Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive upper and lower motor neuron (LMN) loss. As ALS and other neurodegenerative diseases share genetic risk factors, we performed whole-exome sequencing in ALS patients focusing our analysis on genes implicated in neurodegeneration. Thus, variants in the DHTKD1 gene encoding dehydrogenase E1 and transketolase domain containing 1 previously linked to 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth (CMT) disease type 2, and spinal muscular atrophy (SMA) were identified. In two independent European ALS cohorts (n = 643 cases), 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants predicted to be deleterious. Four DHTKD1 variants were previously described pathogenic variants, seven were recurrent, and eight were located in the E1_dh dehydrogenase domain. Nonsense variants located in the E1_dh domain were significantly more prevalent in ALS patients versus controls. The phenotype of ALS patients carrying DHTKD1 variants partially overlapped with CMT and SMA by presence of sensory impairment and a higher frequency of LMN-predominant cases. Our results argue towards rare heterozygous DHTKD1 variants as potential contributors to ALS phenotype and, possibly, pathogenesis.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by upper and lower motor neuron loss, commonly leading to death due to respiratory paralysis within three to five years after disease onset [1]
In cases with absence of UMN signs, the diagnosis of progressive muscular atrophy (PMA) was made after careful exclusion of disease mimics, including search for conduction blocks by extensive nerve conduction studies (NCS) and cerebrospinal fluid analysis to rule out immune-mediated neuropathies, genetic testing for deletions or point mutations in the SMN1 gene or expansion of the CAG repeat in the androgen receptor gene, and/or muscle biopsies [2]
A candidate gene-based strategy was applied prioritizing rare (MAF ≤ 0.5%), non-silent variants not present in in-house controls and predicted to be deleterious in 694 genes associated with neurodegeneration, revealing the DHTKD1 gene as the only gene harboring such variants in two patients (Supplementary Table S1)
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by upper and lower motor neuron loss, commonly leading to death due to respiratory paralysis within three to five years after disease onset [1]. Some of the genes identified in ALS patients are causative for other neurodegenerative disorders, such as C9orf and TARDBP for frontotemporal dementia (FTD) and Parkinson’s disease, and SPG7 and SPG11 for hereditary spastic paraplegia, indicating shared pathomechanisms [4,5,6,7]. It appears as though most, if not all ALS genes may be pleiotropic [8]
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