20210518_LBSLとHBSL_LBSLのnovel variants

@HBSLとLBSL（Front Cell Neurosci 2021;14:626610）

  • Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL): DARS1 mutation
  • Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL): DARS2 mutation

    • Relatively mild disease course with childhood or adolescent onset and slowly progressive pyramidal, cerebellar, and dorsal column dysfunction

  • いずれもaspartyl-tRNA synthetaseをencodeするgene。
    • DARS1: cytosolic aspartyl-tRNA synthetase (AspRS)をcode
    • DARS2: mitochondrial counterpart (mt-AspRS)をcode
  • MRI: LBSL (n=83)
     
     

    など

     
    • Supratentorial
    • Cerebral WM with subcortical sparing, 92.8%
    • Posterior limb of the internal capsule, 81.9%
    • Posterior part of the corpus callosum, 77.1%
    • Infratentorial
    • Lateral corticospinal tracts or dorsal columns of the spinal cord, 89.2%
    • Pyramidal tract and/or medial lemniscus, 94%
    • Superior cerebellar peduncles, 73.5%
    • Inferior cerebellar peduncles, 69.9%
    • Cerebellar white matter, 88%
  • MRI: HBSL (n=15) 

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644624/

    など。No lactate elevation has been described in HBSL.

    • Supratentorial
    • Homogeneous cerebral WM abnormality, 80%
    • Corpus callosum, 60%
    • Posterior limb of the internal capsule, 60%
    • Brainstem
    • Pyramidal tract, 53.3%
    • Cerebellum
    • WM, 26.7%
    • Superior cerebellar peduncle, 60%
    • Inferior cerebellar peduncle, 53.3%
    • Spinal cord
    • Dorsal columns, 100% (13/13)
    • Lateral corticospinal tracts, 90.9% (10/11)
  • Clinically:かなりoverlapがある。
  • Clear lack of peripheral neuropathy and lower motor neuron signs in HBSL patients
    • Both: onsetが早いほうがより重篤かつ進行性。lower limb spasticity, other pyramidal signs
    • Neither: extra-neurological signs. このselective neurological phenotypeは多くのARS-related diseasesでも認められる特徴。
      • 一部例外がある。例えば
        • AARS2 mutation: severe cardiomyopathy, (ovarioleukodystrophy)
    • LBSL: birth–43 years (mean, 7 y.o.); peripheral neuropathy, visual and hearing changes
    • HBSL: 4 months–18 years (mean, 3.5 y.o.)

 

@Novel LBSL phenotypes (Neurol Genet 2021;7:e559)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105885/

  • 2 MRI phenotypes
  • ちなみに既存のMRI診断基準は https://pubmed.ncbi.nlm.nih.gov/23065766/ 参照 (2007 & 2012改訂)。
    • Early severe cerebral hypoplasia/atrophy (group 1, n=9)
      • ほぼ全員が出生時にmicrocephalyあり。eye contactなし、あるいは出生後すぐに消失し、てんかんを生じる。
    • White matter abnormalities without long tract involvement (group 2, n=6)
      • microcephalyは経過中1例のみ。1例にsevere epilepsy, eye contact lost, all motor milestones lost, and died at age 2 years
  • MRI features of
    • Group 1
      • tortuous vessels at the brain surface(6/9), cerebral hypoplasia and atrophy (9/9), diffusion restriction in WM (7/9)
    • Group 2
      • rarefied or cystic cerebral WM (6/6; 長期の変化？), diffusion restriction in WM (4/4)
  • Group 1でのtortuous vesselsについて

    • Secondary neovascularization may be more likely and is perhaps related to the dramatic cortical neuronal cell death or profound energy deficiency related to cortical mitochondrial dysfunction and energy depletion. 

    • Menkes disease や cerebellar arteries in NUBPL variantsに類似。
    • これらの疾患はいずれもmitochondrial dysfunctionと関連している。