GM1 gangliosidosis …

Neurogenetic Disorders

Updated 04.19.2025
Released 11.04.1993
Expires For CME 04.19.2028

GM1 gangliosidosis

Authors: Margie A Ream MD PhD, Sarah Mangold DO

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Editor: Andrea Gropman MD

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GM1 gangliosidosis

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Introduction

Overview

GM1 gangliosidosis is a lysosomal storage disorder that causes neurodegeneration. It is due to a deficiency of beta-galactosidase. Three different phenotypes are known, including an infantile variant (type 1), a juvenile form (type 2, consisting of subtypes 2a and 2b), and an adult or chronic form. Morquio B disease results from a genetic variant in beta-galactosidase, but this variant does not result in neurodegeneration. In this article, the authors review the history, pathogenesis, and therapeutic approaches (both current and experimental) for these conditions.

Key points

	• GM1 gangliosidosis is a lysosomal storage disorder caused by deficiency in beta-galactosidase.
	• There are three main phenotypes: infantile, juvenile, and adult.
	• The pathogenesis of GM1 gangliosidosis is multifactorial and includes mitochondrial dysfunction and neuroinflammation.
	• Enzyme activity, single gene testing, and whole exome or genome sequencing can be used to make a diagnosis of GM1 gangliosidosis.
	• Various therapeutic approaches are being considered in GM1 gangliosidosis.

Historical note and terminology

Ganglioside storage diseases are a heterogeneous group of inherited disorders characterized by progressive neurologic deterioration and the intraneuronal accumulation of gangliosides and their complex metabolites.

Landing and colleagues first recognized GM1 gangliosidosis as a distinct entity in 1964 (22). The associated enzymatic deficiency of beta-galactosidase was later identified in the brain, liver, spleen, and kidney as well as in white blood cells shortly thereafter (33).

Clinical manifestations

Presentation and course

	• GM1 gangliosidosis has three distinct phenotypic presentations: an infantile form (type 1), a juvenile form (type 2, with subtypes 2a and 2b), and an adult or chronic form (type 3).
	• Morquio B disease is also due to pathogenic variants in the gene beta-galactosidase but does not cause neurodegeneration.

Type 1. Type 1 is the most severe form leading to rapidly progressive neurologic impairment due to accumulation of GM1 gangliosides. This disease typically presents within the first 6 months of life but can also present with transient or persistent hydrops fetalis in utero (21). Delayed milestones or regression in developmental milestones is one of the first symptoms, along with hypotonia, dyspnea, and nystagmus; also, some are born prematurely. Median age of symptom onset in one cohort was 3 months of age (23). Seizures generally occur after the first 6 months of age and become a predominant feature over time, often medication resistant. Other features include a macular cherry-red spot (observed in about 50% of patients), coarse facies usually associated with the Hurler syndrome phenotype (ie, frontal bossing, depressed nasal bridge, widened upper lip, and large maxilla), gingival hypertrophy, hypotonia, hypoactivity, edema of the hands and face, and hepatosplenomegaly. Infants also display an exaggerated startle response. Skeletal involvement including kyphoscoliosis and beaking of the vertebrae are also present and become more apparent over time. Angiokeratoma corporis diffusum and congenital epidermal melanocytosis in unusual regions (extensive lesions that can be seen on the anterior trunk or the dorsum of hands and feet) are present in some patients. On laboratory analysis, vacuolated lymphocytes and eosinophils are often present (with abnormally sparse and enlarged granules in the peripheral blood smear). Those who survive the first year are generally blind and deaf, with death usually occurring by 2 years of age, with mean overall survival being 23 months, often due to complications such as aspiration pneumonia or cardiomyopathy (08; 23).

