Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
This article includes discussion of GM2 gangliosidoses, familial amaurotic idiocy, HEXA deficiency, HEXB deficiency, Sandhoff disease, Tay-Sachs disease, B variant of GM2 gangliosidoses, B1 variant of GM2 gangliosidoses, O variant of GM2 gangliosidoses, and AB variant of GM2 gangliosidoses. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
GM2 gangliosidoses are caused by beta-hexosaminidase deficiency. There are 2 major phenotypes: Tay-Sachs disease, caused by beta-hexosaminidase A deficiency, and Sandhoff disease, caused by beta-hexosaminidase A and B deficiency. In this article, the authors discuss approaches to the diagnosis and treatment of GM2 gangliosidosis. Different phenotypes require special diagnostic approaches. Different phenotypes require special diagnostic approaches. Treatment of GM2 gangliosidosis with substrate synthesis inhibition, enzyme replacement therapy with highly phosphomannosylated enzyme, and pharmacological chaperones are currently being investigated, and new chaperones have been added to the trials.
• Tay-Sachs disease and Sandhoff disease are lysosomal storage disorders.
• Tay-Sachs disease is caused by a deficiency of beta-hexosaminidase A.
• Sandhoff disease is caused by a deficiency of beta-hexosaminidase A and B.
• Carrier detection in risk populations is successful in prevention.
The first clinical description of what is now known as GM2 gangliosidosis occurred in 1881 when a British ophthalmologist, Warren Tay, described a peculiar bright-red macula in a child with mental and physical retardation (58). Bernard Sachs later described the clinical findings and noted the enlarged pyramidal neurons in this disorder, which he called "familial amaurotic idiocy" (52). The ophthalmologist who examined Sachs’ patient used the expression, “cherry-red macula.” The identification of a novel group of sialic acid–containing glycolipids in brains of these patients led to the initial biochemical understanding of Tay-Sachs disease (33). These acidic glycosphingolipids were called "gangliosides" because their highest concentrations in normal brain were found in ganglion cells. GM2 ganglioside is the primary ganglioside stored in Tay-Sachs disease (56). The enzymatic defect in Tay-Sachs disease, a deficiency of the lysosomal enzyme beta-hexosaminidase A, was identified in 1969 (45). Deficiency of beta-hexosaminidase A and B became known as “Sandhoff disease” (53). The genes for each of the beta-hexosaminidase subunits were found to map to different chromosomes; the alpha subunit, encoded by HEXA, localizes to chromosome 15 and the beta subunit, encoded by HEXB, maps to chromosome 5 (08; 12). Knowledge about the molecular genetic aspects of the beta-hexosaminidase enzymes began after HEXA was cloned by Myerowitz and associates (43) and was further advanced when the HEXA and HEXB genomic structures were characterized (49; 48).
Tay-Sachs disease: beta-hexosaminidase A deficiency.
Infantile onset (Tay-Sachs disease). The infantile onset Tay-Sachs disease begins within the first few months of life. The first symptom is an excessive startle response to noise, tactile stimuli, or light flashes. This startle response in patients with Tay-Sachs disease differs from the Moro response of normal infants and consists of a quick extension of the arms and legs, frequently with clonic movements. This exaggerated startle response in Tay-Sachs disease does not attenuate with stimulus repetition. As the disease progresses, motor development slows, and the children are unable to learn to sit. Other motor skills, such as rolling, purposeful hand movements, and head control, are frequently lost. Axial hypotonia, increased extremity tone, and hyperreflexia are common physical signs. Decreased vocalizations and loss of awareness of the environment occur as the disease progresses.
One of the characteristic ophthalmological findings in Tay-Sachs disease is the presence of a macular cherry red spot that occurs in over 90% of infants with this disease. The storage of lipid within the retinal ganglion cells causes a whitish discoloration of most of the retina. The fovea, however, does not contain the bipolar ganglion cells and retains the normal red color, which appears accentuated by the contrasting white retina. The fovea gradually becomes a cherry-brown color, and the retina assumes a yellow-white appearance (32). Because the rod and cone cells in the retina are not affected by lipid, the loss of vision that frequently occurs by the end of the first year is due to cerebral pathology. On electron microscopic evaluation, lipid also appears to be stored within the corneal endothelium (19).
