Tay-Sachs Disease

Etiology

Tay-Sachs disease belongs to a group of autosomal recessively inherited lysosomal storage disorders called GM2 gangliosidoses. GM2 gangliosides accumulate inside lysosomes, primarily affecting the nervous system and resulting in neuronal dysfunction and neurodegeneration. The other GM2 gangliosidoses are Sandhoff disease and the AB variant.[1]

Tay-Sachs disease is an autosomal recessive disorder caused by a mutation in HEXA, which encodes the enzymes beta-hexosaminidase A. HEXA is located at 15q23. More than 130 mutations have been identified, including single gene deletions, substitution, insertion splicing alteration, duplication, and complex gene rearrangements.[2] Very rare founder variants of Tay-Sachs disease have been identified recently in India.[3]

Epidemiology

Tay-Sachs disease is rare in the general population, and the incidence is about 1 in 100,000 live births in the United States (US), whereas the carrier frequency is about 1 in 250.[4][5] The disease is more frequent in the people of Ashkenazi Jewish heritage. Epidemiological studies on carrier states in the Jewish community in the US showed a prevalence of about 1 in 29 and 1 in 3500 live births affected by Tay-Sachs disease.[6] A Cajun community in Lousiana, an old-order Amish community in Pennsylvania, and non-Jewish French Canadians living near St Lawrence also have a high incidence of Tay-Sachs disease.[1]

Pathophysiology

Tay-Sachs disease is caused by beta-hexosaminidase A (Hex A) deficiency, responsible for GM2 ganglioside degradation. Alpha and beta subunits of Hex A are synthesized at the endoplasmic reticulum. The enzyme is transported to the Golgi network following glycosylation, intramolecular disulfide bond formation, and dimerization in the endoplasmic reticulum. The most important step is posttranslational modification of the enzyme with mannose-6-phosphate, which helps the lysosome recognize the enzyme. The presentation of GM2 ganglioside to the active site of Hex A requires an activator protein GM2A, which makes the enzyme lipophilic.[7][8]

Gangliosides are the major glycolipid of the neuronal cell membrane, ensuring normal cellular activity.[9] Ganglioside expression in the brain is highly region-specific, highly regulated, and correlated with neurodevelopmental milestones, including neural tube formation, neuritogenesis, axonogenesis, synaptogenesis, and myelination. Ganglioside accretion occurs as early as the 10th week of gestation and continues through 5 years of life. Ganglioside expression also plays a significant role in modulating ion channel and receptor signaling, ensuring optimum function and adaption of neuronal circuits involved in neurotransmission, memory, and learning.

However, deficiency of Hex A causes an accumulation of the gangliosides up to toxic levels, especially in the neurons. While it is clear that the accumulation of ganglioside is the cause, the exact mechanism that translates the primary insult into neuronal death is unclear.[10] Progressive neurodegeneration, microglia proliferation, and accumulation of the complex lipids in neuronal macrophages occur.[10] Other pathological processes in the disease include abnormal endosomal transport, impaired autophagy, progressive accumulation of alpha-synuclein, and anti-ganglioside antibodies.[11]

Histopathology

Hexaminidase levels are virtually absent from all the tissues, including plasma and leucocytes. Ganglioside accumulation is seen in all tissues but predominately in the central and autonomic nervous systems and the retina. Patients with acute infantile Tay-Sachs have an excessive accumulation of GM2 ganglioside (at least 12% of dry weight). In contrast, adult forms have less accumulation and may even be restricted to specific regions. For example, the cortex is almost unaffected in adult forms, whereas brainstem nuclei, spinal cord, and hippocampus are markedly affected.[12][13] 

Histopathological examination reveals neurons are ballooned with cytoplasmic vacuoles, constituting lysosomes distended with ganglioside. Sudan Black B and Oil Red O staining are typically positive.[14] Under electron microscopy, a whorled configuration within lysosomes resembling onion-skin layers is the most prominent type seen. GM2 gangliosides accumulate in the retinal ganglion cells, particularly in the margins of the macula, causing cherry-red spots.Ganglion cells are densely packed around the fovea, and swelling in this area leads to a grey-white appearance. In contrast, the center of the fovea lacks ganglion cells, which allows it to maintain a reddish appearance. Toxic accumulation of intralysosomal gangliosides causes early visual symptoms.[14]

History and Physical

Tay-Sachs disease manifests a broad spectrum of clinical features. This disease process has infantile, juvenile, and adult-onset types.

