Tay-Sachs disease

Alternate names

GM2 gangliosidosis, type 1; HexA deficiency; B variant GM2 gangliosidosis; Hexosaminidase A deficiency; Hexosaminidase alpha-subunit deficiency (variant B); Sphingolipidosis, Tay-Sachs; TSD; Gangliosidosis GM2 , type 1

Definition

Tay-Sachs disease is a rare inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord. People with Tay-Sachs disease do not have enough of an enzyme called beta-hexosaminidase A. The less enzyme a person has, the more severe the disease and the earlier that symptoms appear.

Forms

There are 3 forms of Tay-Sachs disease, distinguished by the general age of onset: Infantile form

• The most common severe form, with symptoms appearing in the first few months of life.
• Symptoms include a loss of skills learned (regression), seizures, and loss of muscle and mental functions.
• Children with this form do not survive past early childhood.

Juvenile form

• A form with a range of severity, with symptoms appearing any time during childhood (but usually between ages 2 and 5).
• Symptoms include behavior problems, gradual loss of skills, frequent respiratory infections, and seizures.
• People with this form typically do not survive past their teenage years.

Late onset/adult form

• The least severe form, with symptoms appearing in late childhood to adulthood.
• Symptoms may include clumsiness, muscle weakness, psychiatric disorders, and gradual loss of skills, often leading to the need for mobility assistance.
• Intellect and behavior become impaired in some cases. The lifespan varies from shortened to unaffected.

Epidemiology

Tay-Sachs disease is very rare in the general population. The genetic mutations that cause this disease are more common in people of Ashkenazi (eastern and central European) Jewish heritage than in those with other backgrounds. The mutations responsible for this disease are also more common in certain French-Canadian communities of Quebec, the Old Order Amish community in Pennsylvania, and the Cajun population of Louisiana.

Cause

• Mutations in the HEXA gene cause Tay-Sachs disease. The HEXA gene provides instructions for making part of an enzyme called beta-hexosaminidase A, which plays a critical role in the brain and spinal cord.
• This enzyme is located in lysosomes, which are structures in cells that break down toxic substances and act as recycling centers. Within lysosomes, beta-hexosaminidase A helps break down a fatty substance called GM2 ganglioside.
• Mutations in the HEXA gene disrupt the activity of beta-hexosaminidase A, which prevents the enzyme from breaking down GM2 ganglioside.
• As a result, this substance accumulates to toxic levels, particularly in neurons in the brain and spinal cord.
• Progressive damage caused by the buildup of GM2 ganglioside leads to the destruction of these neurons, which causes the signs and symptoms of Tay-Sachs disease.
• Because Tay-Sachs disease impairs the function of a lysosomal enzyme and involves the buildup of GM2 ganglioside, this condition is sometimes referred to as a lysosomal storage disorder or a GM2-gangliosidosis.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

The first symptoms of Tay-Sachs disease may appear from infancy to adulthood, depending on how much beta-hexosaminidase A enzyme activity a person has (if any). In the most common form, the infantile form, infants have no enzyme activity, or an extremely low level (less than 0.1%).

• They typically appear healthy in the newborn period, but develop symptoms within 3 to 6 months of age. The first symptom may be an exaggerated startle response to noise. Infants with this form begin to lose milestones such as rolling and sitting (regression) and develop muscle weakness, which gradually leads to paralysis.
• They also lose mental functions and become increasingly unresponsive to their surroundings. By 12 months of age, they begin to deteriorate more rapidly, developing blindness, seizures that are hard to treat, and difficulty swallowing.
• Infants with this form of Tay-Sachs disease typically do not survive past 4 years of age. The most common cause of death is complications from lung inflammation (bronchopneumonia).

The juvenile form is less common and is characterized by having very little enzyme activity, typically less than 1% of normal activity.

• Depending on exactly how much activity there is, symptoms may begin any time during childhood, most commonly between ages 2 and 5.
• Children with this form often develop frequent infections, behavioral problems, and have more slowly progressive loss of movement control, speech, and mental function. They may also begin to have seizures and lose their vision.
• Children with the juvenile form often spend several years having no responsiveness or awareness before passing away in late childhood or adolescence. Infection is a common cause of death.