During the second year of life, macrocephaly becomes apparent, presumably caused by intraneuronal storage of gangliosides and other lipids, reactive gliosis, and disturbance of fluid balance. The children may develop seizures that can be induced, on occasion, by auditory stimuli. Nocturnal seizures may present as gelastic (laughing) seizures. Expression of inflammatory mediators in the central nervous system has also been reported. Mucopolysaccharidosis forms are caused by a mutation in any of 11 distinct hydrolases that function in glycosaminoglycan degradation. Ganglioside accumulation has been shown to disrupt lysosomal function, leading to multiorgan failure and death (09). The visceral organs, skeletal structures, and peripheral nervous system are spared in this form of the disorder.
Between 2 and 3 years of age, the children become severely cognitively impaired, decerebrate, blind, and unable to respond to most stimuli. Feeding becomes difficult and constipation is a common problem. Seizures, often complicated by apnea, may worsen. Autonomic disturbances, manifesting as fever, circulatory changes in the skin, and cyanosis, frequently develop. By the age of 4 to 5 years, the children become increasingly cachectic and develop bronchopneumonia. Inflammatory response and increased levels of cytokines TNF-alpha and IL-5 have been reported to contribute to the rapid progression of Tay-Sachs disease (24).
Juvenile (B1) variant. The B1 variant may present as a juvenile form in children who are homozygous for the DN allele (p.Arg178His) (21; 16). Loss of cognition and speech as well as gait disturbances and neurologic deterioration slowly progress in these patients. Patients who are compound heterozygous for the DN allele and another mutation may be more severely affected.
Late-onset. The late-onset (juvenile or adult) variant GM2 gangliosidosis patients, frequently of Ashkenazi Jewish background, have an indolent clinical presentation. Although this variant has been called the "adult-onset variant," the disease usually begins in childhood. Although early gross motor development is normal, these children are often considered clumsy and awkward. An intention tremor, frequently seen in the first decade, may be the first indication of a neurologic problem. Dysarthria also develops early in many patients and difficulties in school may also be apparent. A specific phenotype of late-onset GM2 gangliosidosis, with slowly progressive dystonia and dementia beginning in the first few years of life, has also been described.
During adolescence, proximal muscle weakness begins with fasciculations and atrophy that has an appearance of juvenile-onset spinal muscular atrophy. Development of a broad-based ataxic gait usually follows, making walking even more difficult. Psychiatric symptoms may occur in nearly 50% of patients and include inattention, anxiety, paranoia, suicidal ideation, postpartum depression, catatonic schizophrenia, and occasionally episodes of hallucinations. These patients frequently are able to ambulate with assistance until the sixth decade. Late onset has been expanded with an additional case showing the same manifestations as shown above. Such cases are often difficult to diagnose as Tay-Sach disease because they don’t follow the usual course of Tay-Sach disease. The diagnosis is reached due the curiosity of the clinician (15).
Sandhoff disease: beta-hexosaminidase A and B deficiency (O variant).
Infantile-onset. The age of onset, duration, neurologic symptoms, and ophthalmologic signs in patients with Sandhoff disease are identical to those seen in Tay-Sachs disease. The only clinical differences that may rarely be present in patients with Sandhoff disease are mild hepatosplenomegaly (secondary to storage of globoside) and bony deformities. On bone marrow biopsy, foam cells have been demonstrated in a few patients (34).
Late-onset. A juvenile-onset variant occurs after 1 year of age. These children begin with clumsiness and gait ataxia and later develop dystonic posturing and seizures but do not have the cherry-red macula.
Adult-onset patients follow a similar clinical course to chronic late onset adult forms of beta-hexosaminidase A deficiency. It is expected that new mutations can be discovered in the classic disease and in mild form (30).
GM2-activator deficiency (AB variant).
