Tay-Sachs disease

What is Tay-Sachs disease?

Tay-Sachs disease is a rare but very serious neurometabolic disorder. It is caused by insufficient enzyme activity resulting from mutations in the HEXA gene. The onset of the disease varies widely depending on the severity of the enzyme deficiency — from early infancy all the way to adulthood. At present there is no effective treatment that would halt or reverse the progression of the disease.

What causes Tay-Sachs disease?

The disease is caused by a deficiency of the lysosomal enzyme beta-hexosaminidase A. Under normal circumstances this enzyme breaks down GM2 ganglioside — a complex lipid that is an important component of cell membranes. When the enzyme does not work, these substances accumulate in the lysosomes, which leads to cell dysfunction and cell death — neurons are affected in particular.

The enzyme deficiency is caused by mutations in the HEXA gene. The disease is inherited in an autosomal recessive manner — for it to manifest, the mutation must be present on both strands of DNA. Historically it was more common in the Ashkenazi Jewish population, but thanks to genetic counselling its incidence has fallen. Different combinations of mutations lead to different degrees of severity and different ages of onset — from infantile forms with almost zero enzyme activity to adult forms in which patients may work until retirement age.

What are the symptoms of Tay-Sachs disease?

Infantile form

The infantile form appears between the third and sixth month of life, presenting with muscle twitches and exaggerated startle reactions. An eye examination reveals a “cherry-red spot”, followed by developmental regression, spasticity, epileptic seizures and macrocephaly. By the age of two to three, most affected children enter a vegetative state with no response to their surroundings and require feeding through a gastrostomy.

Juvenile form

The juvenile form begins between the ages of two and five with delayed speech and stagnation of acquired skills. Spasticity, difficulty swallowing and seizures develop gradually. Vision deteriorates later. The disease progresses more slowly than the infantile form, but adolescence usually brings a vegetative state.

Late-onset form (LOTS)

Late-onset disease appears from adolescence through to middle age. Progressive weakness of the quadriceps and hip flexors causes difficulty standing up, climbing stairs and moving around. Speech becomes rapid and hard to understand. About 30% of patients develop an atypical psychosis requiring psychiatric treatment. Cognitive function remains preserved; many patients keep working until retirement.

How is Tay-Sachs disease diagnosed?

Early infantile forms present with developmental stagnation, vision problems, a cherry-red spot and macrocephaly — these signs lead the paediatric neurologist towards the diagnosis. Brain imaging shows gliosis and cortical atrophy without signs of leukodystrophy. The work-up includes enzymatic measurement of beta-hexosaminidase A in serum and leukocytes, followed by molecular analysis of the HEXA gene.

Juvenile and late-onset forms are diagnostically challenging because of their rarity and the overlap of their symptoms with other neurodegenerative diseases. Modern diagnostics use next-generation sequencing — gene panels or whole-exome testing. In adults, the combination of quadriceps weakness, impaired articulation and cerebellar atrophy on MRI is grounds for investigation. Electromyography demonstrating axonal polyneuropathy, together with elevated creatine kinase, should lead to enzymatic testing.

Can Tay-Sachs disease be treated?

At present only symptomatic and supportive treatment exists. Care for paediatric patients focuses on physiotherapy to ease spasticity and pain, assistive equipment, feeding through a gastrostomy, and psychological support for the family. Attempts at gene therapy have not yet produced conclusive results.

Treatment of the adult form is advancing through clinical trials. Substrate reduction therapy with venglustat (2020–2024) proved ineffective. Phase 2 studies with N-acetyl-L-leucine (IB-1001) delivered promising results for neurological symptoms. The FDA has approved an oral preparation in the USA under the trade name Aqneursa as a disease-modifying treatment for the late-onset form of Tay-Sachs disease. The approval process at the European Medicines Agency (EMA) is under way.

Patient organisations abroad

Several organisations around the world are dedicated to Tay-Sachs disease and related disorders. Their experience, research news and materials are a valuable source of information for families.