Schindler disease is caused by mutations (changes) in the NAGA gene. The NAGA gene provides instructions for making the enzyme alpha-N-acetylgalactosaminidase. This enzyme works in the lysosomes which are sections within cells that digest and recycle materials. The enzymes in the lysosomes help break down glycoproteins and glycolipids which consist of sugar molecules attached to certain proteins and fats. The mutations in the NAGA gene disrupt the ability of the alpha-N-acetylgalactosaminidase enzyme to carry out its role of breaking down glycoproteins and glycolipids. This causes these substances to build up in the lysosomes which leads to a breakdown of these cells which will eventually die. This cell damage in the nervous system and other tissues and organs in the body lead to the symptoms present in Schindler disease. There are three types of Schindler disease. Type I, also called infantile type is the most severe form and symptoms usually show around the age of 8-15 months. Type II, also called Kanzaki disease is a milder form of the condition and usually occurs in adulthood. Type III is in between type I and II in terms of severity, with symptoms starting in infancy.

Type I Babies with Schindler disease type I appear healthy at birth but start showing symptoms by the age of 8 to 15 months. Symptoms include: • no longer developing new skills • losing skills, they had already acquired (developmental regression) • blindness • seizures • loss of awareness of their surroundings • unresponsive This is the most severe form of the condition. Individuals with Schindler disease type I usually do not survive past early childhood. Type II (Kanzaki Disease) Type II is a milder form of the disorder and usually appears in adulthood. Symptoms include: • mild cognitive impairment • hearing loss • weakness • loss of sensation • angiokeratomas (clusters of enlarged blood vessels that form small, dark red spots on the skin) Type III Schindler disease type III is in between types I and II in terms of severity. Symptoms usually first show in infancy. Symptoms include: • developmental delay • seizures • weakened and enlarged heart (cardiomyopathy) • enlarged liver (hepatomegaly) • behavioural problems in early childhood with some features of autism (only in some patients)

Schindler disease is caused by mutations (changes) in the NAGA gene which disrupt the alpha-N-acetylgalactosaminidase enzyme.

When diagnosing Schindler disease, healthcare professionals look at the individual’s medical history, symptoms associated with the disorder and a carry out a variety of specialized tests. Specialised urine tests can show increased levels of certain complex compounds in the urine associated with the condition. Enzyme tests can also be done to determine reduced activity of the alpha-NAGA enzyme. The diagnosis can be confirmed through molecular genetic testing by identifying mutations (changes) in the NAGA gene. Prenatal (before birth/during pregnancy) testing is available in the UK for families where mutations have been detected.

There are no specific treatments for Schindler disease. The treatment for this condition is aimed at specific symptoms that are present in the individual. Genetic counselling may be beneficial for the individuals with this condition and their families. Other treatments are focused on support for the patient and their family.