TY - JOUR
T1 - LBSL
T2 - Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations
AU - Stellingwerff, Menno D
AU - Figuccia, Sonia
AU - Bellacchio, Emanuele
AU - Alvarez, Karin
AU - Castiglioni, Claudia
AU - Topaloglu, Pinar
AU - Stutterd, Chloe A
AU - Erasmus, Corrie E
AU - Sanchez-Valle, Amarilis
AU - Lebon, Sebastien
AU - Hughes, Sarah
AU - Schmitt-Mechelke, Thomas
AU - Vasco, Gessica
AU - Chow, Gabriel
AU - Rahikkala, Elisa
AU - Dallabona, Cristina
AU - Okuma, Cecilia
AU - Aiello, Chiara
AU - Goffrini, Paola
AU - Abbink, Truus E M
AU - Bertini, Enrico S
AU - Van der Knaap, Marjo S
N1 - Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
PY - 2021/4
Y1 - 2021/4
N2 - Objective: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes.Methods: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function.Results: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-5'-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function.Conclusions: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.
AB - Objective: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes.Methods: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function.Results: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-5'-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function.Conclusions: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.
U2 - https://doi.org/10.1212/NXG.0000000000000559
DO - https://doi.org/10.1212/NXG.0000000000000559
M3 - Article
C2 - 33977142
SN - 2376-7839
VL - 7
SP - e559
JO - Neurology: Genetics
JF - Neurology: Genetics
IS - 2
M1 - e559
ER -