Congenital disorders of glycosylation
Mar. 02, 2023
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This article includes discussion of GM1 gangliosidosis, familial neurovisceral lipoidosis, generalized gangliosidosis, Landing disease, pseudo-Hurler disease, Tay-Sachs disease with visceral involvement, infantile variant of GM1 gangliosidosis, juvenile variant of GM1 gangliosidosis, adult variant of GM1 gangliosidosis, and chronic variant of GM1 gangliosidosis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
GM1 gangliosidosis is caused by a deficiency of beta-galactosidase-1. Three different phenotypes are known, with infantile being the most severe. The gene for beta-galactosidase-1 (GBL1) is located on the short arm of chromosome 3, and specific mutations are responsible for the different phenotypes. In this article, the authors cite therapeutic approaches in animal models using chemical chaperones, adeno-associated virus (AAV)-mediated gene therapy, and intracerebral stem cell therapy. Efforts have focused on exploring the effect of various pharmacological chaperones on the activity of the mutant enzyme in the different alleles. Lysosomal storage diseases often manifest with cherry red macular spots. Diagnosis is based on clinical features and specific biochemical and enzymatic patterns. In uncertain cases, genetic testing with next generation sequencing can establish a diagnosis, especially in milder or atypical phenotypes. Research has shown that early-onset genetic testing is being considered among families to interpret potential threats.
• GM1 gangliosidosis is a lysosomal storage disorder. | |
• There are several phenotypes: infantile, juvenile, and adult. | |
• There is a Morquio-like phenotype. |
Ganglioside storage diseases are a group of heterogeneous inherited disorders characterized by progressive neurologic deterioration and the intraneuronal accumulation of gangliosides and their complex metabolites. Landing and colleagues first recognized gangliosidosis as a distinct entity (25). The associated enzymatic deficiency of beta-galactosidase-1 was first identified in the brain, liver, spleen, and kidney and shortly thereafter in white blood cells (37). In 1976, a variant of Morquio disease with spondyloepiphyseal dysplasia, keratan sulfate in urine, and beta-galactosidase-1 deficiency was described (33). Because this enzyme deficiency is different than that in Morquio A disease, the Morquio with beta-galactosidase deficiency has been referred to as Morquio B.
The molecular basis of the phenotypes of beta-galactosidase-1 deficiency has become clearer following the cloning of the GBL1 gene. The gene for beta-galactosidase-1 (GLB1) maps to the short arm of chromosome 3 and contains 16 exons (39). The mutations that give the phenotype of GM1 gangliosidosis are different than those in Morquio B (39). The crystal structure of human beta-galactosidase gives clearer insight regarding the molecular defects of beta-galactosidase and the disease-causing mutations (36).
GM1 gangliosidosis has 3 distinctly different phenotypic presentations: an infantile variant (type 1), a juvenile form (type 2), and an adult or chronic form (type 3). Type I is the most severe form and results in neurologic impairment caused by accumulation of GM1 gangliosides, typically within the first 6 months of life. Other features include a macular cherry-red spot, coarse facies, and hepatosplenomegaly. Vacuolated lymphocytes and eosinophils with abnormally sparse and enlarged granules are characteristic findings in the peripheral smear. In the infantile form, neonates have edema of the face and extremities, are hypotonic and hypoactive, and have facial features usually associated with the Hurler phenotype such as frontal bossing, depressed nasal bridge, widened upper lip, and large maxilla. Corneal clouding is unusual and a cherry-red spot of the macula is present in about 50% of patients. Hepatomegaly and modest splenomegaly are present. Intellectual psychomotor development is initially slow and retarded and then regresses rapidly. Skeletal involvement with kyphoscoliosis and beaking of the vertebrae become more apparent over time. Seizures generally occur after the first 6 months and then become a more dominant feature as time goes on. Angiokeratoma corporis diffusum and unusual mongolian blue spots 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. Cases have also presented with transient or persistent hydrops fetalis (03).
The infantile form is characterized by a rapidly progressive course with severe central nervous system degeneration and death by 1 to 2 years of age commonly due to aspiration pneumonia or cardiomyopathy (11). Abnormal myelination related to a direct metabolic damage on oligodendrocytes has been shown to occur in some animal models of lysosomal storage diseases. This feature contains an infantile-onset in the first months of life, therefore indicating that neuronal storage disorders may be 1 of the primaries responsible for central nervous system hypomyelination (11). Supportive care is typically given because there is no effective treatment of the underlying disorder (26).
