Papers by Hannu Laaksovirta
ERJ Open Research, Sep 17, 2020
Introduction: The prevalence of long-term invasive mechanical ventilation via tracheostomy in chr... more Introduction: The prevalence of long-term invasive mechanical ventilation via tracheostomy in chronic respiratory insufficiency is largely unknown. We aimed to clarify prevalence and aetiology of the use of home invasive mechanical ventilation (HIMV) in Finland in 2015-2019. Methods: Information on HIMV patients was collected yearly from all Finnish Hospital District patient registries between 1 January 2015 and 1 January 2019. Data included underlying diagnosis, time from diagnosis to HIMV initiation, treatment length, mortality and basic sociodemographic data. Results: In 2015, we had 107 HIMV patients. During the follow-up we received 34 new patients (24.1%) and 46 patients (32.6%) died. In 2019, we had 95 HIMV patients and the prevalence in Finland was 2.0 in 100 000. The most common diagnoses were motor neurone disease (29.1%) and spinal cord injuries (19.9%). Mean duration of HIMV among all patients on 1 January 2019 was 12.3 years and among deceased patients, 11.2 years. Treatment durations ranged from 7.7 years for motor neurone disease patients to 47.3 years for post-polio syndrome patients. Most patients (81.6%) used HIMV 24 h•day −1. Conclusions: HIMV is a rare, long-lasting treatment, most often used in chronic hypoventilation caused by chronic neurological disease. Based on our 4 year follow-up the prevalence of HIMV seems to be diminishing in Finland. Treatment duration and survival vary greatly depending on the underlying diagnosis. Most of the patients were totally dependent on HIMV, requiring 24-h care. @ERSpublications Home invasive mechanical ventilation is a rare treatment; in 2019, the prevalence in Finland was 2.0 in 100 000. The treatment durations are long, averaging 12 years, but the duration and survival vary greatly depending on the underlying diagnosis.
Neurology Genetics, Mar 14, 2022
Background and Objectives To analyze the frequencies of major genetic variants and the clinical f... more 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 C9orf72 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 firstor 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. C9orf72 expansion (C9pos) 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. C9pos or SOD1 p.D91A homozygosity was found in 328 (40%) of the 815 patients. We compared demographic and clinical characteristics between C9pos and patients with unknown cause of ALS (Unk). We found that the age at onset was significantly earlier and survival markedly shorter in the C9pos vs Unk patients with ALS. The shortest survival was found in bulbar-onset male C9pos patients, whereas the longest survival was found in Unk limb-onset males. Older age at onset associated consistently with shorter survival in C9pos and Unk patients in both limb-onset and bulbaronset groups. There were no significant differences in the frequencies of bulbar-onset and limbonset patients in C9pos and Unk groups. ALS-frontotemporal dementia (FTD) was more common in C9pos (17%) than in Unk (4%) patients, and of all patients with ALS-FTD, 70% were C9pos. Discussion These results provide further evidence for the short survival of C9orf72-associated ALS. A prominent role of the C9orf72 and SOD1 variants was found in the Finnish population. An unusually high frequency of C9pos was also found among patients with sporadic ALS. The enrichment of these 2 variants likely contributes to the high incidence of ALS in Finland.
Journal of Neuroimmunology, Dec 1, 1991
The presence of free immunoglobulin light chains (FLCs) in the cerebrospinal fluid (CSF) and sera... more The presence of free immunoglobulin light chains (FLCs) in the cerebrospinal fluid (CSF) and sera of patients with human immunodeficiency virus-1 (HIV-1) infection, multiple sclerosis (MS), and neurologically healthy control individuals was investigated by paying special attention to ensure that only truly free light chains would be detected. The FLCs were extracted by specifically binding them to Sepharose-coupied anti-FLC monoclonal antibodies, and thereafter they were electrophoresed and immunoblotted with monoclonal antibodies to both light chain (LC) isotypes. A frequent occurrence of kappa and lambda FLCs was found in both CSF and sera of HIV-1 infected patients. In HIV-1 infection and in MS, the frequency of FLCs of the CSF was equal. In healthy controls, only occasional weak FLCs were observed in either CSF or serum. FLC bands of the CSF from patients with HIV-1 infection tended to be more intensive than those of the appropriately diluted sera. Both intrathecal synthesis of FLCs and their transudation from sera through the impaired blood-brain barrier (BBB) may contribute to this. Increasing severity of general HIV-1 infection was accompanied by an increase of FLC intensity in sera. A qualitative demonstration of FLC in the CSF may be meaningful only in the absence of altered BBB function.
