Publications by authors named "Manu Jokela"

24 Publications

  • Page 1 of 1

Genotype-phenotype correlations in recessive titinopathies.

Genet Med 2020 Dec 11;22(12):2029-2040. Epub 2020 Aug 11.

Folkhälsan Research Center, Helsinki, Finland.

Purpose: High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort.

Methods: We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families).

Results: Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362-364).

Conclusion: Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.
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http://dx.doi.org/10.1038/s41436-020-0914-2DOI Listing
December 2020

Mutations in the J domain of DNAJB6 cause dominant distal myopathy.

Neuromuscul Disord 2020 01 19;30(1):38-46. Epub 2019 Nov 19.

Neuromuscular Research Center, Tampere University Hospital and Tampere University, P.O. box 100, FIN-33014 Tampere, Finland; Folkhälsan Research Center, Helsinki, Finland and University of Helsinki, Medicum, Helsinki, Finland.

Eight patients from five families with undiagnosed dominant distal myopathy underwent clinical, neurophysiological and muscle biopsy examinations. Molecular genetic studies were performed using targeted sequencing of all known myopathy genes followed by segregation of the identified mutations in the affected families using Sanger sequencing. Two novel mutations in DNAJB6 J domain, c.149C>T (p.A50V) and c.161A>C (p.E54A), were identified as the cause of disease. The muscle involvement with p.A50V was distal calf-predominant, and the p.E54A was more proximo-distal. Histological findings were similar to those previously reported in DNAJB6 myopathy. In line with reported pathogenic mutations in the glycine/phenylalanine (G/F) domain of DNAJB6, both the novel mutations showed reduced anti-aggregation capacity by filter trap assay and TDP-43 disaggregation assays. Modeling of the protein showed close proximity of the mutated residues with the G/F domain. Myopathy-causing mutations in DNAJB6 are not only located in the G/F domain, but also in the J domain. The identified mutations in the J domain cause dominant distal and proximo-distal myopathy, confirming that mutations in DNAJB6 should be considered in distal myopathy cases.
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http://dx.doi.org/10.1016/j.nmd.2019.11.005DOI Listing
January 2020

Oligogenic basis of sporadic ALS: The example of p.Ala90Val mutation.

Neurol Genet 2019 Jun 23;5(3):e335. Epub 2019 Apr 23.

Department of Clinical Genetics (L.K.), Helsinki University Hospital; Department of Medical Genetics (L.K.), University of Helsinki, Helsinki, Finland; Molecular Neurology (K.K., M.V., P.J.T.), Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland; Department of Medical Genetics (S.M.), University of Helsinki, Helsinki, Finland and Turku; University Hospital (S.M.), Laboratory Division, Genetics and Saske, Department of Medical Genetics, Turku, Finland; Department of Neurology (H.L.), Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland; Neuromuscular Research Center (M.J., B.U.), Tampere University Hospital and University of Tampere, Tampere, Finland; Division of Clinical Neurosciences (M.J.), Turku University Hospital and University of Turku, Turku, Finland; Folkhälsan Research Center (B.U.), Biomedicum, University of Helsinki, Helsinki, Finland; Institute of Biomedicine (P.P., J.S.), University of Turku; Turku University Hospital (P.P., J.S.), Laboratory Division, Genetics and Saske, Department of Medical Genetics, Turku, Finland; Department of Pathology (A.P.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Laboratory of Neurogenetics (B.J.T.), National Institute on Aging, National Institutes of Health, Bethesda, MD; Merck & Co. (D.J.S.), Inc., West Point, PA; Department of Clinical Genetics (M.P.), Helsinki University Hospital; Department of Medical Genetics (M.P.), University of Helsinki, Helsinki, Finland; Department of Neurology (P.J.T.), Helsinki University Hospital; and Department of Pathology (L.M.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objective: To characterize the clinical and neuropathologic features of patients with amyotrophic lateral sclerosis (ALS) with the superoxide dismutase 1 () 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 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 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 and mutations. One patient was compound heterozygous for p.Ala90Val and p.Asp91Ala.

Conclusions: Our data suggest that the penetrance of 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 founder mutation.
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http://dx.doi.org/10.1212/NXG.0000000000000335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481226PMC
June 2019

A novel COL6A2 mutation causing late-onset limb-girdle muscular dystrophy.

