Tay-Sachs Disease

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

  • Mutation of the HEXA gene (15q23-p24) 
  • > 130 HEXA gene mutations have been identified.
  • Autosomal recessive 


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


  • 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


  • Inadequate activity of Hex-A → accumulation of the cell membrane glycolipid GM₂ ganglioside in the neuronal lysosomes 
  • This leads to cell 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 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
  • Signs and symptoms:
    • Exaggerated startle reaction to sounds (hyperacusis)
    • Unusual eye movements
    • Blindness
    • Macular “cherry-red” spot on fundoscopic exam
    • Progressive hearing loss
    • Muscle weakness
    • Hypotonia → spasticity
    • Myoclonic jerks
    • 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
    • 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

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
    • Dysarthria
    • Dyskinesis
    • Choreoathetosis
    • Psychosis 
    • Proximal muscle wasting and weakness

Diagnosis and Management


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


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 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 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 onset and presentations. Clinical manifestations include failure to thrive, feeding difficulty, hypotonia, progressive muscle weakness, hypertrophic cardiomyopathy, and respiratory failure. The diagnosis is made by measuring enzyme activity and molecular gene analysis. Management includes supportive measures and enzyme replacement.
  • 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 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 (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.


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