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 normal during the first year. Early signs include ataxia, dysarthria, and strabismus. These are followed by mental regression, lethargy, progressive spastic quadriparesis, and seizures. Children with an early appearance of myoclonus and myoclonic seizures have also been reported (15). In contrast to the infantile form, pseudo-duplex Hurler features are absent; there is less hepatosplenomegaly, and skeletal films reveal only mild radiographic changes. The lifespan of a child with the juvenile form is between 3 and 10 years.
In the adult (chronic) form, gait disturbance and spinocerebellar symptoms usually begin in the teenage period (range 3 to 30 years), but the main clinical signs of dystonia in the neck and extremities, dysarthria, facial grimacing, and parkinsonian features become prominent in adulthood. Tanaka and colleagues have reported an 11-year-old with clumsiness since early infancy and dystonia beginning in childhood (54). Visceromegaly, skeletal changes, cherry-red macula, and severe intellectual decline are not associated with this variant (58; 60). Campdelacreu and colleagues have reported a 46-year-old woman with adult onset of dystonia with abnormal magnetic resonance signal in the basal ganglia who was found to have GM1 gangliosidosis (09).
Morquio B disease is not associated with neurologic deficits. Keratan sulfate in urine is excreted in excess as in Morquio A; the dysostosis multiplex seen in Morquio B is similar to that of Morquio A.
GM1 gangliosidosis is a progressive disorder with the rate of deterioration dependent on the clinical subtype.
A 7-month-old presented with seizures, edema of the lower extremities, and angiokeratoma rash over the lower abdomen and legs. He had swollen scrotum and hepatosplenomegaly. Eye examination revealed a cherry-red spot. Enzyme studies revealed deficiency of beta-galactosidase, and the diagnosis of GM1 gangliosidosis was made. The patient died at 1 year of age.
Despite clinical and pathological differences, the genetic defect in all forms of GM1 gangliosidosis appears to be a mutation of a structural gene, GLB1, which codes for acid 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 (31; 29; 41; Suzuki 1992; 60). An alternatively spliced transcript, S-Gal, results from the skipping of exons 3, 4, and 6 with a frameshift due to retention of exon 5. S-Gal has been shown to be the elastin binding protein receptor, which functions as a “chaperone-like” protein for correct targeting of tropoelastin (08). The more chronic course of the juvenile and adult forms of GM1 gangliosidosis appears to correlate with the persistence of higher residual enzyme activity. These increased levels are sufficient to permit embryonic and early postnatal development but ultimately lead to neuronal accumulation of GM1 ganglioside, resulting in clinical symptomatology later in life. It has been suggested that the presence of visceromegaly, dysmorphism, and skeletal involvement is dependent on the extent of residual beta-galactosidase-1 activity for nonganglioside substrates such as keratosulfate-like glycosaminoglycans, asialo-GM1, galactose-oligosaccharides, and glycoproteins (32). Hence, a mutant enzyme deficient in activity for galactose-oligosaccharides and keratosulfate-like glycosaminoglycans would produce visceral accumulation and skeletal manifestations, respectively.
Genotype-phenotype correlation has been studied. More than 100 mutations of the GLB1 gene have been identified. Most patients were compound heterozygous, leading to variability in clinical phenotype (18; 07).
Gangliosides are glycosphingolipids, consisting of a hydrophobic ceramide (N-acylsphingosine), a hydrophilic oligosaccharide moiety, containing 1 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 lipid. The highest concentration of ganglioside 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. The GM1 beta-galactosidase-1 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 (10; 34). In addition to saposin B, the GM1 beta-galactosidase also joins with alpha-neuraminidase, cathepsin A (also known as protective protein), and N-acetylgalactosamine-6 sulfatase (Morquio A enzyme), which combine into a large 1.27 MDa complex (08). Deficiency of the cathepsin A protein results in the combined deficiency of beta-galactosidase-1 and alpha-neuraminidase, which is called “galactosialidosis.” Within this complex, beta-galactosidase-1 recognizes the terminal beta-linked galactose moieties that are removed by hydrolysis.
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 (59).
Delayed myelination has also been noted on pathological studies of children with infantile onset GM1 gangliosidosis (14). It has been proposed that the abnormal storage of partially degraded compounds in chondrocytes might explain the retarded bone formation in patients with GM1 gangliosidosis (01).
Animal models for GM1 gangliosidosis have been described. The dog model has been extensively studied; animal models may be of help with gene therapy experiments. Itoh and colleagues have used targeted disruption of the beta-galactosidase gene (20). Fibroblasts from the knock-out mouse with GM1 gangliosidosis were treated with galactonojirimycin, an analogue of galactose, which restored the mutant enzyme activity in the mouse and human beta-galactosidase-1 deficient fibroblasts (56). Such trials may be carried to human GM1 gangliosidosis patients.