J Neurol 2019 Jul 8;266(7):1649-1654. Epub 2019 Apr 8.

Neuromuscular Research Center, Department of Neurology, Tampere University and University Hospital, Tampere, Finland.

Limb-girdle muscular dystrophies (LGMD) are genetic disorders characterized by weakness of predominantly proximal limb and trunk muscles due to progressive loss of muscle tissue. Collagen VI-related muscular dystrophies usually display more generalized muscle involvement combined with contractures and/or hyperlaxity of distal finger joints. LGMD-like phenotype of collagenopathy has only rarely been described and as reported is usually of childhood onset. We identified a Finnish family with COL6A2-related LGMD with autosomal dominant inheritance and very late onset at 40-60 years of age. Since the mutation was previously unreported, the pathognomonic findings on muscle MRI were the decisive clue for the correct diagnosis.
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http://dx.doi.org/10.1007/s00415-019-09307-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586699PMC
July 2019

An unusual ryanodine receptor 1 (RYR1) phenotype: Mild calf-predominant myopathy.

Neurology 2019 04 6;92(14):e1600-e1609. Epub 2019 Mar 6.

From the Neuromuscular Research Center (M. Jokela, S.L., J.P., B.U.), Department of Neurology, University Hospital and University of Tampere; Division of Clinical Neurosciences (M. Jokela), Department of Neurology, Turku University Hospital and University of Turku; Kiinamyllynkatu 4-8 (M. Jokela), Turku, Finland; Unità Operativa Complessa di Neurologia (G.T.), Dipartimento di Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Folkhälsan Institute of Genetics and Department of Medical Genetics (A.V., P.-H.J., S.V., M. Johari, M.S.), Haartman Institute, University of Helsinki, Finland; Institute of Pediatric Neurology (E.M., M.P.), Catholic University School of Medicine, Rome, Italy; Department of Pathology (S.H.), Fimlab Laboratories, Tampere University Hospital, Finland; Metabolic and Neuromuscular Unit (M.D.), Meyer Hospital, Florence, Italy; Department of Pediatric Neurology (P.I.), Children's Hospital, University of Helsinki and Helsinki University Hospital; Department of Neurology (P.H.), Kuopio University Hospital and University of Eastern Finland; and Department of Neurology (B.U.), Vasa Central Hospital, Finland.

Objective: To identify the genetic defect causing a distal calf myopathy with cores.

Methods: Families with a genetically undetermined calf-predominant myopathy underwent detailed clinical evaluation, including EMG/nerve conduction studies, muscle biopsy, laboratory investigations, and muscle MRI. Next-generation sequencing and targeted Sanger sequencing were used to identify the causative genetic defect in each family.

Results: A novel deletion-insertion mutation in ryanodine receptor 1 () was found in the proband of the index family and segregated with the disease in 6 affected relatives. Subsequently, we found 2 more families with a similar calf-predominant myopathy segregating with unique -mutated alleles. All patients showed a very slowly progressive myopathy without episodes of malignant hyperthermia or rhabdomyolysis. Muscle biopsy showed cores or core-like changes in all families.

Conclusions: Our findings expand the spectrum of -related disorders to include a calf-predominant myopathy with core pathology and autosomal dominant inheritance. Two families had unique and previously unreported mutations, while affected persons in the third family carried 2 previously known mutations in the same dominant allele.
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http://dx.doi.org/10.1212/WNL.0000000000007246DOI Listing
April 2019

Recessive PYROXD1 mutations cause adult-onset limb-girdle-type muscular dystrophy.

J Neurol 2019 Feb 4;266(2):353-360. Epub 2018 Dec 4.

Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.

Objective: To describe adult-onset limb-girdle-type muscular dystrophy caused by biallelic variants in the PYROXD1 gene, which has been recently linked to early-onset congenital myofibrillar myopathy.

Methods: Whole exome sequencing was performed for adult-onset neuromuscular disease patients with no molecular diagnosis. Patients with PYROXD1 variants underwent clinical characterization, lower limb muscle MRI, muscle biopsy and spirometry. A yeast complementation assay was used to determine the biochemical consequences of the genetic variants.

