Makindo Medical Notes

Niemann-Pick disease results from a loss of sphingomyelinase, an enzyme found in lysosomes that is essential for breaking down molecules like sphingomyelin. This leads to the pathological accumulation of sphingomyelin in various organs and tissues.

About

• Niemann-Pick disease is an autosomal recessive lysosomal storage disorder.
• It involves the accumulation of sphingomyelin due to a deficiency in the enzyme sphingomyelinase (Types A and B) or defective cholesterol transport in Type C.

Aetiology

• Sphingomyelinase deficiency: This enzyme is essential for metabolizing sphingomyelin, a type of lipid found in cell membranes.
• Genetic mutations: Different mutations are responsible for various types of Niemann-Pick disease:
  • Type A and B: Mutations in the SMPD1 gene.
  • Type C1 and C2: Mutations in the NPC1 or NPC2 genes affect cholesterol transport.
• More common in certain populations, particularly Ashkenazi Jews (Types A and B).

Populations Affected

• Ashkenazi Jewish population (NPA and NPB)
• French Canadian population of Nova Scotia (Type D, now considered a variant of Type C or NPC)
• Maghreb region (Tunisia, Morocco, and Algeria) of North Africa (NPB)
• Spanish-American population of southern New Mexico and Colorado (NPC)

Types

• Type A: Caused by mutations in the SMPD1 gene, leading to severe sphingomyelinase deficiency.
• Type B: Also caused by SMPD1 gene mutations, but patients retain some enzyme activity, resulting in a milder form.
• Type C1/C2: Result from mutations in the NPC1 or NPC2 genes, leading to impaired cholesterol trafficking in cells, affecting the brain and other organs.

Clinical Features

• Type A: Presents in infancy with hepatosplenomegaly by 3 months, failure to thrive, psychomotor regression, interstitial lung disease, recurrent infections, respiratory failure, cherry-red spot on the macula, and death typically in early childhood.
• Type B: Presents in mid-childhood with similar symptoms to Type A but less severe. Patients often have short stature and survive into adulthood.
• Type C1/C2: Characterized by progressive neurological symptoms, including ataxia, vertical supranuclear gaze palsy, dystonia, intellectual decline, dysphagia, and seizures. Liver and lung disease (e.g., severe liver disease, interstitial lung disease) are also common.

Investigations

• Full Blood Count (FBC): Pancytopenia due to hypersplenism.
• Liver Function Tests (LFTs): Elevated liver enzymes, raised cholesterol (HDL) and triglycerides (TGs).
• Chest X-ray (CXR): May show reticulonodular shadowing indicative of interstitial lung disease.
• Pulmonary Function Tests (PFTs): Demonstrates restrictive lung disease in advanced cases.
• Echocardiogram: May reveal valvular dysfunction in some patients.
• Enzyme Assay: Measures sphingomyelinase activity in peripheral white blood cells or cultured fibroblasts for Types A and B.
• Genetic Mutation Analysis: Can identify mutations in SMPD1, NPC1, or NPC2. Prenatal diagnosis via genetic testing is possible.

Management

• Type A: Supportive care is the only option, as there is no cure. Symptom management includes addressing respiratory issues and providing palliative care.
• Type B: Management may include:
  • Cholesterol-lowering medications (e.g., statins) to manage elevated cholesterol levels.
  • Transfusions for anaemia or other hematological abnormalities caused by hypersplenism.
  • Oxygen therapy for lung disease.
• Type C: Miglustat (Zavesca) may slow the progression of neurological symptoms in some patients. Supportive care is also essential to manage neurological and systemic complications.