• Niemann-Pick disease type C (NPC) is different molecularly and biochemically from types A and B and is more common than types A and B combined.
• It is caused by mutations in:
  • NPC1 → responsible for most cases
  • NPC2
• Unlike most lysosomal storage diseases, NPC is mainly a defect of intracellular lipid transport.
• Normally:
  NPC1 + NPC2 → transport free cholesterol from lysosomes → cytoplasm (Fig. 4.6).
• In NPC:
  NPC1/NPC2 defect → cholesterol cannot leave lysosomes properly → cholesterol accumulates.
• Affected cells also accumulate gangliosides such as:
  • GM1
  • GM2
• Clinical manifestations vary widely.
• The common childhood form causes:
  • ataxia → poor coordination
  • vertical supranuclear gaze palsy → impaired voluntary vertical eye movement
  • dystonia
  • dysarthria
  • psychomotor regression

KEY CONCEPT

• NPC = NPC1/NPC2 mutation → defective lysosomal cholesterol transport → cholesterol + GM1/GM2 accumulation.
• Main childhood manifestations are progressive neurologic abnormalities.

CONCEPTUAL EXAMPLE

• Cholesterol enters lysosome but cannot be transported out → progressively accumulates → cellular dysfunction, especially neurologic disease.

Gaucher Disease

• Gaucher disease is caused by mutations producing deficiency of glucocerebrosidase.
• It is an autosomal recessive lysosomal storage disease.
• Normally, glucocerebrosidase removes glucose from glucocerebroside during glycolipid breakdown.
• In Gaucher disease: ↓ glucocerebrosidase → failure to degrade glucocerebroside → glucocerebroside accumulates in macrophages
• Macrophages normally break down glycolipids from old blood cells, particularly in:
  • liver
  • spleen
  • bone marrow
• Accumulated lipid enlarges macrophages → Gaucher cells.
• Gaucher cells contain enlarged lysosomes and show characteristic cytoplasm resembling “wrinkled tissue paper” (Fig. 4.15).
• Disease manifestations result not only from stored lipid but also from macrophage activation.
• Activated macrophages release increased:
  • IL-1
  • IL-6
  • TNF
• There are three major variants.
• Type 1 – chronic nonneuronopathic form:
  • accounts for about 99% of cases
  • no CNS involvement
  • bone abnormalities occur in about 70%–100%, including:
    • osteopenia
    • focal lytic lesions
    • osteonecrosis
  • causes hepatosplenomegaly
  • spleen may become massively enlarged
  • Gaucher cells accumulate in liver, spleen, lymph nodes, and bone marrow
  • marrow replacement and cortical erosion → skeletal lesions + cytopenias
  • compatible with long survival
• Carrier frequency for type 1 is particularly high in the Ashkenazi Jewish population, about 1 in 12.
• Type 2 – acute infantile neuronopathic form:
  • neurologic disease begins in infancy
  • severe neurologic deterioration
• Type 3 – chronic neuronopathic form:
  • neurologic manifestations appear later
  • generally milder than type 2
• Types 2 and 3 may show:
  • convulsions
  • progressive mental deterioration
  • liver and spleen involvement
• Glucocerebrosidase mutations are also strongly associated with Parkinson disease.
• Patients with Gaucher disease have about a 20-fold increased risk of Parkinson disease.
• About 5%–10% of patients with Parkinson disease have mutations involving glucocerebrosidase.
• Diagnosis may involve:
  • measurement of glucocerebrosidase activity in leukocytes or cultured fibroblasts
  • DNA testing
• Two established treatments for type 1 Gaucher disease include:
  • Enzyme replacement therapy
    • lifelong recombinant glucocerebrosidase infusion
  • Substrate reduction therapy
    • inhibits glucosylceramide synthase
    • → ↓ production of glucocerebroside
    • → ↓ storage burden
• Substrate reduction therapy may:
  • decrease spleen and liver size
  • improve blood counts
  • improve skeletal function
• Gene therapy using genetically modified hematopoietic stem cells is also being explored.

KEY CONCEPT

• Gaucher disease = glucocerebrosidase deficiency → glucocerebroside accumulation in macrophages → Gaucher cells.
• Gaucher cell = “wrinkled tissue paper” cytoplasm.
• Type 1 = no CNS disease + hepatosplenomegaly + bone disease.
• Type 2 = severe infantile neurologic disease.
• Type 3 = later, milder neurologic disease.
• Gaucher disease is strongly associated with increased Parkinson disease risk.

CONCEPTUAL EXAMPLES

• Macrophage cannot digest glucocerebroside → lysosomes fill with lipid → Gaucher cell.
• Gaucher cells fill spleen → massive splenomegaly.
• Gaucher cells replace bone marrow → cytopenias + bone lesions.
• Enzyme replacement supplies missing glucocerebrosidase → reduces stored substrate.

Mucopolysaccharidoses

• Mucopolysaccharidoses (MPSs) are lysosomal storage diseases caused by defective breakdown of mucopolysaccharides → excessive tissue accumulation.
• Mucopolysaccharides are components of the extracellular matrix produced mainly by connective-tissue fibroblasts.
• Most are secreted, while some are normally degraded inside lysosomes by several enzymes.
• Different enzyme deficiencies produce different MPS types, classified from MPS I to MPS VII.
• Stored substances may include:
  • dermatan sulfate
  • heparan sulfate
  • keratan sulfate
  • sometimes chondroitin sulfate
• Common manifestations include:
  • hepatosplenomegaly
  • skeletal deformities
  • heart-valve abnormalities
  • subendothelial arterial deposits, especially in coronary arteries
  • brain involvement
• Coronary deposits → impaired coronary blood flow → myocardial infarction + cardiac decompensation.
• Most patients may also develop:
  • coarse facial features
  • corneal clouding
  • joint stiffness
  • intellectual disability
• Excess stored mucopolysaccharides are often excreted in the urine.
• Almost all MPS disorders are autosomal recessive.
• Important exception: Hunter syndrome → X-linked recessive.
• MPS type I (Hurler syndrome):
  • caused by deficiency of α-L-iduronidase
  • mucopolysaccharides accumulate in:
    • mononuclear phagocytes
    • fibroblasts
    • vascular endothelial cells
    • vascular smooth-muscle cells
  • Lysosomes become enlarged and vacuolated → cells appear swollen with clear cytoplasm.
  • Storage in neurons → intellectual disability.
  • Life expectancy is usually about 6–10 years.
  • Death commonly results from cardiac complications.
• MPS type II (Hunter syndrome):
  • caused by deficiency of L-iduronate sulfatase
  • X-linked
  • usually has a milder course than Hurler syndrome
  • characteristically lacks corneal clouding
  • diagnosis is based mainly on enzyme measurement in leukocytes
  • routine DNA diagnosis is difficult because many different mutations can cause the disease

KEY CONCEPT

• MPS = lysosomal enzyme deficiency → failure to degrade mucopolysaccharides → storage in multiple tissues.
• Hurler = MPS I → α-L-iduronidase deficiency → autosomal recessive + corneal clouding.
• Hunter = MPS II → L-iduronate sulfatase deficiency → X-linked recessive + no corneal clouding.
• Both may affect skeleton, liver/spleen, heart, vessels, and nervous system.

CONCEPTUAL EXAMPLES

• Missing lysosomal enzyme → mucopolysaccharides cannot be fully broken down → lysosomes enlarge and cells swell.
• Storage in liver and spleen → hepatosplenomegaly.
• Storage in neurons → intellectual disability.
• Coronary arterial deposits → reduced myocardial blood supply → myocardial infarction.
• Hurler has corneal clouding; Hunter typically does not.