European Journal of Human Genetics, Apr 24, 2013
Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognised domina... more Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognised dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. Six-hundred and twenty ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length 42 Mb were identified, and 3568 rare segments remained after filtering 'common' segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, P ¼ 0.05). Two-thousand and seventeen ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (P ¼ 1 Â 10 À5), a greater proportion of cases harboured homozygosity (P ¼ 2 Â 10 À5), a longer average length of segment (P ¼ 1 Â 10 À5), a longer total genome coverage (P ¼ 1 Â 10 À5), and a higher rate of these segments overlapped with RefSeq gene regions (P ¼ 1 Â 10 À5), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9-4.8 Mb, and chromosome 5 in the 65 Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS, which are not identified as common variants in GWAS.
Epilepsia, Mar 1, 1996
Midazolam is a short-acting benzodiazepine which is used as an oral hypnotic agent in several cou... more Midazolam is a short-acting benzodiazepine which is used as an oral hypnotic agent in several countries. We studied the pharmacokinetic and pharmacodynamic aspects of an oral 15-mg dose of midazolam in 6 patients with epilepsy who are also taking carbamazepine (CBZ) or phenytoin (PHT). We compared results with those obtained in 7 noninduced control subjects. Plasma concentrations and effects of midazolam were measured for 10 h. In patients with epilepsy, the area under the plasma concentration-time curve (AUC) of midazolam (mean 2 SEM) was only 5.7% (0.60 ? 0.16 vs. 10.5 ? 0.6 pgmin/ml), and the peak midazolam concentration was 7.4% (5.2 2 1.2 vs. 70.4 ? 9.0 ng/ml) of its value in con
Neurobiology of Aging, Dec 1, 2019
The hexanucleotide repeat expansion in C9orf72 is a common cause of amyotrophic lateral sclerosis... more The hexanucleotide repeat expansion in C9orf72 is a common cause of amyotrophic lateral sclerosis/ frontotemporal dementia and also rarely found in other psychiatric and neurodegenerative conditions. Alleles with >30 repeats are often considered an expansion, but the pathogenic repeat length threshold is still unclear. It is also unclear whether intermediate repeat length alleles (often defined either as 7e30 or 20e30 repeats) have clinically significant effects. We determined the C9orf72 repeat length distribution in 3142 older Finns (aged 60e104 years). The longest nonexpanded allele was 45 repeats. We found 7e45 repeats in 1036/3142 (33%) individuals, 20e45 repeats in 56/3142 (1.8%), 30e45 repeats in 12/3142 (0.38%), and expansion (>45 repeats) in 6/3142 (0.19%). There was no apparent clustering of neurodegenerative or psychiatric diseases in individuals with 30e45 repeats indicating that 30e45 repeats are not pathogenic. None of the 6 expansion carriers had a diagnosis of amyotrophic lateral sclerosis/frontotemporal dementia but 4 had a diagnosis of a neurodegenerative or psychiatric disease. Intermediate length alleles (categorized as 7e45 and 20e45 repeats) did not associate with Alzheimer's disease or cognitive impairment.
Suomen lääkärilehti, 2018
Amyotrofisessa lateraaliskleroosissa eli ALStaudissa liikehermojen tuhoutuminen johtaa tahdonalai... more Amyotrofisessa lateraaliskleroosissa eli ALStaudissa liikehermojen tuhoutuminen johtaa tahdonalaisen lihaksiston surkastumiseen ja kuolemaan. Suomessa siihen sairastuu vajaat 200 ihmistä vuodessa. Osalla voidaan osoittaa geenivirhe. Euroopassa ainoa ALS:n hoitoon hyväksytty lääke on rilutsoli. Sen teho on vaatimaton: elinaika pitenee keskimäärin kolme kuukautta (1). Toistaiseksi ei tiedetä, miten voisi tunnistaa potilaat, jotka hyötyvät rilutsolista. Yhdysvalloissa FDA hyväksyi toukokuussa 2017 ALS:n hoitoon edaravonin (Radicava). Se on pyratsoloneihin kuuluva yhdiste, jonka neuroprotektiivisen vaikutuksen ajatellaan välittyvän ns. vapaiden radikaalien poistomekanismien kautta. Lääke on hyväksytty myös Etelä-Koreassa ja Japanissa vuodesta 2015. Myyntilupaa on haettu Kanadassa. Edaravonia annetaan 60 mg laskimoon kahden viikon jaksoissa. Tietoa siitä, kuinka pitkään lääkitystä on mielekästä jatkaa, ei ole. Internetin tietojen perusteella hoitojakson hinta on yli 1 500 euroa. Teoriassa Suomessakin potilas saattaa hankkia lääkettä ja pyytää terveydenhuoltoa järjestämään sen annon.
