General description

Niemann-Pick disease type C is a rare neurovisceral lysosomal storage disorder characterized by impaired intracellular cholesterol and lipid transport, resulting in progressive neurological deterioration.

Niemann-Pick disease type C is a genetically determined disorder with an estimated incidence of approximately 1:120,000-1:150,000 live births. Unlike Niemann-Pick types A and B (which involve acid sphingomyelinase deficiency), NPC is primarily a disorder of intracellular cholesterol trafficking.

Niemann-Pick disease type C is caused by mutations in one of two genes: NPC1 (responsible for approximately 95% of cases) or NPC2 (accounting for the remaining 5%). Both genes encode proteins that function cooperatively in transporting cholesterol and other lipids within the cell. The disease follows an autosomal recessive inheritance pattern, requiring mutations in both copies of either gene to manifest the disease.

Niemann-Pick disease type C exhibits remarkable clinical heterogeneity, with age of onset and specific symptoms varying significantly between individuals, even within the same family. The disease spectrum ranges from a rapidly fatal neonatal disorder to a chronic progressive condition remaining undiagnosed into adulthood.

Classification by Age of Onset

1. Perinatal/Neonatal Presentation (birth to 3 months)
   • Systemic manifestations: Fetal ascites, hepatosplenomegaly, prolonged jaundice, thrombocytopenia, lung disease
   • Neurological manifestations: Hypotonia (weak muscle tone)
2. Early Infantile Onset (3 months to <2 years)
   • Systemic manifestations: Hepatosplenomegaly (sometimes the only initial symptom)
   • Neurological manifestations: Central hypotonia, delayed developmental milestones, speech delay, dysphagia, and early signs of vertical supranuclear gaze palsy (VSGP)
3. Late Infantile Onset (2 to <6 years)
   • Systemic manifestations: Hepatosplenomegaly or splenomegaly (with or without neurological symptoms)
   • Neurological manifestations: Developmental delays or regression, clumsiness, frequent falls, progressive ataxia, dystonia, dysarthria, dysphagia, seizures, and cataplexy (sudden muscle weakness often triggered by laughter)

4. Juvenile Onset (6 to <15 years)

   • Initial symptoms often include school problems, gait abnormalities, and clumsiness
   • Progressive development of ataxia, dysarthria, and cognitive decline
   • Vertical supranuclear gaze palsy (a cardinal diagnostic feature)
   • Cataplexy and seizures may be present

5. Adult Onset (≥15 years)

   • Often presents initially with psychiatric disturbances that may precede neurological symptoms
   • Neurological symptoms include ataxia, dysarthria, cognitive impairment, and vertical supranuclear gaze palsy
   • Psychiatric manifestations include psychosis, depression, and bipolar disorder