Niemann Pick Disease

1. INTRODUCTION AND CLASSIFICATION

• Definition: A heterogeneous group of autosomal recessive lysosomal storage disorders.
• Historical Classification: Types A, B, C, and D.
• Modern Classification (Based on biochemical defect):
  1. Acid Sphingomyelinase Deficiency (ASMD): Encompasses NPD Types A and B. Caused by deficiency of acid sphingomyelinase (ASM).
  2. Niemann-Pick Disease Type C (NPC): A disorder of cellular cholesterol and lipid trafficking. (Type D is now considered a variant of NPC).

PART I: ACID SPHINGOMYELINASE DEFICIENCY (ASMD) - TYPES A & B

1. ETIOLOGY AND GENETICS

• Gene: SMPD1 gene on chromosome 11p15.
• Enzyme Defect: Deficiency of Acid Sphingomyelinase (ASM).
• Inheritance: Autosomal Recessive.
• Pathophysiology:
  • Accumulation of Sphingomyelin (primary substrate) and cholesterol (secondary) in lysosomes.
  • Affects reticuloendothelial system (monocytes/macrophages) and hepatocytes.
  • Niemann-Pick Cell: Large, lipid-laden foam cell (>20–90 μm) with "mulberry" or "soap-bubble" appearance (vacuolated cytoplasm) found in bone marrow and tissues.

2. CLINICAL PHENOTYPES

A. Type A: Infantile Neurovisceral ASMD (Severe)

• Onset: Early infancy (3–6 months).
• Demographics: High prevalence in Ashkenazi Jewish population.
• Visceral:
  • Hepatosplenomegaly: Massive, early onset.
  • Feeding difficulties, failure to thrive (FTT).
  • Xanthomas and brownish-yellow skin discoloration.
• Neurologic:
  • Rapid Neurodegeneration: Loss of motor milestones, hypotonia progressing to spasticity and rigidity.
  • Apathy and loss of social contact.
• Ophthalmologic: Cherry-Red Spot on macula (approx. 50–100% of cases).
• Prognosis: Death typically by 2–3 years of age due to respiratory failure.

B. Type B: Chronic Visceral ASMD (Non-Neuronopathic)

• Onset: Variable (childhood to adulthood); pan-ethnic.
• Neurologic: Normal intellect; usually no primary neurodegeneration (though minor signs may exist).
• Visceral:
  • Significant Hepatosplenomegaly (Spleen > Liver).
  • Liver dysfunction: Fibrosis, cirrhosis, portal hypertension.
• Pulmonary (Major Morbidity):
  • Interstitial Lung Disease (ILD) due to foam cell infiltration.
  • Recurrent respiratory infections, dyspnea, exercise intolerance.
  • CXR/CT: "Ground-glass" opacities or reticulonodular pattern.
• Hematologic: Thrombocytopenia (hypersplenism), leukopenia.
• Skeletal: Osteopenia, bone pain, growth retardation.
• Cardiovascular: Atherogenic lipid profile (low HDL, high LDL/TG).

3. DIAGNOSIS (ASMD)

• Enzyme Assay (Gold Standard): Deficient ASM activity in peripheral leukocytes or cultured fibroblasts (<5% in Type A, residual in Type B).
• Molecular Genetics: SMPD1 gene sequencing.
• Biomarkers: Elevated Lyso-sphingomyelin (Lyso-SM-509).
• Bone Marrow: Foam cells (Sea-blue histiocytes) – suggestive but not specific.

4. MANAGEMENT (ASMD)

• Enzyme Replacement Therapy (ERT):
  • Olipudase alfa: Recombinant human acid sphingomyelinase. First and only approved treatment for non-CNS manifestations of ASMD (Type B and visceral Type A).
  • Effect: Reduces spleen/liver volume, improves lung function.
• Supportive Care:
  • Nutritional support (NG tube for Type A).
  • Management of coagulopathy/splenomegaly.
  • Pulmonary toilet and oxygen support.

PART II: NIEMANN-PICK DISEASE TYPE C (NPC)

1. ETIOLOGY AND GENETICS

• Definition: Lipid storage disorder characterized by defective intracellular trafficking of unesterified cholesterol and glycolipids.
• Genes:
  • NPC1 (95% cases): Chromosome 18q. Membrane-bound protein.
  • NPC2 (5% cases): Soluble lysosomal protein.
• Inheritance: Autosomal Recessive.
• Pathophysiology:
  • Defect in egress of cholesterol from late endosomes/lysosomes.
  • Accumulation of unesterified cholesterol, sphingosine, and glycosphingolipids (GM2/GM3 gangliosides) in the brain and viscera.

2. CLINICAL PRESENTATION (HIGHLY VARIABLE)

Can present from fetal life to adulthood.

A. Visceral / Perinatal

• Fetal: Fetal ascites, Hydrops fetalis.
• Neonatal:
  • Prolonged Neonatal Jaundice: Cholestatic jaundice (often transient) is a classic early sign.
  • Hepatosplenomegaly (HSM): Can be isolated.

B. Neurologic (The Hallmark)

• Vertical Supranuclear Gaze Palsy (VSGP):
  • Pathognomonic sign.
  • Inability to look down (early) or up, with preserved oculocephalic reflexes (doll's eye).
  • Patients may use head-thrusting to compensate.
• Gelastic Cataplexy: Sudden loss of muscle tone triggered by laughter (highly specific).
• Cerebellar Ataxia: Gait unsteadiness, frequent falls.
• Dystonia/Spasticity: Progressive motor decline.
• Cognitive:
  • Pediatric: Developmental delay, regression, school failure.
  • Adult: Early-onset dementia, psychosis, schizophrenia-like syndrome.
• Dysphagia/Dysarthria: Leading to aspiration pneumonia.

C. Clinical Subtypes by Age

• Early Infantile (<2 yrs): Delay, hypotonia, HSM.
• Late Infantile (2–6 yrs): Ataxia, clumsiness, VSGP, regression.
• Juvenile (6–15 yrs): School failure, ataxia, VSGP, cataplexy.
• Adult: Psychiatric presentation, dementia, ataxia.

3. DIAGNOSIS (NPC)

• Biomarkers (First-line):
  • Plasma Oxysterols: Cholestane-3β,5α,6β-triol (C-triol) is markedly elevated.
  • Lyso-SM-509: Elevated.
• Molecular Genetics: Sequencing of NPC1 and NPC2 genes.
• Filipin Staining (Historical Gold Standard):
  • Cultured skin fibroblasts stained with filipin (fluorescent antibiotic).
  • Shows intense perinuclear fluorescence indicating accumulation of unesterified cholesterol. (Now reserved for inconclusive genetic/biochemical cases).

4. MANAGEMENT (NPC)

• Substrate Reduction Therapy (SRT):
  • Miglustat (N-butyldeoxynojirimycin):
    • Inhibits glucosylceramide synthase.
    • Only approved therapy for neurologic manifestations in many countries.
    • Slows progression of neurological symptoms.
    • Side Effects: Diarrhea, weight loss.
• Experimental/Emerging:
  • 2-Hydroxypropyl-beta-cyclodextrin (HPβCD): Intrathecal/IV. Mobilizes cholesterol.
  • Arimoclomol: Heat shock protein amplifier.
• Symptomatic:
  • Anticholinergics/Botox for dystonia.
  • Tricyclic antidepressants for cataplexy.
  • Gastrostomy for dysphagia.

COMPARISON TABLE (SUMMARY)