Abstract
Around 10% of all amyotrophic lateral sclerosis (ALS) cases are familial and around 3–5% are fused-in-sarcoma (FUS)-related in Europe. We report a 43-year-old patient with a pathogenic FUS mutation (c.1561C>G p.(Arg521Gly) who presented at our clinic with chorea and subsequently with progressive symptoms of classical ALS. As a result of progressive upper and lower motor neurone deterioration, chorea disappeared and death occurred 2.5 years after the onset of the first manifestations. This first description adds chorea as a possible pleiotropic clinical feature in FUS-related ALS. It further warrants to systematically ask and check for chorea in ALS patients and their relatives.
Introduction
Amyotrophic lateral sclerosis (ALS) is the most common motor neurone disease (MND), which strikes on average at around the age of 50 to 70 years. Around 10% of ALS cases are familial and in Europe, some 3–5% are fused-in-sarcoma (FUS)-related (Citation1). Mutations in this gene are known to cause a familial or sporadic ALS type 6 phenotype (Citation1,Citation2), including young-onset ALS, ALS/frontotemporal dementia (FTD) and rarely pure FTD (Citation1,Citation3). De novo mutations are known to cause rapid-onset juvenile ALS phenotypes (Citation4).
Repeat expansions in C9orf72 are known to generate pleiotropic features. FUS mutations are also associated with various clinical characteristics, such as a bulbar onset or a long survival (Citation5). Prominent weakness of the neck and upper limbs were reported in patients with R521C and R521G-FUS-mutations (Citation6); cortical myoclonus has also been described (Citation7).
To the best of our knowledge, chorea has not yet been described in relation to FUS mutations. This case report illustrates the extensive genetic pleiotropy in ALS and the need for systematic collection of potential pleiotropic features of patients with (sporadic) ALS and their families.
Case report
A 43-year-old woman, whose earlier medical history was unremarkable, had been experiencing involuntary and unpredictable movements first in her legs and later in her arms since mid-2016. In 2017, she felt a weakness of first her right arm, a few months later of both legs and subsequently of her left arm. During this time, she developed dysphagia, dysarthria, and orthopnoea. She noticed upper leg fasciculations and arm muscle atrophy.
In March 2018, generalized fasciculations, a mild paresis of the tongue, the neck flexors, and the neck extensors were seen. In addition, choreoathetotic movements of the arms were found in combination with severe proximal, as well as mild distal paresis and atrophy. Chorea and hyperreflexia were present in the legs, without a paresis at that time. Her slow vital capacity measured with a spirometer was reduced (supine position 45% of predicted).
Electromyogram showed spontaneous activity and broad polyphasic muscle potentials, fulfilling El Escorial criteria in the cervical, thoracic and lumbosacral regions. Further ancillary investigations are listed in .
Table 1 Ancillary investigations.
To summarize, this is a 43-year-old patient with a 2-year history of chorea. The 12-month-history of progressive weakness of the tongue, arms and legs with fasciculations and hyperreflexia, atrophy and signs of bulbar palsy best fit a diagnosis of ALS. No genetic cause of movement disorders was discovered. We considered MND, including ALS with extrapyramidal involvement in a young patient with a fast progression rate. Further genetic testing was performed, including all recently identified ALS genes. DNA-sequencing revealed a pathogenic mutation in FUS with the substitution of arginine by glycine at residue 521 (c.1561C>G p.(Arg521Gly). The disease led to death 2.5 years after the onset of the first manifestations. Family history did not show any peculiarities, except for a brother with “Alzheimer’s disease”.
Discussion
This case report appears to be the first description of a c.1561C>G p.(Arg521Gly)-FUS-mutation generating clinically significant MND in combination with chorea. However, additional cases are needed to confirm the presumed relationship.
BSCL2-, SOD1- or C9orf72-mutations illustrate the concept of genetic pleiotropy. Repeat expansions in C9orf72 can generate ALS phenotypes, familial FTD, movement disorders (Huntington-like disease), a young age at onset or even symptom-free patients (Citation8,Citation9,Citation10). Therefore, the C9orf72 seemed to be the most likely cause.
Our findings suggest that chorea and ALS eventually share a common molecular pathway, independent of C9orf72. The inheritance is probably de novo, given the relatively young onset and rapid progression, but we did not have the chance to examine her parental DNA. As over 50 FUS-mutations have been described previously, including the one reported here (Citation10), determining the mechanisms of pleiotropy is challenging. The ALS phenotype resulting from the mutations R521C and R521G seemed to be very similar (Citation6). Our patient also had weakness of neck and proximal muscles.
Conclusion
These findings assert the pathogenicity of R521G in ALS. Chorea as a symptom can now be added to the possible clinical manifestations of FUS-related ALS and underlines the pleiotropy of this mutation and ALS in general. It implies the need to check for this symptom in patients with ALS and to enquire about its presence in ALS-patients’ family members.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
Acknowledgements
We would like to thank the patient’s family for their approval for this project.
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