GM1 Gangliosidosis 

Updated: Apr 24, 2018
Author: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Background

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).[1] 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. [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, 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. There are several possible mechanisms by which the gangliosidoses may cause their pathological hallmarks. Accumulation of toxic asialo-compound and lyso-compound GM1 ganglioside derivatives is believed to be neuropathic.[1] In addition, the ganglioside meganeurites and ectopic dendrites could alter the electrical properties of the neuron, leading to neural dysfunction.[10] Recently, inflammation has been investigated as having a major role in pathogenesis and could explain some of the neuronal dysfunction.[11, 10]

Emerging evidence suggests that mitochondrial function may be diminished in lysosomal storage disorders, resulting in alterations in mitochondrial mass, morphology, and function.[12] Altered mitochondrial morphology could lead to a reduced availability of ATP at synapses, leading to some of the impaired neurotransmission and neuronal degradation seen in lysosomal storage disorders.[13, 12]

Epidemiology

Frequency

United States

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.[2]

International

An unusually high incidence of 1 case per 3700 live births has been reported in the population of Malta.[14]

Mortality/Morbidity

The infantile form of GM1 gangliosidosis (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

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.[15, 1]

Sex

All 3 types of GM1 gangliosidosis are inherited as autosomal recessive traits and have equal sex distributions.

Age

The infantile form (type 1) of GM1 gangliosidosis 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.

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 GM1 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.

Lysosomes are cytoplasmic organelles that are found in nearly all animal cells. They contain various active hydrolytic enzymes (hydrolases) that are used to break down biological molecules.

When there is a genetic defect in a lysosomal enzyme, the activity of the enzyme may be altered, resulting in the accumulation of materials meant for degradation.[13] This results in a lysosomal storage disease such as Pompe disease, mucopolysaccharidoses, oligosaccharidoses, Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy.

In addition to ineffective enzymes, there are also disorders that result from deficiency of activator proteins, as in GM2 gangliosidosis.

In the case of GM1 gangliosidosis, gangliosides fail to have their terminal galactose removed, and the deficient activity of β-galactosidase results in accumulation of gangliosides in neurons, causing the brain pathology and neurodegeneration in this disorder.[13]

 

Presentation

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, 16]

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, 17]

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

See the list below:

  • 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 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)[18, 19, 20]

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 GLB1 gene has been isolated and is located on chromosome band 3p21.33. More than 165 disease-causing types of mutations have been identified in the acid β -galactosidase gene, including missense/nonsense, duplication/insertion, and splice site abnormalities.[21] The wide variety in GLB1 mutations causes the variable symptomology in GM1 gangliosidosis, and the severity and age of onset of disease are directly related to the severity of the genetic mutation.[11]

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]

Complications

Patients with GM1 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.

 

DDx

 

Workup

Approach Considerations

Whole exome sequencing (WES) is quickly becoming more clinically available, and, with next-generation sequencing, the rate of throughput has increased exponentially. Previously, WES was avoided owing to its high cost and slow timescale in the return of results. Now that the cost of WES testing is substantially lower and quicker to return results, it has been adopted as a powerful tool in the diagnostician’s arsenal.[22, 23]

Patients with GM1 gangliosidosis present with highly variable symptomology, sometimes complicating diagnosis based on clinical evaluation. Thus, WES should be considered as a primary method of diagnostic evaluation to identify for GLB1 gene mutation. A case report described a girl who presented with progressive neurologic deterioration, macular cherry-red spot, and cornea verticillata. Her clinicians suspected G M1 gangliosidosis, but enzymatic blood testing and β-galactosidase assay returned normal findings. Following a trio WES study, they identified a paternally inherited GLB1 mutation and diagnosed her with G M1 gangliosidosis.[24] Without WES, the complications of the traditional screening panels would have left this case undiagnosed. 

Laboratory Studies

Acid β -galactosidase activity

Diagnosis of GM1 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.[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 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.[25]

Molecular analysis

Molecular analysis of the β -1 galactosidase gene (GLB1) is clinically available.[21, 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 β -galactosidase genotyping

Molecular diagnosis by direct sequencing can be useful for detecting heterozygous carriers and affected patients.[26, 21]

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.[1]

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.[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 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.[1]

In dogs and cats, immunohistochemical methods have been shown to detect GM1 gangliosides before diagnosis could be made using molecular analysis techniques. This technique is useful for retrospective diagnosis of suspected cases of GM1 gangliosidosis postmortem.[27]

 

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 GM1 gangliosidosis; however, no long-term benefit was reported.[28] Presymptomatic cord-blood hematopoietic stem-cell transplantation has been advocated by some as a possible treatment because of success in other lysosomal storage disorders.[29]

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 GM1 gangliosidosis is ongoing but has not advanced to human trials.[2] In cats, AAV gene therapy has shown significant therapeutic benefit, resulting in near-normal function up to 5 years posttreatment.[30]

Researchers at the University of Minnesota are conducting a 5-year longitudinal phase 4 study using a combination of miglustat and the ketogenic diet for infantile and juvenile G M1 gangliosidosis.[31] An Italian study published in June 2017 used miglustat as treatment in three patients with GM1 gangliosidosis (2 juvenile, 1 adult) and showed a reduction of disease progression and, in some measures, reversal of symptoms.[32]

Consultations

See the list below:

  • 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[33]

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 with GM1 gangliosidosis may benefit from physical and occupational therapy.

 

Medication

Medication Summary

Currently, drug therapy is not a component of the standard of care for GM1 gangliosidosis.