Tay-Sachs Disease

Tay-Sachs disease is an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancelysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. This disease is highly prevalent in the Ashkenazi Jewish population. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Diagnosis is made by measurement of hexosaminidase A and beta-hexosaminidase enzyme activity. Currently, there is no cure for this disease, and treatment is aimed at improving the patient’s quality of life.

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Overview

Etiology

Tay-Sachs disease is a lysosomal storage disorder caused by a deficiency in the hexosaminidase A (Hex-A) enzyme. 

  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of the HEXA gene (15q23-p24) 
  • > 130 HEXA gene mutations have been identified.
  • Autosomal recessive 

Classification

Tay-Sachs disease is classified into 3 variants based on age of onset and enzyme activity.

  • Infantile, classic acute:
    • Most common
    • Type I GM2 gangliosidosis
    • < 0.1% of normal Hex-A enzyme activity
  • Juvenile onset, subacute:
    • Rare
    • Type III GM2 gangliosidosis
    • 1% of normal Hex-A enzyme activity
  • Adult onset:
    • Very rare
    • Chronic GM2 gangliosidosis
    • < 10% of normal Hex-A enzyme activity

Epidemiology

  • In the general population: 
    • Incidence: 1 in 320,000 live births
    • Carrier rate in the general population: 1 in every 250–300 people.
  • Higher prevalence in those of Central and Eastern European or Ashkenazi Jewish descent:
    • 100 times more prevalent in Ashkenazi Jewish individuals
    • 1 in every 29 Ashkenazi Jewish individuals in the United States and 1 in every 60 Moroccan Jews carry HEXA mutations.
  • Other populations with high carrier rates:
    • Old Order Amish in Pennsylvania
    • French Canadians in Quebec
    • Individuals of Cajun descent in Louisiana
    • Those with Irish ethnicity

Pathophysiology

  • Inadequate activity of Hex-A → accumulation of the cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane glycolipid GM₂ ganglioside in the neuronal lysosomes 
  • This leads to cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death → progressive neurodegeneration
Lysosomal storage pathway for tay-sachs disease

The lysosomal storage pathway:
Tay-Sachs disease results from hexosaminidase A deficiency, resulting in a build-up of GM2 ganglioside.

Image by Lecturio. License: CC BY-NC-SA 4.0

Clinical Presentation

Tay-Sachs disease is a neurodegenerative disorder with a variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables clinical presentation depending on the variant.

Infantile, classic acute Tay-Sachs disease

  • Time course:
    • Normal appearance at birth
    • Onset by 5 months of age
    • Rapid disease progression
    • Death by 4 years of age, often due to pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
  • Signs and symptoms:
    • Exaggerated startle reaction to sounds (hyperacusis)
    • Unusual eye movements
    • Blindness
    • Macular “cherry-red” spot on fundoscopic exam
    • Progressive hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
    • Muscle weakness
    • Hypotonia → spasticity
    • Myoclonic jerks
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Difficulty swallowing
    • Paralysis
Cherry-red spot

Cherry-red spot:
The macula is normally red. Pallor develops around the red macula due to glycolipid accumulation, giving the appearance of a cherry-red spot. The spot usually develops by age 1 in Tay-Sachs disease, and can also be found in other lysosomal storage disorders.

Image: “Cherry red spot” by Jonathan Trobe, M.D. License: CC BY 3.0

Juvenile onset, subacute

  • Time course:
    • Increased heterogeneity of disease 
    • Onset between 2 and 10 years of age
    • Slow disease progression
    • Death by age 15, often due to pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
    • Some cases may be aggressive, resulting in death in 2‒4 years.
  • Signs and symptoms:
    • Deterioration of gait:
      • Clumsiness
      • Incoordination (ataxia)
    • Worsening cognition and speech
    • Blindness due to: 
      • Optic atrophy
      • Retinitis pigmentosa
    • Frequent infections
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures

Adult onset, chronic

  • Time course:
    • Heterogeneity in phenotype and progression of disease
    • Onset from adolescence to anytime in adulthood
    • Death in the 5th‒6th decade of life
  • Signs and symptoms:
    • Subtle clumsiness
    • Progressive muscle weakness
    • Ataxia
    • Tremor
    • Dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia
    • Dysarthria
    • Dyskinesis
    • Choreoathetosis
    • Psychosis 
    • Proximal muscle wasting and weakness

Diagnosis and Management

Diagnosis

Testing is pursued following clinical suspicion. Prenatal screening is also possible via chorionic villus sampling or amniocentesis.

  • Hex-A assay: identification of low to no levels of Hex-A and normal to elevated levels of beta-hexosaminidase
  • Molecular genetic testing: confirms HEXA gene mutations

Management

There is no cure for Tay-Sachs disease. Management is supportive, focused on controlling symptoms and improving quality of life.

