• Gangliosidoses are lysosomal storage diseases in which gangliosides accumulate, mainly in the brain.
• They occur because of deficiency of lysosomal enzymes needed to break down these glycolipids.
• Depending on the stored ganglioside, they are divided into:
  • GM1 gangliosidoses
  • GM2 gangliosidoses
• Tay-Sachs disease is the most common gangliosidosis.
• It is caused by loss-of-function mutations affecting the α-subunit of hexosaminidase A.
• Hexosaminidase A is required to degrade GM2 ganglioside.
• Therefore: ↓ Hexosaminidase A → failure of GM2 degradation → GM2 accumulation, especially in the brain
• More than 100 mutations have been identified.
• Most mutations interfere with:
  • proper protein folding
  • normal intracellular transport
• Because of a founder effect, Tay-Sachs disease is more common in people of Ashkenazi Jewish ancestry.
• In this population, the estimated carrier frequency is about 1 in 30.
• Ashkenazi Jews originated mainly from Eastern and Central Europe and form most of the Jewish population in the United States.
• Heterozygous carriers can be detected by:
  • measuring hexosaminidase activity in serum
  • DNA sequencing

KEY CONCEPT

• Tay-Sachs = Hexosaminidase A α-subunit defect → GM2 ganglioside cannot be degraded → GM2 accumulates mainly in the brain.
• Increased prevalence in Ashkenazi Jewish populations.
• Carrier detection → enzyme assay or DNA sequencing.

CONCEPTUAL EXAMPLES

• Hexosaminidase A is defective → lysosome cannot remove GM2 → GM2 progressively accumulates.
• GM2 accumulates mainly in neural tissue → brain is the major affected site.
• Healthy person with one mutant allele → may be identified as a carrier by enzyme testing or DNA analysis.

Pathogenesis

• In Tay-Sachs disease, absence of hexosaminidase A → GM2 ganglioside accumulates in many tissues.
• Although GM2 may accumulate in the heart, liver, spleen, and nervous system, the main clinical effects come from involvement of:
  • CNS neurons
  • autonomic neurons
  • retina
• GM2 accumulates within:
  • neurons
  • axons
  • glial cells
• Affected cells become swollen and sometimes foamy (Fig. 4.13A).
• Electron microscopy shows onion-skin–like whorled membranes inside lysosomes (Fig. 4.13B).
• These changes occur throughout:
  • brain and spinal cord
  • peripheral nerves
  • autonomic nervous system
  • retina
• In the retina:
  • surrounding ganglion cells become swollen and pale
  • the relatively unaffected central macula appears as a contrasting cherry-red spot.
• The exact mechanism of neuronal injury is not fully known.
• Many mutant proteins are misfolded → activate the unfolded protein response.
• If chaperones cannot stabilize the abnormal enzyme:
  misfolded protein → proteasomal degradation → less enzyme activity → toxic substrate accumulation in neurons.
• This has led to trials of molecular chaperone therapy:
  • synthetic chaperones enter the brain
  • bind mutant protein
  • improve folding
  • may restore enough enzyme activity to improve cell function
• In the common acute infantile form:
  • 3–6 months → motor weakness begins
  • then → progressive neurologic impairment
  • blindness develops
  • neurologic dysfunction becomes increasingly severe
  • death usually occurs by 2–3 years

Niemann-Pick Disease Types A and B

• Types A and B are caused by deficiency of acid sphingomyelinase.
• This enzyme normally breaks down:

Sphingomyelin → ceramide + phosphorylcholine

• Enzyme deficiency → sphingomyelin accumulation.
• These disorders are more common in individuals of Ashkenazi Jewish ancestry.
• The acid sphingomyelinase gene is preferentially expressed from the maternal chromosome because the paternal gene is epigenetically silenced.
• Type A:
  • severe sphingomyelinase deficiency
  • sphingomyelin accumulates in macrophages and neurons
  • macrophages become filled with lipid → foamy cytoplasm (Fig. 4.14)
  • electron microscopy shows lysosomes with concentric membranous structures called “zebra bodies”
• Organs most affected because of abundant phagocytic cells:
  • spleen
  • liver
  • bone marrow
  • lymph nodes
  • lungs
• Splenomegaly may be marked.
• CNS involvement is also severe:
  • neurons become enlarged and vacuolated from lipid accumulation
  • disease presents in infancy with:
    • massive organomegaly
    • severe neurologic deterioration
  • death usually occurs within the first 3 years
• Type B:
  • mutant sphingomyelinase retains some activity
  • causes organomegaly
  • usually no neurologic manifestations
• Diagnosis can be made by:
  • measuring sphingomyelinase activity in leukocytes
  • molecular genetic testing

KEY CONCEPT

• Tay-Sachs → hexosaminidase A deficiency → GM2 accumulation, especially in neurons → neurodegeneration + cherry-red spot.
• Niemann-Pick A/B → acid sphingomyelinase deficiency → sphingomyelin accumulation.
• Type A → severe enzyme loss → organomegaly + severe CNS disease.
• Type B → residual enzyme activity → organomegaly with little/no neurologic disease.

CONCEPTUAL EXAMPLES

• Hexosaminidase A absent → GM2 fills neurons → cells swell → progressive neurologic decline in Tay-Sachs.
• Retina becomes pale around the macula → central macula stands out as a cherry-red spot.
• Severe sphingomyelinase deficiency → lipid-filled macrophages + neuronal storage → Niemann-Pick type A.
• Partial sphingomyelinase activity → storage mainly in organs without major CNS damage → Niemann-Pick type B.