Results: We identified four patients with biallelic PYROXD1 variants. Three patients, who had symptom onset in their 20s or 30s, were homozygous for the previously described p.Asn155Ser. The fourth patient, with symptom onset at age 49, was compound heterozygous for p.Asn155Ser variant and previously unknown p.Tyr354Cys. All patients presented with a LGMD-type phenotype of symmetric muscle weakness and wasting. Symptoms started in proximal muscles of the lower limbs, and progressed slowly to involve also upper limbs in a proximal-predominant fashion. All patients remained ambulant past the age of 60. They had restrictive lung disease but no cardiac impairment. Muscle MRI showed strong involvement of anterolateral thigh muscles. Muscle biopsy displayed chronic myopathic changes. Yeast complementation assay demonstrated the p.Tyr354Cys mutation to impair PYROXD1 oxidoreductase ability.

Conclusion: PYROXD1 variants can cause an adult-onset slowly progressive LGMD-type phenotype.
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http://dx.doi.org/10.1007/s00415-018-9137-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373352PMC
February 2019

Homozygous Nonsense Mutation p.Q274X in TRIM63 (MuRF1) in a Patient with Mild Skeletal Myopathy and Cardiac Hypertrophy.

J Neuromuscul Dis 2019;6(1):143-146

Department of Neurology, Neuromuscular Research Center, University Hospital and University of Tampere, Finland.

TRIM63 mutations have been described as a potential cause for cardiac and skeletal myopathy in only one family so far. We describe a new patient carrying the same homozygous TRIM63 nonsense mutation c.739 C>T p.Q247X, that was originally reported in two members of a Spanish family manifesting cardiac hypertrophy. One of these original patients also had an additional heterozygous mutation in TRIM54 and a much more severe phenotype also involving skeletal muscles, and a digenic inheritance was therefore suggested. Our case report confirms the role of TRIM63 as a new cardiac myopathy gene, although it is unclear whether the homozygous p.Q247X mutation alone is sufficient to cause an additional skeletal myopathy.
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http://dx.doi.org/10.3233/JND-180350DOI Listing
January 2020

Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases.

Neurobiol Dis 2018 11 6;119:159-171. Epub 2018 Aug 6.

Université Côte d'Azur, Inserm, CNRS, IRCAN, CHU de Nice, France. Electronic address:

Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late-onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different levels of severity, we compared their effects in patient cells. Unlike affected individuals bearing the p.Ser59Leu mutation, patients presenting with SMAJ phenotype have neither mitochondrial myopathy nor mtDNA instability. The expression of CHCHD10 mutant allele leads to disassembly of mitochondrial contact site and cristae organizing system (MICOS) with mitochondrial dysfunction and loss of cristae in patient fibroblasts. We also show that G66V fibroblasts do not display the loss of MICOS complex integrity and mitochondrial damage found in S59L cells. However, S59L and G66V fibroblasts show comparable accumulation of phosphorylated mitochondrial TDP-43 suggesting that the severity of phenotype and mitochondrial damage do not depend on mitochondrial TDP-43 localization. The expression of the CHCHD10 allele is responsible for mitochondrial network fragmentation and decreased sensitivity towards apoptotic stimuli, but with a less severe effect than that found in cells expressing the CHCHD10 allele. Taken together, our data show that cellular phenotypes associated with p.Ser59Leu and p.Gly66Val mutations in CHCHD10 are different; loss of MICOS complex integrity and mitochondrial dysfunction, but not TDP-43 mitochondrial localization, being likely essential to develop a severe motor neuron disease.
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http://dx.doi.org/10.1016/j.nbd.2018.07.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015038PMC
November 2018

CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency.

Hum Mol Genet 2018 02;27(4):706-715

Department of Neurology, Ulm University, 89081 Ulm, Germany.

Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p.R15L and p.G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p.P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p.R15L and p.G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p.R15L, but not of CHCHD10 p.G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p.G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p.P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.
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http://dx.doi.org/10.1093/hmg/ddx436DOI Listing
February 2018

Botulinum toxin alleviates dysphagia of patients with inclusion body myositis.

J Neurol Sci 2017 Sep 24;380:142-147. Epub 2017 Jul 24.

Department of Otorhinolaryngology-Head and Neck Surgery, Turku University Hospital and University of Turku, Turku, Finland.

Objectives: Oropharyngeal dysphagia is a disabling and undertreated symptom that often occurs in patients with sporadic inclusion body myositis (s-IBM). In this study, we examined the effect of botulinum neurotoxin A (BoNT-A) injections to the cricopharyngeus muscle (CPM) of patients with s-IBM and dysphagia.

