Niemann–Pick disease

Niemann–Pick Disease
• Definition
• Classification
• Pathophysiology
• Clinical Features
• Diagnosis
• Treatment

Definition: Niemann–Pick disease is a rare inherited lysosomal storage disorder caused by defects in lipid metabolism. It leads to the accumulation of sphingomyelin or cholesterol within lysosomes of various cells, especially in the liver, spleen, lungs, bone marrow, and brain. It is usually inherited in an autosomal recessive manner.

Classification: Niemann–Pick disease is divided into several types:

Type A (Infantile Neurovisceral)
• Cause: Deficiency of acid sphingomyelinase (ASM).
• Onset: Infancy.
• Features: Severe hepatosplenomegaly, failure to thrive, progressive neurodegeneration, cherry-red spot in macula (like in Tay–Sachs).
• Prognosis: Fatal, usually by 2–3 years of age.

Type B (Chronic Visceral)
• Cause: Partial ASM deficiency.
• Onset: Childhood/adolescence.
• Features: Hepatosplenomegaly, interstitial lung disease, normal or near-normal neurologic function.
• Prognosis: Many survive into adulthood.

Type C (Cholesterol Trafficking Defect)
• Cause: Mutation in NPC1 or NPC2 gene → impaired intracellular cholesterol transport.
• Onset: Variable (infancy to adulthood).
• Features: Hepatosplenomegaly, progressive neurodegeneration, vertical supranuclear gaze palsy (classic finding), ataxia, dystonia, dysarthria, psychiatric symptoms.
• Prognosis: Progressive, often fatal in childhood or adolescence, but later-onset cases survive longer.

Type D
• A variant of type C, described in the Nova Scotia population.

Pathophysiology:
• Type A & B: Accumulation of sphingomyelin due to acid sphingomyelinase deficiency.
• Type C/D: Accumulation of unesterified cholesterol & glycolipids due to defective intracellular trafficking.
• Characteristic finding: Foam cells (lipid-laden macrophages).

Clinical Features:
• Hepatosplenomegaly
• Pulmonary involvement (interstitial disease, recurrent infections)
• Neurological impairment (especially in type A & C)
• Failure to thrive
• Cherry-red macula spot (type A & some type C cases)

Diagnosis:
• Enzyme assay (ASM activity for types A & B)
• Genetic testing (NPC1, NPC2 mutations)
• Filipin staining of cultured fibroblasts (cholesterol storage, for type C)
• Bone marrow: Foam cells, sea-blue histiocytes
• Imaging: Organomegaly, lung infiltrates, cerebral atrophy

Treatment:
• Supportive care (nutrition, respiratory support, seizure control)
• Enzyme replacement therapy (ERT): Under research for ASM deficiency
• Substrate reduction therapy: Miglustat approved for type C
• Hematopoietic stem cell transplantation: Limited benefit
• Prognosis varies with type (worst in type A, better in type B, variable in type C)