Evidence for Non-Mendelian Inheritance in Spastic Paraplegia 7.

BACKGROUND: Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP). OBJECTIVES: We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP. METHODS: We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole-exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls. RESULTS: The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24-6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49-13.07, P = 0.005). Similar results were obtained after including only genetically-undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05-365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function. CONCLUSIONS: Our results provide evidence for complex inheritance in SPG7-associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance. © 2021 International Parkinson and Movement Disorder Society.

Genetic and Epidemiological Study of Adult Ataxia and Spastic Paraplegia in Eastern Quebec.

OBJECTIVE: To estimate the minimum prevalence of adult hereditary ataxias (HA) and spastic paraplegias (HSP) in Eastern Quebec and to evaluate the proportion of associated mutations in identified genes. METHODS: We conducted a descriptive cross-sectional study of patients who met clinical criteria for the diagnosis of HA (n = 241) and HSP (n = 115) in the East of the Quebec province between January 2007 and July 2019. The primary outcome was the prevalence per 100,000 persons with a 95% confidence interval (CI). The secondary outcome was the frequency of mutations identified by targeted next-generation sequencing (NGS) approach. Minimum carrier frequency for identified variants was calculated based on allele frequency values and the Hardy-Weinberg (HW) equation. RESULTS: The minimum prevalence of HA in Eastern Quebec was estimated at 6.47/100 000 [95% CI; 6.44-6.51]; divided into 3.73/100 000 for autosomal recessive (AR) ataxias and 2.67/100 000 for autosomal dominant (AD) ataxias. The minimum prevalence of HSP was 4.17/100 000 [95% CI; 4.14-4.2]; with 2.05/100 000 for AD-HSP and 2.12/100 000 for AR-HSP. In total, 52.4% of patients had a confirmed genetic diagnosis. AR cerebellar ataxia type 1 (2.67/100 000) and AD spastic paraplegia SPG4 (1.18/100 000) were the most prevalent disorders identified. Mutations were identified in 23 genes and molecular alterations in 7 trinucleotides repeats expansion; the most common mutations were c.15705-12 A > G in SYNE1 and c.1529C > T (p.A510V) in SPG7. CONCLUSIONS: We described the minimum prevalence of genetically defined adult HA and HSP in Eastern Quebec. This study provides a framework for international comparisons and service planning.

Exposure to Pesticides and Welding Hastens the Age-at-Onset of Parkinson's Disease.

BACKGROUND: The age-at-onset (AAO) of Parkinson's disease (PD) is thought to be influenced by environmental factors and polygenic predispositions. Professional exposures to pesticides and toxic metals were shown to be associated with an earlier onset in small sample studies. AIM OF STUDY: The aim of this study was to confirm the association between professional exposures to pesticides and toxic metals and the AAO of PD, on a larger cohort of patients, defined with a clinic-based ascertainment scheme. METHODS: We used an incident cohort of 290 patients recruited through three designated movement disorder clinics in the province of Quebec, Canada. Patients completed a detailed questionnaire regarding professional exposures to pesticides and toxic metals. We compared the AAO in patients without prior professional exposure (N = 170) and those with exposure to pesticides (N = 53) or toxic metals through welding (N = 30). We further subdivided patients exposed to pesticides according to the frequency and proximity of their contacts. RESULTS: Patients with prior exposure to pesticides (AAO = 54.74 years) or toxic metals (54.27 years) had a significantly earlier AAO compared to the control group (59.26 years) (p = 0.003). In those exposed to pesticides, closer (p = 0.03) and more frequent (p = 0.02) contacts were negatively correlated with AAO. CONCLUSION: Exposure to pesticides and toxic metals were both associated with an earlier onset of PD, an effect that was greater with higher levels of exposure, both in terms of frequency and proximity.

