Schindler disease




Schindler disease is a very rare, lysosomal storage disorder, caused by a deficiency in the enzyme alpha-NAGA (alpha-N-acetylgalactosaminidase). Resulting deficiency in NAGA activity leads to excessive lysosomal accumulation of glycosphingolipids throughout the body.

Exact prevalence of NAGA deficiency is unknown but fewer than 20 cases have been reported to date in patients of German, Dutch, Spanish, Japanese, French and Moroccan origin.


Extreme clinical variability has been reported. Cases of NAGA deficiency have been divided into 3 clinical subtypes: NAGA deficiency type I, type II and type III.

In the Type I infantile form, infants will develop normally until about a year old. At this time, the affected infant will begin to lose previously acquired skills involving the coordination of physical and mental behaviors. Additional neurological and neuromuscular 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.

 In Type II adult form, symptoms are milder and may not appear until the individual is in his or her 30s. Angiokeratomas, an increased coarsening of facial features, and mild intellectual impairment are likely symptoms. The involvement of nervous system is usually very small.

 Type III is considered an intermediate clinical form. Symptoms vary, ranging from intellectual impairment, neurological dysfunction and seizures to milder neurological and psychiatric issues such as speech and language delays or mild autism-like symptoms.


All individuals with NAGA deficiency have mutations in the alpha-N-acetylgalactosaminidase gene on chromosome 22. Inheritance follows autosomal recessive pattern.

A number of different NAGA mutations have been identified. There is however no direct genotype-phenotype correlation in view of the clinical heterogeneity of the reported cases.


Prenatal diagnosis is theoretically possible by mutation analysis of the NAGA gene after amniocentesis or chorionic villus sampling but as the clinically different forms of the disease have been mapped to the same gene they cannot be determined prenatally. Genetic counselling should be offered to affected families.


Reduced activity of the NAGA enzyme assessed by enzyme tests (assays) on white blood cells (leukocytes), blood plasma or cultured lymphoblasts or fibroblasts, or through urinalysis by thin layer chromatography for oligosaccharide and glycopeptide profiles that revealed increased levels of these complex compounds. Confirmation may be sought by mutation analysis of the NAGA gene.


Prognosis is variable depending on the type of NAGA deficiency, with type 1 having the worst (usually dying within 4 years of birth) and the other types having fairer outcomes. Evidence-based mortality rates or life expectancy figures are not available due to the very small number of patients.


There is no known cure for Schindler disease. Treatment of this disorder is symptomatic and supportive. It includes the maintenance of satisfactory nutrition and hydration, management of infectious diseases (possibly by antibiotic shielding), control of seizures by anti-epileptic drugs, reduction of spasticity or pain with medication, adequate positioning, physiotherapy to prevent joint contractures or pneumonia, and aspiration prophylaxis potentially including tube feeding. Recent studies identify NAGA deficiency as a typical protein folding disorder. As such, investigational studies are examining whether it is amenable to pharmacological chaperone approaches or enzyme replacement therapy. Gene therapy is being studied as another possible approach to therapy for some lysosomal storage disorders.


[1] Wang AM, Schindler D, Desnick R (November 1990). "Schindler disease: the molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes an infantile neuroaxonal dystrophy". J. Clin. Invest. 86 (5): 1752–6.

[2] Cantz M, Ulrich-Bott B (1990). "Disorders of glycoprotein degradation". J. Inherit. Metab. Dis. 13 (4): 523–37. doi:10.1007/BF01799510. PMID 2122119