Knowledge on rare diseases and orphan drugs

The prevalence of the disease is 1 case per 320 000 live births. It is more common in the Ashkenazi Jewish and French-Canadian populations.

Three forms have been described according to age of onset. The infantile form begins between 3 and 6 months of age for the early infantile (before 12 months) and between 12 and 24 months for the late infantile. The earliest signs are an incessant startle response to noise, and a progressive loss of vision. Psychomotor regression appears during the second semester of life with hypotonia, amaurosis, rapidly pharmaco-resistant epilepsy and progressive macrocephaly. A cherry-red macular spot is nearly always present, strongly evocative even not specific. Muscular weakness progresses and leads to paralysis. The disorder degenerates into a state of decerebration and is fatal during childhood. In the juvenile form, onset is between ages 2 and 10 with progressive cerebellar ataxia, leading to dystonia, behavioral disorders, loss of intellectual capacities, and a state of decerebration and death during the second decade. The late-onset form begins around the age of 10 or later, and is often not diagnosed until adulthood. The onset is insidious with a progressive course. Three initial clinical presentations are described: i) proximal lower limbs weakness with amyotrophy due to a motor neuropathy (mimicking progressive spinal amyotrophy; first complaint: difficulty to climb stairs) that eventually extends to upper limbs and distal parts of the limbs; ii) cerebellar ataxia; iii) more rarely psychotic symptoms with mood disorder. In the course of the disease the motor neuropathy almost always occurs, other motor symptoms may occur (dysarthria, swallowing disorder). Cognition is usually preserved.

The causative gene HEXA encodes the alpha subunit of hexosaminidase A and is located on chromosome 15(15q23).

When Tay-Sachs is suspected, hexosaminidase A enzymatic activity on blood leukocytes is always very low compared to normal values (around 0% for the severe infantile form, around 10-15% for the late-onset form). This should be confirmed by HEXA gene sequencing. The diagnosis may be firstly suggested by pathogenic variants findings from a panel of genes, or exome or genome, and should be confirmed by hexosaminidase A enzymatic activity measurement.

GM2 gangliosidosis, AB variant, may perfectly mimic Tay-Sachs disease due to variants in GM2A gene which codes for a protein that activates hexosaminidase enzyme. In this disease, hexosaminidase A enzymatic activity is normal.

Genetic prenatal and preimplantation testing is available.

There is no specific efficient treatment for Tay-Sachs disease. Treatment is symptomatic.

For the pediatric form of Tay-Sachs, the severity is correlated to age of onset, with a more rapid regression in early infantile form leading to death around 2-4 years of age, whereas death occurs in the second decades in the juvenile form. All patients will have pharmaco-resistant epilepsy in the advanced stages of the disease. For the adult form, the disease is usually very slow progressive and may last decades. Patients are progressively disabled, may lost the ability to walk and have difficulties for upper limbs utilization, speech, swallowing, and may more rarely have cognitive symptoms.

Last update: November 2023 - Expert reviewer(s): Dr Bénédicte HERON - Dr Yann NADJAR | MetabERN*

* European Reference Network