Acid Sphingomyelinase Deficiency

Introduction
Acid sphingomyelinase deficiency (ASMD), also known as Niemann–Pick disease types A, A/B, and B, is a rare lysosomal storage disorder caused by deficient activity of the enzyme acid sphingomyelinase. This leads to abnormal accumulation of sphingomyelin in multiple organs, including the liver, spleen, lungs, bone marrow, and in severe cases, the central nervous system. Clinical manifestations range from hepatosplenomegaly and interstitial lung disease to growth delays and neurodegeneration. Treatment focuses on disease modification with enzyme replacement therapy and supportive measures to manage symptoms and prevent complications.

1. Disease-Specific Therapy

• Olipudase alfa (Xenpozyme): The first and only enzyme replacement therapy approved for ASMD types A/B and B (non-CNS-involving forms).

  • Dosage: Initiated at a low intravenous dose (0.03 mg/kg every 2 weeks) and gradually titrated to the full maintenance dose of 3 mg/kg every 2 weeks, depending on patient tolerance.

  • Benefits: Improves lung function (DLCO), reduces spleen and liver volume, and enhances quality of life.

  • Limitations: Not effective in preventing or reversing CNS disease due to inability to cross the blood-brain barrier.

2. Supportive and Symptomatic Management

• Hematology: Management of anemia, thrombocytopenia, or bleeding tendencies with transfusions or hematology support as needed.

• Pulmonary care: Oxygen supplementation, bronchodilators, and pulmonary rehabilitation for interstitial lung disease.

• Hepatology: Monitoring for liver dysfunction, portal hypertension, or cirrhosis; avoidance of hepatotoxic medications.

• Cardiology: Surveillance for dyslipidemia and cardiovascular risk, with consideration of statin therapy.

• Nutrition and growth: Dietary counseling, nutritional support, and monitoring for failure to thrive in pediatric patients.

3. Experimental and Investigational Approaches

• Gene therapy: Preclinical and early clinical studies are ongoing to deliver functional SMPD1 gene copies.

• Substrate reduction therapy (SRT): Agents aiming to reduce sphingomyelin synthesis are being explored, though none are yet standard of care.

4. Lifestyle and Preventive Measures

• Avoidance of contact sports or trauma due to splenomegaly and bleeding risk.

• Vaccination against respiratory pathogens (e.g., pneumococcal and influenza vaccines) to reduce pulmonary complications.

• Regular physical activity within tolerance to maintain mobility and respiratory function.

5. Multidisciplinary Care

• Management requires a coordinated approach involving geneticists, pulmonologists, hepatologists, hematologists, and nutrition specialists.

• Psychological and social support for patients and families is crucial given the chronic and often progressive nature of the disease.