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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and retinal vasculopathy with cerebral leukodystrophy and systemic manifestations (RVCL-S) are the most common forms of rare monogenic early-onset cerebral small vessel disease and share clinical, and, to different extents, neuroradiological and neuropathological features. However, whether CADASIL and RVCL-S overlapping phenotype may be explained by shared genetic risk or causative factors such as TREX1 coding variants remains poorly understood. To investigate this intriguing hypothesis, we used exome sequencing to screen TREX1 protein-coding variability in a large multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic CADASIL-like Caucasian patients from the USA, Portugal, Finland, Serbia and Turkey. We report 2 very rare and likely pathogenic TREX1 mutations: a loss of function mutation (p.Ala129fs) clustering in the catalytic domain, in an apparently sporadic 46-year-old patient from the USA and a missense mutation (p.Tyr305Cys) in the well conserved C-terminal region, in a 57-year-old patient with positive family history from Serbia. In concert with recent findings, our study expands the clinical spectrum of diseases associated with TREX1 mutations., Competing Interests: Disclosure statement All the authors declare no competing financial or personal interests that can influence the presented work. Written informed consent was obtained for each individual and the study was approved by the appropriate institutional review boards., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by pathogenic variants in the NOTCH3 gene. In Finland, the majority of CADASIL patients carry the pathogenic founder variant c.397C>T, (p.Arg133Cys), but the spectrum of other NOTCH3 variants has not been investigated previously. The aim of the study was to investigate the spectrum and prevalence of NOTCH3 variants Finnish CADASIL patients and to examine the clinical features associated with them., Materials and Methods: The spectrum of NOTCH3 variants and the clinical features associated with them were retrospectively examined in 294 Finnish CADASIL patients tested during January 1996 to October 2021 in the Medical Genetics laboratory of Department of Genomics of Turku University Hospital, where practically all samples of patients with suspected CADASIL in Finland are investigated., Results: The most common NOTCH3 variants in the study cohort were c.397C>T, (p.Arg133Cys) (68%) and c.3206A>G p.(Tyr1069Cys) (18%), but other less common NOTCH3 variants were detected in as many as 14% of the patients. Eight of the detected NOTCH3 variants were novel: c.520T>A,p.(Cys174Ser), c.836A>G,p.(Gln279Arg), c.1369T>G,p.(Cys457Gly), c.1338C>G,p.(Cys446Trp), c.1564T>G,p.(Cys522Gly), c.2848T>G,p.(Cys950Gly), c.6102dup,p.(Gly2035Argfs*60), and c.2410+6C>G. Other NOTCH3 variants than p.Arg133Cys and p.Tyr1069Cys were more often associated with more severe clinical features., Conclusion: This study revealed the genetic and clinical spectrum of CADASIL in the Finnish population. Sequencing of the whole NOTCH3 gene performing a gene-panel or exome sequencing is recommended when suspecting CADASIL., (© 2022 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Objectives: The genetic background of vascular cognitive impairment (VCI) is poorly understood compared to other dementia disorders. The aim of the study was to investigate the genetic background of VCI in a well-characterized Finnish cohort., Materials & Methods: Whole-exome sequencing (WES) was applied in 45 Finnish VCI patients. Copy-number variant (CNV) analysis using a SNP array was performed in 80 VCI patients. This study also examined the prevalence of variants at the miR-29 binding site of COL4A1 in 73 Finnish VCI patients., Results: In 40% (18/45) of the cases, WES detected possibly causative variants in genes associated with cerebral small vessel disease (CSVD) or other neurological or stroke-related disorders. These variants included HTRA1:c.847G>A p.(Gly283Arg), TREX1:c.1079A>G, p.(Tyr360Cys), COLGALT1:c.1411C>T, p.(Arg471Trp), PRNP: c.713C>T, p.(Pro238Leu), and MTHFR:c.1061G>C, p.(Gly354Ala). Additionally, screening of variants in the 3'UTR of COL4A1 gene in a sub-cohort of 73 VCI patients identified a novel variant c.*36T>A. CNV analysis showed that pathogenic CNVs are uncommon in VCI., Conclusions: These data support pathogenic roles of variants in HTRA1, TREX1 and in the 3'UTR of COL4A1 in CSVD and VCI, and suggest that vascular pathogenic mechanisms are linked to neurodegeneration, expanding the understanding of the genetic background of VCI., (© 2022 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Cerebral small vessel disease (CSVD) is the most important cause of vascular cognitive impairment (VCI). Most CSVD cases are sporadic but familial monogenic forms of the disorder have also been described. Despite the variants identified, many CSVD cases remain unexplained genetically. We used whole-exome sequencing in an attempt to identify novel gene variants underlying CSVD. A cohort of 35 Finnish patients with suspected CSVD was analyzed. Patients were screened negative for the most common variants affecting function in NOTCH3 in Finland (p.Arg133Cys and p.Arg182Cys). Whole-exome sequencing was performed to search for a genetic cause of CSVD. Our study resulted in the detection of possibly pathogenic variants or variants of unknown significance in genes known to associate with CSVD in six patients, accounting for 17% of cases. Those genes included NOTCH3, HTRA1, COL4A1, and COL4A2. We also identified variants with predicted pathogenic effect in genes associated with other neurological or stroke-related conditions in seven patients, accounting for 20% of cases. This study supports pathogenic roles of variants in COL4A1, COL4A2, and HTRA1 in CSVD and VCI. Our results also suggest that vascular pathogenic mechanisms are linked to neurodegenerative conditions and provide novel insights into the molecular basis of VCI.

