Alpha-N-acetylgalactosaminidase deficiency

Alpha-N-acetylgalactosaminidase deficiency, or Schindler disease, is a rare inherited lysosomal storage disorder that affects the nervous system and can cause developmental regression, seizures, and distinctive facial features.

Overview

This disorder is caused by a deficiency in the enzyme alpha-N-acetylgalactosaminidase. It is categorized into three types based on the age of onset and severity of symptoms.

Types and Symptoms

• Type I (Severe): Babies appear healthy at birth but show developmental regression by age 2. Symptoms include weak muscle tone (hypotonia), vision and hearing loss, and seizures. Children eventually become unresponsive.
• Type II (Mild): Typically diagnosed in adulthood. Features include mild cognitive impairment, sensorineural hearing loss, peripheral neuropathy, and angiokeratomas (clusters of enlarged blood vessels appearing as dark red skin spots).
• Type III (Intermediate): Characterized by developmental, speech, and language delays, infantile seizures, and features of autism spectrum disorder. Skeletal issues such as lower back, hip, and knee pain, as well as cervical spondylosis, may occur.

Causes

Variants in the NAGA gene cause this deficiency. The NAGA gene provides instructions for the alpha-N-acetylgalactosaminidase enzyme, which functions in lysosomes to break down glycoproteins and glycolipids. When this enzyme is altered, these substances accumulate, leading to cell malfunction and death, particularly within the nervous system.

Inheritance

This condition is inherited in an autosomal recessive pattern. Both copies of the gene in each cell must have a variant to cause the disorder. Parents of an affected individual each carry one copy of the altered gene but typically do not show symptoms.