Patients, Materials And Methods: A single-center retrospective study involving 40 biopsy-proven s-IBM-patients treated in the District of Southwest Finland from 2000 to 2013. The incidence of dysphagia, rate of aspirations, rate of aspiration pneumonias and treatment results of dysphagia were analyzed. Patients treated for dysphagia were evaluated before and after surgery by video-fluoroscopy and/or using a questionnaire.

Results: Twenty-five of the 40 s-IBM patients (62.5%) experienced dysphagia. BoNT-A was injected a median of 2 times (range 1-7) in 12 patients with dysphagia. Before the injections 7 patients reported aspiration, none afterwards. The corresponding figures for aspiration pneumonia were 3 and 0. All of these patients had normal swallowing function 12months (median, range 2-60) after the last injection.

Conclusion: BoNT-A injections to the CPM alleviate the dysphagia of s-IBM patients reversibly and appear to reduce the rate of aspiration effectively.
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http://dx.doi.org/10.1016/j.jns.2017.07.031DOI Listing
September 2017

Gluteus maximus hypertrophy: A diagnostic clue in four and a half LIM domain 1-mutated reducing body myopathy.

Neuromuscul Disord 2017 10 23;27(10):962-963. Epub 2017 Jun 23.

Neuromuscular Research Center, Tampere University Hospital and University of Tampere, Tampere, Finland; Department of Neurology, Vasa Central Hospital, Vasa, Finland; Folkhälsan Genetic Institute, Department of Medical Genetics, Helsinki University, Helsinki, Finland.

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http://dx.doi.org/10.1016/j.nmd.2017.06.014DOI Listing
October 2017

mutations and motor neuron disease: the distribution in Finnish patients.

J Neurol Neurosurg Psychiatry 2017 03 3;88(3):272-277. Epub 2016 Nov 3.

Neuromuscular Research Center, Tampere University and University Hospital, Tampere, Finland.

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http://dx.doi.org/10.1136/jnnp-2016-314154DOI Listing
March 2017

Evolving neuromuscular phenotype in a patient with a heterozygous CHCHD10 p.G66V mutation.

J Neurol 2016 Jul 13;263(7):1461-2. Epub 2016 May 13.

Department of Neurology, Neuromuscular Research Center, University Hospital, University of Tampere, Tampere, Finland.

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http://dx.doi.org/10.1007/s00415-016-8134-zDOI Listing
July 2016

Distinct Muscle Biopsy Findings in Genetically Defined Adult-Onset Motor Neuron Disorders.

PLoS One 2016 21;11(3):e0151376. Epub 2016 Mar 21.

Neuromuscular Research Center, Department of Neurology, University Hospital and University of Tampere, Tampere, Finland.

The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary "myopathic" changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151376PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801364PMC
August 2016

Towards a European Registry and Biorepository for Patients with Spinal and Bulbar Muscular Atrophy.

J Mol Neurosci 2016 Mar 7;58(3):394-400. Epub 2016 Jan 7.

Clinic of Neurology, Ulm University, 89081, Ulm, Germany.

Pathomechanisms of spinal and bulbar muscular atrophy (SBMA) have been extensively investigated and are partially understood, but no effective treatment is currently available for this disabling disorder. Its rarity, the slow disease progression, and lack of sensitive-to-change outcome measures render design and conduction of clinical trials a challenging task. Therefore, it is fundamental to strengthen the network of clinical centers interested in SBMA for clinical trial readiness. We propose to create and maintain an International SBMA Registry where as many well-characterized patients as possible can be included, with the following aims: facilitate planning of clinical trials and recruitment of patients, define natural history of the disease, characterize epidemiology, develop standards of care, and inform the community of patients about research progresses and ongoing trials. We also aim at developing harmonized and coordinated biorepositories. The experience obtained during the last years in the field of other neuromuscular disorders and of Huntington disease offers valuable precedents.
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http://dx.doi.org/10.1007/s12031-015-0704-5DOI Listing
March 2016

Distal myopathies in Finnish patients.

