ALS in Finland: Major Genetic Variants and Clinical Characteristics of Patients With and Without the Hexanucleotide Repeat Expansion.

BACKGROUND AND OBJECTIVES

To analyze the frequencies of major genetic variants and the clinical features in Finnish patients with amyotrophic lateral sclerosis (ALS) with or without the hexanucleotide repeat expansion.

METHODS

A cohort of patients with motor neuron disease was recruited between 1993 and 2020 at the Helsinki University Hospital and 2 second-degree outpatient clinics in Helsinki. Finnish ancestry patients with ALS fulfilled the diagnosis according to the revised El Escorial criteria and the Awaji-criteria. Two categories of familial ALS (FALS) were used. A patient was defined FALS-A if at least 1 first- or second-degree family member had ALS, and FALS-NP, if family members had additional neurologic or psychiatric endophenotypes.

RESULTS

Of the 815 patients, 25% had FALS-A and 45% FALS-NP. expansion () was found in 256 (31%) of all patients, in 58% of FALS-A category, in 48% of FALS-NP category, and in 23 or 17% of sporadic cases using the FALS-A or FALS-NP definition. or p.D91A homozygosity was found in 328 (40%) of the 815 patients. We compared demographic and clinical characteristics between and patients with unknown cause of ALS (). We found that the age at onset was significantly earlier and survival markedly shorter in the vs patients with ALS. The shortest survival was found in bulbar-onset male patients, whereas the longest survival was found in limb-onset males. Older age at onset associated consistently with shorter survival in and patients in both limb-onset and bulbar-onset groups. There were no significant differences in the frequencies of bulbar-onset and limb-onset patients in and groups. ALS-frontotemporal dementia (FTD) was more common in (17%) than in (4%) patients, and of all patients with ALS-FTD, 70% were .

DISCUSSION

These results provide further evidence for the short survival of -associated ALS. A prominent role of the and variants was found in the Finnish population. An unusually high frequency of was also found among patients with sporadic ALS. The enrichment of these 2 variants likely contributes to the high incidence of ALS in Finland.