Genetic background of late-onset spinal motor neuronopathy

The aim of this study was to find and describe the genetic background of a new form of spinal muscular atrophy (SMA). Late-onset spinal motor neuronopathy (LOSMoN), later named spinal muscular atrophy, Jokela type (SMAJ), is a relatively benign autosomal dominant form of a lower motor neuron disorder. Disease onset is after the age of 30-40 years, and SMAJ is characterized by initial painful cramps and fasciculations affecting the proximal and distal muscles of the upper and lower limbs. The disease is slowly progressive, resulting in weakness and mild to moderate muscle atrophy later in life. SMAJ was originally identified in two families in Eastern Finland. The genome-wide scan study performed for these families showed that the disease is linked to chromosome 22q11.2-q13.2. The disease-associated haplotype was identical in both families, suggesting a founder effect. The founder hypothesis was also confirmed later, as several other unrelated patients carrying the same haplotype were identified. The disease-causing mutation, c.197G>T p.G66V in CHCHD10, was detected by whole-genome sequencing. The mutation was present in all then identified 55 SMAJ patients belonging to 17 families. At the same time, other dominant mutations in CHCHD10 were described to cause a wide range of neurological disorders. CHCHD10 was the first SMA-causing gene identified that encodes for a mitochondrial protein. The prevalence and clinical outcome of CHCHD10 mutations in Finnish neuromuscular disease patients were clarified in a screening study. The only detected mutation was c.197G>T p.G66V, and all patients carrying this mutation had a phenotype restricted to SMAJ. The prevalence of c.197G>T p.G66V was estimated to be around 4/100 000 in Finland, i.e. approximately 200 symptomatic SMAJ patients. The results of this study confirm that SMAJ is a genetically distinct entity caused by a dominant mutation c.197G>T p.G66V in CHCHD10. This finding enables genetic testing of SMAJ, providing patients with an accurate diagnosis and prognosis. According to our genotyping results, c.197G>T p.G66V is a founder mutation in Finland, all SMAJ patients having common ancestry. SMAJ was shown to be relatively common in Finland. It is clearly the most common CHCHD10-related disease reported, and in Finland it may be the most common form of SMA. Because SMAJ seems to be absent from other populations, it can be considered a part of the Finnish disease heritage.Tämän tutkimuksen tavoitteena oli kuvata LOSMoN-taudin eli myöhään alkavan spinaalisen motoneuronitaudin geneettinen tausta. LOSMoN, joka sittemmin nimettiin Jokela-tyypin spinaaliseksi lihasatrofiaksi (SMAJ), on suhteellisen lievä, autosomissa vallitsevasti periytyvä alemman motoneuronin sairaus. Tauti alkaa 30-40 vuoden iässä, ja sen alkuoireita ovat kivuliaat lihaskrampit ja lihasnykinät, joita esiintyy proksimaalisesti ja distaalisesti sekä ala- että yläraajoissa. Tauti on hitaasti etenevä, ja se johtaa lihasten heikkouteen sekä lievään tai keskivaikeaan lihasten surkastumiseen myöhäisellä iällä. SMAJ tunnistettiin alun perin kahdessa itäsuomalaisessa perheessä. Koko genomin kartoituksessa näiden perheiden taudin havaittiin kytkeytyvän kromosomialueeseen 22q11.2-q13.2. Tautiin kytkeytyvä haplotyyppi oli molemmissa perheissä samanlainen, mikä viittaa siihen, että perheiden taudilla on yhteinen alkuperä. Tämä perustajavaikutus saatiin vahvistettua, kun tutkimuksessa löydettiin muita, alkuperäisiin perheisiin kuulumattomia potilaita, joilla oli sama tautiin kytkeytyvä haplotyyppi. Taudin aiheuttava mutaatio, CHCHD10-geenin muutos c.197G>T p.G66V, löydettiin koko genomin sekvensoinnilla. Kyseinen mutaatio havaittiin kaikilta siihen mennessä tunnistetuilta 55 SMAJ-potilaalta, jotka kuuluivat 17 eri perheeseen. Samaan aikaan CHCHD10-geenin muiden vallitsevasti periytyvien mutaatioiden kuvattiin aiheuttavan erilaisia neurologisia sairauksia. CHCHD10 oli ensimmäinen mitokondriaalista proteiinia koodaava geeni, jonka on kuvattu aiheuttavan spinaalista lihasatrofiaa. CHCHD10¬-geenin mutaatioiden yleisyyttä ja niiden aiheuttamia tauteja selvitettiin suomalaisille neuromuskulaaritautipotilaille toteutetussa seulontatutkimuksessa. Ainoa tutkimuksessa havaittu mutaatio oli c.197G>T p.G66V, ja kaikkien sitä kantavien potilaiden taudinkuva vastasi SMAJ:a. Mutaation c.197G>T p.G66V yleisyydeksi Suomessa arvioitiin noin 4/100 000, mikä tarkoittaa noin 200 oireista SMAJ-potilasta. Tämä tutkimus osoitti, että SMAJ on geneettisesti erillinen tauti, joka johtuu vallitsevasti periytyvästä CHCHD10-geenin c.197G>T p.G66V –mutaatiosta. Tutkimuksen tulosten myötä SMAJ:lle on voitu kehittää geenitesti, jonka avulla potilaat voivat saada taudilleen oikean diagnoosin ja ennusteen. Genotyypitystulokset osoittivat, että c.197G>T p.G66V on perustajamutaatio suomalaisväestössä. Tämän tutkimuksen perusteella SMAJ on Suomessa suhteellisen yleinen tauti. SMAJ on selvästi yleisin CHCHD10-geeniin liitetyistä taudeista, ja Suomessa se on mahdollisesti yleisin SMA:n muoto. Koska SMAJ:a ei ilmeisesti esiinny muissa väestöissä, sitä voidaan pitää osana suomalaista tautiperintöä

