Infantile neurovisceral acid sphingomyelinase deficiency (ORPHA:77292)
A rare, autosomal recessive, acid sphingomyelinase deficiency characterized clinically by onset in infancy or early childhood with failure to thrive, hepatosplenomegaly, interstitial lung disease and rapidly progressive neurodegenerative disorders.
Epidemiology
The birth prevalence of acid sphingomyelinase deficiency (combined both Niemann-Pick disease (NPD) types A and B) is estimated between 1/167,000-250,000 in Europe. Niemann-Pick disease type A (NPD-A) is more prevalent in the Ashkenazi Jewish population, where the estimated birth rate is estimated at 1/33,000.
Clinical description
The first symptom in NPD-A is hepatosplenomegaly, usually noted in the first few months of life. Other non-neurological findings include feeding problems, failure to thrive, gastrointestinal complaints (e.g., constipation, diarrhea, and vomiting), recurrent respiratory infections, persistently elevated transaminases, and irritability. Early neurological manifestations include muscular hypotonia, weakness and feeding difficulties. Affected infants have decreased linear growth and body weight. By 6 months of age, global development delay becomes evident and regression of developmental milestones is noted. With advancing age, the loss of motor function and the deterioration of intellectual capabilities are progressively debilitating. A classic cherry-red spot of the macula of the retina is eventually present in all affected children after 6 months of age. Interstitial lung disease results in frequent respiratory infections and often respiratory failure. Osteoporosis is common, presumably due to infiltration and poor nutrition.
Etiology
NPDA is caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene (locus 11p15.4), leading to decreased activity of acid sphingomyelinase (ASM), which results in lysosomal accumulation of sphingomyelin (SM) and secondary increases in the concentrations of cholesterol and other lipids.
Diagnostic methods
The diagnosis of NPD-A is established by detection of biallelic pathogenic variants in SMPD1 and/or residual acid sphingomyelinase enzyme activity (in peripheral blood lymphocytes, cultured skin fibroblasts or dry blood spots (DBS)). The de-acylated form of sphingomyelin (lyso-SPM) is increased in NPD-A and could be measured in plasma and DBS. Bone marrow examination reveals the histochemical characteristic, ''Niemann-Pick'' foam cells.
Differential diagnosis
Differential diagnoses include other lysosomal storage diseases such as Gaucher disease, GM1-and GM2-gangliosidosis, Niemann-Pick disease type C, lysosomal acid lipase deficiency, hematologic malignancy, and primary hepatic disease (e.g., fatty liver, autoimmune, chronic hepatitis B-related, cryptogenic cirrhosis).
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk is possible by testing of ASM enzyme activity or by DNA analysis if both SMPD1 pathogenic variants in the family are known.
Genetic counseling
NPD-A is inherited in an autosomal recessive manner. Genetic counseling should be offered to at-risk couples informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Currently, only supportive care is available for patients with NPD-A. The disease is best managed by an interprofessional team that includes a gastroenterologist, endocrinologist, neurologist, and geneticist. Also, family care, nursing support, and social support are an integral part of the management.
Prognosis
The clinical course is characterized by a brief period of normal development followed by a severe neurodegenerative course and death in the first 5 years of life.

                            Last update: 
                            April 2021


                            - Expert reviewer(s): 
                            Dr Ekaterina ZAKHAROVA