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PEROXISOMES


Leukoencephalopathy with Dystonia & Motor neuropathy (NBIA)
  Sterol carrier protein 2 (SCP2; SCPx) ; Chromosome 1p32.3; Recessive
Peroxisomal Acyl-CoA oxidase (ACOX1) Deficiency
  Acyl-CoA oxidase 1, Palmitoyl (ACOX1) ; Chromosome 17q25.1; Recessive
  • Epidemiology: > 30 patients
  • Genetics
  • 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 & Hearing loss: Optic atrophy
    • 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
    • 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)




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References
1. Neuron 2020;106:589-606.e6

7/31/2020