Tay-Sachs disease- a case based discussion

Case details

A boy was born normal but started flinching at loud noises (enhanced startle response) at the age of 6 months. The child initially could sit up, but then regressed so that he could not roll over or recognize his parents.

Ophthalmological examination revealed a central red area of the retina surrounded by white tissue (Cherry red spot).

What is the treatment for this disease?

Case Discussion

The child is suffering from Tay Sach’s disease (GM2 Gangliosidosis). The disease is named after the British ophthalmologist Warren Tay who first described the red spot on the retina of the eye, and the American neurologist Bernard Sachs who described the cellular changes of Tay-Sachs and noted an increased prevalence in the Eastern European Jewish (Ashkenazi) population

Basic Concept

Gangliosides have been isolated from the ganglion cells, neuronal bodies, dendrites, spleen and RBC stroma. The highest concentration is found in the grey matter of the brain. Structurally they contain a long-chain fatty acid, alcohol sphingosine, a carbohydrate moiety which is usually glucose/ and or galactose, and at least one molecule of N-acetyl –Neuraminic acid (NANA)(Figure-1). Four important types of Gangliosides are GM-1, GM-2, GM-3, and GD-3.GM-1 is a more complex ganglioside and is known to be the receptor for cholera toxin in the human intestine. Gangliosides are the main components of membranes. They also serve as receptors for circulating hormones and thereby influence various biochemical processes in the cells.

Case details

The GM2 Gangliosidosis also called Tay-Sach’s disease results from the deficiency of ß-hexosaminidase activity and the lysosomal accumulation of GM2 gangliosides, particularly in the central nervous system, causing severe effects (neurodegeneration). The child in the given case was born normal but developed progressive deterioration of the neurological functions. This is characteristic of this disease

Tay-Sachs disease

Biochemical defect

There is a deficiency of ß hexosaminidase A enzyme. This Lysosomal enzyme removes amino hexose groups from Gangliosides (figure-1), Subsequently, the other components are hydrolyzed by other specific enzymes. In its deficiency, the gangliosides are not degraded thus accumulate in various tissues, especially nervous tissue.

Figure-1- Structure of Ganglioside GM3

[ß-Hexosaminidase occurs as two isozymes: ß-hexosaminidase A, which is composed of one a and one ß subunit, and ß-hexosaminidase B, which has two ß subunits. ß-hexosaminidase A deficiency results from mutations in the a subunit and causes Tay-Sachs disease, whereas mutations in the ß-subunit gene result in the deficiency of both ß-hexosaminidase A and B and cause Sandhoff disease.]

Figure-2- Cherry red spot on the macula

Inheritance

It is inherited as an autosomal recessive trait, with a predilection in the Ashkenazi Jewish population, where the carrier frequency is about 1/25.

Clinical symptoms and Classification

Tay-Sachs disease is classified in variant forms, based on the time of onset of neurological symptoms.

Infantile TSD- patients with this disease are born normal, but they develop loss of motor skills, increased startle reaction, macular pallor and retinal cherry-red spot(Figure-2). Affected children develop normally till the age of 5-6 months, then decreased eye contact, hyperacusis (Exaggerated startle response) to noise are noted. The progressive development of idiocy and blindness are diagnostic of this disease and they are due to wide-spread injury to ganglion cells, in brain and retina. The cherry-red spot about the macula is due to the destruction of retinal ganglion cells exposing the underlying vasculature(Figure-2). Macrocephaly not associated with hydrocephalus may be there. Convulsions are seen in severe cases.

Juvenile TSD- Extremely rare, Juvenile Tay-Sachs disease usually presents itself in children between 2 and 10 years of age. They develop cognitive, motor, speech difficulties (dysarthria), swallowing difficulties (dysphagia), unsteadiness of gait (ataxia), and spasticity. Patients with Juvenile TSD usually die between 5–15 years.

Adult/Late-Onset TSD- A rare form of the disorder, known as Adult Onset Tay-Sachs disease or Late Onset Tay-Sachs disease (LOTS), occurs in patients in their 20s and early 30s. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of LOTS, which present in adolescence or early adulthood, include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly schizophrenic-like psychosis.

Diagnosis

The diagnosis of infantile Tay-Sachs disease is usually suspected in an infant with neurologic features and a cherry-red spot.

Enzymatic Assays-Definitive diagnosis is by determination of the level of ß-hexosaminidase A in isolated blood leukocytes.

Fine needle Aspiration Cytology of brain tissue – can show the degree of neuronal degeneration. FNAC has a great potential for diagnosis and follow-up of Tay-Sachs disease

Prenatal screening-Future at-risk pregnancies for both disorders can be monitored by prenatal diagnosis by amniocentesis or chorionic villus sampling.

Carrier screening– Identification of carriers within families is also possible by ß-hexosaminidase A and B determination. Indeed, for Tay-Sachs disease, carrier screening of all couples in whom at least one member is of Ashkenazi Jewish descent is recommended before the initiation of pregnancy to identify couples at risk. These studies can be conducted by the determination of the level of ß-hexosaminidase A activity in peripheral leukocytes or plasma.

Treatment

No cure for this disease. Symptomatic treatment is given. Enzyme replacement therapy and Gene therapy are under trial. Although experimental work is underway, no current medical treatment exists for infantile TSD. Patients receive palliative care to ease the symptoms. Infants are given feeding tubes when they can no longer swallow. Improvements in palliative care have somewhat lengthened the survival of children with TSD, but no current therapy is able to reverse or delay the progress of the disease.

Prognosis

Prognosis is bad and death occurs in the early years of life.