  • Medications to control seizures and treatment of psychosis in adults
  • Nonmedical and supportive care:
    • Protect airway and provide respiratory support:
      • Manage chest congestion with chest physiotherapy.
      • Oxygen administration
      • Tracheostomy tube when at risk of aspiration
      • Assisted ventilatory support based on expected disease course and family preference
    • Proper nutrition and hydration:
      • High-calorie diet with semisolid or puréed food (administer via gastrostomy tube, if necessary)
      • Special techniques and strategies for nursing infants
      • Percutaneous endoscopic gastrostomy
    • Physical therapy to improve motor skills and decrease spasticity
  • Other therapeutic modalities in development:
    • Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow transplant
    • Enzyme-replacement therapy
    • Enzyme-enhancing therapy
    • Cell transplantation
    • Substrate-reduction therapy
    • Gene therapy

Differential Diagnosis

  • Sandhoff disease (SD): a lysosomal storage disorder caused by a deficiency in both Hex-A and B. Juvenile SD is characterized by progressive neurodegeneration starting at the age of 6 months. Clinical manifestations are similar to infantile Tay-Sachs disease, including hyperacusis, macular cherry-red spot, blindness, and seizures. Organomegaly and skeletal abnormalities are distinct from Tay-Sachs disease. Diagnosis is made by measurement of Hex-A and B as well as genetic analysis. Management is supportive. 
  • Niemann-Pick disease Niemann-Pick disease Niemann-Pick disease (NPD) is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation. Type A and type B result from mutations in the SMPD-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type C results from NPC1 or NPC2 gene mutations, which are needed for intracellular transport of lipids. Niemann-Pick Disease type A (NPD-A): a lysosomal storage disorder caused by an acid sphingomyelinase enzyme deficiency. The disease is characterized by progressive neurodegeneration starting within a few months of life and resulting in death by age 3. Clinical manifestations are similar to Tay-Sachs disease, including a macular cherry-red spot, difficulty feeding, loss of motor skills, and hypotonia. The presence of organomegaly distinguishes NPD from Tay-Sachs disease. Diagnosis includes measurement of sphingomyelinase enzyme activity and genetic testing. Management is supportive. 
  • Pompe disease (glycogen storage disease II): a lysosomal and glycogen storage disorder caused by acid alpha-glucosidase (GAA) deficiency. There are 3 types of Pompe disease, with variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables onset and presentations. Clinical manifestations include failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive, feeding difficulty, hypotonia, progressive muscle weakness, hypertrophic cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. Hypertrophic Cardiomyopathy, and respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure. The diagnosis is made by measuring enzyme activity and molecular gene analysis. Management includes supportive measures and enzyme replacement.
  • Fabry disease Fabry disease Fabry disease (FD), also known as Anderson-Fabry disease, is an X-linked recessive lysosomal storage disorder and the 2nd most common of the lysosomal storage disorders. Fabry disease is caused by a deficiency in the alpha-galactosidase enzyme (alpha-Gal A), resulting in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in lysosomes. Fabry Disease: a lysosomal storage disorder caused by alpha-galactosidase A (GLA) deficiency. The deficiency results in glycophospholipid deposition in the vascular endothelium and smooth muscle cells. Clinical manifestations include paresthesias involving the hands and feet, purplish skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions (angiokeratomas), decreased sweating, cardiovascular complications, and renal disease. Diagnosis is made with measurement of GLA enzyme activity. Management includes supportive measures and enzyme replacement.
  • Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease (GD): a lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebrosidase. Infantile GD presents within 6 months of life with progressive neurodegeneration, loss of motor skills, hypotonia, feeding difficulties, and death before the age of 3 years. Hepatosplenomegaly makes GD distinct from Tay-Sachs disease. Diagnosis is made by measurement of acid beta-glucosidase activity and confirmed with genetic analysis. Management is supportive.

References

  1. Sutton, V.R., and Meng, L. (2021). Gene Interpretation: HEXA (Tay-Sachs disease gene). In Wilkins-Haug, L., and Slavotinek A. (Eds.). UpToDate. Retrieved May 13, 2021, from https://www.uptodate.com/contents/gene-test-interpretation-hexa-tay-sachs-disease-gene
  2. Ramani, P.K., Sankaran, B.P. (2020). Tay-Sachs Disease. Stat Pearls. Retrieved May 13, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK564432/
  3. Takeda, K., et al. (1990). Fine interpretation of beta hexosaminidase A alpha subunit on 15q23-q24. Tohoku J Exp Med. 160(2), 203–211. https://pubmed.ncbi.nlm.nih.gov/2141199/
  4. National Institutes of Health. Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics and Rare Diseases Information Center. Tay-Sachs Disease. Retrieved May 13, 2021, from https://rarediseases.info.nih.gov/diseases/7737/tay-sachs-disease
  5. Drucker, L., Proia, R.L., and Navon, R. (1992). Identification and rapid detection of three Tay-Sachs mutations in the Moroccan Jewish population. Am J Hum Genet. 51(2), 371–377. https://pubmed.ncbi.nlm.nih.gov/1322637/
  6. Demczko, M. (2020). Tay-Sachs disease and Sandhoff disease. MSD Manual Professional Version. Retrieved June 14, 2021, from https://www.msdmanuals.com/professional/pediatrics/inherited-disorders-of-metabolism/tay-sachs-disease-and-sandhoff-disease
  7. Nelson, Jr., S.L., and Gerstein, B.Y. (2018). GM2 gangliosidoses. In Rohena, L.O. (Ed.), Medscape. Retrieved June 14, 2021, from https://emedicine.medscape.com/article/951943-overview#a1

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