Infantile Tay-Sachs Disease

Infantile Tay-Sachs disease is a prototype of degenerative diseases of grey matter in infancy. The infant is usually normal at birth, and the symptoms start between 3 to 6 months but can manifest as early as 1 week of life.[9] Nonhydrops fetalis can be the initial presentation representing prenatal involvement. The classical initial clinical features are mild motor weakness, irritability, and hypersensitivity to auditory and other sensory stimuli. An exaggerated startle (auditory myoclonus) response is considered an initial and helpful sign in the diagnosis.

A cherry-red spot in the retina visualized during fundoscopic examination is almost a near-specific finding in patients with Tay-Sachs disease (see Image. Tay-Sachs Disease).[15][16] This finding has been noted as early as 2 days of life. The cherry-red spot is due to attenuation of the normal color of the macula and choroid contrasted with pallor produced by the swollen ganglion cells in the remainder of the retina. By 6 months of age, all the patients develop this finding; by 12 to 18 months, vision is reduced; and by 30 months, most patients become blind. Patients also develop narrowing of retinal vessels, nystagmus, and optic atrophy.[17] The child can also have doll-like facies.

Neurological symptoms are the hallmark of Tay-Sachs disease. Infants are usually hypotonic from birth and present with developmental delays or regression by 4 to 6 months of age. Symptoms rapidly progress by 8 to 10 months, spontaneous and voluntary movements diminish, and the infant becomes progressively less responsive.[18][19] The patient also develops seizures by 12 months, typically of the tonic-myoclonic type. Spasticity and seizures mark the final phase of the illness. Myoclonic seizures can be massive and multiple and often refractory to medications, with more than two-thirds of patients needing more than 2 anticonvulsants.[20] Generalized, focal, and gelastic seizures can also occur. Around the same age, the patient also develops ataxia, dyskinesia, sleep disturbances, episodes of screaming, and irritability. By 18 months of age, patients usually develop macrocephaly.[21] Increasing head circumference is due to reactive cerebral gliosis and not hydrocephalus. By 2 years, patients deteriorate and develop decerebrate posturing, dysphagia, and progress to an unresponsive and vegetative state. 

Cardiovascular complications are rare but can occur due to the accumulation of the substrate. Prolonged QT intervals and nonspecific T-wave changes are reported.[22] Hepatosplenomegaly is typically absent in Tay-Sachs disease. Patients often develop infections, and respiratory infections are reported frequently as the cause of death. Interestingly, Tay-Sachs carriers are more resistant to mycobacterial infection, which typically lack alpha units and alpha-beta heterodimer of beta-hexosaminidase, and have increased production of HexB (beta subunit) by as much as 200%. The beta subunit of HexB confers resistance against mycobacterial infection.[23]

Juvenile Tay-Sachs Disease

Juvenile Tay-Sachs disease manifests in early childhood between ages 2 to 10, caused by the reduced activity level of Hex A. The earlier the onset of the symptoms, the more quickly the disease progresses. Early symptoms include incoordination, clumsiness, and muscle weakness. Other common symptoms include ataxia, dysarthria, dysphagia, and the progression of spasticity.[24] A cherry-red spot is not consistently observed. Optic atrophy and retinitis pigmentosa can be observed later in life.[25] A vegetative state with decerebrate posturing occurs by age 10 to 15 and is followed within a few years by death, usually from a respiratory infection. 

Adult Tay-Sachs Disease

Adult Tay-Sachs disease is a very rare disorder, and diagnosis is often delayed at least by 8 years.[26] The adult form is less aggressive, resulting from a small mutation and high residual activity of Hex A, which demonstrates at least 5% to 20% of normal activity. Typical symptoms start in adolescence or early adulthood but can appear later,in those aged between 20 and 30.[27] Affected individuals have several different phenotypes, including progressive lower motor neuron disease, cognitive impairment, psychiatric symptoms or depression, dystonia, and cerebellar symptoms of dysarthria, ataxia, and tremor.[28] Mentation and verbal skills are affected later in the course of illness. Psychiatric features are also common in adult-onset Tay-Sachs disease. About 40% of individuals develop psychiatric manifestations without dementia, including recurrent psychotic depression, hebephrenic schizophrenia with disorganization of thoughts, delusion and hallucination, paranoia, and bipolar symptoms.[29][30] In any patient with psychiatric illness, the presence of cognitive decline or neurological symptoms should raise suspicion of storage disorders.