CHCHD10 mutations and motor neuron disease: the distribution in Finnish patients.

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Novel mutation in TNPO3 causes congenital limb-girdle myopathy with slow progression

Objective We report a second family with autosomal dominant transportinopathy presenting with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness. Methods Patients had clinical examinations, muscle MRI, EMG, and muscle biopsy studies. The MYOcap gene panel was used to identify the gene defect in the family. Muscle biopsies were used for histopathologic and protein expression studies, and TNPO3 constructs were used to study the effect of the mutations in transfected cells. Results We identified a novel heterozygous mutation, c.2757delC, in the last part of the transportin-3 (TNPO3) gene in the affected family members. The mutation causes an almost identical frameshift affecting the stop codon and elongating the C-term protein product of the TNPO3 transcript, as was previously reported in the first large Spanish-Italian LGMD1F kindred. TNPO3 protein was increased in the patient muscle and accumulated in the subsarcolemmal and perinuclear areas. At least one of the cargo proteins, the splicing factor SRRM2 was normally located in the nucleus. Transiently transfected mutant TNPO3 constructs failed to localize to cytoplasmic annulate lamellae pore complexes in cells. Conclusions We report the clinical, molecular genetic, and histopathologic features of the second transportinopathy family. The variability of the clinical phenotype together with histopathologic findings suggests that several molecular pathways may be involved in the disease pathomechanism, such as nucleocytoplasmic shuttling, protein aggregation, and defective protein turnover.Peer reviewe

Expanding the importance of HMERF titinopathy : new mutations and clinical aspects

ObjectiveHereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and considered quite rare. Respiratory insufficiency is an early symptom. A collection of families and patients with muscle disease suggestive of HMERF was clinically and genetically studied.MethodsAltogether 12 new families with 19 affected patients and diverse nationalities were studied. Most of the patients were investigated using targeted next-generation sequencing; Sanger sequencing was applied in some of the patients and available family members. Histological data and muscle MRI findings were evaluated.ResultsThree families had several family members studied while the rest were single patients. Most patients had distal and proximal muscle weakness together with respiratory insufficiency. Five heterozygous TTN A-band mutations were identified of which two were novel. Also with the novel mutations the muscle pathology and imaging findings were compatible with the previous reports of HMERF.ConclusionsOur collection of 12 new families expands mutational spectrum with two new mutations identified. HMERF is not that rare and can be found worldwide, but maybe underdiagnosed. Diagnostic process seems to be complex as this study shows with mostly single patients without clear dominant family history.Peer reviewe