L'exposition à des pesticides et à des métaux toxiques associés à la soudure diminue l'âge d'apparition de la maladie de Parkinson. Contexte: Il est courant de penser que l'âge d'apparition de la maladie de Parkinson (MP) est influencé par des facteurs environnementaux et des prédispositions polygéniques. À cet égard, on a montré, dans des études portant sur des échantillons plus restreints, que l'exposition à des pesticides et à des métaux toxiques lors d'une activité professionnelle était associée à un âge d'apparition de cette maladie plus précoce. Objectif de l'étude: Confirmer cette association à l'aide d'une cohorte de patients plus nombreux, cohorte établie en fonction d'un plan clinique de définition des cas (clinic-based ascertainment scheme). Méthodes: Notre étude a donc reposé sur une cohorte de 290 patients recrutés au Québec au sein de trois cliniques des troubles du mouvement préalablement désignées. Les patients choisis ont alors répondu à un questionnaire complet en ce qui concerne leur exposition à des pesticides et à des métaux toxiques dans le cadre de leur travail. Nous avons ensuite comparé l'âge d'apparition de la MP chez des patients n'ayant pas été exposés à ces éléments (n = 170) à l'âge d'apparition de la MP chez ceux ayant été exposés à des pesticides (n = 53) ou à des métaux toxiques associés à la soudure (n = 30). Plus encore, nous avons subdivisé les patients exposés à des pesticides selon la fréquence et le niveau de proximité de leurs contacts avec ces éléments. Résultats: L'âge d'apparition de la MP chez les patients préalablement exposés à des pesticides (54,74 ans) ou à des métaux toxiques (54,27 ans) s'est révélé notablement plus précoce en comparaison avec l'âge d'apparition de notre groupe témoin (59,26 ans ; p = 0,003). Chez ceux ayant été exposés à des pesticides, des contacts plus étroits (p = 0,03) et plus fréquents (p = 0,02) ont été corrélés négativement à l'âge d'apparition de la MP. Conclusion: En somme, l'exposition à des pesticides et à des métaux toxiques a été associée à un âge d'apparition de la MP plus précoce, corrélation qui s'est avérée plus importante avec un accroissement des niveaux d'exposition, qu'il s'agisse de fréquence ou de proximité.

Original tandem duplication in FXIIIA gene with splicing site modification and four amino acids insertion causes factor XIII deficiency.

: Recessive mutations of F13A gene are reported to be responsible of FXIIIA subunit deficiency (FXIIIA). In all, some intronic nucleotide changes identified in this gene were investigated by in-silico analysis and occasionally supported by experimental data or reported in some cases as a polymorphism. To determine the molecular defects responsible of congenital factor XIII deficiency in Libyan patient, molecular analysis was performed by direct DNA sequencing of the coding regions and splice junctions of the FXIIIA subunit gene (F13A). A splicing minigene assay was used to study the effect of this mutation. Bioinformatics exploration was fulfilled to conceive consequences on protein. A 12-bp duplication straddling the border of intron 9 and exon 10 leads to two 3' acceptor splice sites, resulting in silencing of the downstream wild 3' splice site. It caused an in-frame insertion of 12 nucleotides into mRNA and four amino acids into protein. Bioinformatic analysis predicts that the insertion of four amino acids affects the site 3 of calcium binding site, which disturbs the smooth function of the FXIIIA peptide causing the factor XIII deficiency. This study showed that a small duplication seems to weaken the original 3' splice site and enhance the activation of a new splice site responsible for an alternative splicing. It would be interesting to examine the underlying molecular mechanism involved in this rearrangement.

Effects of Bronchial Thermoplasty on Airway Smooth Muscle and Collagen Deposition in Asthma.

RATIONALE: The aim of bronchial thermoplasty is to improve asthma symptoms by reducing central airway smooth muscle mass. Up to now, the reduction of smooth muscle mass has been documented for only 1 group of 10 patients who had 15% or more of their pretreatment total bronchial biopsy area occupied by smooth muscle. OBJECTIVES: To evaluate the effects of bronchial thermoplasty on airway smooth muscle mass and airway collagen deposition in adult patients with asthma, regardless of pretreatment smooth muscle area. METHODS: Seventeen patients with asthma underwent bronchial thermoplasty over the course of three visits. At Visit 1, bronchial biopsies were taken from the lower lobe that was not treated during this session. At Visit 2 (3-14 wk after the first visit), all 17 patients underwent biopsy of the lower lobe treated during the first procedure. At Visit 3 (7-22 wk after the first visit), nine patients agreed to undergo biopsy of the same lower lobe. Histological and immunohistochemical analyses were performed on the biopsy specimens. MEASUREMENTS AND MAIN RESULTS: Bronchial thermoplasty decreased airway smooth muscle from 12.9 ± 1.2% of the total biopsy surface at Visit 1 to 4.6 ± 0.8% at Visit 2 (P < 0.0001). For the nine patients who underwent a third biopsy, mean airway smooth muscle area was 5.3 ± 1.3% at Visit 3 (P = 0.0008 compared with baseline). Bronchial thermoplasty also decreased Type I collagen deposition underneath the basement membrane from 6.8 ± 0.3 µm at Visit 1 to 4.3 ± 0.2 µm at Visit 2 (P < 0.0001) and to 4.4 ± 0.4 µm for nine patients at Visit 3 (P < 0.0001 compared with baseline). Over the course of 1 year after treatment, the doses of inhaled corticosteroid, the number of severe exacerbations, and asthma control all improved (P ≤ 0.02). CONCLUSIONS: For patients with severe asthma, bronchial thermoplasty reduced the smooth muscle mass of treated airway segments, regardless of the baseline level of muscle mass. Treatment also altered the deposition of collagen. At follow-up, bronchial thermoplasty improved asthma control; however, the limited number of subjects did not allow us to evaluate possible correlations between these improvements and the studied histological parameters. Further studies are needed to confirm these results and evaluate their persistence.