Duodecim 2016;132(18):1635-44

Distal myopathies are a group of rare muscular dystrophies comprising more than 20 different genetic entities. The first distal myopathy in Finland, tibial muscular dystrophy, was identified more than 20 years ago. Muscle weakness predominantly affects the feet and hands, although variable weakness can be detected clinically and on muscle MRI in the proximal muscles in the later stages of the disease. Advanced molecular genetic techniques have enabled identification of several distinct distal myopathies in Finland. The clinical findings of different distal myopathies overlap, but there are also distinguishable differences that might help final genetic diagnostics.
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January 2018

Diagnostic Clinical, Electrodiagnostic and Muscle Pathology Features of Spinal and Bulbar Muscular Atrophy.

J Mol Neurosci 2016 Mar 16;58(3):330-4. Epub 2015 Nov 16.

Neuromuscular Research Center, Tampere University and Hospital, Tampere, Finland.

Kennedy's disease or spinal and bulbar muscular atrophy (SBMA) is a multi-system disorder affecting adult males, which is characterized by weakness of limbs and faciobulbar muscles primarily due to loss of lower motor neurons. Besides the obvious motor neuronopathy, additional findings in a substantial proportion of SBMA patients include sensory neuropathy and signs of androgen deficiency, such as poor sexual functioning and reduced fertility with gynaecomastia. The presence of elevated glucose, liver pathology or dyslipidaemia is less consistent features. We review the striking clinical, electrodiagnostic and muscle pathology features characteristic of Kennedy's disease, which has some peculiar and diagnostically useful features not observed in many other neuromuscular disorders.
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http://dx.doi.org/10.1007/s12031-015-0684-5DOI Listing
March 2016

Reply: To PMID 25428574.

Ann Neurol 2015 Nov 31;78(5):831-2. Epub 2015 Aug 31.

Department of Neurology, Vasa Central Hospital, Helsinki.

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http://dx.doi.org/10.1002/ana.24465DOI Listing
November 2015

Spontaneous activity in electromyography may differentiate certain benign lower motor neuron disease forms from amyotrophic lateral sclerosis.

J Neurol Sci 2015 Aug 3;355(1-2):143-6. Epub 2015 Jun 3.

Neuromuscular Research Center, Tampere University and Hospital, Tampere, Finland.

There is limited data on electromyography (EMG) findings in other motor neuron disorders than amyotrophic lateral sclerosis (ALS). We assessed whether the distribution of active denervation detected by EMG, i.e. fibrillations and fasciculations, differs between ALS and slowly progressive motor neuron disorders. We compared the initial EMG findings of 43 clinically confirmed, consecutive ALS patients with those of 41 genetically confirmed Late-onset Spinal Motor Neuronopathy and 14 Spinal and Bulbar Muscular Atrophy patients. Spontaneous activity was more frequently detected in the first dorsal interosseus and deltoid muscles of ALS patients than in patients with the slowly progressive motor neuron diseases. The most important observation was that absent fibrillations in the first dorsal interosseus muscle identified the benign forms with sensitivities of 66%-77% and a specificity of 93%. The distribution of active denervation may help to separate ALS from mimicking disorders at an early stage.
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http://dx.doi.org/10.1016/j.jns.2015.06.002DOI Listing
August 2015

Late onset spinal motor neuronopathy is caused by mutation in CHCHD10.

Ann Neurol 2015 Jan 12;77(1):163-72. Epub 2014 Dec 12.

Neuromuscular Research Center, Tampere University and University Hospital, Tampere.

Objective: A study was undertaken to identify the responsible gene defect underlying late onset spinal motor neuronopathy (LOSMoN/SMAJ; Online Mendelian Inheritance in Man #615048), an autosomal dominant disease mapped to chromosome 22q11.2.

Methods: The previous genetic linkage approach by microsatellite haplotyping was continued in new families. A whole genome sequencing was performed to find all possibly pathogenic mutations in the linked area. The detected variations were verified by Sanger sequencing.

Results: Six new SMAJ families were identified based on the unique founder haplotype. A critical recombination in 1 family restricted the linked area to 727kb between markers SHGC-106816 and D22S345. In whole genome sequencing a previously unknown mutation c.197G>T p.G66V in CHCHD10 was identified. The mutation was shown to segregate with the disease in 55 patients from 17 families.

Interpretation: Mutation c.197G>T p.G66V in CHCHD10 is the cause of the lower motor neuron syndrome LOSMoN/SMAJ. During the preparation of this article other mutations were reported to cause frontotemporal dementia-amyotrophic lateral sclerosis syndrome, indicating that the CHCHD10 gene is largely important for the motor and cognitive neuronal systems.
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http://dx.doi.org/10.1002/ana.24319DOI Listing
January 2015

Late-onset spinal motor neuronopathy - a common form of dominant SMA.