In rare cases, deficits of the GM2 activator have been known to act as a substrate-specific cofactor for the degradation of GM2 gangliosides by hexosaminidase (10). These patients have similar clinical courses to the infantile-onset Tay-Sachs. The storage of glycolipids and the pathological features are also identical to what is found in the infantile-onset Tay-Sachs disease. The activator deficiency is caused by a small molecular weight protein required for the activation of HexA.
Children with Tay-Sachs disease or Sandhoff disease have a shortened life span, with complications of cachexia and aspiration pneumonia causing death by 4 to 5 years of age. The B1 variant often begins later in the first decade, and despite worsening mental and motor abilities, these children may survive until the end of the second decade. Those with late-onset GM2 gangliosidosis may have a normal life span despite the progressive proximal weakness, ataxia, and possible development of psychiatric symptoms.
Juvenile onset. This 2.75-year-old boy presented for neurologic evaluation because of the development of an uncoordinated gait. He had normal early motor development with sitting at the age of 6 months and standing by 9 to 10 months, but a mild delay in walking that occurred at 16.5 months. Between 24 and 28 months the child developed a problem with balance and gait ataxia. Also at this time the child developed a startle response to loud noise and bright light. Expressive language was mildly delayed, with only 2-word phrases noted by 2.5 years of age. The examination of the eyes showed nystagmus on lateral gaze and evidence of a cherry-red macula on the funduscopic examination.
The child had diffusely increased deep tendon reflexes with bilateral extensor plantar responses. After hearing a loud clap, the child developed a generalized startle response that did not attenuate to repeated stimuli. The gait was wide-based and ataxic, and past-pointing was noted on reaching for objects. MRI of brain was normal, and EEG was slow but without epileptiform discharges. A skin biopsy for electron microscopy demonstrated lysosomal inclusions compatible with a glycolipid storage disease.
Beta-hexosaminidase A activity was markedly reduced to a sulfated artificial substrate. Molecular studies revealed the most common so-called B1 HEXA mutation, p.Arg178His, on 1 allele with another mutation also present.
Tay-Sachs disease is caused by a defect in the alpha subunit of the enzyme beta-hexosaminidase A. Sandhoff disease (O variant) is due to a defect in the alpha and beta subunit, with a resulting deficiency of the beta-hexosaminidase A and B enzymes. The AB variant of GM2 gangliosidosis is the result of a deficiency of the activator protein that permits the enzymatic degradation of GM2 gangliosidosis by beta-hexosaminidase A. All of the variant forms of GM2 gangliosidosis are inherited as an autosomal recessive trait.
The genes encoding the beta-hexosaminidase alpha subunit and beta subunits are similar in structure. The gene for the alpha subunit, known as HEXA, is 35 kb and maps to chromosome 15q23-24, whereas the beta-subunit gene, HEXB, is 45 kb and maps to chromosome 5q11.2-13.3 (57). Both genes have coding regions of approximately 1600 nucleotides, contain 14 exons and 13 introns, and have nearly 60% nucleotide and amino acid homology, suggesting common ancestry (35; 49; 48). The essential promoter element for the HEXA gene is located in a region between 100 bp and 60 bp upstream of the start codon, whereas the promoter element for the HEXB gene is found between 150 bp and 90 bp upstream of the initiation codon (44).
Mutations affecting the HEXA and HEXB genes. There are over 130 mutations in the alpha subunit HEXA (28). The most common mutations are missense mutations, but nonsense mutations, splice-site alterations, single codon deletions, large deletions, and frameshifts due to small deletions and insertions have all been described. The phenotype usually correlates with the less severe allele.
Among the Ashkenazi Jewish population, 3 mutations are predominant:
(1) A 4-nucleotide insertion (TATC) in exon 11(c.1278ins4). This 4-bp mutation accounts for approximately 81% of all HEXA mutations in the Jewish population.
(2) A mutation in intron 12 (c.1421+1G> C) is found in approximately 15% of the Jewish population.
(3) A missense mutation in exon 7, p.Gly269Ser is found in juvenile and adult forms of Tay-Sachs disease (2% of the Jewish population).
