Is it HSP, CMT, PLS or ALS?

Gene testing helps with diagnosis

Whole exome sequencing (WES) is found to help with differential diagnosis of HSP, CMT, PLS and ALS, which are difficult to distinguish clinically early in the disease course. This study of 139 cases found that gene testing helped resolve diagnostic challenges in a significant percentage of cases.

Background and objectives: Primary lateral sclerosis (PLS) is a motor neuron disease characterised by loss of the upper motor neurons. Most patients present with slowly progressive spasticity of the legs, which may also spread to the arms or bulbar regions. It is challenging to distinguish between PLS, early-stage amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). The current diagnostic criteria advise against extensive genetic testing. This recommendation is, however, based on limited data.

Methods: We aim to genetically characterize a PLS cohort using whole exome sequencing (WES) for genes associated with ALS, HSP, ataxia and movement disorders (364 genes) and C9orf72 repeat expansions. Patients fulfilling the definite PLS criteria by Turner et al. and with available DNA samples of sufficient quality were recruited from an on-going, population-based epidemiological study. Genetic variants were classified according to the ACMG criteria and assigned to groups based on disease association.

Results: WES was performed in 139 patients and the presence of repeat expansions in C9orf72 was analysed separately in 129 patients. This resulted in 31 variants of which 11 were (likely) pathogenic. (Likely) pathogenic variants resulted in 3 groups based on disease association: ALS-FTD (C9orf72, TBK1), pure HSP (SPAST, SPG7), “ALS-HSP-CMT overlap” (FIG4, NEFL, SPG11).

Discussion: In a cohort of 139 PLS patients, genetic analyses resulted in 31 variants (22%) of which 10 (7%) (likely) pathogenic associated with different diseases (predominantly ALS and HSP). Based on these results and the literature, we advise to consider genetic analyses in the diagnostic work-up for PLS.

SOURCE:  J Neurol. 2023 Aug;270(8):3970-3980.  

doi: 10.1007/s00415-023-11746-7. Epub 2023 May 3.  PMID: 37133535 © 2023. The Author(s).

Genetic characterization of primary lateral sclerosis

Eva M J de Boer  1 Balint S de Vries  1 Maartje Pennings  2 Erik-Jan Kamsteeg  2 Jan H Veldink  1 Leonard H van den Berg  1 Michael A van Es  3

1. Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.

2. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

3. Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.

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