Type 2. The late infantile (type 2a) or juvenile (type 2b) forms have a later onset, typically has a slower course, and less skeletal and visceral involvement. Some authors separate type 2a (symptom onset between 7 and 24 months) and type 2b (symptom onset between 2 to 3 years) (23). Affected children are usually free of symptoms during the first year of life. Early neurologic signs include ataxia, dysarthria, hypotonia, and strabismus. These are followed by developmental regression (often with loss of language by 3 years of age), lethargy, progressive spastic quadriparesis, and seizures. Early onset of myoclonus and myoclonic seizures has as well as epileptic spasms have also been reported (14; 23). Seizures are more common in type 2a, manifesting often before the age of 5, and are less common but not infrequent in type 2b (09). In contrast to the infantile form, pseudo-Hurler features (scoliosis, skeletal deformities of the hands, growth delays, progressive joint contractures, coarse facial features, clouding of the corneas, intellectual disability) and hepatosplenomegaly are frequently absent, and skeletal films reveal only mild radiographic changes. Low bone density without pathologic fractures and odontoid hypoplasia can be seen in late infantile disease. More recently, in contrast to type 1 disease, patients with type 2 disease were found to have normal or near normal hearing, lack of hepatosplenomegaly, and absence of cherry-red maculae on fundoscopic exam. Cardiac manifestations have been described, including thickened aortic and mitral valves and aortic root dilation in some patients with type 2b disease (09). The lifespan of type 2 GM1 gangliosidosis is typically between 3 and 10 years, with mean overall survival in a French cohort being 9.1 years of age (23).

Type 3. In the adult (chronic) form, gait disturbance and spinocerebellar symptoms usually begin in adolescence with significant variability in age of onset (range 3 to 30 years). The main clinical signs of dystonia in the neck and extremities, dysarthria, facial grimacing, and parkinsonian features become prominent in adulthood. Visceromegaly, skeletal changes, cherry-red macula, and severe intellectual decline are not associated with this variant (49; 51).

Morquio B disease. Morquio B disease is also due to a pathogenic variant in beta-galactosidase. Unlike GM1 gangliosidosis, Morquio B disease is not associated with neurologic deficits. Instead, Morquio B disease can cause dysostosis multiplex and an excess of keratan sulfate excreted in the urine.

Prognosis and complications

GM1 gangliosidosis is a progressive disorder, and the rate of deterioration is dependent on the clinical subtype. As with most neurodegenerative disorders due to enzyme deficiency, earlier age of onset generally predicts more rapid disease progression.

Clinical vignette

A 7-month-old presented with seizures, edema of the lower extremities, and angiokeratoma over the lower abdomen and legs. He had a swollen scrotum and hepatosplenomegaly. Eye examination revealed a cherry-red spot in the macula. Enzyme studies revealed deficiency of beta-galactosidase, and the diagnosis of GM1 gangliosidosis was made. The patient died at 1 year of age.

Biological basis

	• The pathogenesis of GM1 gangliosidosis is multifactorial but is related to an elevation of gangliosides (especially GM1).
	• Mitochondrial dysfunction and disruptions to neurotransmitter systems contribute to the pathogenesis of GM1 gangliosidosis.

Etiology and pathogenesis

Gangliosides are glycosphingolipids consisting of a hydrophobic ceramide (N-acylsphingosine), which is a hydrophilic oligosaccharide moiety containing one or more sialic acid (N-acetylneuraminic acid) residues. They are major constituents of the outer leaf of neuronal plasma membranes and make up an estimated 10% of total membrane lipids. The highest concentration of gangliosides is in brain gray matter, and GM1, GD1A, GD1D, and GT1B make up more than 90% of the total gangliosides. The functions of gangliosides in the neuron are unclear; they have been postulated to have a role in cell differentiation, in survival and maintenance, in neurogenesis, in cell-to-cell interaction, and as specific receptors.

Under normal conditions, gangliosides (including GM1) are degraded in lysosomes. Beta-galactosidase is necessary to remove the terminal galactose of the GM1 molecule. Prior to enzyme degradation, a sphingolipid activator protein (SAP-1, also called saposin B) located within the lysosome recognizes the membrane-bound GM1 ganglioside, solubilizes it, and forms a water-soluble ganglioside-activator complex (31).

