Knowledge on rare diseases and orphan drugs

The prevalence of the disease is 1/380,000 live births.

The clinical picture is almost identical to that of Tay-Sachs disease: three forms have been described according to age of onset. The infantile form begins at 3-6 months of age for the early infantile (< 12 months) and 12-24 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 pharmacoresistant epilepsy and progressive macrocephaly. A cherry-red macular spot is nearly always present and is strongly evocative even if not specific. Light visceromegaly or cardiomyopathy may be present in infantile Sandhoff disease, contrary to infantile Tay-Sachs disease. Muscular weakness progresses and leads to paralysis. The disorder degenerates into a state of decerebration and is fatal during childhood. Onset of the juvenile form is at 2-10 years of age, with progressive cerebellar ataxia, dystonia, behavioral disorders, and cognitive regression. Death occurs during the second decade. The adult form begins around the age of 10 or later, and is often not diagnosed until adulthood. The onset is insidious with a progressive course. Two 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) generalized cerebellar ataxia (more rarely dystonia). 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 HEXB encodes the beta subunit of hexosaminidase A and hexosaminidase B and is located on chromosome 5 (5q13.3).

Hexosaminidase A and hexosaminidase B enzymatic activities on blood leukocytes is always very low compared to normal values (around 0% for severe infantile form, around 10-15% for adult form). Diagnosis should be confirmed by HEXB gene sequencing. The diagnosis may be firstly suggested by pathogenic variants findings from a panel of genes, or exome or genome sequencing, and should be confirmed by hexosaminidase A and hexosaminidase B enzymatic activities measurement. Abnormal oligosaccharides urinary excretion may be detected in Sandhoff disease.

GM2 gangliosidosis, AB variant (GM2A gene variant), may perfectly mimic Sandhoff or Tay-Sachs diseases, but with normal hexosaminidase A and B enzymatic activities. In adults the differential diagnoses include proximal spinal muscular atrophy and autosomal recessive diseases causing cerebellar ataxia (e.g. Niemann Pick disease type C).

Prenatal diagnosis is available: a complete study of hexosaminidases A and B activities, and HEXB gene sequencing for the propositus and both parents is requested before prenatal diagnosis may be done for the fetus.

Transmission is autosomal recessive; at-risk couples (both parents are carriers of a pathogenic variant) have a 25% risk of having an affected child at each pregnancy.

There is no specific and efficient treatment for Sandhoff disease. Treatment is symptomatic.

For the pediatric forms: the severity is correlated to age of onset, with a more rapid regression in the early infantile form leading to death around 2-4 years of age, whereas death occurs in the second decade in the juvenile form. All patients will have pharmacoresistant 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 lose the ability to walk and have difficulties for upper limbs utilization, speech, swallowing, and may more rarely have cognitive symptoms.

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

* European Reference Network