Term
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Definition
- Single Membrane organelles in the cytoplasm in all eukaryotes; several 100/cell
- ALKALINE pH
- Anabolic and Catabolic Functions
- From division of pre-existing peroxisomes or proteins imported into pre-existing peroxisome membrane vesicles
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Term
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Definition
Anabolic - Plasmalogen biosynthesis
- Cholesterol & bile acid biosynthesis
Catabolic - beta-oxidation of fatty acids (VLCFA)
- phytanic acid alpha-oxidation
- H2O2 metabolism
- metabolism of glycolate (intermediate of ser->gly)
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Term
| Peroxisome Targeting Signals |
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Definition
- PTS1: carboxy-terminal (ser-lys-leu)
- PTS2: amino-terminal (9aa)
Bind to specific receptors for transport peroxisomal proteins to and into peroxisomes. |
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Term
| Peroxisome Assembly (Pex) Genes |
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Definition
- Encode proteins (peroxin) required for matrix protein import and peroxisome division
- Encode for PTS receptors and proteins involved in peroxisomal biosynthesis (peroxins or the peroxisomal assembly proteins)
- 14 Human PEX genes
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Term
| Peroxisome Biogenesis Disorders |
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Definition
- Reduced or absent number of peroxisomes; multiple enzymes affected
- recent studies indicate that the primary defects in these disorders are in peroxisomal integral membrane proteins required for recognition and proper import of enzymes into the peroxisome
- nearly all matrix proteins are mis-localizedto cytosol
- defecs in PEX genes that encode peroxins, proteins involved in peroxisomal biogenesis
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Term
| Cellular and biochemical consequences of biogenesis mutants include: |
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Definition
- peroxisomes absent or reduced in number
- catalase in cytosol
- decreasd levels of plasmalogens
- increased levels of very long chain fatty acids
- increased urinary excretion of dicarboxylic acids
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Term
| Two subtypes of disorders of peroxisome biogenesis |
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Definition
- Zellweger syndrome spectrum
- Rhizomelic Condrodysplasia Punctata
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Term
| Physical Characteristics of Zellweger Cerebrohepatorenal Syndrome |
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Definition
- Dysmorphic face; eye abnormalities
- Severe weakness and hypotonia
- Neonatal Seizures
- Renal Cortical Cysts
- Hepatomegaly and impared liver function
- Severe psychomotor retardation
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Term
| Zellweger Cerebrohepatorenal Syndrome |
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Definition
- "Prototype" of the PBDs
- Autosomal recessive
- Incidence ~ 1/60,000
- Most common peroxisomal disorder to present in childhood
- Apparent at birth; typically die within 1-2 years
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Term
| Rhizomelic Chondrodysplasia Type I |
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Definition
- clincally distinct from other peroxisomal disorders
- Primary Defect: Mutations in Pex7 gene (encodes the receptor for a subset of peroxisomal matrix enzymes that contain the PTS2 targeting signal)
- mutations in the gene affect import of a subset of matrix enzymes while leaving othes intact
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Term
| Clinical aspects of Rhizomelic Chondrodysplasia Punctata Type I |
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Definition
- Marked reduction of plasmalogen levels and impairment of plasmalogen synthesis
- Increased levels of phytanic acid; impaired ability to oxidize
- Presence of unprocesed form of 3-oxoacyl-CoA thiolase
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Term
| Physical characteristics of Rhizomelic Chondrodysplasia Punctata Type I |
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Definition
- Severe disproportionate shortening of proximal limbs
- microcephaly
- cataracts
- ichthyosis
- severe psychomotor retardation
- death during first year of life
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Term
| Mutation analysis of PEX genes |
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Definition
- 2 mutations in PEX1 account for 56% of ZS
- 2 mutations in PEX7 account for 65% RCDP
- Association of severe mutations with severe disease
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Term
| Defects in Single Peroxisomal Enzymes |
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Definition
- X-linked adrenoleukodystrophy
- Acatalasemia
- Hyperoxaluria type I
- Acyl-CoA oxidase deficiency
- Bifunctional enzyme deficiency
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Term
| X-Linked Adrenoleukodystrophy |
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Definition
- most common peroxisomal disorder
- Normal early development; rapid downhill course with onset between 4-8 years of age
- hyperactive, withdrawn
- visual and hearing impairment, lossof speech
- degenerative neurologic disorder
- adrenal insufficiency
- abnormal accumulation of VLCFAs in brain white matter and adrenal cortex
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Term
| Diagnosis of X-Linked ALD |
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Definition
- Elevated VLFCAs in males (>99% males have abnormalvalues +/- symptoms)
- VLCFA assay identifies ~85% female carriers
- Mutation in ALDP - transporter protein, most likely necessary to transport VLCFA into peroxisomes
- Molecular diagnosis - ABCD1 gene (primarily for carrier status and prenatal)
- -ALDP-1/2 transporter of ATP binding cassette
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Term
| Treatment of X-Linked ALD |
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Definition
- Manage adrenal insufficiency
- Bone marrow transplant for cerebral form if detected early in course (but high risk procedure)
- Dietary therapy - "Lorenzo's Oil" - normalizes the levels of VLCFAs - efficacy still ont clear; benefit limited
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