The m.7510T > C mutation: Hearing impairment and a complex neurologic phenotype

Objectives: Mutations in mitochondrial DNA cause a variety of clinical phenotypes ranging from a mild hearing impairment (HI) to severe encephalomyopathy. The MT-TS1 gene is a hotspot for mutations causing HI. The m.7510T>C mutation in MT-TS1 has been previously associated with non-syndromic HI in four families from different ethnic backgrounds.Materials and Methods: We describe the clinical, genetic, and histopathological findings in a Finnish family with the heteroplasmic m.7510T>C mutation in mitochondrial DNA.ResultsThe family proband presented with a progressive mitochondrial disease phenotype including migraine, epilepsy, mild ataxia, and cognitive impairment in addition to HI. One young adult presented with HI only. Other family members had a mild phenotype comprising ataxia and tremor in addition to HI. Mutation heteroplasmy was 90% in the blood of maternal grandmother and 99% in the muscle and blood of the three other family members. Muscle histology was consistent with mitochondrial myopathy in three family members. The mitochondrial haplogroup of the family was a different branch of the haplogroup H than in the previous reports of this mutation.Conclusion: Our results suggest that, in addition to sensorineural HI, the m.7510T>C mutation is associated with a spectrum of mitochondrial disease clinical features including migraine, epilepsy, cognitive impairment, ataxia, and tremor, and with evidence of mitochondrial myopathy

Mutation m.15923A>G in the MT-TT gene causes mild myopathy - case report of an adult-onset phenotype

Background: Only five patients have previously been reported to harbor mutations in the MT-TT gene encoding mitochondrial tRNA threonine. The m.15923A > G mutation has been found in three severely affected children. One of these patients died within days after birth and two had a phenotype of myoclonic epilepsy with ragged red fibers (MERRF) in early childhood. We have now found the mutation in an adult patient with mild myopathy.Case presentation: The patient is a 64-year-old Finnish man, who developed bilateral ptosis, diplopia and exercise intolerance in his fifties. Family history was unremarkable. Muscle histology showed cytochrome c-oxidase (COX) negative and ragged red fibres. The m.15923A > G mutation heteroplasmy was 33% in the skeletal muscle and 2% in buccal epithelial cells. The mutation was undetectable in the blood. Single-fibre analysis was performed and COX-negative fibres had a substantially higher heteroplasmy of 92%, than the normal fibres in which it was 43%.Conclusions: We report the fourth patient with m. 15923A > G and with a remarkably milder phenotype than the previous three patients. Our findings and recent biochemical studies suggest that the mutation m.15923A > G is a definite disease-causing mutation. Our results also suggest that heteroplasmy of the m.15923A > G mutation correlates with the severity of the phenotype. This study expands the catalog of the phenotypes caused by mutations in mtDNA

Cognitive impairment is not uncommon in patients with biallelic RFC1 AAGGG repeat expansion, but the expansion is rare in patients with cognitive disease

Introduction: The biallelic repeat expansion (AAGGG)(exp) in RFC1 causes cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). Recently, cognitive impairment has been reported in patients with CANVAS and a broader neurodegenerative process associated with RFC1 has been suggested. Furthermore, rare cases of multiple system atrophy, Parkinson's disease, amyotrophic lateral sclerosis or CANVAS with features of dementia with Lewy bodies have been found. Objective: We hypothesized that the biallelic (AAGGG)(exp) is associated with neurodegeneration manifested as cognitive symptoms and that atypical RFC1 disease may be found among patients with cognitive disorder. Methods: Clinical data on nine patients with biallelic (AAGGG()exp) were reviewed and 564 patients with Alz-heimer's disease or frontotemporal dementia (FTD) were investigated for biallelic RFC1 (AAGGG)(exp). Results: Five patients with biallelic (AAGGG)(exp) were found with a cognitive impairment and in four of them the phenotype resembled FTD. However, biallelic (AAGGG)(exp) was not detected among patients with Alzheimer's disease or FTD. Conclusion: Cognitive impairment is a feature in patients with the biallelic (AAGGG)(exp), but the pathogenic expansion seems to be rare in patients with dementia. Studies on patients with diverse phenotypes would be useful to further explore the involvement of RFC1 in neuronal degeneration and to identify atypical phenotypes, which should be taken into account in clinical practice.Peer reviewe