Defective lysosomal degradation of GM1 leads to an increased amount of this ganglioside at the endoplasmic reticulum membranes -- specifically in glycosphingolipid-enriched microdomains (GEMs) that mediate endoplasmic reticulum and mitochondrial connections. The accumulation of GM1 in the GEMs induces depletion of endoplasmic reticulum Ca2+ stores and activation of the unfolded protein response (46). The accumulation of GM1 within the GEMs also disrupts mitochondrial membrane potentials, which causes the activation of the mitochondrial apoptosis pathway (39). It was previously hypothesized that markers of neuroinflammation (such as TNF-alpha, TNF-beta 1, and IL-1 beta), which are known to be increased in GM1 gangliosidosis, played an important role in the pathogenesis of the disease (17). Newer studies have postulated that the pathophysiology of GM1 is driven primarily by alterations to neurodegenerative processes, oxidative phosphorylation, and neuroactive ligand-receptor interactions, which in turn impair neurotransmitter and neuronal circuitry. Neuroinflammation does not appear to be a principle driving factor, in contrast to other neurologic conditions such as X-linked adrenoleukodystrophy (26).

Despite clinical and pathological differences, the genetic defect in GM1 gangliosidosis appears to be a pathogenic variant of a structural gene, GLB1, which codes for beta-galactosidase; this gene is located on the short arm of chromosome 3. The human gene spans greater than 62.5 kb and contains 16 exons. Several variants have been identified in the infantile, juvenile, and adult forms (30; 28; 35; 51). There seems to be an inverse relationship between residual enzyme activity and disease severity as the more chronic course of the juvenile and adult forms of GM1 gangliosidosis appears to correlate with the persistence of higher residual enzyme activity. However, this is not true in all cases. To better predict genotype-phenotype relationships, new computer modeling approaches are being developed (25). It is known, however, that GM1 accumulation is less pronounced in the juvenile type and distinctly more focal in the chronic variant, with neuronal storage of gangliosides predominantly in the basal ganglia and cerebellum and only slight to moderate elevation in the cortex, thalamus, substantia nigra, and brainstem nuclei. This selective neuronal involvement is thought to reflect a more active turnover of gangliosides in the affected areas (50).

Delayed myelination has been observed in pathological studies of children with infantile-onset GM1 gangliosidosis (12). Delayed bone formation has also been described in patients. It has been proposed that the abnormal storage of partially degraded compounds in chondrocytes might explain this delay in bone formation (02).

Diagnostic workup

	• The diagnosis of GM1 gangliosidosis can be suspected based on history and physical exam.
	• Enzyme activity assays and genetic testing establish the diagnosis.
	• Imaging modalities, including MRI or CT of the head, and x-ray of the ribs, long bones, and vertebrae can also be used to help support the diagnosis.

The diagnosis of GM1 gangliosidosis is primarily based on clinical criteria (including history of developmental regression and physical exam findings, such as a cherry-red spot, hypotonia, distinct facies, and hepatosplenomegaly) in addition to the demonstration of deficient activity of beta-galactosidase. However, the use of genetic panels and whole-exome or whole genome sequencing is being increasingly used for diagnosis. Single gene testing and panels can also be used to make the diagnosis of GM1 gangliosidosis. Panels that include GLB1, including several leukodystrophy and ataxia gene panels, can be found at the genetic testing registry offered by the NIH https://www.ncbi.nlm.nih.gov/gtr/.

In addition to genetic testing, enzyme activity assays can be used as a screen for GM1 gangliosidosis. Most enzyme activity assay systems measure the capability of enzyme-containing samples (such as serum, peripheral blood leukocytes, cultured fibroblasts, or amniotic fluid) to hydrolyze a synthetic substrate, such as glycosides of 4-methyl-umbelliferone or p-nitrophenol (41). However, these assays can have false negatives and false positives (16).

MRI of the brain may show nonspecific changes in the gray matter, except in adult variants in which there are bilateral symmetrical high-intensity lesions in the putamen on T2-weighted and proton-density images (48). Thalamic hyperdensities on CT have been observed in the infantile form (20). The combination of hyperintensity of T2-weighted signal of the white matter and the basal ganglia on MRI suggests the diagnosis of GM1 gangliosidosis, although these findings are nonspecific and have been found in GM2 gangliosidosis as well (44). Cerebellum, cortical, corpus callosum, and brainstem atrophy have also been described in type 2 disease, which were shown to worsen over time on repeat MRIs (09). Magnetic resonance spectroscopy, when used, can demonstrate an increase in choline (both glycerophosphorylcholine and phosphocholine) and a decrease in N-acetylaspartate (when normalized to creatine) within the thalamus (38).

