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A very rare lysosomal storage disease that is clinically and pathologically heterogeneous and is characterized by deficient NAGA activity.
ORPHA:3137Classification level: Disorder
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 1, type 2 and type 3 (see these terms). Type 1 is characterized by infantile-onset neuroaxonal dystrophy, type 2 is described in adult patients with angiokeratoma corporis diffusum and minimal involvement of the nervous system and type 3 is an intermediate clinical form with manifestations 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 (NAGA; 22q13.2) but not all develop neurological symptoms. 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. It has been suggested that other factors or genes contribute to the occurrence of neurological symptoms but there is no conclusive evidence to confirm this theory.
The currently known cases were identified through 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.
Differential diagnosis depends on the type of NAGA deficiency and may include infantile neuroaxonal dystrophy, associated with mutations in the PLA2G6 gene, pantothenate kinase-associated neurodegeneration, associated with mutations in the PANK2 gene and other lysosomal diseases, including Fabry disease, due to different lysosomal enzyme defects or unknown factors (see these terms).
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.
NAGA deficiency follows an autosomal recessive pattern of inheritance. Genetic counseling should therefore be offered to affected families.
Management and treatment
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.
Prognosis is variable depending on the type of NAGA deficiency, with type 1 having the worst 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.
- Summary information
- Polski (2013, pdf)