[2]
  • GM1 gangliosidosis is an autosomal recessive disease; therefore, affected individuals inherit 2 copies of the nonfunctioning gene. Carriers (ie, individuals with 1 functioning and 1 nonfunctioning gene) have no clinical manifestations.
    • The gene has been isolated and is located on chromosome band 3p21.33. Various types of mutations have been identified in the acid β -galactosidase gene, including missense/nonsense, duplication/insertion, and splice site abnormalities.[13]
    • Genotype and phenotype correlations are being delineated to provide a molecular explanation for clinical variability. The amount of residual enzyme activity has some correlation with disease subtype and severity.[1]
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Contributor Information and Disclosures
Author

David H Tegay, DO, FACMG  Associate Professor of Medicine and Medical Genetics, New York College of Osteopathic Medicine at the New York Institute of Technology; Assistant Professor of Pediatrics, Stony Brook University Medical Center

David H Tegay, DO, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Osteopathic Association, American Society of Human Genetics, and Federation of American Societies for Experimental Biology

Disclosure: Nothing to disclose.

Specialty Editor Board

Ian Krantz, MD  Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia

Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG  Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Shari Fallet, DO, to the original writing and development of this article.

References

  1. Suzuki Y, Oshima A, Nanba E. B-Galactosidase deficiency (B-Galactosidosis): GM1 gangliosidosis and Morquio B disease. In: 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.

  2. Brunetti-Pierri N, Scaglia F. GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab. Aug 2008;94(4):391-6. [Medline].

  3. Suzuki K. Neuropathology of late onset gangliosidoses. A review. Dev Neurosci. 1991;13(4-5):205-10. [Medline].

  4. 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. Nov 2004;19(11):1334-41. [Medline].

  5. Roze E, Paschke E, Lopez N, et al. Dystonia and parkinsonism in GM1 type 3 gangliosidosis. Mov Disord. Oct 2005;20(10):1366-9. [Medline].

  6. 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. Jan 3 2012;[Medline].

  7. 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. Jan 13 2012;287(3):1801-12. [Medline]. [Full Text].

  8. Lenicker HM, Vassallo Agius P, Young EP, Attard Montalto SP. Infantile generalized GM1 gangliosidosis: high incidence in the Maltese Islands. J Inherit Metab Dis. Sep 1997;20(5):723-4. [Medline].

  9. Severini MH, Silva CD, Sopelsa A, et al. High frequency of type 1 GM1 gangliosidosis in southern Brazil. Clin Genet. Aug 1999;56(2):168-9. [Medline].

  10. 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. Jan 2011;56(1):98-100. [Medline]. [Full Text].

  11. Hanson M, Lupski JR, Hicks J, Metry D. Association of dermal melanocytosis with lysosomal storage disease: clinical features and hypotheses regarding pathogenesis. Arch Dermatol. Jul 2003;139(7):916-20. [Medline].

  12. Snow TM. Mongolian spots in the newborn: do they mean anything?. Neonatal Netw. Jan-Feb 2005;24(1):31-3. [Medline].

  13. 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].

  14. Chamoles NA, Blanco MB, Iorcansky S, et al. Retrospective diagnosis of GM1 gangliosidosis by use of a newborn-screening card. Clin Chem. Nov 2001;47(11):2068. [Medline]. [Full Text].

  15. 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].

  16. 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].

  17. 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. Apr 2009;154(4):609-11. [Medline].

  18. [Guideline] Cunningham M, Cox EO. Hearing assessment in infants and children: recommendations beyond neonatal screening. Pediatrics. Feb 2003;111(2):436-40. [Medline].

 
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