The late onset form, sometimes called the adult or chronic form, is also less common and is characterized by having less than 10% of normal enzyme activity.

• Symptoms and severity vary more among people with this form. Symptoms may begin in childhood to adulthood, but the disease is often not diagnosed until adolescence or adulthood.
• Neurological impairment is slowly progressive and may lead to clumsiness and loss of coordination, muscle weakness, tremors, difficulty speaking or swallowing, and uncontrollable muscle spasms and movements.
• Many people eventually need mobility assistance. In some people with this form, the first obvious symptom is a severe psychiatric disorder such as schizophrenia.
• Impaired intellect or dementia may or may not develop. Some people with the late onset form have a shortened lifespan due to the disease, while others do not.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Ataxia
• Blindness
• Cherry red spot of the macula
• Developmental regression(Loss of developmental milestones)
• EEG abnormality
• Global developmental delay
• Hearing impairment(Deafness)
• Hemiplegia/hemiparesis(Paralysis or weakness of one side of body)
• Hyperreflexia(Increased reflexes)
• Increased muscle lipid content(Fat accumulation in muscle fibers)
• Intellectual disability, progressive(Mental retardation, progressive)
• Macrocephaly(Increased size of skull)
• Psychomotor deterioration
• Seizure

30%-79% of people have these symptoms

• Hepatomegaly(Enlarged liver)
• Muscular hypotonia(Low or weak muscle tone)
• Myotonia
• Optic atrophy
• Recurrent respiratory infections(Frequent respiratory infections)
• Spasticity(Involuntary muscle stiffness, contraction, or spasm)
• Splenomegaly(Increased spleen size)

Diagnosis

Acute infantile Tay-Sachs disease should be suspected in infants with the following clinical findings:[1].

• Progressive weakness and loss of motor skills beginning between ages three and six months
• Decreased attentiveness
• An increased or exaggerated startle response
• A cherry-red spot of the fovea centralis of the macula of the retina
• A normal-sized liver and spleen
• Generalized muscular hypotonia with sustained ankle clonus and hyperreflexia
• Onset of seizures beginning around age 12 months
• Progressive macrocephaly with proportionate ventricular enlargement on neuroimaging beginning at age 18 months

Subacute juvenile Tay-Sachs disease should be suspected in individuals with the following clinical findings:

• A period of normal development until ages two to five years followed by a plateauing of skills and then loss of previously acquired developmental skills
• Progressive spasticity resulting in loss of independent ambulation
• Progressive dysarthria, drooling, and eventually absent speech
• Normal-sized liver and spleen
• Onset of seizures
• Progressive global brain atrophy on neuroimaging

Late-onset Tay-Sachs disease should be suspected in individuals with the following clinical findings:

• Onset of symptoms in teens or adulthood
• Progressive neurogenic weakness of antigravity muscles in the lower extremities and frequent falls
• Dysarthria, tremor, and incoordination
• Acute psychiatric manifestations including psychosis (which can be the initial manifestation of disease)
• Isolated cerebellar atrophy on neuroimaging.

HEX A enzymatic activity testing. Testing identifies absent to near-absent HEX A enzymatic activity in the serum, white blood cells, or other tissues in the presence of normal or elevated activity of the beta-hexosaminidase B (HEX B) enzyme

• Individuals with acute infantile TSD have no or extremely low HEX A enzymatic activity.
• Individuals with subacute juvenile or late-onset TSD have some minimal residual HEX A enzymatic activity.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Treatment

• Currently, there is no cure for Tay-Sachs disease, and there is no treatment that stops or slows the progression of the disease.
• Treatment aims to relieve some of the symptoms, manage infections, prevent complications, and increase quality of life as much as possible.
• Treatment for symptoms may include anticonvulsants to control seizures in children, and antipsychotic medications for psychiatric disorders in adults.
• Of note, tricyclic antidepressants are thought to be ineffective, and they may actually inhibit the little enzyme activity that may be present in some people with the disease.
• Preventing complications involves getting adequate nutrition and hydration, preventing airway obstruction, and avoiding severe constipation with food additives, stool softeners, or laxatives.

NIH genetic and rare disease info

• NIH info on Tay-Sachs disease

Tay-Sachs disease is a rare disease.

Tay-Sachs disease Resources
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