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies.

Objective: To characterize the clinical and neuropathologic features of patients with amyotrophic lateral sclerosis (ALS) with the superoxide dismutase 1 ( SOD1 ) p.Ala90Val mutation, as well as the mutation frequency and the role of oligogenic mechanisms in disease penetrance., Methods: An index patient with autopsy-proven ALS was discovered to have the SOD1 p.Ala90Val mutation, which was screened in 2 Finnish ALS cohorts (n = 453). Additional contributing variants were analyzed from whole-genome or whole-exome sequencing data., Results: Seven screened patients (1.5%) were found to carry the SOD1 heterozygous mutation. Allele-sharing analysis suggested a common founder haplotype. Common clinical features included limb-onset, long disease course, and sensory symptoms. No TDP43 pathology was observed. All cases were apparently sporadic, and pedigree analysis demonstrated that the mutation has reduced penetrance. Analysis of other contributing genes revealed a unique set of additional variants in each patient. These included previously described rare ANG and SPG11 mutations. One patient was compound heterozygous for SOD1 p.Ala90Val and p.Asp91Ala., Conclusions: Our data suggest that the penetrance of SOD1 p.Ala90Val is modulated by other genes and indicates highly individual oligogenic basis of apparently sporadic ALS. Additional genetic variants likely contributing to disease penetrance were very heterogeneous, even among Finnish patients carrying the SOD1 founder mutation.

We studied the effect of regular inhalations of low-dose and high-dose fenoterol and low-dose and high-dose combinations of fenoterol and ipratropium bromide in maintenance treatment of 120 adults with moderately severe asthma. We used a double-blind, randomized, parallel group design comparing 12 weeks of treatment with four regimens: fenoterol, 100 micrograms/dose; fenoterol, 200 micrograms/dose; fenoterol, 50 micrograms; and ipratropium, 20 micrograms/dose in a single inhaler (Berodual) and fenoterol, 100 micrograms and ipratropium, 40 micrograms/dose in a single inhaler (Duovent). During the baseline and active treatment period the patients recorded PEFR in the morning and evening, symptoms and use of a rescue inhaler. Changes in twice daily peak expiratory flow rates or asthma symptoms did not show any significant differences among the four treatment regimens during the 12 weeks compared with the baseline period. Use of the rescue inhaler did not differ among the four groups during the active treatment. The patients' assessment of the efficacy of the active treatment favored the low-dose fenoterol and low-dose combination. More side effects were recorded in the high-dose combination group during the first 4 weeks compared with the other groups. We conclude that in maintenance therapy of chronic asthma high doses of fenoterol alone or in combination with ipratropium bromide offer no clinical advantage over low doses. On the contrary, the low-dose fenoterol and the low-dose combination are better accepted and tolerated by the patients.

By electron-microscopy, we have shown that airway epithelial changes occur in farmer's lung, at a level which is even as high as the carina of the right upper lobe. When spores were apparent in the bronchial lumen, ciliated and goblet cells had disappeared, and in some specimens, even basal cell layers. In general, the ciliated cells were those most affected; the cell destruction is that of bronchitis, with the cilia being less affected than the rest of the ciliated cell. Ciliogenesis is stimulated but it does not keep pace with the cell destruction, which advances more rapidly. Disturbed ciliogenesis is suggested. The pathogenesis of epithelial damage is obscure. By reason of epithelial damage, it is suggested that the superficial afferent nerves in the bronchial epithelium are susceptible to irritation; degranulating mast cells in the vicinity of the epithelial nerves may also be involved in the bronchial hyperreactivity observed in some patients. Mast cells were found in the alveoli; these might influence alveolar ventilation. The alveoli presented granulomas characteristic of farmer's lung.

