Familial motor neuron disease: co-occurrence of PLS and ALS (-FTD)

Abstract

Objective

To report the frequency and characteristics of patients diagnosed with primary lateral sclerosis (PLS) with a positive family history for motor neuron diseases (MND) in the Netherlands and to compare our findings to the literature.

Methods

Patients were identified through our ongoing, prospective population-based study on MND in The Netherlands, which also includes a standardized collection of patient characteristics, genetic testing, and family history. Only patients meeting the latest consensus criteria for definite PLS were included. The family history was considered positive for MND if any family members had been diagnosed with PLS, amyotrophic lateral sclerosis (ALS)(-FTD), or progressive muscular atrophy (PMA). Additionally, the literature was reviewed on PLS cases in which MND co-occurred within the same family.

Results

We identified 392 definite PLS cases, resulting in 9 families with a PLS patient and a positive family history for MND (2.3%). In only one of these pedigrees, a pathogenic variant (C9orf72 repeat expansion) was found. Our literature review revealed 23 families with a co-occurrence of PLS and MND, with 12 of them having a potentially pathogenic genetic variant.

Conclusions

The consistent observation of PLS patients with a positive family history for MND, evident in both our study and the literature, implies the presence of shared underlying genetic factors between PLS and ALS. However, these factors are yet to be elucidated.

Keywords:

• primary lateral sclerosis
• motor neuron disease
• familial

Acknowledgments

We are grateful to the families who contributed with their time on partaking in our study.

Declaration of interest

Leonard van den Berg: declares fees to his institution from Biogen, Wave, Amylyx, Ferrer, and Cytokinetics for being on a scientific advisory board; fees to his institution from Amylyx for a lecture; an unrestricted educational grant from Takeda; and is the Chair of ENCALS and TRICALS.

Jan Veldink: reports to have sponsored research agreements with Biogen and Astra Zeneca. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement n° 772376 – EScORIAL.

Michael van Es: has consulted for Biogen, and has received travel grants from Shire (formerly Baxalta), performs work as a medical monitor for an on-going trial from Ferrer (NCT05178810) with fees going to his institution. MAvE receives funding support from the Netherlands Organization for Health Research and Development (Vidi scheme), The Thierry Latran Foundation, the Motor Neurone Disease Association, FIGHT-MND and the ALS Foundation Netherlands. He is also a member of the European Reference Network for Rare Neuromuscular Diseases (ERN-NMD).