eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

GM1 Gangliosidosis

Updated: Jun 8, 2009

Introduction

Background

G_M1 gangliosidosis is an autosomal recessive lysosomal storage disorder characterized by the generalized accumulation of G_M1 ganglioside, oligosaccharides, and the mucopolysaccharide keratan sulfate (and their derivatives). Deficiency of the lysosomal hydrolase, acid b -galactosidase, causes G_M1 gangliosidosis and Morquio disease type B (ie, mucopolysaccharidosis type IVB).¹ Three clinical subtypes of G_M1 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.²
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

Pathophysiology

Acid β -galactosidase is a lysosomal hydrolase that catalyzes the removal of the terminal β -linked galactose from glycoconjugates (eg, G_M1 ganglioside), generating G_M2 ganglioside. It also functions to degrade other β -galactose–containing glycoconjugates, such as keratan sulfate. Enzyme activity is markedly reduced in patients with G_M1 gangliosidosis. Deficiency of acid β -galactosidase results in the accumulation of glycoconjugates in body tissues and their excretion in urine. G_M1 ganglioside and its derivative asialo-G_M1 ganglioside (GA1), glycoprotein-derived oligosaccharides, and keratan sulfate are found at elevated intracellularconcentrations.¹

Gangliosides are normal components of cell membranes, particularly neurons, and G_M1 is the major ganglioside in the vertebrate brain. Accumulation of toxic asialo-compound and lyso-compound G_M1 ganglioside derivatives is believed to be neuropathic.¹

Frequency

United States

G_M1 gangliosidosis is a rare disorder, and data concerning incidence are not widely available. The estimated incidence is 1:100,000-200,000 live births.²

International

An unusually high incidence of 1 case per 3700 live births has been reported in the population of Malta.⁶

Mortality/Morbidity

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.

Race

G_M1 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.^7,1

Sex

All 3 types of G_M1 gangliosidosis are inherited as autosomal recessive traits and have equal sex distributions.

Age

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.

Clinical

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
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

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
- Macular cherry-red spots
  - Present in as many as 50% of affected infants
  - May be found in other genetic disorders (eg, mucolipidosis type I, Niemann-Pick disease, Krabbe disease, Tay-Sachs disease)
- Optic atrophy
- Corneal clouding
Dysmorphic features
- Frontal bossing
- Depressed nasal bridge and broad nasal tip
- Large low-set ears
- Long philtrum
- Gingival hypertrophy and macroglossia¹
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)^8,9

Causes

All 3 forms of G_M1 gangliosidosis are caused by deficiency in acid b -galactosidase activity.²
G_M1 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 b -galactosidase gene, including missense/nonsense, duplication/insertion, and splice site abnormalities.¹⁰
- 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

Differential Diagnoses

GM2 Gangliosidoses
I-Cell Disease (Mucolipidosis Type II)
Mucopolysaccharidosis Type IH
Mucopolysaccharidosis Type IV
Sialidosis (Mucolipidosis I)
Wilson Disease

Workup

Laboratory Studies

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 G_M1 gangliosidosis and heterozygote carriers; therefore, screening for heterozygote carriers using enzyme analysis is not reliable.¹
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 G_M1 gangliosidosis but is a nonspecific indicator seen in a variety of lysosomal storage disorders.
Dried blood spots: Diagnosis of G_M1 gangliosidosis has been made based on dried blood spots from newborn screening filter paper, even after 15 months in storage.¹¹
Molecular analysis: Molecular analysis of the β -1 galactosidase gene (GLB1) is clinically available.^10,2

Imaging Studies

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.¹
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.

Other Tests

Electrocardiography: Signs of cardiomyopathy may be observed.
Electroencephalography: This test may reveal generalized dysrhythmia and epileptogenic foci.

Procedures

Acid b -galactosidase genotyping: Molecular diagnosis by direct sequencing can be useful for detecting heterozygous carriers and affected patients.^12,10
Lumbar puncture: G_M1 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.¹
Skin biopsy: Obtaining a skin biopsy may be useful to establish acid b -galactosidase activity in cultured fibroblasts.
Prenatal diagnosis: Prenatal diagnosis has been performed successfully by assay of b -galactosidase activity in cultured amniocytes or amniotic chorionic villi.¹ Mutation identification allows prenatal or preimplantation genetic diagnosis.

