Niemann-Pick disease type A (NPD-A) is a rare and severe inherited lysosomal storage disorder that falls under the broader category of sphingolipidoses. It is caused by mutations in the SMPD1 gene, which leads to a deficiency of the enzyme acid sphingomyelinase. This deficiency results in the accumulation of sphingomyelin, a type of fatty substance, within various tissues and organs. Its prevalence is less than 1 case per 1.000.000 people.
Niemann-Pick disease type A genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Niemann-Pick disease is classified into four subtypes:
- Niemann-Pick disease type A is the most severe, resulting in deficient sphingomyelinase activity. It affects younger children and causes neurological deficits and growth disturbances. Patients present with hepatosplenomegaly (enlarged liver and spleen), recurrent lung infections, and thrombocytopenia or reduced platelet counts. Typical neurological symptoms of early-onset Niemann-Pick disease include vertical supranuclear gaze palsy, ataxia or loss of muscle coordination, slurred speech, difficulty swallowing, and involuntary muscle twitching.
- Niemann-Pick disease type B is less severe and may produce hepatosplenomegaly, thrombocytopenia, and interstitial lung disease. Neurological involvement is minimal.
- Niemann-Pick disease type C has a heterogeneous clinical presentation and includes systemic, neurological, and psychiatric involvement. It usually manifests in adulthood but may appear earlier. Unlike NPD-A and NPD-B, it is caused by pathogenic variants in the NPC1 gene.
- Niemann-Pick disease type E is the least common and develops in adults.
Critical features of Niemann-Pick disease type A include:
- Onset: Symptoms of NPD-A typically appear in early infancy, often within the first few months of life.
- Hepatosplenomegaly: Enlargement of the liver (hepatomegaly) and spleen (splenomegaly) is a common feature due to the accumulation of sphingomyelin in these organs.
- Neurological Involvement: Neurological symptoms are a hallmark of NPD-A and include developmental regression, progressive intellectual disability, and loss of motor skills.
- Cherry-Red Spot: An eye examination may reveal a cherry-red spot at the retina's center. This finding is characteristic but not specific to NPD-A.
- Respiratory Difficulties: Respiratory problems may occur, and affected individuals may experience difficulty breathing.
- Failure to Thrive: Infants with NPD-A often exhibit poor growth and failure to thrive.
- Seizures: Seizures may occur in some individuals with NPD-A.
- Joint Abnormalities: Joint abnormalities, such as contractures, may be present.
- Supranuclear Gaze Palsy: A specific type of eye movement disorder called supranuclear gaze palsy may be observed.
- Rapid Disease Progression: NPD-A is a rapidly progressing disorder, and affected individuals typically have a shortened lifespan, often not surviving beyond early childhood.
Niemann-Pick disease type A follows an autosomal recessive inheritance pattern, meaning that individuals with NPD-A inherit two mutated copies of the SMPD1 gene, one from each parent.
There is currently no cure for Niemann-Pick disease type A, and treatment is primarily supportive, focusing on managing symptoms and providing palliative care.
Genetic counseling is essential for families affected by Niemann-Pick disease type A to understand the inheritance pattern, assess the risk of having affected children, and discuss available reproductive options. Due to the severity of the condition, early diagnosis is crucial for providing supportive care and interventions to improve the quality of life for affected individuals.
Diagnosis of the deficiency is established by detecting pathogenic variants in the SMPD1 gene or by quantifying the residual ASM enzyme activity, usually less than 10% of the activity in healthy individuals (in peripheral blood lymphocytes or cultured skin fibroblasts).
Although up to 180 pathogenic variants in SMPD1 have been identified as causing the disease, three of them account for more than 90% of the pathogenic alleles in individuals of Ashkenazi Jewish ancestry with Niemann-Pick disease type A. The frequency of the three mutations in this population is between 1:800 and 1:100. Two of them are missense variants, c.1493G>T and c.911T>C, and the third, c.996del, is a single nucleotide deletion resulting in a reading frame shift and the introduction of a premature stop codon.
Niemann-Pick disease type A genetic testing analyzes the 18 most frequent pathogenic mutations of the SMPD1 gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