Acta Neurologica Scandinavica, Jul 30, 2015
Intrafamilial clinical variability in individuals carrying the CHCHD10 mutation Gly66Val.
European Journal of Neurology, Apr 1, 2008
We measured serum levels of neurotrophic cytokines ciliary neurotrophic factor (CNTF) and leukaem... more We measured serum levels of neurotrophic cytokines ciliary neurotrophic factor (CNTF) and leukaemia inhibiting factor (LIF) in 96 patients either with familial amyotrophic lateral sclerosis (FALS, n = 18) or sporadic ALS (SALS, n = 78) and in 27 inflammatory neurological controls (13 multiple sclerosis and 14 Guillain-Barreś yndrome) and in 27 healthy controls. Serum level of CNTF was significantly higher in ALS patients than in inflammatory neurological controls or healthy controls, and significantly higher in patients with ALS onset from upper or lower extremities than in patients with a purely bulbar onset of the disease. Serum CNTF levels did not significantly differ between patients with FALS and SALS, and it did not correlate with the age of onset or duration of the disease. No detectable serum levels of LIF were observed in the patient groups or in the healthy controls.
Frontiers in Neurology, Sep 14, 2022
Objectives: Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disease that usual... more Objectives: Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disease that usually leads to death within a few years from diagnosis. The risk factors for ALS are still largely unknown. However, it is assumed that environmental factors play a role in disease onset. Occupation is suggested as a potential risk factor, but findings are inconsistent. The aim of this study was to assess the association of occupation with ALS in Finland. Register data were used to avoid recall bias and to obtain a large enough sample to detect the potential associations. Methods: This case-control study included ALS cases that occurred between and in Finland (n = ,). ALS cases were identified from the causes of death register. For each ALS case, six controls were selected matched for sex and birth-year. The date of death of the ALS case was set as index date. Information on occupation was obtained from Statistics Finland for all subjects. The focus was on the longest-held occupation on-digit level (groups). The association of occupation with ALS was analyzed using conditional logistic regression. Results: Compared to "clerical work and other o ce work," the risk of ALS was increased in "packing and wrapping work" (OR. , % CI .-.), "laundering, dry cleaning and pressing work" (OR. , % CI .-.), and "travel service work" (OR. , CI .-.). A decreased risk was found in "planning, administrative and research work in the technical fields" (OR. , % CI .-.). Of the significant associations identified, only "travel service work" was significant after FDR multiple testing correction. Conclusions: This study identified occupations in which the risk of ALS was increased. Further studies are needed to pinpoint the potential exposures in these occupations that may trigger the disease.
Frontiers in Genetics
C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) ... more C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008*C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707*T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophi...
Genome-wide Analyses Identify KIF5A as a Novel ALS Gene Highlights d Loss-of-function mutations i... more Genome-wide Analyses Identify KIF5A as a Novel ALS Gene Highlights d Loss-of-function mutations in KIF5A are a cause of amyotrophic lateral sclerosis d ALS-associated KIF5A mutations are distinct from HSP and CMT mutations in KIF5A d Identification of KIF5A highlights the role of cytoskeleton in ALS pathogenesis
JAMA Neurology, 2021
IMPORTANCE Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by ag... more IMPORTANCE Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. OBJECTIVE To identify the genetic variants associated with juvenile ALS. DESIGN, SETTING, AND PARTICIPANTS In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. MAIN OUTCOMES AND MEASURES De novo variants present only in the index case and not in unaffected family members. RESULTS Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. CONCLUSIONS AND RELEVANCE These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
SSRN Electronic Journal, 2020
We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) an... more We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range: 40 to 64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes, but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes, and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
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Papers by Hannu Laaksovirta