We classified the radiologic findings of 93 patients with acute or subacute farmer's lung (FL) disease by type and severity of the change in chest x-ray film. Acute radiologic changes, further divided as nodular, ground-glass, or striated patchy opacities, were found in 78/93 patients at the first evaluation; 11 showed chronic changes (radiologic "fibrosis"), which persisted unchanged throughout the follow-up period; and four initially had a normal chest x-ray film. Patients were followed up 23 months on an average. The more severe the radiologic change at the first evaluation, the more impaired the diffusing capacity (Dsb). Severe radiologic changes disappeared more slowly than the less severe ones. The differences in the initial pulmonary function values between the two groups disappeared during the follow-up. The type of acute change did not predict the recovery of respiratory performance. Treatment with oral corticosteroids did not affect the outcome of lung function or appearance of chronic changes, although corticosteroids seemed to hasten the disappearance of diffuse opacities. At the final evaluation, the chest x-ray film was normal in 55/93 patients. Chronic changes were detected in 38 patients. Severe radiologic appearance and striated patchy opacities predisposed to development of chronic changes.

We studied the clinical course of eighty-six patients with farmer's lung for a period of 5 years. The patients were first evaluated at an acute or sub-acute stage of the disease and 1, 3, 6, 12 and 60 months thereafter. Special attention was paid to the development of lung function and radiological findings with reference to corticosteroid treatment and antigen contact during the follow-up. Many of the patients were severely ill at the acute stage of the disease. Most of the recovery took place during the first month. Significant improvement of lung function happened up to 6 months, thereafter the improvement was insignificant. After 5 years, respiratory symptoms were reported by 65% and minor respiratory dysfunction (lowered diffusing capacity) was observed in about 40% of the farmers. Thirty-two per cent of the patients showed diffuse opacities in chest X-ray. Corticosteroid treatment had no effect on long term prognosis. There was no difference in the recovery of lung function between those who returned to work compared with those who did not. Exacerbations happened in 8% of the patients during the follow-up. We conclude that respiratory symptoms, minor airway dysfunction and mild radiological fibrosis are common findings after 5 years of an acute or sub-acute stage of the farmer's lung. However, in Finland two-thirds of the patients return back to their previous occupation of farming and cattle feeding.

In this prospective study of farmer's lung disease 93 patients were subjected to a follow-up period of an average of 18.6 months. The patients were initially divided into three groups, each receiving corticosteroids either for four weeks, twelve weeks, or not at all, if the disease was less severe. Lung function, clinical findings and chest radiography were recorded at intervals of one, three, six and 12 months and every six months after that. Corticosteroid treatment seemed to have no marked influence on the course of lung function or the prognosis of working capacity. Twelve-week treatment did not produce better results than four-week. However, corticosteroids diminished the appearance of fibrotic changes in chest radiograms. It is concluded that corticosteroids should be given to severely ill patients to ameliorate symptoms, but no apparent benefit is derived from long-term treatment. Eighty-five per cent of patients continued farming and cattle-feeding after recovery. The severity of the initial attack and the occurrence of relapses were found to be the most important factors influencing respiratory performance, subjective symptoms and working capacity in patients with farmer's lung.

This study reviews the results of five clinical studies dealing with farmer's lung (FL). The total number of patients included was 107, with a mean age of 49 years. All patients were farmers with dairy cattle. The clinical symptoms, auscultatory findings, chest radiography, laboratory data, partial pressure of oxygen in arterial blood at rest (PaO2), dynamic spirometry (FVC and FEV1) and lung diffusing capacity of carbon monoxide (DLco) were recorded at the first visit to the hospital and one, three, six and twelve months later during the follow-up and every six months after that. Half of the patients with FL reported insidious onset of the disease, and 28% reported acute onset. Dyspnoea was reported by all patients, coughing was almost as common. A considerable proportion of the patients reported muscle and joint pains. Diffuse opacities were detected in the chest radiograms of 99 patients (93%): the more severe the radiological change, the more impaired the DLco value. A normal chest radiogram was seen in eight of the 107 patients at the first evaluation. Half of the patients showed a restrictive type of impairment of ventilatory function at the first evaluation. Lung diffusing capacity was less than 80% of the predicted value in 89% of the patients. Ninety-nine patients were initially challenged with histamine and twenty-two of them (22%) showed increased bronchial responsiveness. Bronchial hyper-reactivity was transient in most of the patients and might also fluctuate with exacerbation of FL symptoms. Specimens of the airway epithelium of FL patients were taken by rigid bronchoscope from five patients for electronmicroscope studies. Extensive bronchial damage to the airway epithelium associated with the presence of spore-like fungi was observed. Aspiration biopsy of the spleen was carried out on ten FL patients during their first visit to the hospital. Granuloma-like reactions were detected in the aspiration biopsy material of five FL patients. The granulomatous changes in the spleen had disappeared when the procedure was repeated on two patients at an asymptomatic stage of the disease. Ninety-three patients were included in a follow-up study with a mean follow-up period of 18.6 months. The patients with clinically less severe disease were observed without medication. It appeared that corticosteroid medication was usually started if the DLco value was less than 65% of the predicted value. Fourteen patients with a DLco value less than 65% were observed without medication and served as a control group for those on medication.(ABSTRACT TRUNCATED AT 400 WORDS)