Additional clues to the diagnosis of early forms of GM1 include radiographic alterations of ribs and long bones (wide in the center and tapering at the ends) or beaking and hypoplasia of vertebrae. Biopsies of bone marrow, skin, conjunctiva, and rectum can reveal the presence of stored material and foam cells containing periodic acid-Schiff–positive droplets in their cytoplasm. Other hints to the diagnosis include isolated elevation in serum aspartate transaminase. It should be noted however, that this can also be seen in GM2 gangliosidosis (19).

In addition to the above tests, new techniques to find novel serum and CSF biomarkers for GM1 gangliosidosis are currently under investigation. This includes using nuclear magnetic resonance spectroscopy to identify abnormalities in the number of amino acid and lipid metabolites in the serum and CSF (36). In addition, using the novel MRI technique differential tractography, fiber tract loss over time was found to correlate with clinical symptom severity in patients with GM1 and could serve as a potential biomarker of disease burden and progression (24; 52).

Management

	• The treatment of GM1 gangliosidosis is currently symptomatic.
	• New therapies that aim to change the prognosis of this disease are being developed, including gene-targeted therapies.

Outcomes

There is currently no cure for GM1 gangliosidosis, and treatment is largely based on symptoms. Guidelines exist for the care of patients with leukodystrophies (01; 18). Unlike other neurometabolic disorders (ie, globoid cell leukodystrophy or Krabbe disease, MPS I, and MPS II), allogeneic bone marrow transplantation performed early in life has not been successful in altering the clinical course in either a canine model or a patient with presymptomatic juvenile-onset GM1 gangliosidosis (32; 42). There are, however, several different therapies under investigation, including substrate reduction therapy (SRT), chaperone-mediated therapies (CMT), enzyme replacement therapy (ERT), stem cell transplantation, and gene therapy, which could potentially change the prognosis of this disease. Additional treatment strategies include gene editing, as CRISPR/Cas-adenine base editing has been shown to normalize beta-galactosidase in vitro (37).

SRT. SRT uses inhibitors to reduce the buildup of toxic metabolites. One such inhibitor being explored is NB-DNJ (miglustat) and NB-DGJ. These agents, which can cross the blood-brain barrier, reduce the production of GM1 ganglioside through inhibition of ceremide glucosyltransferase. SRT strategies are limited, as they can only prevent the formation of new substrates and do not have the capability to degrade substrate that has already accumulated (13).

CMT. Pharmacological chaperones are molecules that aim to enhance the activity of a dysfunctional enzyme and are under investigation for the treatment of several lysosomal storage disorders (03).

These compounds are classified into different chemical classes, including sugar derivatives, iminosugars, 4-epi-isofagomine derivatives, and valienamine derivatives. It is important to note that the effects of CMT are genotype specific. For example, galactose was shown to be an effective chaperone in adult GM1 gangliosidosis fibroblasts in patients with the mild pathogenic variant p.R442Q (05). In contrast, the iminosugars, N-butyl deoxynojirimycin (NB-DGJ), and fluorous iminoalditol (DLHex-DGJ) enhance the catalytic activity and localization of beta-galactosidase in some mild alleles of GLB1 (10; 40; 11; 45). Five new trihydroxypiperidine iminosugars have been investigated and have demonstrated enhancement in B-Gal enzyme activity (07). A more comprehensive list of chaperones and genotype information can be found in the article written by Rha and colleagues (38).

ERT. To date, ERT has not been successfully used to treat GM1 gangliosidosis in humans. However, there are ongoing efforts to improve delivery of recombinant human beta-galactosidase to the brain using intracerebroventricular injections (06), as well as intravenous administration where enzymes have been fused to antibodies for transferrin, a method that has demonstrated crossing the blood brain barrier in a mouse model for mucopolysaccharidosis I (13). This same mechanism of enzyme fused to antibodies for transferrin has been used to assist blood-brain-barrier penetration for patients with MPS II, with additional investigation ongoing into the insulin receptor as an additional target for CNS penetration (43; 34). In addition, studies are being conducted to determine the optimal timing of beta-galactosidase replacement to prevent potential side effects (27).

