Page 218 - Concise Pathology for Exam Preparation ( PDFDrive )

8 Genetic and Paediatric Disorders 203

• Accumulation of insoluble intermediates may lead to the following:
• Organ enlargement (hepatosplenomegaly or cardiomegaly).
• CNS involvement (neuronal damage).
• Macrophage activation and cytokine release aiding to widespread cellular dysfunction
• Traditionally, lysosomal storage diseases are classified based on the biochemical nature
of the substrate or accumulated metabolite.
Examples:
• Tay–Sachs disease: G M2 gangliosidosis
• Enzyme deficiency: lysosomal hexosaminidase (a-subunit).
• Metabolite accumulation: G M2 ganglioside.
• It is primarily seen in Ashkenazi Jews.
• Patients are normal at birth but develop signs of severe mental retardation within 6
months.
• There is blindness, a cherry-red spot in the macula, muscle weakness, flaccidity and
death by 2–3 years.
• Histopathology shows ballooned neurons with cytoplasmic vacuoles which are actu-
ally distended lysosomes containing gangliosides which stain with fat stains like oil
red O and Sudan black B. Retinal ganglion cells show the same changes. The normal
colour of the macular choroid appears exaggerated due to the pallor of the adjacent
swollen ganglion cells resulting in the ‘cherry-red spot’.
• Niemann–Pick disease
• Enzyme deficiency: sphingomyelinase.
• Metabolite accumulation: sphingomyelin, primarily in macrophages (imparting a
bubbly appearance) and in neurons.
• Three variants: A, B and C; in the more severe type A, there is severe neuronal damage
and mental retardation, massive hepatosplenomegaly and deterioration of psychomo-
tor function (disease is fatal in early life).
• In type B, neuronal damage is not present.
• Type C was initially thought to be a variant of types A and B but is now considered a
distinct clinicopathological and genetic entity. It is caused by mutations in two closely
related genes—NPC1 and NPC2. Niemann–Pick type C is due to a primary defect in
free cholesterol transport from the lysosomes to the cytoplasm and resultant accumu-
lation in different organs especially in the nervous system. Patients have ataxia, dys-
arthria and psychomotor regression.
• Gaucher disease
• AR disorder; most common lysosomal storage disease.
• Enzyme deficiency: glucocerebrosidase or glucosylceramidase (primarily noted in
Ashkenazi Jews).
• Normally, the glycolipids derived from the breakdown of senescent blood cells are
sequentially degraded (glucocerebrosidase cleaves glucose from ceramide). In Gau-
cher disease, the degradation stops at the level of glucocerebroside, which accumu-
lates in the macrophages and CNS. Adverse results of Gaucher disease are caused not
only by the accumulated glucocerebroside but also due to activation of macrophages
which release various cytokines (IL 1, IL 2 and TNF).
• The most common, type I (chronic nonneuronopathic form), accounts for 99% of cases
of Gaucher disease. The glucocerebrosides accumulate in the mononuclear phagocytic
system without affecting the CNS. Distended lysosomes give the macrophages a charac-
teristic fibrillary or wrinkled tissue paper appearance (called ‘Gaucher cells’). There
is massive hepatosplenomegaly, skeletal involvement (producing bone erosions and frac-
tures), involvement of bone marrow (producing pancytopenia) and lymphadenopathy.
• Types II (acute neuronopathic type) and III (intermediate between types I and II) have
variable CNS involvement. Type II disease shows no preferential involvement of Jews
and has an infantile acute cerebral pattern of presentation. Progressive CNS involve-
ment leads to an early death. Type III disease shows systemic involvement with CNS
disease which begins late in adolescence or adulthood.
• Metachromatic leukodystrophy
• Enzyme deficiency: arylsulfatase A.

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