Histologic Findings

Cytoplasmic distention is observed diffusely within neurons and glial cells (with numerous membranous cytoplasmic bodies) because of accumulated G_M1 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.¹

Treatment

Medical Care

Currently, no effective medical treatment is available for the underlying disorder in patients with G_M1 gangliosidosis. Bone marrow transplantation was successful in an individual with infantile/juvenile G_M1 gangliosidosis; however, no long-term benefit was reported.¹³ Presymptomatic cord-blood hematopoietic stem-cell transplantation has been advocated by some as a possible treatment because of success in other lysosomal storage disorders.¹⁴
Symptomatic treatment for some neurologic sequelae is available but does not significantly alter the clinical course.
Active research in the areas of enzyme replacement and gene therapy for G_M1 gangliosidosis is ongoing but has not advanced to human trials.²

Consultations

Clinical geneticist - For initial evaluation and diagnosis, to counsel families regarding recurrence risk, and to help provide prenatal testing for future pregnancies
Neurologist - For symptomatic therapy of multiple neurologic sequelae
Cardiologist - To evaluate for cardiomyopathy
Orthopedist - To evaluate for dysostosis multiplex
Ophthalmologist - To evaluate for ocular stigmata
Otolaryngologist and audiologist - To assess for hearing loss¹⁵

Diet

No specific dietary modifications have been shown to significantly alter the clinical course.
Infants may ultimately require tube feeding to provide adequate intake of energy; however, nutritional support does not change the disease course, and some families may choose to forgo invasive alimentation procedures.

Activity

Neurologic and orthopedic sequelae may preclude adequate physical activity, and patients may benefit from physical and occupational therapy.

Medication

Currently, drug therapy is not a component of the standard of care for this condition.

Follow-up

Complications

Patients with G_M1 gangliosidosis are at risk for aspiration pneumonia and recurrent respiratory infections resulting from neurologic compromise.
Congestive heart failure may result secondary to cardiomyopathy.
Atlantoaxial instability can develop because of abnormally shaped cervical vertebrae. If this occurs, patients should be monitored, and they eventually should undergo surgical stabilization to avoid the risk of spinal cord injury.

Prognosis

Infantile (type 1): Death usually occurs during the second year of life because of infection and cardiopulmonary failure.¹
Juvenile (type 2): Death usually occurs before the second decade of life.¹
Adult (type 3): Phenotypic variability is marked, but progressive development of neurologic sequelae usually leads to a shortened lifespan.¹

Patient Education

Families of patients with G_M1 gangliosidosis require education regarding the disease manifestations and potential complications.
A discussion of the genetic basis of the disorder should include recurrence risks and methods of carrier identification.
Genetic counseling should be available for at-risk couples to explain risk and options in future pregnancies, including prenatal diagnosis.

Miscellaneous

Medicolegal Pitfalls

Counsel patients and their families regarding the 25% risk in each pregnancy for couples with two carriers to have offspring with G_M1 gangliosidosis and the potential options of prenatal or preimplantation genetic diagnosis.

References

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. 8^th ed. McGraw-Hill Professional; 2001:3775-810.
Brunetti-Pierri N, Scaglia F. GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab. Aug 2008;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. Nov 2004;19(11):1334-41. [Medline].
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].
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].
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].
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].
Snow TM. Mongolian spots in the newborn: do they mean anything?. Neonatal Netw. Jan-Feb 2005;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].
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].
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. Apr 2009;154(4):609-11. [Medline].
[Guideline] Cunningham M, Cox EO. Hearing assessment in infants and children: recommendations beyond neonatal screening. Pediatrics. Feb 2003;111(2):436-40. [Medline].

Keywords

G_M1 gangliosidosis, acid beta-galactosidase-1 deficiency, GLB1 deficiency, Morquio disease type B, Norman-Landing disease, Landing disease, lysosomal storage disorder, ganglioside accumulation, oligosaccharide accumulation, mucopolysaccharide accumulation, keratan sulfate, dementia, coarse facial features, hepatosplenomegaly, generalized skeletal dysplasia, macular cherry-red spots, scoliosis, treatment, diagnosis

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.

Medical Editor

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.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

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.

CME Editor

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, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, 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.

Acknowledgments

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.

Further Reading