Mutations (1) and (2) are characteristic of infantile Tay-Sachs disease. All 3 mutations detect 98% of Jewish mutations and are being successfully used for carrier screening of Tay-Sachs disease among the Ashkenazi population.
In the non-Jewish population, about 32% have mutation 1, common in the Jewish population, the nucleotide insertion in exon 11 (c.1278ins4), and 14% have a splice site mutation that results in a 17 base pair insertion (c. 1073+G> A). In Spain, 32.4% of patients have mutation c.459+5G>A. Patients homozygous for c. 459 +5G>A had the infantile form of the disease, and at least 1 allele of p.R178H led to a milder form (22).
Pseudodeficiency alleles do not cause a disease but are encountered with carrier testing; R247W occurs in 2% of Jewish and 32% of non-Jewish populations, and R249W occurs in 4% of non-Jewish populations.
Targeted mutation analysis includes the panel of 6 mutations mentioned above and is successfully used for carrier testing in risk populations. Some laboratories that screen for Tay-Sachs mutations may include select mutations that occur in high frequency in certain populations. For example, a 7.6-kb deletion at the 5' end of the gene that is found in 80% of the alleles in French-Canadians, the B1 variant caused by a p.Arg178His mutation in northern Portugal, and a GT substitution at the 3' splice site of intron 5 in the Japanese population.
There are over 20 mutations in the HEXB (beta subunit) described in a broad ethnic spectrum of the population (23). A common mutation noted in approximately 50% of patients with Sandhoff disease, especially French and French-Canadian individuals, consists of a 16 kb deletion in 1 or both of the HEXB alleles (34). A CT substitution in exon 11 is associated with a mutation that causes a 3' splice site selection alteration. A mutation of p.Pro504Ser in the HEXB gene, results in inability of the beta-hexosaminidase A enzyme to hydrolyze the natural substrate but not the artificial substrate,
GM2-activator (GM2A) protein and gene. The GM2-activator protein is a 25 kd glycoprotein that is required for the hydrolysis of GM2 ganglioside in vivo and also acts as a general glycolipid transport protein (38). The GM2-activator protein acts as a detergent to form a water-soluble complex between the hydrophobic glycolipid GM2 ganglioside and beta-hexosaminidase A. The functional GM2A gene contains 4 exons and is at least 16 kb in length. The activator protein contains 162 amino acids and is mapped to chromosome 5 (18). Four mutations, consisting of p.Cys107Arg and p.Arg169Pro substitutions, a 1 bp deletion resulting in a frame shift, and a 3 bp deletion resulting in the deletion of Lys88, have been identified in the GM2-activator protein. A pseudogene that does not cause a disease has been identified and localized to chromosome 3.
Pathology. The neuropathologic findings in the GM2 gangliosidoses consist of neurons distended 2 to 3 times the normal size. Histological studies of enlarged neurons reveal storage of a fine cytoplasmic material that pushes the nuclei and Nissel substance to the periphery. On ultrastructural studies, this storage material appears as concentrically arranged lamellar structures known as membranous cytoplasmic bodies. Using serial analysis of gene expression (SAGE) in the cerebral cortex from patients with Tay-Sachs and Sandhoff diseases, it was determined that a large fraction of the elevated genes was related to control of inflammation, which could lead to neuronal loss (42).
Glycolipids and oligosaccharides, which are substrates for either beta-hexosaminidase A or B, are stored in lysosomes in patients with GM2 gangliosidosis. Glycolipids that have a terminal beta-N-acetylglucosamine accumulate in this disorder. GM2 ganglioside is the major glycolipid that accumulates in these patients, but other glycolipids also accumulate.
Sandhoff disease differs from other forms of GM2 gangliosidoses in that globotetraosyl ceramide (globoside) is stored in visceral organs (23). Oligosaccharides that have a terminal beta-N-acetylglucosamine are stored throughout the body in Sandhoff disease only and not in other forms of GM2 gangliosidoses. Urinary oligosaccharide excretion especially is increased in infantile Sandhoff disease.