Defective lysosomal degradation of GM1 leads to an increased amount of this ganglioside at the endoplasmic reticulum membranes, where it induces depletion of endoplasmic reticulum Ca2+ stores and activation of the unfolded protein response (55). The GM1 accumulates specifically in glycosphingolipid-enriched microdomains (GEMs) of the mitochondria-associated endoplasmic reticulum membranes. At these GEMs, GM1 interacts with the InsP3 receptor Ca2+ channel and, in turn, leads to mitochondrial Ca2+ overload, ultimately activating the mitochondrial part of apoptosis (45).
GM1 gangliosidosis occurs worldwide, and there does not appear to be a predilection for a particular group. All variants are transmitted as autosomal recessive traits.
Carrier detection for genetic counseling and prenatal diagnosis and preimplantation genetic diagnostic testing are available. It is possible to have variations in the level of enzyme activity, and there could be overlap between normal homozygote and heterozygotes carriers. The level of the enzyme in heterozygotes cannot be relied on in all cases; if the mutations within a family are known, gene diagnosis is more reliable. More and more families are relying on genetic testing, especially those who show early-onset of the disease or other similar ones.
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, might suggest a systemic disorder of sphingolipid (Niemann-Pick disease, Gaucher disease), mucopolysaccharide (MPS-1H, Hurler syndrome), or glycoprotein metabolism (fucosidosis, mannosidosis). A cherry-red spot retinopathy may indicate several gray matter diseases, including Niemann-Pick, Tay-Sachs, or disorders of sialic acid metabolism. 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 needs to be considered in a patient with Morquio phenotype.
The diagnosis of GM1 gangliosidosis is based primarily on clinical criteria and the demonstration of deficient activity of beta-galactosidase-1. Most assay systems measure the capability of enzyme-containing samples (serum, peripheral blood leukocytes, cultured fibroblasts, or amniotic fluid) to hydrolyze a synthetic substrate such as glycosides of 4-methyl-umbelliferone or p-nitrophenol. These substrates, however, will not allow the diagnosis of all variants of GM1 gangliosidosis. For example, when infantile GM1 gangliosidosis is due to deficiency of sphingolipid activator protein-1, diagnostic enzymatic assays use natural substrate or sphingolipid loading tests on cultured skin fibroblasts (48). Normal levels of beta-galactosidase activity have been found in the plasma and serum of a DNA-confirmed case of juvenile GM1 gangliosidosis (19). Exome sequencing has been used to diagnose juvenile onset GM1 gangliosidosis (42). A case with intermediate GM1 gangliosidosis and Morquio B phenotype has been described (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. Microscopically, the presence of stored material can be confirmed in biopsies of bone marrow, skin, conjunctiva, and rectum. These samples reveal foam cells containing periodic acid-Schiff positive droplets in their cytoplasm. MRI scanning 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 (57). Thalamic hyperdensities on CT have been found in the infantile form (23). The combination of hyperintensity of T2-weighted signal of the white matter and the basal ganglia on MRI suggests the diagnosis of GM1 gangliosidosis (and GM2 as well) (50). Site-specific dysmyelinogenesis has been reported in a 15 month old as well as in animal models (21).
In uncertain cases, genetic testing with next-generation sequencing can establish a diagnosis, especially in milder or atypical phenotypes (30). Research has shown that early-onset genetic testing is being considered among families to interpret potential threats (24).
In clinical findings aspartate transaminase was used as a biomarker of neurocytolysis in infantile gangliosidosis. Elevated serum aspartate transaminase was found in all GM1 and GM2 gangliosidosis patients confirming that this biomarker can be used as a biochemical diagnostic clue for patients with gangliosidosis (22).
Genetic diagnosis for GM1 gangliosidosis was possible by combining chromosomal microarray analysis and whole exome sequencing. A study was performed on a family that presented with an autosomal recessive inheritance but the clinical diagnosis was impossible to determine due to the difference in clinical expression that the patients presented at the onset of the disease. The combination of chromosomal microarray analysis and whole exome sequencing allowed the fast diagnosis of 3 patients with juvenile-onset GM1 gangliosidosis by reducing the number of genetic variants to be analyzed (04).
