Peroxisomal Disorders Flashcards
A 2-month-old male infant is brought to the clinic due to poor feeding, hypotonia, and seizures. Physical examination reveals craniofacial dysmorphism, including a flattened facies and a large fontanelle. The infant also has hepatomegaly and jaundice. Laboratory studies show elevated very-long-chain fatty acids (VLCFA) and pipecolic acid levels. Genetic testing reveals a mutation in the PEX gene. Which of the following best explains the underlying pathophysiology of this condition?
A) Impaired peroxisomal alpha-oxidation of branched-chain fatty acids
B) Defective biogenesis of peroxisomes
C) Defective beta-oxidation of fatty acids in mitochondria
D) Impaired lysosomal degradation of sphingolipids
E) Dysfunction of mitochondrial oxidative phosphorylation
Answer: Defective biogenesis of peroxisomes
Explanation: Zellweger Syndrome is an autosomal recessive disorder caused by mutations in PEX genes, leading to defective biogenesis of peroxisomes. This results in the accumulation of very-long-chain fatty acids (VLCFA) and pipecolic acid, as peroxisomes are essential for their metabolism. The clinical features include hypotonia, seizures, craniofacial abnormalities, hepatomegaly, and early death. Diagnosis is supported by elevated VLCFA levels and genetic testing.
Incorrect Answers:
A) Impaired alpha-oxidation of branched-chain fatty acids occurs in Refsum Disease, leading to phytanic acid buildup, not VLCFA accumulation.
C) Beta-oxidation of fatty acids occurs in mitochondria and is not primarily affected in peroxisomal disorders like Zellweger Syndrome.
D) Lysosomal degradation of sphingolipids is impaired in lysosomal storage diseases (e.g., Gaucher, Niemann-Pick), not in Zellweger Syndrome.
E) Dysfunction of mitochondrial oxidative phosphorylation causes mitochondrial myopathies, not peroxisomal disorders.
What are the key functions of peroxisomes?
- beta-oxidation of very-long-chain fatty acids (VLCFA)
- alpha-oxidation of branched-chain fatty acids
- catabolism of amino acids, ethanol
- synthesis of bile acid
- synthesis of plasmalogen (needed for white matter synthesis)
What is the genetic inheritance pattern of the Zellweger Syndrome?
Autosomal recessive
What is the pathophysiology of Zellweger Syndrome?
Autosomal recessive disorder of peroxisome biogenesis due to mutated PEX genes, leading to VLCFA and pipecolic acid accumulation.
This leads to decreased myelination and abnormal CNS development.
What are the clinical features of Zellweger Syndrome?
Hypotonia, seizures, jaundice, craniofacial dysmorphism, hepatomegaly, and early death
What is the genetic inheritance pattern of the Refsum Disease?
Autosomal recessive
What is the underlying defect in Refsum Disease?
Defective alpha-oxidation due to an inability to degrade phytanic acid
What are the clinical features of Refsum Disease?
Vision loss (retinitis pigmentosa), anosmia, hearing loss, ataxia, ichthyosis (thickened skin), peripheral neuropathy, and cardiac conduction defects
How is Refsum disease managed?
Treatment: diet, plasmapheresis.
How is Adrenoleukodystrophy inherited?
X-linked recessive.
What is the underlying mutation in Adrenoleukodystrophy?
Mutation in the ABCD1 gene, leading to defective beta-oxidation of VLCFA
What are the clinical features of Adrenoleukodystrophy?
VLCFA buildup:
- destroys the adrenal glands, causing adrenal crisis
- destroys the white matter of the brain
- destroys the testes
- progressive neurologic decline, and death