Induced pluripotent stem cells were generated from 2 patients with Tay-Sachs disease. The dermal fibroblast lines of these patients were obtained and further differentiated into neural stem cells. These neural stem cells were shown to contain the characteristic phenotype that can be useful for the study of the disease pathogenesis and for the evaluation of drug efficacy. It was found that enzyme replacement therapy with recombinant Hex A protein in addition to cyclodextrin and tocopherol significantly reduced the lipid accumulation in a Tay-Sachs disease cell model (63).
Tay-Sachs disease is inherited as an autosomal recessive disorder. People of Eastern or Central European Jewish ancestry have a predilection for this disease, but other populations, specifically French-Canadians, also have a higher than average incidence of the disease. The carrier frequency is estimated to be 1 in 31 (0.032) in the Jewish population and 1 in 277 (0.006) in non-Jewish populations (29).
Carrier testing in high-risk populations (Ashkenazi Jewish) has provided an effective means to identify couples at risk for having an affected infant. Heterozygote screening programs are complicated, however, by benign pseudodeficiency mutations that cause low beta-hexosaminidase A enzyme without clinical disease.
The rare variants that cannot be detected by routine enzyme screening are the AB variant (activator deficiency) carriers, whose levels are within the normal range, and the B1 variant (binding site affinity mutation) carriers, who usually have levels in the low normal range.
Targeted mutational analysis with 6 common mutations can be used for carrier detection in Ashkenazi Jewish populations, and extended mutation panels can be used to detect mutations common in other populations.
Carrier detection and genetic counseling of at-risk populations and prevention of births of children with the disease by alternative reproduction methods, including preimplantation genetic testing, has reduced the incidence of Tay-Sachs disease by more than 90% (28). Lew and colleagues documented further indicators of success of preconception carrier testing, which showed a decline in the expected birth rate of Tay-Sachs disease among Jewish births, and no Tay-Sachs disease in parents that were screened previously (36).
The excessive startle response and cherry-red macula, which are seen early in the course of the infantile variant of GM2 gangliosidosis, may also be present at a later time in patients with GM1 gangliosidosis. In contrast, however, patients with GM1 gangliosidosis also have organomegaly, dysostosis multiplex, and coarsened features. A cherry-red macula may be seen in infants with Niemann-Pick disease, but in this disease a loss of auditory acuity is seen rather than a heightened auditory response. Neuraminidase deficiency or sialidosis, which is also associated with a cherry-red spot, commonly presents with myoclonic seizures and gait disturbance in the second decade of life but is not associated with severe hypotonia and developmental deterioration. In metachromatic leukodystrophy there may be lipid storage within the retinal ganglion cells, but the clinical course is consistent with white matter disease, and an exaggerated startle response and seizures are not present early in the disease presentation.
The late-onset forms of GM2 gangliosidosis have presentations that may resemble progressive dystonia, Kugelberg-Welander syndrome, amyotrophic lateral sclerosis, Friedreich ataxia, and other forms of spinocerebellar ataxia. The early childhood appearance of dysarthria and ataxia may differentiate a chronic form of GM2 gangliosidosis from other disorders.
DNA diagnostic studies are often used together with panel screening Jewish diseases, including Tay-Sachs. Such tests are essential for prenatal diagnosis, preimplantation, and excluding pseudodeficiency state. Enzyme analysis remains an effective means of diagnosing patients with GM2 gangliosidosis in the event DNA testing is non-informative. Beta-hexosaminidase is heat labile, so Tay-Sachs can be differentiated from Sandhoff disease. Beta-hexosaminidases A and B can be tested by means of artificial substrates in either serum or leukocytes. The diagnosis of patients with the AB variant, however, is complicated because they appear to have normal beta-hexosaminidase A and B activity when using an artificial substrate but lack the GM2 activator protein necessary for in vivo degradation of GM2 ganglioside. These AB variant patients can be diagnosed if the natural substrate is tested both with and without the GM2 activator protein, or if CSF is examined for the presence of GM2 ganglioside (50). The B1 variant will not be detected using the usual artificial substrates but will show low activity when tested with the sulfated artificial substrates.