Pharmacological chaperones aimed to enhance the activity of the mutant enzyme are a promising therapy for GM1 gangliosidosis. Such an approach has been successful using miglustat in the treatment of Gaucher disease. Galactose was shown to be an effective chaperone in adult GM1 gangliosidosis fibroblasts in patients with the mild mutation p.R442Q (06). There are several newer classes of chaperones: imino sugars, N-butyldeoxynojirimycin (NB-DGJ), and fluorous iminoalditol DLHex-DGJ. These chaperones have shown enhanced catalytic activity of beta-galactosidase and normalization of transport and lysosomal processing, particularly in mild alleles (12; 47; 13; 53). Another chaperone, N-octyl-4-epi-beta-valienamine (NOEV) stabilizes the mutant enzyme in mild mutations (17; 51). N-nonyl-deoxygalactonojirimycin has enhanced β-galactosidase in lysosomes of patient cell lines with missense mutations (43). NOEV is a very dose-dependent treatment due to its strong inhibitory capabilities, which may endanger its clinical effectiveness. Compound bearing N-cyclohexylmethyl substituent exhibited the best chaperone (8.5-fold activity increase) versus inhibitor ratio, although the result remains to be validated in vivo (44). The use of chaperones can be effective with mild cases because of the residual enzyme activity. Miglustat is still being used with reasonable success in prolonging the life of the patient. This is a FDA approved method of treatment. Promising pharmacological chaperones are being explored by Suzuki and colleagues (52).
Glycomimetic-based pharmacological chaperones for GM1 gangliosidosis have showed significant enzyme activity increases in mouse fibroblasts expressing human GM1 β-Gal variants and GM1 gangliosidosis. An investigation on the effect of the N-alkyl substituent on the chaperoning properties led to the identification of methyl 6-{[N2-(dansyl)-N6-(1,5-dideoxy-D- galactitol-1,5-diyl)-L-lysyl]amino} hexanoate as a potent inhibitor of human lysosomal β-Gal activity (44).
Allogeneic bone marrow transplantation performed early in life has not been successful in altering the clinical course in a canine model (35). Bone marrow transplant from a compatible donor was tried in a patient with presymptomatic juvenile-onset GM1 gangliosidosis. The patient showed no improvement despite successful engraftment and normalization of white cell beta-galactosidase-1 (49).
Gene therapy has previously been shown to be effective in a mouse model of GM1 gangliosidosis with either intravenous administration of an adenoviral vector or intracerebroventricular injection of an adeno-associated virus containing cDNA for β-galactosidase (16).
Although evidence that gene therapy for this condition is effective in a mouse model is a positive step, the mouse brain is 1000 times smaller than that of a human infant and clearly more studies need to be performed should this therapy ever translate to humans. There has been an impressive improvement in long-term clinical effects including mortality, with the mean survival of treated cats greater than 4.7 times that of untreated GM1 gangliosidosis cats (16).
Enzyme replacement therapy is not available yet for GM1 gangliosidosis, which is a form of therapy that has become more acceptable for other lysosomal storage diseases. Peripheral organs have responded favorably to enzyme replacement therapy but the brain has not benefited because of the blood-brain barrier. There are indications that hyaluronidase can facilitate the entry of enzyme to the brain (27). Studies on the uptake and processing of mutant and recombinant GLB1 may be the first step before enzyme therapy for GM1 gangliosidosis is tried (38; 40).
Adeno-associated virus (AAV)-mediated gene delivery has been suggested to correct the enzyme defect in the GM1 gangliosidosis mouse model (05). Baek and colleagues injected AAV vector in the thalamus of mice, which seems to serve as a reservoir for distribution for the mouse brain (02). No such experiments have been performed in humans.
Sawada and colleagues injected mesenchymal stem cells derived from mouse bone marrow mixed with fetal brain cells into the ventricle of newborn mice (46). The stem cell transplantation did not achieve long-term therapeutic effect.
The effect of pregnancy on the adult-type of GM1 gangliosidosis is unknown.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Reuben Matalon MD PhD
Dr. Matalon of University of Texas Medical Branch has no relevant financial relationships to disclose.
See ProfileLisvania M Delgado-Pena MS2
Ms. Delgado of Trinity School of Medicine has no relevant financial relationships to disclose.
See ProfileBrianna M Young MS2
Mrs. Young of Trinity School of Medicine has no relevant financial relationships to disclose.
See ProfileDena Rae Matalon MD
Dr. Matalon of Stanford University has no relevant financial relationships to disclose.
See ProfileRaphael Schiffmann MD
Dr. Schiffmann of Baylor Scott & White Research Institute received research grants from Amicus Therapeutics, Takeda Pharmaceutical Company, Protalix Biotherapeutics, and Sanofi Genzyme.
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