Single gene disorders associated with defects in enzymes md pathology exam question give robbins based answer

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Single-gene disorders associated with defects in enzymes

Mutations in a single gene may produce either a reduced quantity of a normal enzyme or an abnormal enzyme with reduced activity. This creates a metabolic block. Most enzyme-defect disorders are autosomal recessive, because about 50% enzyme activity in heterozygotes is usually sufficient for normal function. Important exceptions include certain X-linked conditions, such as G6PD deficiency and Lesch-Nyhan syndrome.

Consequences of enzyme defects

An enzymatic block produces disease by one or more of the following mechanisms:

Accumulation of substrate or upstream metabolites
- The substrate proximal to the metabolic block accumulates.
- Accumulated substrate, intermediates, or products diverted into minor pathways may be toxic.
- Examples
  - Galactosemia: deficiency of galactose-1-phosphate uridyltransferase causes accumulation of galactose metabolites and tissue injury.
  - Lysosomal storage diseases: deficiency of lysosomal degradative enzymes causes progressive accumulation of complex substrates in lysosomes.
  - α1-antitrypsin deficiency: failure to inhibit neutrophil elastase allows elastin destruction in lung alveoli, resulting in emphysema.
Deficiency of an essential end product
- A metabolic block may prevent synthesis of a product necessary for normal structure or function.
- Example: albinism
  - Deficiency of tyrosinase impairs conversion of tyrosine to melanin.
  - Reduced or absent melanin produces hypopigmentation.
Excess formation of intermediates due to loss of feedback inhibition
- If the final product normally inhibits an upstream enzyme, its deficiency permits excess pathway activity and overproduction of intermediates.
- Example: Lesch-Nyhan syndrome
  - Due to deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT).
  - Purine salvage is impaired, leading to increased de novo purine synthesis and excess uric acid production.
Inability to detoxify harmful substances or respond to environmental stress
- The phenotype may be apparent only after exposure to a drug, food, infection, or other stressor. This is the basis of pharmacogenetics.
- Example: G6PD deficiency
  - Reduced NADPH generation prevents maintenance of reduced glutathione in erythrocytes.
  - Oxidant stress, for example infection, primaquine, sulfonamides, or fava beans, precipitates hemolysis.

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 127.

Important examples of enzyme-defect disorders

Defective enzyme/protein	Disorder	Major consequence
Phenylalanine hydroxylase	Phenylketonuria	Accumulation of phenylalanine and toxic metabolites
Galactose-1-phosphate uridyltransferase	Galactosemia	Galactose metabolite accumulation and tissue injury
Tyrosinase	Albinism	Decreased melanin synthesis
Hexosaminidase A	Tay-Sachs disease	GM2 ganglioside accumulation in neurons
Acid sphingomyelinase	Niemann-Pick disease types A and B	Sphingomyelin accumulation
Glucocerebrosidase	Gaucher disease	Glucocerebroside accumulation in macrophages
HPRT	Lesch-Nyhan syndrome	Hyperuricemia and neurologic dysfunction
Adenosine deaminase	Severe combined immunodeficiency	Toxic purine metabolite accumulation, lymphocyte dysfunction
G6PD	G6PD deficiency	Oxidant-induced hemolytic anemia
α1-antitrypsin	α1-antitrypsin deficiency	Unopposed elastase causing emphysema; abnormal protein retention in liver
Factor VIII	Hemophilia A	Defective coagulation

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 127.

Lysosomal storage diseases

These are an important group of single-gene disorders due to deficiency of lysosomal acid hydrolases or defects in lysosomal enzyme targeting.

Pathogenesis

Lysosomes contain many hydrolytic enzymes that degrade complex macromolecules.
Lysosomal enzymes are synthesized in rough ER and processed in the Golgi apparatus.
In the Golgi, enzymes receive a mannose-6-phosphate (M6P) tag.
M6P receptors recognize the tag and direct enzymes to lysosomes.
A defect in a lysosomal enzyme, or in its M6P-dependent targeting, prevents degradation of its substrate.
The partially degraded substrate accumulates in lysosomes, causing enlargement and dysfunction of cells.

Accumulation can affect:

Macrophages in liver, spleen, lymph nodes, and bone marrow
Neurons, producing progressive neurologic deterioration
Other visceral and mesenchymal cells

Common pathologic features include:

Hepatosplenomegaly
Lymphadenopathy
Cytoplasmic vacuolation or foamy cells
Progressive neurodegeneration in many disorders
Lysosomal inclusions demonstrable by electron microscopy

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 134.

Major lysosomal storage diseases

Disease	Enzyme defect	Stored substrate	Important features
Tay-Sachs disease	Hexosaminidase A	GM2 ganglioside	Severe neurodegeneration, exaggerated startle response, cherry-red macula; no hepatosplenomegaly
Niemann-Pick disease types A and B	Acid sphingomyelinase	Sphingomyelin	Foam cells, hepatosplenomegaly; type A has severe neurologic disease and early death
Gaucher disease	Glucocerebrosidase	Glucocerebroside	Hepatosplenomegaly, cytopenias, bone disease; macrophages have wrinkled-paper cytoplasm
Fabry disease	α-Galactosidase A	Ceramide trihexoside	X-linked; angiokeratomas, neuropathic pain, renal and cardiac disease
Krabbe disease	Galactocerebrosidase	Galactocerebroside	Severe neurologic deterioration; globoid cells
Metachromatic leukodystrophy	Arylsulfatase A	Cerebroside sulfate	Demyelination with progressive neurologic impairment
Hurler syndrome	α-L-Iduronidase	Dermatan sulfate and heparan sulfate	Coarse facial features, skeletal deformities, hepatosplenomegaly, developmental delay
Hunter syndrome	Iduronate sulfatase	Dermatan sulfate and heparan sulfate	X-linked; resembles Hurler but no corneal clouding
I-cell disease	Failure of M6P tagging of lysosomal enzymes	Multiple substrates	Enzymes are secreted instead of delivered to lysosomes; severe skeletal and developmental abnormalities

Glycogen storage diseases

Glycogenoses are inherited defects in enzymes involved in glycogen synthesis or degradation. They cause excess glycogen accumulation, most often in liver, skeletal muscle, heart, or all three.

General clinicopathologic patterns

Predominant liver involvement: hepatomegaly, hypoglycemia, growth retardation.
Predominant muscle involvement: exercise intolerance, muscle cramps, weakness.
Predominant cardiac involvement: cardiomegaly and heart failure.

Important examples

Disease	Enzyme defect	Main tissues involved	Important features
Von Gierke disease, type I	Glucose-6-phosphatase	Liver, kidney	Severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia
Pompe disease, type II	Lysosomal acid α-glucosidase	Heart, skeletal muscle	Cardiomegaly, hypotonia, heart failure in infantile form
Cori disease, type III	Debranching enzyme	Liver, muscle	Hepatomegaly, milder hypoglycemia
McArdle disease, type V	Muscle glycogen phosphorylase	Skeletal muscle	Exercise intolerance, cramps, myoglobinuria

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 140.

Conclusion

Single-gene enzyme defects produce disease mainly by:

toxic accumulation of substrates,
deficiency of essential end products,
excessive intermediate production caused by loss of feedback control, or
failure to detoxify injurious substances.

Lysosomal storage diseases and glycogen storage diseases are major pathologic examples because enzyme deficiency causes characteristic intracellular accumulation of substrates and progressive organ dysfunction.

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