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PEROXISOMES

• Peroxisome: General
  • Single-membrane organelle
  • Present in nearly all eukaryotic cells
• Peroxisome functions
  • H₂O₂ metabolism
  • Ether-Phospholipid biosynthesis
  • Bile acid; Cholesterol; Plasmalogen synthesis
  • β-Oxidation: Fatty acids (Long & Very long chain)
  • Very-long chain Fatty acid-CoA
    • Types: C26:0 & C24:0
    • Enzymes in pathway
      • Acyl-CoA Oxidase 1, Palmitoyl (ACOX1; Straight-chain acyl-CoA oxidase)
      • D-bifunctional protein
      • Thiolases: 3-Ketoacyl-CoA thiolase; Sterol carrier protein X
  • Branched chain Fatty acid-CoA
    • Types
      • Pristanoyl-CoA
      • Bile acid intermediates: THCA; Dihydroxycholestanoic acid (DHCA)
    • Enzymes in pathway
      • Branched-chain acyl-CoA oxidase
      • D-bifunctional protein
      • Thiolase: Sterol carrier protein X
  • Other: Amino acid & Purine metabolism
• Peroxisome contents: > 60 enzymes
• Peroxisome disorders: Classification & Disorders
  • Single enzyme: Affects single metabolic pathway
    • Hyperoxaluria type I
    • Refsum syndromes (Peroxisome Biogenesis Disorders)
    • Adrenoleukodystrophy
      • X-linked (ALDP)
    • Rhizomelic chondrodysplasia punctata (RCDP) : DHAPAT
    • β-Oxidation disorders
      • α-Methylacyl-CoA racemase (AMACR) deficiency
        • Type II
        • Type III (dihydroxyacetone phosphate acyltransferase)
      • D-bifunctional protein
      • Straight-chain acyl-CoA oxidase
    • Sterol carrier protein 2
      • Leukoencephalopathy with Dystonia & Motor neuropathy
  • Peroxisomal biosynthesis
    • General
      • Disorders affect all of the metabolic pathways of peroxisome
      • Disorders can result from mutations in any > 14 genes: PEX genes
      • Peroxins: Products of PEX genes
      • PEX gene function: Peroxisome biogenesis
    • Disorders
      • Neonatal adrenoleukodystrophy (NALD): PEX10
      • Zellweger syndrome: PEX10
      • Refsum disease, Adolescent or young adult: PEX7
      • Ataxia
        • SCABD1: PEX6
        • PEX10
      • Infantile Refsum disease (IRD)
        • PEX1: PBD1A (Zellweger) ; PBD1B (NALD/IRD)
        • PEX2: PBD5A ; PBD5B
      • Rhizomelic chondrodysplasia punctata (RCDP), Type I : PEX7
      • Mulibray nanism: TRIM37
  • ALS: DAO
  • Also see: OPDM
• Metabolic profiles
  • X-linked ALD (ALDP): High Very long chain fatty acids (VLCFA)
  • Refsum syndromes: High Phytanic acid
  • AMACR: High Pristanic acid & di-/tri-hydroxycholestanoic acids
• Peroxisome: External link

• Epidemiology: 2 families
• Mutations: Homozygous or Heterozygous; Nonsense; 545_546insA, c.349C>T, c.121G>T
• SCP2 protein
  • Peroxisomal
  • Facilitates transport of cholesterol to mitochondria for first step in steroidogenesis
  • Thiolase
  • Breakdown of branched chain fatty acids
  • Low levels in Zellweger syndrome
  • Mutations: Absent activity
• Clinical
  • Onset age: 2nd to 4th decade
  • Extrapyramidal
    • Head tremor: Dystonic
    • Spasmodic torticollis
  • Motor: Tone increased
  • Reflexes
    • Tendon: Arms increased; Legs reduced
    • Plantar relex: Flexor
  • Sensation: Reduced vibration & proprioception
  • Eye: Saccadic movements
  • Cerebellar: Asymmetric ataxia; Nystagmus; Gait disorder
  • Hyposmia
  • Endocrine
    • Hypergonadotrophic hypogonadism
    • Azoospermia
  • Differential diagnosis: AMACR deficiency
• Laboratory
  • MRI
    • Leukoencephalopathy
    • T2 hypointensity in thalamus, pons & occipital cortex
  • CSF: Normal
  • Pristanic acid: Increased
  • NCV
    • Motor neuropathy: Axon loss; Conduction block in legs
    • Sensory: small amplitude SNAPs
  • Evoked potentials: Abnormal corticospinal tracts & posterior columns

Epidemiology: > 30 patients Genetics Mutations: Loss of function Allelic disorder: Mitchell syndrome ACOX1 protein Fatty acid β-oxidation of VLCFA First & Rate-limiting enzyme Major producer of hydrogen peroxide (H2O2) Tissue Expression: Glia Clinical Onset ages: < 3 years Hypotonia Seizures Behavior: Loss of learning & speaking skills Vision loss: Optic atrophy Hearing loss Muscle tone: Increased Course Progressive Often death in childhood Laboratory Very long chain Fatty acids: Increased Brain MRI: Leukodystrophy; Brain atrophy Pathology: Demyelination Pontomedullary corticospinal tracts Cerebellar white matter ACOX1 variant: Mitchell Syndrome 1 Epidemiology: 12 patients Genetics Inheritance: de novo; Dominant effect Mutation Missense: N237S (Most or all patients) Heterozygous ACOX1 protein Mutant protein Gain-of function Increased ROS in glia Clinical Onset ages: 3 to 14 years Polyneuropathy Sensory loss Large fiber modalities Ataxia Motor NCV: Axon loss Spinal cord Paraparesis Leg weakness Sensory loss Bladder & Bowel Δ Course: Progressive Hearing loss: Early in disease Cognition Reduced in later disease Progressive loss Ataxia Course Episodic Demyelination Progressive Possible treatments Riboflavin N-Acetylcysteine amide (NACA) ? Immuno-modulation Laboratory NCV: Axon loss CMAP & SNAP amplitudes: Reduced Course: Progressive MRI Spinal cord pathology Dorsal column Atrophy White matter Demyelination: U-fiber sparing Nerve pathology Axon loss: Chronic & Active CNS pathology White matter & Spinal cord tracts Oligodendrocyte pathology VLCFA: Normal

Mitchell Syndrome Spinal Cord Atrophy & Posterior Cord lesions (T2 signal)