Neuromuscul Disord 2014 Mar 26;24(3):259-68. Epub 2013 Nov 26.

Neuromuscular Research Center, Tampere University and University Hospital, Tampere, Finland; Department of Neurology, Vasa Central Hospital, Vasa, Finland.

We previously described two Finnish families with a new autosomal dominant late-onset spinal motor neuronopathy that was mapped to chromosome 22q11.2-q13.2. In the current screening study of 43 lower motor neuron disease patients from Finland and Sweden, we identified 26 new late-onset spinal motor neuronopathy patients sharing the founder haplotype. In addition to the main symptoms and signs: painful cramps, fasciculations, areflexia and slowly evolving muscle weakness, new features such as mild bulbar findings, were identified. The disease is relatively benign in terms of life expectancy and rate of disability progression, and it is therefore noteworthy that three patients were initially misdiagnosed with ALS. Significant recombinants in this new patient cohort restricted the disease locus by 90% to 1.8Mb. Late-onset spinal motor neuronopathy seems not to be very rare, at least not in Finland, with 38 patients identified in a preliminary ascertainment.
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http://dx.doi.org/10.1016/j.nmd.2013.11.010DOI Listing
March 2014

[The expanding spectrum of LGMD--recently discovered disease genes are important also in Finnish patients].

Duodecim 2013 ;129(19):2011-20

TYKS, neurologia.

Limb-girdle muscular dystrophies (LGMD) are autosomal disorders with a range of manifestations varying from almost asymptomatic late-onset patients to severe childhood onset forms. Recently identified disease genes explain the majority of LGMD cases in Finland. Prognosis, potential cardiac and respiratory complications and symptomatic treatment options differ in different LGMD subtypes. This means that the gold standard of diagnosis is the molecular genetic definition of the disease in each patient. Despite evolving sequencing techniques, the clinical, pathological, neurophysiological and imaging characterisation of patients will not become obsolete, but rather, even more important during the next years to enable targeted genetic diagnostics.
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December 2013

Autosomal dominant late-onset spinal motor neuronopathy is linked to a new locus on chromosome 22q11.2-q13.2.

Eur J Hum Genet 2012 Nov 25;20(11):1193-6. Epub 2012 Apr 25.

Neuromuscular Research Unit, University of Tampere, Tampere, Finland.

Spinal muscular atrophies (SMAs) are hereditary disorders characterized by degeneration of lower motor neurons. Different SMA types are clinically and genetically heterogeneous and many of them show significant phenotypic overlap. We recently described the clinical phenotype of a new disease in two Finnish families with a unique autosomal dominant late-onset lower motor neuronopathy. The studied families did not show linkage to any known locus of hereditary motor neuron disease and thus seemed to represent a new disease entity. For this study, we recruited two more family members and performed a more thorough genome-wide scan. We obtained significant linkage on chromosome 22q, maximum LOD score being 3.43 at marker D22S315. The linked area is defined by flanking markers D22S686 and D22S276, comprising 18.9 Mb. The region harbours 402 genes, none of which is previously known to be associated with SMAs. This study confirms that the disease in these two families is a genetically distinct entity and also provides evidence for a founder mutation segregating in both pedigrees.
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http://dx.doi.org/10.1038/ejhg.2012.76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477865PMC
November 2012

Double trouble: spinal muscular atrophy type II and seropositive myasthenia gravis in the same patient.

Neuromuscul Disord 2012 Feb 20;22(2):129-30. Epub 2011 Aug 20.

Department of Neurology, Turku University Central Hospital, Turku, Finland.

Autosomal recessive proximal spinal muscular atrophy is caused by deletions in the survival of motor neuron (SMN1) gene, while autoimmune myasthenia gravis is an acquired disorder. An association between these two diseases has not been reported. Our patient with intermediate spinal muscular atrophy (SMA type II) did not need alimentary or respiratory aid until age 51 when he suddenly developed bulbar weakness and respiratory insufficiency. Seropositive myasthenia gravis was confirmed and the corresponding symptoms resolved on treatment.
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http://dx.doi.org/10.1016/j.nmd.2011.07.011DOI Listing
February 2012