AUTHOR INFORMATION

Section 1 of 11

Authored by David H Tegay, DO, FACMG, Clinical Research Scholar, Assistant Professor of Pediatrics and Internal Medicine, Co-Director, Division of Medical Genetics, Stony Brook University Hospital

Coauthored by Shari Fallet, DO, Chief, Division of Genetics, Assistant Clinical Professor of Human Genetics and Pediatrics, Children's Hospital of New Jersey at Newark Beth Israel Medical Center

David H Tegay, DO, FACMG, is a member of the following medical societies: American College of Medical Genetics, American Medical Association, American Osteopathic Association, and American Society of Human Genetics

Edited by Ian Krantz, MD, Assistant Professor, Department of Pediatrics, University of Pennsylvania and Children's Hospital of Philadelphia; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	David H Tegay, DO, FACMG
Editor's Email:	Ian Krantz, MD

eMedicine Journal, April 18 2006, VOLUME 7, Number 4

INTRODUCTION

Section 2 of 11

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). Three clinical subtypes of G_M1 gangliosidosis exist, 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.

Pathophysiology: Acid b-galactosidase is a lysosomal hydrolase that catalyzes the removal of the terminal b-linked galactose from glycoconjugates (eg, G_M1 ganglioside), generating G_M2 ganglioside. It also functions to degrade other b-galactose–containing glycoconjugates, such as keratan sulfate. Enzyme activity is markedly reduced in patients with G_M1 gangliosidosis. Deficiency of acid b-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 intracellular concentrations.

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

Frequency:

• In the US: G_M1 gangliosidosis is a rare disorder, and data concerning incidence are not widely available.

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

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 vary greatly.

Race: G_M1 gangliosidosis is found in all races, although specific alleles can be identified in certain ethnic groups. A large number of Japanese patients with the adult form has been reported.

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.

• The adult form (type 3) typically presents during childhood or adolescence.

CLINICAL

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History:

• Infantile: 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 can exist in the appearance and progression of the typical dysmorphic features. As many as 50% of affected infants have a macular cherry-red spot.



• 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).



• 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.

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)

  • Ataxia (adult subtype)

  • Dementia (adult subtype)

  • Speech and swallowing disturbance (adult subtype)
  
  
  
• 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 macroglossia
  
  
  
• 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) (have been reported in a number of cases)

Causes:

• All 3 forms of G_M1 gangliosidosis are caused by deficiency in acid b-galactosidase activity.



• 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.
  
  
  
  • Genotype and phenotype correlations are being delineated to provide a molecular explanation for clinical variability. Presumably, the amount of residual enzyme activity determines disease subtype and severity.
  
  
  

DIFFERENTIALS

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GM2 Gangliosidoses
I-Cell Disease (Mucolipidosis Type II)
[Mucolipidosis Type I (Alpha-Neuraminidase Deficiency-Sialidosis)]

Mucopolysaccharidosis Type IH
Mucopolysaccharidosis Type IV
Wilson Disease

Other Problems to be Considered:

Galactosialidosis (combined a-neuraminidase and b-galactosidase deficiency)
Oligosaccharidosis (eg, mannosidosis, fucosidosis, sialidosis)
Parkinson disease
Isolated dystonia

WORKUP

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Lab Studies:

• Acid b-galactosidase activity: Diagnosis can be confirmed by measurement of acid b-galactosidase activity in peripheral blood leukocytes. Patients with the infantile form have almost no enzyme activity, while 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.



• 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: 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.



• Diagnosis of G_M1 gangliosidosis has been made based on dried blood spots from newborn screening filter paper, even after 15 months in storage.



• Molecular analysis of the b-1 galactosidase gene (GLB1) is clinically available.

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.



• 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.



• 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.



• Skin biopsy: Obtaining a skin biopsy may be useful to establish acid b-galactosidase activity in cultured fibroblasts.



• Prenatal diagnosis has been performed successfully by assay of b-galactosidase activity in cultured amniocytes or amniotic chorionic villi. Mutation identification would allow prenatal or preimplantation genetic diagnosis.

TREATMENT

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Medical Care:

• Currently, no effective medical treatment is available for the underlying disorder. Bone marrow transplantation was successful in an individual with infantile/juvenile G_M1 gangliosidosis; however, no long-term benefit was reported. Presymptomatic cord-blood hematopoietic stem-cell transplantation has been advocated by some as a possible treatment because of success in other lysosomal storage disorders.



• 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.

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 loss

Diet: No specific dietary modifications have been shown to significantly alter the clinical course. Infants ultimately may 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

Section 7 of 11

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

FOLLOW-UP

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Complications:

• Patients 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.



