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Background: Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disorder characterized by adult-onset progressive muscle atrophy, flaccid paresis, and bulbar palsy. In addition, increasing evidence indicates that SBMA is a multisystem disorder with prominent non-motor symptoms, such as sensory neuropathy, androgen insensitivity, and glucose intolerance. This study aimed to further characterize the clinical manifestations and biomarker profile in a large Swedish SBMA cohort.

Methods: 49 genetically confirmed SBMA patients were identified from a motor neuron disease database at Umeå University Hospital, Sweden. CAG repeat length in the androgen receptor (AR) gene was assessed by RP-PCR. Blood samples were analyzed for cardiovascular and muscle biomarkers. Clinical data were collected from medical records and interviews, with autopsy findings reviewed in two cases.

Results: The mean CAG repeat length was 43.1, with a mean age at motor symptom onset of 58.6 years. Notably, 19% of patients initially presented with sensory symptoms. High prevalence of hypertonia (70%), diabetes mellitus (39%), and cardiac disease (38%) was observed. Elevated troponin levels were common, and pNfL (neurofilament light chain in plasma) was elevated in seven patients, likely reflecting combined cerebrovascular and cardiovascular comorbidity. Importantly, two of these seven patients exhibited rapid disease progression, and a concomitant diagnosis of ALS was confirmed histopathologically.

Discussion: This cohort was characterized by a relatively low number of AR gene CAG repeats and a late onset of motor symptoms. Sensory symptoms frequently occurred before motor decline. Cardiovascular disease and diabetes were common comorbidities and, in some cases, preceded neurological symptoms. These findings underscore the need for improved clinical awareness of the heterogeneous presentation of SBMA and support routine cardiovascular monitoring to reduce diagnostic delays and prevent early mortality.

Background: Nucleotide repeat expansions are associated with an increased risk of various symptoms and disorders, buttheir pleiotropic effects are not yet fully understood. Huntington’s disease (HD), spinobulbar muscular atrophy (SBMA),and C9ORF72 hexanucleotide repeat expansion (HRE)-associated amyotrophic lateral sclerosis (ALS) share underlying nucleotide repeat expansions that disrupt gene function and lead to neurodegeneration. Northern Sweden is suggested to harbor high frequencies of such disorders, but regional prevalence and phenotypic characteristics remain insufficiently defined. The aim of this thesis was to investigate nucleotide repeat expansion-related disorders in northern Sweden with focus on prevalence, genotype-phenotype interactions and pathology in HD, SBMA and ALS.

Method: Individuals with HD were identified through electronic medical records in two Swedish counties and comparisons made with national registry data. ALS and SBMA cases were retrieved from the Neurodatabase registry at the Department of Clinical Sciences/Neurosciences, Umeå University and the Department of Neurology, Umeå University Hospital. From the adhering biobank, blood samples were collected for analyses of biomarkers as well as genetic analyses of repeat sizes in the HTT, AR, and C9ORF72 genes. Clinical phenotypes were evaluated using medical records.Neuropathological assessment was performed on brain samples from selected autopsies of motor neuron disease (MND) individuals with HTT gene expansions and SBMA with atypical clinical progression.

Results: The prevalence of HD in the region of Jämtland was found to be high (22.1/100,000). HTT gene expansions within intermediate range were not enriched among ALS patients and did not modify ALS phenotype. However, neuropathological examinations revealed huntingtin inclusions in ALS patients with intermediate and reduced penetrance HTT gene expansions. Both HD and SBMA cases carried CAG repeat expansions in the lower pathogenic range (mean 41.1 and 43.1 respectively). SBMA patients frequently exhibited non-motor symptoms and cardiovascular comorbidities, and elevated plasma neurofilament light chain levels indicated atypical disease or cerebrovascular involvement. Evidence of concomitant ALS pathology was found in two SBMA cases. C9ORF72 HRE-associated ALS had a five year earlier onset (p<0.001), a nine-month shorter disease duration (p=0.044), and a higher incidence of cognitive symptoms (p=0.013) compared to sporadic ALS. Beyond MND and FTD (frontotemporal dementia), families of C9ORF72 HRE patients showed increased frequencies of other forms of dementia (p=0.046) and psychotic disorders (p=0.013) compared to families of sporadic ALS.

Conclusion: This thesis highlights the role of gene repeat expansions in the neurodegenerative disorders HD, SBMA, and C9ORF72 HRE-associated ALS. The prevalence of HD in northern Sweden was fourfold higher than the European average. In the investigated ALS cohort, no association was observed between intermediate-range HTT expansions and ALS phenotype. SBMA patients harboring lower-range AR expansions exhibited a heterogeneous clinical spectrum, including frequent sensory and cardiovascular manifestations. In C9ORF72 HRE-associated ALS, distinct cognitive and psychiatric features were found further emphasizing the pleiotropic effects of the C9ORF72 HRE mutation. Collectively, these findings underscore the importance of heightened clinical vigilance in the assessment of patients suffering from MND, particularly those harboring repeat expansions.

Background and Objectives Myasthenia gravis (MG), an autoimmune disease characterized by fluctuating muscle weakness, is believed to result from complex gene-environment interactions, yet few risk factors have been identified. The objective of this study was to determine the effect of nicotine and alcohol on MG disease risk.