Beta-hexosaminidases A and B. The beta-hexosaminidase isoenzymes can be separated according to their electrophoretic mobility and their thermal and pH stability. The enzyme beta-hexosaminidase A is composed of 1 alpha subunit and 1 beta subunit (alpha-beta), whereas beta-hexosaminidase B is composed of 2 beta subunits (beta-beta). These subunits are incapable of hydrolyzing terminal beta-linked N-acetylhexosamines in the monomeric state and must form a dimer in order to function. The beta-hexosaminidases A and B are active against neutral glycolipids, oligosaccharides, and glycoproteins that contain terminal beta-N-acetylhexosamines, but only beta-hexosaminidase A is capable of hydrolyzing GM2 ganglioside, beta-linked glycosaminoglycans containing glucosamine-6-sulfate, and 6-sulfated artificial substrates.
Neuroradiological studies may be normal early in life; however, the CT brain scans in children with GM2 gangliosidosis eventually show increased density in the basal ganglia and white matter (17). Hyperdensity of the thalami on CT scan and decreased intensity on T2-weighted MRI may be characteristically seen in both Tay-Sachs and Sandhoff disease (11). Increased density on CT scan may later appear in deep cerebral nuclei and in cerebral cortical zones (66). Hypomyelination with diffusely increased signal of the white matter is common in the infantile form of GM2 ganglioside (05). As the disease progresses, MRI demonstrates atrophy with widening of the cerebral sulci and an increase in the ventricular size, and T1-weighted images exhibit hyperintensity in the basal ganglia, thalamus, and cerebral cortex (41). Late-onset forms of GM2 gangliosidosis have prominent cerebellar atrophy, especially of the vermis, but a normal-appearing cerebral cortex on CT or MRI scans (55).
Early EEG in Tay-Sachs disease will frequently show slowing, but when seizures develop multifocal spikes may appear. Nerve conduction velocities are usually normal, but electromyograms in patients with late-onset disease will show evidence of denervation with spontaneous activity (fasciculations, fibrillation potentials, and positive sharp waves) and high-amplitude polyphasic motor units. The electroretinogram is normal.
The CSF in GM2 gangliosidosis does not reveal any abnormality of cell count, protein, or glucose, but GM2 ganglioside is present in large quantities when the CSF is examined by thin-layer chromatography or high-performance liquid chromatography (31).
Urinary oligosaccharides show an abnormal pattern in patients with Sandhoff disease (O variant of GM2 gangliosidosis), a finding that can be used to differentiate this variant from Tay-Sachs disease (B variant) and GM1 gangliosidosis (65).
Electron microscopic analysis of skin, conjunctiva, and rectal mucosa biopsies frequently shows storage of membranous cytoplasmic bodies or other electron-dense storage material within nerve cells and myelinated and unmyelinated axons (62).
There are no effective or approved specific means of treatment for the GM2 gangliosidoses (23). Thus, the management is confined to supportive care and appropriate treatment of associated problems such as seizures and infections. Valproic acid appears to be the most efficacious anticonvulsant, and clonazepam and other benzodiazepines may prove effective in controlling severe irritability and psychiatric symptoms (51). There are no approved treatments for infantile gangliosidoses. Substrate reduction therapy using miglustat has been tried but is limited by gastrointestinal side effects. Development of effective treatments will require identification of meaningful outcomes in the setting of rapidly progressive and fatal diseases (61).
Neuraminidase 3 and 4. In 1 study, Pan and associates demonstrated that 2 mammalian enzymes, neuraminidase 3 and 4, play important roles in catabolic processing of brain gangliosides by cleaving terminal sialic acid residues in their glycan chains (47). In neuraminidase 3 and 4 double-knockout mice, GM3 ganglioside is stored in microglia, vascular pericytes, and neurons, causing micro- and astrogliosis, neuroinflammation, accumulation of lipofuscin bodies, and memory loss, whereas their cortical and hippocampal neurons have lower rate of neuritogenesis. In vitro double-knockout mice also have reduced levels of GM1 ganglioside and myelin in neuronal axons. Neuraminidase 3 deficiency drastically increased storage of GM2 in the brain tissues of an asymptotic mouse model of Tay-Sachs disease, indicating that this enzyme is responsible for the metabolic bypass of β-hexosaminidase A deficiency (47).
