Niemann-Pick disease type A

Niemann-Pick disease type A is a very rare, inherited lysosomal storage disorder that primarily affects infants and young children. It results from pathogenic variants in the SMPD1 gene, which impair the activity of acid sphingomyelinase, leading to toxic buildup of sphingomyelin in many tissues. Early signs usually appear within the first months of life, and both the nervous system and organs such as the liver and spleen are involved. The condition affects fewer than one in a million people worldwide, and severity and symptoms vary widely between individuals.

After a period of apparently typical early development, affected children experience a phase of developmental regression marked by loss of previously acquired skills such as sitting or babbling. Neurological features dominate the clinical picture and include global developmental delay, delayed myelination of the central nervous system, progressive loss of motor abilities, irritability, and eventually inability to walk. Cognitive and other developmental abilities decline in parallel with motor function. A characteristic finding on eye examination is a cherry-red spot of the macula. Visceral involvement is often what first brings the child to medical attention. Feeding difficulties, poor weight gain, and failure to thrive can begin in infancy, sometimes accompanied by prolonged neonatal jaundice. Progressive enlargement of the liver and spleen (hepatosplenomegaly) is almost universally present and may be associated with elevated liver enzymes. Less common problems can include ascites or an unusually large head size (macrocephaly). Not all individuals experience all features, and severity varies considerably.

Niemann-Pick disease type A is caused by pathogenic variants in the SMPD1 gene. SMPD1 provides instructions for making acid sphingomyelinase, an enzyme that breaks down sphingomyelin inside lysosomes. When the enzyme is deficient or absent, sphingomyelin accumulates within cells, damaging the brain, liver, spleen, and other tissues. The disorder is inherited in an autosomal recessive pattern. A child must receive one non-working copy of SMPD1 from each parent to be affected. Parents who each carry a single altered copy are usually healthy but have a 25 percent chance with every pregnancy of having a child with the condition. Because the disease is extremely rare, it is more likely to occur when parents share a common ancestor, which increases the chance that both carry the same rare genetic change. Genetic counseling is recommended for families to discuss carrier testing, family planning options, and implications for other relatives.

Currently, management focuses on supportive care and symptom management. Treatment is tailored to each child and typically involves a multidisciplinary team that may include neurology, hepatology, nutrition, physical and occupational therapy, and palliative care specialists. Long-term management includes regular surveillance to monitor liver size and function, assess nutritional status, track neurodevelopmental changes, and address emerging complications early. Families are encouraged to maintain close communication with their care team to adjust interventions as needs evolve, and genetic counseling should be part of comprehensive care planning.

Niemann-Pick disease type A is typically severe, and many children experience progressive neurological decline alongside worsening organ involvement. However, outcomes depend on factors such as overall symptom burden, timing of diagnosis, and access to specialized supportive care. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists familiar with lysosomal storage disorders, participate in disease registries, and seek genetic counseling to understand future planning and support resources.

Several clinical trials are currently investigating new treatments aimed at modifying disease progression. Individuals interested in participating can search ClinicalTrials.gov or consult their healthcare team about eligibility.