Evaluation

The classical clinical findings of progressive weakness with developmental delay or regression, inattentiveness, and exaggerated startle response with physical findings of a cherry-red spot, generalized hypotonia with sustained clonus, or hyperreflexia should warrant further evaluation for gangliosidoses. The first step in the evaluation involves the demonstration of Hex A and total Hexosaminidase levels in the serum. Individuals with the infantile form of Tay-Sachs disease have no or extremely low enzyme activity (0% to 5%) in addition to normal or elevated Beta hexosaminidase levels (HEX B isoenzyme). Individuals with juvenile or adult forms have low enzyme activity (10% to 15%). If the initial testing shows reduced enzyme activity and the patient is from an Azheknazi or French Canadian background, consider targeted gene testing.[31]

Genetic Studies

The first step in carrier testing for Ashkenazi Jewish ancestry depends on whether comprehensive Ashkenazi Jewish carrier screening is desired or only Tay-Sachs screening is required.[32] A comprehensive Ashkenazi Jewish carrier panel includes Tay-Sachs, Canavan disease, familial dysautonomia, Gauchers, Bloom disease, Niemann Pick type A and B, Mucolipidosis IV, and Fanconi anemia type C.

Molecular genetic testing includes sequencing, targeted analysis for pathogenic variants, and deletion/duplication analysis. The targeted analysis is performed if the enzyme activity is absent or low on the initial assay. The panel consists of 6 common pathogenic variants. The panel includes 3 null alleles p.Tyr427IlefsTer5, c.1421+1G>C, and c.1073+G>A, which in the homozygous or compound heterozygous state is associated with Tay-Sachs disease. Allele p.Gly269Ser is associated with an adult-onset form of Hex A deficiency. Two pseudodeficiency alleles (p.Arg247Trp and p.Arg249Trp) are not associated with neurological disease but with reduced degradation of the synthetic substrate when Hex A activity is determined in vitro.[33] The test results must be interpreted carefully because the pseudodeficiency allele does not reduce the enzyme activity with the natural substrate in vivo. About 35 % of non-Jewish individuals identified as heterozygotes by Hex A enzyme testing are carriers for the pseudodeficiency allele, whereas it is 2% in the Jewish population.

Prenatal testing on fetal cells can be performed by chorionic villus sampling at 10 to 12 weeks of gestation or by amniocentesis at 15 to 18 weeks of gestation in families where the Hex A enzyme assay shows parents are heterozygous and molecular genetic testing has ruled out a pseudodeficiency allele in either parent. In families with identified pathogenic variants, preimplantation genetic testing is an option.

Imaging Studies

Neuroradiological findings in Tay-Sachs disease are described in 3 phases of the clinical course.[34][35] In the initial phase, cerebral white matter and basal ganglia show hypodensity in computed tomography (CT) and T2 hyperintense signal changes on magnetic resonance imaging (MRI) (see Image. Brain MRI of Tay-Sachs Disease). Caudate nuclei are enlarged and extend into the lateral ventricle in the first and second phases. The brain becomes atrophic in the final phase. The combination of hyperdensity on CT images and T2-weighted hypointense/T1-weighted hyperintense MRI signal involving bilateral thalami suggests Tay-Sachs disease.[36] 

Magnetic resonance (MR) spectroscopy demonstrated an increase in myoinositol/creatinine and choline/creatinine ratio with a decrease in N-acetyl aspartate/creatinine ratio. MR spectroscopy is sensitive and specific to neuroaxonal damage in late-onset Tay-Sachs disease.[37] MR spectroscopy might be a good tool for detecting and quantifying neuronal damage and monitoring the treatment response in patients with late-onset Tay-Sachs disease using pharmacological agents to reduce ganglioside accumulation. Pontocerebellar atrophy is an imaging hallmark of late- or adult-onset Tay-Sachs disease.[38]

Treatment / Management

Treatment of Tay-Sachs disease is largely supportive with the goals of providing adequate nutrition, controlling seizures, managing the infectious sequelae, protecting the airway, and early aggressive physical and occupational therapy. Seizure control usually requires multiple antiepileptics. However, seizures become progressive and change in pattern, so frequent dose changes and initiating new medications are essential. As the child with Tay-Sachs disease becomes more disabled and debilitated, good bowel management becomes essential. Therapeutic modalities for Tay-Sachs disease include enzyme replacement therapy, cell transplantation, substrate reduction therapy, enzyme enhancing therapy, and gene therapy.[4]

Enzyme Replacement Therapy 

Enzyme replacement therapy is a promising option for Tay-Sachs disease. Currently, enzyme replacement therapy is less effective in Tay-Sachs disease due to the inability to cross the blood-brain barrier and prevent neurological complications. Results in a recent encouraging report showed that using a recombinant chimeric protein composed of Hex A linked to 2 blood-brain barrier entry elements (dual trojan horse protein), a transferrin receptor binding sequence, and a granulocyte-colony stimulating factor yielded good outcomes.[39] Another major challenge in enzyme replacement therapy is synthesizing both subunits. The synthetic Hex A is treated with alpha-mannosidase to expose mannose-6 residues on the N-glycans.[40]

Enzyme Enhancing Therapy

Most mutations causing Tay-Sachs disease are not localized to the active site but often cause instability of native folded protein. Strategies to reduce the substrate include using molecules called chaperones to stabilize the enzyme. Interestingly, the pharmacological chaperones used are enzyme-specific competitive inhibitors. A trial of the Hex A inhibitor pyrimethamine demonstrated 4-fold increases in Hex A levels, but clinical benefits are not reported.