Bone marrow transplant. Trials to identify possible effective treatment for GM2 gangliosidoses have been ongoing. Allogenic bone marrow transplantation was performed on a child with Tay-Sachs disease who was 3 years 10 months of age (27). The child continued to show neurologic deterioration, and the natural course of the disease was not changed, although enzyme levels reached heterozygote range. Hematopoietic stem cell therapy in 5 children with GM2 gangliosidoses showed no change in clinical course (07).
Substrate inhibition. Substrate inhibition using N-butyl-deoxynojirimycin (miglustat), which inhibits glycophage lipids synthesis, is being tried with Gaucher disease, Sandhoff disease, and other lipidoses. A human trial with miglustat in 2 patients with infantile Tay-Sachs disease has been reported (06). There was significant drug concentration in the CSF, and macrocephaly was prevented, but the clinical course of the disease did not change. Miglustat was tried in late-onset Tay-Sachs disease and showed no measurable benefits (54). Other attempts to reduce the substrate included using Genz-529468 and NB-DNJ in a mouse model of Sandhoff. The liver size decreased and the motor function and lifespan improved, but the brain GM2 content increased (04). The Sandhoff mice were given intracranial transplantation of neural stem cells (NSCs) with and without intraperitoneal injections of NB-DGJ (02). No additive synergistic effect between NSC and the drug was found.
Enzyme replacement. Enzyme replacement therapy in the Sandhoff mouse model has been tried using a recombinant human HexA (Om4HexA) with a high mannose-6-phosphate (M6P)-type-N-glycan content. Intraventricular administration of the enzyme resulted in decreased concentration of GM2 in the brain and inhibition of chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha). The decrease in central neural storage correlated to improvement of motor dysfunction and prolonged lifespan (60). HexA activity was restored in the brain, and GM2 ganglioside storage was reduced in the Sandhoff mouse (40; 59).
Gene therapy. Intravenous dose of AAV9-HexB in the Sandoff disease mice model has shown better survival results than direct injection in the brain, a more invasive procedure (Walia at al 2015).
Chaperone therapy. Chaperone therapy is 1 of the pharmacological therapies. It allows restoring the metabolic function, to a limited extent, by increasing the quantity of lysosomes when the mutated protein leaks from its natural removal (13). Trials with pyrimethamine (PMT) as a pharmacological chaperone in late-onset Tay-Sachs patients have been conducted (37). Studies showed that a maximum dose of 30 + 24 mg improved HexA levels, speech, and mood, but taking more than the peak dose lead to increased falling (46). Doses of PMT greater than 75 mg lead to increased side effects, whereas the best dose for reduction of HexA was about 50 mg (14). Substrate reduction is being attempted in GM1 and GM2 gangliosidosis, and thus far there has been no clear indication of clinical success (03; 13; 46).
Dysregulation of glutamate receptors has been postulated in the pathology of Sandhoff disease. In a study, an up regulation of a novel form of neuronal pentraxin 1 (NP1-38) in the brains of a mouse model of Sandhoff disease and Tay-Sachs disease was observed (26). In order to determine the impact of NP1 on the pathophysiology of Sandhoff disease mouse models, they generated an Np1−/−Hexb−/− double knockout mouse, and observed extended lifespan, improved righting reflex, and enhanced body condition relative to Hexb−/− mice, with no effect on gliosis or apoptotic markers in the CNS. Sandhoff mouse brain slices revealed a reduction in AMPA receptor-mediated currents and increased variability in total glutamate currents in the CA1 region of the hippocampus; Np1−/−Hexb−/− mice show a correction of this phenotype, suggesting NP1-38 may be interfering with glutamate receptor function (26).
