Schindler disease


Schindler disease

Description, Causes and Risk Factors:

An autosomal-recessive disorder with deficient activity of alpha-N-acetylgalactosaminidase resulting in accumulation of glycoproteins and other substrates that are deposited in terminal axons, primarily in gray matter.

Schindler disease is an inherited disorder that primarily causes Neurological problems. There are three types of Schindler disease. Schindler disease type I, also called the infantile type, is the most severe form. Babies with Schindler disease type I appear healthy at birth, but by the age of 8 to 15 months they stop developing new skills and begin losing skills they had already acquired (developmental regression). As the disorder progresses, affected individuals develop blindness and seizures, and eventually they lose awareness of their surroundings and become unresponsive. People with this form of the disorder usually do not survive past early childhood.

Schindler disease type II, also called Kanzaki disease, is a milder form of the disorder that usually appears in adulthood. Affected individuals may develop mild cognitive impairment and hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss). They may experience weakness and loss of sensation due to problems with the nerves connecting the brain and spinal cord to muscles and sensory cells (peripheral nervous system). Clusters of enlarged blood vessels that form small, dark red spots on the skin (angiokeratomas) are characteristic of this form of the disorder.

Schindler disease type III is intermediate in severity between types I and II. Affected individuals may exhibit signs and symptoms beginning in infancy, including developmental delay, seizures, a weakened and enlarged heart (cardiomyopathy), and an enlarged liver (hepatomegaly). In other cases, people with this form of the disorder exhibit behavioral problems beginning in early childhood, with some features of autism spectrum disorders. Autism spectrum disorders are characterized by impaired communication and socialization skills.

Mutations in the NAGA gene cause Schindler disease. The NAGA gene is located on chromosome 22q13.2 and consists of 9 exons, and family specific mutations are found throughout the gene. The NAGA gene provides instructions for making the enzyme alpha-N-acetylgalactosaminidase. This enzyme works in the lysosomes, which are compartments within cells that digest and recycle materials. Within lysosomes, the enzyme helps break down complexes called glycoproteins and glycolipids, which consist of sugar molecules attached to certain proteins and fats. Specifically, alpha-N-acetylgalactosaminidase helps remove a molecule called alpha-N-acetylgalactosamine from sugars in these complexes. Mutations in the NAGA gene interfere with the ability of the alpha-N-acetylgalactosaminidase enzyme to perform its role in breaking down glycoproteins and glycolipids. These substances accumulate in the lysosomes and cause cells to malfunction and eventually die. Cell damage in the nervous system and other tissues and organs of the body leads to the signs and symptoms of Schindler disease.

Symptoms:

Symptoms such as diminished muscle tone, weakness, involuntary rapid eye movements, vision loss, and seizures may become present. With time, the symptoms worsen and children affected with this disorder will experience a decreased ability to move certain muscles due to muscle rigidity. The ability to respond to external stimuli will also decrease. Other symptoms include neuroaxonal dystrophy from birth, discoloration of skin, telangiectasia or widening of blood vessels.

Diagnosis:

Schindler disease may be diagnosed after birth (postnatally) by a thorough clinical evaluation, detailed patient history, and a variety of specialized tests. Urinary analysis (e.g., oligosaccharide and glycopeptide profiles) may reveal increased levels of certain complex compounds in the urine (e.g., oligosacchariduria and glycopeptiduria). Reduced activity of the alpha-N-acetylgalactosaminidase enzyme may be confirmed by conducting enzyme tests (assays) on cultured white blood cells (leukocytes), blood plasma, and/or certain skin cells (fibroblasts) from affected individuals.

In children with Schindler disease type I, examination of samples of tissue (biopsy) from the rectum's mucosal and muscular layers (submucosal and myenteric plexus) may reveal lysosomal accumulation in extensions of nerve cells (axons) of the vegetative (autonomous) nervous system. Advanced imaging techniques, such as magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) of the brain may reveal degeneration of the outer layer of the brain (cortex), the cerebellum, and the brainstem.

For families with a previous history of Schindler disease, the disorder may be diagnosed before birth (prenatally) by specialized tests such as amniocentesis and/or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, tissue samples are removed from a portion of the placenta. Studies performed on these fluid or tissue samples can reveal that there is reduced activity of the alpha-N-acetylgalactosaminidase enzyme.

Treatment:

Treatment for individuals with this disease aims to provide relief for any symptoms and support in the care of the individual. Individuals with the infantile form may benefit from Physical therapy. Individuals with the adult form may have Laser surgery to remove the skin lesions (angiokeratomas). Also medications may be required if angina is present.

Gene therapy is being studied as another possible approach to therapy for some lysosomal storage disorders. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of active enzyme and prevent pathology. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a "cure." However, at this time, there are many technical difficulties to resolve before gene therapy can succeed.

NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.

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