Niemann-Pick Disease

Niemann-Pick disease comprises lysosomal storage disorders with distinct pathogenesis:

• Types A and B (acid sphingomyelinase deficiency, ASMD; SMPD1, 11p15.4): sphingomyelin accumulation in macrophages. Type A (neuronopathic, infantile), type B (chronic visceral, non-neuronopathic), and an intermediate A/B form. Incidence about 1 in 250,000, more frequent in Ashkenazi Jews (type A) and North Africans (type B)
• Type C (NPC1 in 95%, NPC2 in 5%): defective intracellular cholesterol and glycolipid trafficking, with incidence of about 1 in 100,000. Not a sphingomyelinase deficiency

• Type A: hepatosplenomegaly and failure to thrive from 3 to 6 months, severe hypotonia, progressive neurodegeneration, feeding difficulty, cherry red macular spot (about 50%), interstitial lung disease, and death by 2 to 3 years
• Type B: hepatosplenomegaly, thrombocytopenia, interstitial lung disease (reticulonodular infiltrates, recurrent infections), dyslipidaemia (high LDL, low HDL), growth retardation and delayed puberty, osteopenia, retinal cherry red spot (about 30%), and mild or no neurological disease; survival to adulthood
• Type C: highly variable. Perinatal: prolonged neonatal cholestatic jaundice and hepatosplenomegaly, occasionally fatal liver or lung disease. Infant to child: hepatosplenomegaly, delayed motor milestones, hypotonia. Childhood and adult: vertical supranuclear gaze palsy (the hallmark; saccade loss first), cerebellar ataxia, dysarthria, dysphagia, dystonia, gelastic cataplexy (loss of tone with laughter), seizures, progressive cognitive decline, and psychiatric symptoms (psychosis, depression)

1. ASMD: acid sphingomyelinase activity in leucocytes or dried blood spots (reduced), and SMPD1 sequencing.
2. NPC: plasma oxysterols (cholestane-3-beta,5-alpha,6-beta-triol; elevated; first line screening biomarker), lyso-sphingomyelin-509 and bile acid metabolites; confirmation by NPC1 and NPC2 sequencing; filipin staining of cultured fibroblasts showing perinuclear cholesterol accumulation (now second line).
3. Bone marrow or liver biopsy: foam cells (Niemann-Pick cells) and sea blue histiocytes (supportive, not required).
4. Imaging and function: liver and spleen volumes (MRI), chest CT, DXA, lipid profile, platelet count, brain MRI, saccadic eye movement testing, audiology, and swallow assessment.

• ASMD (type B and A/B): olipudase alfa (recombinant acid sphingomyelinase) IV every 2 weeks, with dose escalation from 0.1 mg/kg to 3 mg/kg (adults) or 0.03 to 3 mg/kg (children) over about 14 weeks to avoid cytokine release and acute reactions; improves spleen volume (about 40% reduction), liver volume, lung diffusing capacity, platelets, and lipids; it does not treat the CNS. Monitor liver enzymes. Type A has no approved therapy.
• Supportive care in ASMD: statin and diet for dyslipidaemia, bone health, splenectomy avoidance (risk of lung disease acceleration), supplemental oxygen for lung disease, and management of bleeding.
• NPC: miglustat 200 mg three times daily in adults (children by body surface area, 100 to 200 mg/m2/day in three doses), a substrate reduction therapy that stabilises neurological progression; adverse effects include diarrhoea, weight loss, tremor, and peripheral neuropathy. Arimoclomol with miglustat and levacetylleucine (4 g/day in adults, weight based in children) were approved for NPC in some regions and slow neurological progression.
• Symptomatic treatment in NPC: antiepileptics (avoid carbamazepine), anticholinergics or botulinum toxin for dystonia and drooling, venlafaxine or modafinil for cataplexy, speech and swallowing therapy, gastrostomy, antipsychotics with caution, and palliative care.
• Experimental therapies: intrathecal cyclodextrin (adrabetadex), gene therapy, and haematopoietic transplantation (ineffective).
• Genetic counselling: 25% recurrence risk; carrier detection and prenatal diagnosis.