Methods The Genes and Environment in Myasthenia Gravis study is a Swedish, nationwide cross-sectional case-control study where prevalent patients with MG were invited to submit an extensive questionnaire on lifestyle and environment. Data collection took place between November 2018 and August 2019, and cases were matched by sex and year of birth to population controls. Year of disease onset was used as index year. Associations between use of alcohol, tobacco smoke, Swedish snuff, and MG risk were investigated using multivariable logistic regression.

Results A total of 1,067 patients with MG (mean age at onset 48 (SD 21) years, 53% female) were matched to 2,087 controls. Any alcohol consumption was associated with a lower MG risk compared with not drinking at all (odds ratio [OR] 0.48, 95% CI 0.39-0.59, p < 0.001, exposed cases n = 616). Effects were observed in a similar direction across disease subtypes, with the strongest association in the late-onset MG group (onset ≥50 years). Although neither cigarette smoke nor use of Swedish snuff affected the disease risk of the whole group, subset specific effects were observed. Smoking at onset was associated with an increased risk of early-onset MG (EOMG, onset 18-49 years; OR 1.60, 95% CI 1.17-2.20, p = 0.003, n = 133), which was accentuated in acetylcholine receptor antibody-positive EOMG (OR 2.08, 95% CI 1.34-3.25, p = 0.001, n = 74). Use of Swedish snuff, which contains high levels of nicotine, at disease onset was also associated with an increased risk of EOMG (OR 1.61, 95% CI 1.02-2.54, p = 0.039, n = 43).

Discussion We observed an inve rse correlation of MG risk and alcohol consumption. Furthermore, smoking and the use of Swedish snuff at disease onset were positively associated with EOMG. We recognize limitations related to retrospective data and limited number of available controls. However, multiple sensitivity analyses were performed supporting the robustness of our results.

Short tandem repeat expansions in the human genome are overrepresented in a variety of neurological disorders. It was recently shown that huntingtin (HTT) repeat expansions with full penetrance, i.e. 40 or more CAG repeats, which normally cause Huntington's disease (HD), are overrepresented in patients with amyotrophic lateral sclerosis (ALS). Whether patients carrying HTT repeat expansions with reduced penetrance, (36-39 CAG repeats), or alleles with intermediate penetrance, (27-35 CAG repeats), have an increased risk of ALS has not yet been investigated. Here, we examined the role of HTT repeat expansions in a motor neuron disease (MND) cohort, searched for expanded HTT alleles, and investigated correlations with phenotype and neuropathology. MND patients harboring C9ORF72 hexanucleotide repeat expansions (HREs) were included, to investigate whether HTT repeat expansions were more common in this group. We found a high prevalence of intermediate (range 5.63%-6.61%) and reduced penetrance (range 0.57%-0.66%) HTT gene expansions in this cohort compared to other populations of European ancestry, but no differences between the MND cohort and the control cohort were observed, regardless of C9ORF72HRE status. Upon autopsy of three patients with intermediate or reduced penetrance HTT alleles, huntingtin inclusions were observed in the caudate nucleus and frontal lobe, but no significant somatic mosaicism was detected in different parts of the nervous system. Thus, we demonstrate, for the first time, huntingtin inclusions in individuals with MND and intermediate and reduced penetrance HTT repeat expansions but more clinicopathological investigations are needed to further understand the impact of HTT gene expansion-related pleiotropy.

Background and Objectives: To describe myasthenia gravis activities of daily living (MG-ADL) in relation to clinical characteristics in a large Swedish nationwide cohort.

Methods: In a cross-sectional prevalence cohort study, the Genes and Environment in Myasthenia Gravis study, performed from November 2018 through August 2019, patients with myasthenia gravis (MG) were invited to submit an extensive 106-item life environment questionnaire, including the MG-ADL score. Patients were classified into early-onset MG (EOMG, <50 years), late-onset MG (LOMG, >= 50 years), or thymoma-associated MG (TAMG). Comparisons of disease-specific characteristics were made between subgroups, sexes, and different MG-ADL scores.

Results: A total of 1,077 patients were included, yielding a 74% response rate: 505 (47%) were classified as EOMG, 520 (48%) LOMG, and 45 (4%) TAMG. Mean age at inclusion was 64.3 years (SD 15.7) and mean disease duration was 14.6 years (SD 14.0). Complete MG-ADL scores (n = 1,035) ranged from 0p to 18p, where 26% reported a score of 0p. Higher MG-ADL scores were associated with female sex, obesity, and diagnostic delay (odds ratio [OR] 1.62, 1.72, and 1.69; p(adj) = 0.017, 0.013, and 0.008) and inversely correlated with high educational attainment (OR 0.59; p(adj) = 0.02), but not with age at inclusion, disease subtype, or disease duration. Almost half of the population (47%) reported MG-ADL >= 3p, corresponding to an unsatisfactory symptom state.

Discussion: In this nationwide study, comprising more than 40% of the prevalent MG population in Sweden, almost half of the patients reported current disease symptoms associated with an unsatisfactory symptom state, indicating the need for improved treatment options.