A 4-month-old boy is being evaluated for a hereditary metabolic disorder after presenting with failure to thrive and developmental delay. He was born outside the United States and had several seizures during the neonatal period. Physical examination reveals an abnormal head shape with a large anterior fontanelle and widely splayed cranial sutures. Profound hypotonia and hepatomegaly are also noted. Biochemical studies show elevated levels of very long chain fatty acids (VLCFAs) and phytanic acid. Cultured skin fibroblasts show impaired ability to oxidize VLCFAs. This patient's condition is best explained by dysfunction of which of the following cellular structures?

Question

A 4-month-old boy is being evaluated for a hereditary metabolic disorder after presenting with failure to thrive and developmental delay.  He was born outside the United States and had several seizures during the neonatal period.  Physical examination reveals an abnormal head shape with a large anterior fontanelle and widely splayed cranial sutures.  Profound hypotonia and hepatomegaly are also noted.  Biochemical studies show elevated levels of very long chain fatty acids (VLCFAs) and phytanic acid.  Cultured skin fibroblasts show impaired ability to oxidize VLCFAs.  This patient's condition is best explained by dysfunction of which of the following cellular structures?

Quizplus · Accepted Answer

11ec160b_36ef_a8a5_9249_4da7a8cb3d6e_MD0001_00 Peroxisomal disorders are rare inborn errors of metabolism in which peroxisomes are either absent or nonfunctional. Very long chain fatty acids (VLCFAs) and certain branched-chain fatty acids (eg, phytanic acid) cannot undergo mitochondrial beta-oxidation; these fatty acids are metabolized by a special form of beta-oxidation (VLCFAs) or by alpha-oxidation (branched-chain fatty acids) within peroxisomes. In peroxisomal disorders, these fatty acids build up in various tissues. Accumulation in neuronal cell membranes leads to neurologic defects due to improper neuronal migration, myelination, and degeneration. This infant most likely has Zellweger syndrome, which is caused by defective peroxisomal biogenesis. It typically presents in early infancy with craniofacial abnormalities (eg, widened sutures, large anterior fontanelle), hepatomegaly, and profound neurologic defects (eg, hypotonia, seizures, developmental delay). Death usually occurs within months of initial presentation. Another common peroxisomal disease is X-linked adrenoleukodystrophy, which is characterized by defective transport of VLCFAs into peroxisomes. Patients present in childhood or adulthood with neurologic deterioration and adrenal insufficiency as VLCFAs accumulate in the central nervous system and adrenal glands. (Choice A) The Golgi apparatus is involved in posttranslational modification of proteins from the rough endoplasmic reticulum. It also routes proteins to their ultimate location (eg, lysosomes, extracellular space) using membrane-bound vesicles. (Choice B) Lysosomes are organelles containing proteins that can digest a diverse range of biomolecules, cellular debris, and engulfed pathogens. Lysosomal storage disorders (eg, mucopolysaccharidoses, sphingolipidoses) result in intracellular accumulation of glycosaminoglycans, glycoproteins, or glycolipids. (Choice C) Mitochondria are responsible for beta-oxidation of most fatty acids, ketogenesis, the TCA cycle and electron transport chain, and the first 2 steps of the urea cycle. Dysfunction can lead to various types of encephalomyopathy. Mitochondria do not metabolize VLCFAs or fatty acids with branch points at odd-numbered carbons. (Choice E) Proteasomes degrade unneeded or defective intracellular proteins into small polypeptides or amino acids. Impaired proteasome function can lead to cell cycle dysregulation, protein aggregation, and defective processing of peptide antigens. (Choice F) The rough endoplasmic reticulum is the site of synthesis for most secretory proteins, integral membrane proteins of the nucleus and cell membrane, and lysosomal proteins. Educational objective: The buildup of very long chain and branched-chain (eg, phytanic) fatty acids due to impaired oxidation is the hallmark of peroxisomal disorders (eg, Zellweger syndrome, adrenoleukodystrophy). Accumulation of these fatty acids in the brain results in permanent neurologic dysfunction. __________ References: Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. (http://www.ncbi.nlm.nih.gov/pubmed/26750748) Zellweger spectrum disorders: clinical overview and management approach. (http://www.ncbi.nlm.nih.gov/pubmed/26627182)

A 4-Month-Old Boy Is Being Evaluated for a Hereditary Metabolic