Stem cell transplantation. Stem cell therapy, both of donor stem cells and genetically modified cells, have been implemented in other lysosomal storage disorders; however, CNS penetration poses challenges for GM1, though there has been some neural enzyme activity noted in preclinical mouse models. Migration of stem cells to the brain is thought to occur due to a chemokine gradient. BMT has been trialed in a 7-month old with juvenile GM1; however, no significant changes to disease progression were observed (13).

Gene therapy. Gene therapy treatments are being developed for GM1 gangliosidosis and have demonstrated reduction of GM1 in both peripheral organs and the CNS, increased lifespan, and restoring enzyme activity (15). There are currently three gene therapy trials underway. The first trial, NCT03952637, started in 2019 and uses adeno-associated virus (AAV) serotype 9 to deliver the human GLB1 gene via an intravenous injection. This trial is still ongoing. In NCT04273269, which started in 2020, AAV serotype rh 10rh10 is being used to deliver the human GLB1 gene via an intracisternal magna (ICM) injection. This trial was terminated before completion due to financial cessation of Lysogene’s activities. In NCT04713475, which started in 2021, AAV serotype hu68 is being used to deliver the GLB1 gene via an ICM injection. This trial is ongoing (13).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Margie A Ream MD PhD

Dr. Ream of Ohio State University College of Medicine received consulting fees from Ionis Pharmaceuticals, Inc.
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Sarah Mangold DO

Dr. Mangold of Nationwide Children's Hospital has no relevant financial relationships to disclose.
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Editor

Andrea Gropman MD

Dr. Gropman of St. Jude Children's Research Hospital has no relevant financial relationships to disclose.
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Former Authors

Harvey S Singer MD
Gita Masand PhD
Reuben Matalon MD PhD
Lisvania M Delgado-Pena MD
Brianna M Young MS2
Dena Rae Matalon MD
Raphael Schiffmann MD
Alex Sunshine MD PhD
Erika Fullwood Augustine MD MS

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity typical

heredity may be a factor

autosomal recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: GM1 gangliosidosis: E75.1
ICD-11: Gangliosidosis: 5C56.00
OMIM: Generalized GM1 gangliosidosis, infantile type: #230500

Generalized GM1 gangliosidosis, juvenile type: #230600

Generalized GM1 gangliosidosis, adult type: #230650

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GM1 gangliosidosis

Associated Disorders

Beta-galactosidase deficiency
Cherry-red spot retinopathy
Dementia
Dysarthria
Dysostosis multiplex
- Dystonia
- Ganglioside storage disease
- Hepatosplenomegaly
- Kyphoscoliosis
- Progressive spastic quadriparesis

Differential Diagnosis

metabolic dysfunction
chronic infection
vasculopathy
toxic encephalopathy
neoplasia
- Niemann-Pick disease
- Gaucher disease
- MPS-1H
- Hurler syndrome
- fucosidosis
- mannosidosis
- Niemann-Pick A
- Niemann-Pick B
- Tay-Sachs disease
- metachromatic leukodystrophy
- disorders of sialic acid metabolism
- leukodystrophies
- neuronal ceroid lipofuscinosis
- atypical late GM2 gangliosidosis
- mitochondrial disorders
- sialidosis
- Alpers syndrome

GM1 gangliosidosis …

GM1 gangliosidosis

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

Cockayne syndrome

GM2 gangliosidoses

Levacetylleucine

HHH syndrome

Hyperargininemia

Citrullinemias types 1 and 2

Ornithine transcarbamylase deficiency

Carbamoyl phosphate synthetase 1 deficiency

GM1 gangliosidosis

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Cockayne syndrome

GM2 gangliosidoses

Levacetylleucine

HHH syndrome

Hyperargininemia

Citrullinemias types 1 and 2

Ornithine transcarbamylase deficiency

Carbamoyl phosphate synthetase 1 deficiency

This is an article preview.
Start a Free Account
to access the full version.