Substrate Reduction Therapy

The rationale behind substrate reduction therapy is balancing substrate synthesis with diminished enzyme degradative power. The substrate-reduction drug miglustat (N-butyldeoxynojirimycin) has succeeded in mouse models but not humans. Currently, the US Food and Drug Administration has not approved the use of miglustat in treating Tay-Sachs disease.

Gene Therapy

Since a single disorder causes Tay-Sachs disease, gene therapy is an excellent therapeutic option. Significant progress has been made in developing adeno-associated virus-based vectors.[41][42][43] The major limitation of adeno-based vectors is their capacity to carry constructs. For clinically significant therapy, a vector should carry Hex A isoenzyme, which should carry alpha and beta subunits. Genome editing therapies using zinc-finger nucleases are being explored. There are a few scattered reports of tumor development in mice models kept alive for a prolonged time following gene therapy, so a cautious approach is warranted. Massive efforts are being invested in developing viral vectors to deliver isoenzymes effectively.[40]

Bone Marrow Transplantation

Another breakthrough approach involves transplanting ex vivo modified multipotent neural cells with human HEXA expression produced by retroviral transduction. Overall, adequate production and distribution of Hex A are required for a better therapeutic effect in Tay-Sachs disease. So far, substrate reduction therapy, bone marrow transplantation, and enzyme replacement therapy have shown low efficacy in preventing neurodegeneration. Hence, a combination of multiple therapies at an early age is essential since myelination defects appear early and worsen with time.

Differential Diagnosis

Activator Deficient Tay-Sachs Disease

Activator deficient Tay-Sachs disease (AB variant) is a variant of Tay-Sachs disease with the classical findings of neuroregression, exaggerated startle response, and a macular cherry-red spot without hepatosplenomegaly. This condition should be considered in patients with classical findings of Tay-Sachs disease but with normal Hex A and Hex B levels. Ganglioside accumulation occurs due to the deficiency of the intralysosomal GM2 glycoprotein required for GM2 ganglioside degradation.[44]

Sandhoff Disease and Other Lysosomal Storage Disorders

Sandhoff disease is characterized by progressive neurodegeneration starting at 6 months of life and is associated with hyperacusis, macular cherry-red spots, and blindness. Throughout the clinical course, diagnosis, and management, Sandhoff disease is indistinguishable from Tay-Sachs disease except for the visceral and bone involvement. Hepatomegaly is common in Sandhoff disease. Sandhoff disease is a severe Tay-Sachs disease caused by a HEXB mutation and is usually not limited to any specific ethnic group. Progressive neurodegeneration with cherry-red spots is common in other lysosomal storage disorders, including GM1 gangliosidoses, infantile Gaucher disease, Niemann-Pick disease type A, and galactosialidosis.

Late-Onset Tay-Sachs Disease Differential Diagnoses

The differential diagnosis for late-onset Tay-Sachs disease with neurological findings includes adolescent-onset spinal muscular atrophy, Friedreich ataxia, amyotrophic lateral sclerosis, Kufs disease (adult-onset neuronal cerebral lipofuscinosis), and late-onset forms of lysosomal storage disorders. The differential diagnosis of adult-onset Tay-Sachs with neuropsychiatric manifestation includes hepatolenticular degeneration, Niemann-Pick disease Type C, cerebrotendinous xanthomatosis, ceroid neuronal lipofuscinosis, metachromatic leucodystrophy, and X-linked adrenoleukodystrophy. All the above diagnoses should be considered in young patients with refractory or unusual neuropsychiatric symptom clusters.

Prognosis

Tay-Sachs disease is a progressive neurodegenerative disease. Progressive neurological deterioration occurs, and the resulting seizures often remain refractory to treatment. Even with the best care, patients with infantile Tay-Sachs disease usually die by the age of 4 to 5. Death usually results from recurrent infections. In late-onset disease, there are progressive gait difficulties and motor impairment, which often requires the use of adaptive equipment and mobility assistance. Concomitant psychiatric symptoms often remain resistant to treatment. Progressive neurological deterioration often leads to a vegetative state, and death usually occurs by 10 to 15 years of age.

Complications

The complications include progressive neurological deterioration, spasticity, refractory seizures, and progressive visual impairment, finally leading to a vegetative state. Patients with late-onset disease develop progressive motor impairment and balance issues and are at risk of falls and developing psychiatric symptoms that

may remain resistant to treatment.