• Juvenile (type 2): Death usually occurs before the second decade of life.



• Adult (type 3): Phenotypic variability is marked, but progressive development of neurologic sequelae usually leads to a shortened lifespan.

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

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Medical/Legal 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.

TEST QUESTIONS

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CME Question 1: Which of the following risk assessments is correct in parents of a child with G_M1 gangliosidosis?

A: The parents have a 50% chance of having another affected child with each subsequent pregnancy.
B: They each have a 50% chance of being a carrier of G_M1 gangliosidosis.
C: They have a 25% chance of having another affected child with each subsequent pregnancy.
D: One of the parents may not be a carrier of G_M1 gangliosidosis.
E: They have no greater chance than the general population of having another affected child in subsequent pregnancies.

The correct answer is C: G_M1 gangliosidosis is an autosomal recessive disorder; therefore, if a couple has a child with G_M1 gangliosidosis, each parent is an obligate carrier. With each subsequent pregnancy, the parents have a 25% chance of having another affected child, a 50% chance of having a child who is unaffected and a carrier for the disease, and a 25% chance of having a child who is unaffected and is not a carrier.

CME Question 2: Which of the following genetic disorders is in the differential diagnosis of a macular cherry-red spot?

A: Mucolipidosis type I
B: Niemann-Pick disease
C: Krabbe disease
D: G_M1 gangliosidosis
E: All of the above

The correct answer is E: Macular cherry-red spots are not unique to G_M1 gangliosidosis. In addition to G_M1 gangliosidosis, mucolipidosis type I, Niemann-Pick disease, Krabbe disease, Tay-Sachs disease, hexosaminidase AB variant, ceroid lipofuscinosis, Farber disease, and sialidosis should be considered in the differential diagnosis of a macular cherry-red spot.

Pearl Question 1 (T/F): A couple has a child with G_M1 gangliosidosis. The mother is currently 11 weeks' pregnant and wants to know if any testing can be performed at this point to determine whether the fetus is affected. The most appropriate response would be to tell her that no testing is available to help make a prenatal diagnosis of G_M1 gangliosidosis at this point.

The correct answer is False: Prenatal diagnosis of G_M1 gangliosidosis by assay of b-galactosidase activity in cultured amniotic fluid or amniotic chorionic villus cells is an established procedure. Therefore, telling this couple that no testing is available to help diagnose G_M1 gangliosidosis in an 11-week-old fetus is incorrect.

Pearl Question 2 (T/F): A 24-year-old man presents with a history of normal early development until age 19 years, when he developed a progressive gait disturbance and dystonia. The physician should reassure the patient that the history is not compatible with a diagnosis of G_M1 gangliosidosis.

The correct answer is False: The adult form of G_M1 gangliosidosis is characterized by normal early development with a variable age of onset of progressive gait or speech disturbance and dystonia. Intellectual deterioration is often unremarkable. The physician should consider the adult form of G_M1 gangliosidosis in the differential.

Pearl Question 3 (T/F): Testing to determine whether a person is a carrier for the G_M1 gangliosidosis gene can be reliably performed by measuring levels of b-galactosidase activity in leukocytes.

The correct answer is False: Since varying degrees of overlap exist between homozygotes without G_M1 gangliosidosis and heterozygote carriers, enzyme diagnosis for heterozygote carriers is not always reliable. Direct gene sequencing provides a more reliable detection method for carriers.

Pearl Question 4 (T/F): An infant with suspected G_M1 gangliosidosis has no macular cherry-red spot on funduscopic examination. This finding indicates that G_M1 gangliosidosis is an unlikely diagnosis in this infant.

The correct answer is False: As many as 50% of infants with G_M1 gangliosidosis have been found to have macular cherry-red spots. Therefore, because many infants with G_M1 gangliosidosis do not have macular cherry-red spots, a diagnosis of G_M1 gangliosidosis is equally likely in an infant without cherry-red spots.

BIBLIOGRAPHY

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• Chamoles NA, Blanco MB, Iorcansky S, et al: Retrospective diagnosis of GM1 gangliosidosis by use of a newborn-screening card. Clin Chem 2001 Nov; 47(11): 2068[Medline][Full Text].
• 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].
• 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].
• 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].
• 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].
• 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].
• Snow TM: Mongolian spots in the newborn: do they mean anything? Neonatal Netw 2005 Jan-Feb; 24(1): 31-3[Medline].
• Suzuki K: Neuropathology of late onset gangliosidoses. A review. Dev Neurosci 1991; 13(4-5): 205-10[Medline].
• 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.
• 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].

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