Asuntomessujen kehittäminen

Osuuskunta Suomen Asuntomessut on järjestänyt asuntomessuja Suomessa vuodesta 1970. Opinnäytetyön tavoitteena oli Valkeakoskella kesällä 2009 järjestettävien asuntomessujen pohjalta tuottaa konkreettisia kehitysideoita tulevia asuntomessuja varten. Tutkimus vastaa siihen, kuinka asuntomessukokemus saadaan messuasiakkaille kokonaisvaltaisesti mielekkäämmäksi. Tutkimuksen osaksi liitetään parannusehdotukset siihen, miten Valkeakosken asuntomessujen internet-sivuista saadaan käyttäjäystävällisemmät. Tutkimus toteutettiin kvalitatiivisena tutkimuksena. Tutkimus toteutettiin avustavaa ryhmää hyödyntämällä. Avustava ryhmä osallistui tutkimuksen kaikkiin kolmeen osa-alueeseen. Tutkimuksen osa-alueita olivat Internet-sivujen analysointi, vierailut Valkeakosken asuntomessuilla sekä ideointi. Vierailuiden aikana toteutettiin lisäksi 40 satunnaisten messuasiakkaiden haastattelua. Toteutuksessa käytettiin hyväksi Tiimiakatemialla opittuja uuden synnyttämisen työkaluja. Tutkimuksen perusteella asuntomessuilla on tehtävä yksinkertaisia ja näkyviä parannuksia. Esille nousi viihtyvyyden kannalta pieniä osa-alueita, joiden toimimattomuus tulee esille suurena puutteena. Asuntomessuja järjestettäessä on otettava huomioon pieniä yksinkertaisia asioita, jotta pohja olisi kunnossa isommille elämyksille. Internet-sivujen osalta esille nousivat myös yksinkertaistavat kehitysideat. Selaamista helpottavaa olisi, jos löydettävissä olisi vain yksi kattava sivusto. Jos useampaa sivustoa pidetään yllä, on niiden välille luotava selkeä yhteys. Nämä tulokset saatiin aikaan käyttäjäystävällisyyden eri osa-alueiden tutkimisen kautta.Co-operative Finnish Housing Fair (Osuuskunta Suomen Asuntomessut) has arranged housing fairs in Finland since 1970. The objective of the thesis was to create concrete development ideas for future fairs based on the housing fair held in Valkeakoski in the summer of 2009. The report answers the question of how the housing fair experience can be made comprehensively more enjoyable for customers. Results include improvement ideas as to how the Valkeakoski housing fair Internet site could be made more user friendly. The study was conducted as a qualitative survey. The study was carried out with the help of an assist group. The assist group took part in all three sectors of the survey. The sectors were analyzing the Internet sites, visiting the Valkeakoski housing fair, and creating ideas. During the visits also an interview of 40 arbitrary fair visitors was made. The realization utilized the birth giving tools used in Team Academy. Based on the study the fair needs some simple but visible improvements. Small issues rose when it came to overall enjoyment, which when not functioning properly will show as a great deficiency. When arranging the housing fair the small and simple details must be kept in mind at all times, so that the larger experiences will have a solid foundation. Simplifying ideas also were created for the Internet pages. It would make browsing as simple and easy as possible if there was only one site covering the entirety of the fair, or if more than one sites are kept, they must have a clear connection to each other. These results were gathered bearing in mind the different areas of user friendliness

Novel compound heterozygous mutation in SACS gene leads to a milder autosomal recessive spastic ataxia of Charlevoix-Saguenay, ARSACS, in a Finnish family

Key Clinical Message Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare disorder outside Quebec causing childhood-onset cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs. A Finnish family with milder form of ARSACS was found to harbor three mutations, p.E1100K, p.N1489S, and p.M1359T, in SACS gene. The mutations segregated with the disease.Peer reviewe