Chondroitin sulfate. It has been found that chondroitin sulfate strongly inhibits the catabolism of membrane-bound GM2 by hex-A in presence of GM2 activator protein in vitro. Some cationic amphiphilic drugs as well as provoking drug-induced phospholipidosis were found to inhibit the hydrolysis of GM2 (01).
Stem cell. Advances in stem cell technology have enabled the generation of disease-specific induced pluripotent stem cells from patient somatic cells. These induced pluripotent stem cells can be differentiated into various types of progenitor cells and mature cells such as neurons, cardiomyocytes, hepatocytes, or retinal pigment epithelial cells for modeling diseases in cell-based assays. In a study neural stem cells differentiated from the patient’s fibroblast dramatically reduced the lipid accumulation (63).
Accumulation of GM2 ganglioside has been observed in 18- to 20-week fetuses (25). Prenatal testing is widely available by means of enzyme analysis of tissue obtained after chorionic villus sampling at 8 to 12 weeks' gestation or later in the pregnancy from cultured cells obtained by amniocentesis. Preimplantation genetic diagnosis is also possible in Tay-Sachs disease using pre-embryo biopsy and gene amplification by polymerase chain reaction (20).
Adults with late-onset forms of GM2 gangliosides do not appear to have problems with fertility and many have children (34).
Although information on this topic is limited, anesthesia does not appear to be a special risk for individuals with GM2 gangliosidoses. In 1 case report, a rectal biopsy was performed without adverse effects, using ketamine-nitrous oxide in conjunction with a lumbar spinal intrathecal block (39).
Reuben Matalon MD PhD
Dr. Matalon of University of Texas Medical Branch has no relevant financial relationships to disclose.See Profile
Lisvania M Delgado-Pena MS2
Ms. Delgado of Trinity School of Medicine has no relevant financial relationships to disclose.See Profile
Brianna M Young MS2
Mrs. Young of Trinity School of Medicine has no relevant financial relationships to disclose.See Profile
Dena Rae Matalon MD
Dr. Matalon of Stanford University has no relevant financial relationships to disclose.See Profile
Raphael Schiffmann MD
Dr. Schiffmann of Baylor Scott & White Research Institute received research grants from Amicus Therapeutics, Takeda Pharmaceutical Company, Protalix Biotherapeutics, and Sanofi Genzyme.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Childhood Degenerative & Metabolic Disorders
Jun. 10, 2021
Childhood Degenerative & Metabolic Disorders
Wilson disease is caused by mutations in ATP7B that result in abnormal copper metabolism, and subsequent excess free copper is toxic. The main clinical categories of neurologic Wilson disease have been traditionally divided variably into tremor, dysarthria, pseudosclerosis (tremor +/- dysarthria), parkinsonism, dystonia, or chorea. The aim of treatment is to reduce the amount of toxic free copper.
Jun. 09, 2021
May. 26, 2021
Childhood Degenerative & Metabolic Disorders
Apr. 12, 2021
Childhood Degenerative & Metabolic Disorders
Smith-Lemli-Opitz syndrome is an autosomal recessive multiple congenital malformation that is associated with intellectual disability. The primary defect
Apr. 09, 2021
Progressive supranuclear palsy (PSP) is a late-onset degenerative disease of the CNS characterized by balance difficulties, vertical gaze palsy, dysarthria, dysphagia, and axial dystonia. Ophthalmoparesis, especially downgaze impairment, is a classic clinical feature of PSP that may appear later in the course of the disorder. Multiple subtypes of PSP have been identified, including the classic Richardson syndrome, progressive supranuclear palsy-parkinsonism (PSP-P), or pure-akinesia-with-gait-freezing (PAGF).
Apr. 07, 2021
Childhood Degenerative & Metabolic Disorders
In this article, the authors review the history of the discovery of phenylketonuria, one of the oldest known inborn errors of metabolism, and review
Apr. 01, 2021
Behavioral & Cognitive Disorders
Mar. 31, 2021