Clinical manifestations

Presentation and course

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

Type 1. Type 1 is the most severe form and results in rapidly progressive neurologic impairment caused by 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 (16). Delayed milestones or loss of milestones is one of the first symptoms. Seizures generally occur after the first 6 months and then become a predominant feature as time goes on. Other features include a macular cherry-red spot (seen in about 50% of patients), coarse facies usually associated with the Hurler phenotype (ie, frontal bossing, depressed nasal bridge, widened upper lip, and large maxilla), an exaggerated startle response, gingival hypertrophy, hypotonia, hypoactivity, edema of the hands and face, hepatosplenomegaly, and vacuolated lymphocytes and eosinophils (with abnormally sparse and enlarged granules in the peripheral blood smear). Skeletal involvement with 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 are present in some patients. Those who survive the first year are generally blind and deaf, with death usually occurring by 2 years of age due to aspiration pneumonia or cardiomyopathy (06).

Type 2. The late infantile or juvenile form has a later onset, typically has a slower course, and shows less skeletal and visceral involvement. Affected children are usually free of symptoms during the first year of life. Early neurologic signs include ataxia, dysarthria, and strabismus. These are followed by regression, lethargy, progressive spastic quadriparesis, and seizures. Early onset of myoclonus and myoclonic seizures has also been reported (10). In contrast to the infantile form, pseudo- Hurler features and hepatosplenomegaly are frequently absent, and skeletal films reveal only mild radiographic changes. Lifespan is between 3 and 10 years.

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 (38; 40).

Morquio B disease. Morquio B disease is also due to a mutation 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 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 neuroinflammation contribute to the pathogenesis of GM1 gangliosidosis.

Etiology and pathogenesis

Gangliosides are glycosphingolipids consisting of a hydrophobic ceramide (N-acylsphingosine), 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. 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 are degraded in lysosomes. Beta-galactosidase is necessary to remove the terminal galactose of the GM1 molecule. Degradation of GM1 occurs in the lysosome. 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 (23).

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 (35). The accumulation of GM1 within the GEMs also disrupts mitochondrial membrane potentials, which causes the activation of the mitochondrial apoptosis pathway (29). In addition to altered cell physiology, markers of neuroinflammation (such as TNF-alpha, TNF-beta 1, and IL-1 beta) are increased in GM1 gangliosidosis (12). The increase in neuroinflammatory markers might be due to a combination of factors, including the proinflammatory nature of gangliosides and increased cell death, although this is not entirely clear (28).

Despite clinical and pathological differences, the genetic defect in GM1 gangliosidosis appears to be a mutation 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 mutations have been identified in the infantile, juvenile, and adult forms (22; 20; 26; 40). 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 (18). 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 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 ganglioside in the affected areas (39).

Delayed myelination has also been noted in pathological studies of children with infantile-onset GM1 gangliosidosis (09). It has been proposed that the abnormal storage of partially degraded compounds in chondrocytes might explain the delayed bone formation in patients with GM1 gangliosidosis (02).

Epidemiology

• GM1 gangliosidosis occurs in people of all ethnicities, but certain populations have a higher prevalence and carrier frequency.

GM1 gangliosidosis is estimated to have an incidence of 1:100,000 to 1:200,000 live births. Although GM1 gangliosidosis occurs worldwide, certain populations have a higher prevalence of some forms of the disease. In Malta, GM1 gangliosidosis has a prevalence of 1 in 3700 live births. The carrier frequency is also higher in Japan, Southern Brazil, Cyprus, and in the Rudari and Roma people of Eastern Europe (21; 28). All variants are transmitted as autosomal recessive traits.

Prevention

• Prevention can be achieved through carrier testing and preimplantation genetic diagnosis.

Carrier detection for genetic counseling, preimplantation genetic diagnostic testing, and prenatal fetal diagnostics are available. Enzyme activity levels are not specific for the diagnosis of GM1 gangliosidosis because there is overlap in activity between affected individuals and carriers. Targeted variant analysis when there is a known genetic diagnosis in a family is sensitive and specific to the diagnosis.

Differential diagnosis

Confusing conditions

Progressive psychomotor deterioration may be caused by numerous pathogenetic processes, including metabolic dysfunction, chronic infection, vasculopathy, toxic encephalopathy, and neoplasia. Hepatosplenomegaly, present in the infantile form of GM1 gangliosidosis, could also suggest a systemic disorder of sphingolipid (such as Niemann-Pick disease or Gaucher disease), mucopolysaccharide (MPS-1H, Hurler syndrome), or glycoprotein metabolism (fucosidosis, mannosidosis). Cherry-red spot retinopathy could also indicate several other diseases, including Niemann-Pick A and B, Tay-Sachs, metachromatic leukodystrophy, or disorders of sialic acid metabolism (36). In children whose symptoms appear in the late infantile or juvenile period, the differential diagnosis includes leukodystrophies, neuronal ceroid lipofuscinosis, atypical late GM2 gangliosidosis, mitochondrial disorders, sialidosis, and Alpers syndrome.

Beta-galactosidase-1 deficiency is seen in patients with Morquio B disease. However, it should be noted that neurodegeneration does not occur in Morquio B disease.

Diagnostic workup

	• The diagnosis of GM1 gangliosidosis depends on history and physical exam.
	• Enzyme activity assays and genetic testing are also useful in establishing a diagnosis.
	• Other 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 establish a diagnosis.

The diagnosis of GM1 gangliosidosis is primarily based on clinical criteria (including history of regression and physical exam findings, such as a cherry-red spot, hypotonia, distinct facies, and hepatosplenomegaly) and the demonstration of deficient activity of beta-galactosidase. It should, however, be noted that the use of genetic panels and whole-exome sequencing is increasingly being used to make the 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 (31). However, these assays can have false negatives (11).

When patients with GM1 gangliosidosis are imaged, MRI of the brain usually shows nonspecific changes in the gray matter, except in the adult variant in which there are bilateral symmetrical high-intensity lesions in the putamen on T2-weighted and proton-density images (37). Thalamic hyperdensities on CT have been found in the infantile form (15). 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 (33). 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 (28).

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 (14).

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 (27).

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; 13). Unlike other neurometabolic disorders (ie, Krabbe, 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 patient with presymptomatic juvenile-onset GM1 gangliosidosis (24; 32). There are, however, several different therapies under investigation, including substrate reduction therapy (SRT), chaperone-mediated therapies (CMT), enzyme replacement therapy (ERT), and gene therapy, which could potentially change the prognosis of this disease.

SRT. SRT uses inhibitors to reduce the buildup of toxic metabolites. One such inhibitor being explored is miglustat. Miglustat reduces the production of GM1 ganglioside through inhibition of glucosylceramide synthase.

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 mutation p.R442Q (04). 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 (07; 30; 08; 34). A more comprehensive list of chaperones and genotype information can be found in the article written by Rha and colleagues (28).

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 (05). In addition, studies are being conducted to determine the optimal timing of beta-galactosidase to prevent potential side effects (19).

Gene therapy. Gene therapy treatments are being developed for GM1 gangliosidosis. 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 10 is being used to deliver the human GLB1 gene via an intracisternal magna (ICM) injection. This trial is ongoing. In NCT04713475, which started in 2021, AAV serotype hu68 is being used to deliver the GLB1 gene via a ICM injection. This trial is ongoing.

Special considerations

Pregnancy

The effect of pregnancy on the adult type of GM1 gangliosidosis is unknown.