Case report: a novel frameshift mutation in the mitochondrial cytochrome c oxidase II gene causing mitochondrial disorder

Background: Mitochondrial cytochrome c oxidase 2, MT-CO2, encodes one of the three subunits, which form the catalytic core of cytochrome c oxidase (COX), complex IV. Mutations in MT-CO2 are rare and the associated phenotypes are variable including nonsyndromic and syndromic forms of mitochondrial diseases.Case presentation: We describe a 30-year-old man with cognitive decline, epilepsy, psychosis, exercise intolerance, sensorineural hearing impairment, retinitis pigmentosa, cataract and lactic acidosis. COX-deficient fibers and ragged red fibers were abundant in the muscle. Sequencing of mitochondrial DNA (mtDNA) revealed a novel frameshift mutation m.8156delG that was predicted to cause altered C-terminal amino acid sequence and to lead to truncation of the COX subunit 2. The deletion was heteroplasmic being present in 26% of the mtDNA in blood, 33% in buccal mucosa and 95% in muscle. Deletion heteroplasmy correlated with COX-deficiency in muscle histochemistry. The mother and the siblings of the proband did not harbor the deletion.Conclusions: The clinical features and muscle histology of the proband suggested a mitochondrial disorder. The m.8156delG deletion is a new addition to the short list of pathogenic mutations in the mtDNA-encoded subunits of COX. This case illustrates the importance of mtDNA sequence analysis in patients with an evident mitochondrial disorder

Finnish Parkinson's disease study integrating protein-protein interaction network data with exome sequencing analysis

Variants associated with Parkinson's disease (PD) have generally a small effect size and, therefore, large sample sizes or targeted analyses are required to detect significant associations in a whole exome sequencing (WES) study. Here, we used protein-protein interaction (PPI) information on 36 genes with established or suggested associations with PD to target the analysis of the WES data. We performed an association analysis on WES data from 439 Finnish PD subjects and 855 controls, and included a Finnish population cohort as the replication dataset with 60 PD subjects and 8214 controls. Single variant association (SVA) test in the discovery dataset yielded 11 candidate variants in seven genes, but the associations were not significant in the replication cohort after correction for multiple testing. Polygenic risk score using variants rs2230288 and rs2291312, however, was associated to PD with odds ratio of 2.7 (95% confidence interval 1.4-5.2; p < 2.56e-03). Furthermore, an analysis of the PPI network revealed enriched clusters of biological processes among established and candidate genes, and these functional networks were visualized in the study. We identified novel candidate variants for PD using a gene prioritization based on PPI information, and described why these variants may be involved in the pathogenesis of PD

Association of biallelic RFC1 expansion with early-onset Parkinson's disease

Background and Purpose: The biallelic repeat expansion (AAGGG)exp in the replication factor C subunit 1 gene (RFC1) is a frequent cause of cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) as well as late-onset ataxia. The clinical spectrum of RFC1 disease has expanded since the first identification of biallelic (AAGGG)exp and includes now various nonclassical phenotypes. Biallelic (AAGGG)exp in RFC1 in patients with clinically confirmed Parkinson's disease (PD) has recently been found. Methods: A nationwide cohort of 273 Finnish patients with early-onset PD was examined for the biallelic intronic expansion in RFC1. The expansion (AAGGG)exp was first screened using extra long polymerase chain reactions (Extra Large-PCRs) and flanking multiplex PCR. The presence of biallelic (AAGGG)exp was then confirmed by repeat-primed PCR and, finally, the repeat length was determined by long-read sequencing. Results: Three patients were found with the biallelic (AAGGG)exp in RFC1 giving a frequency of 1.10% (0.23%–3.18%; 95% confidence interval). The three patients fulfilled the diagnostic criteria of PD, none of them had ataxia or neuropathy, and only one patient had a mild vestibular dysfunction. The age at onset of PD symptoms was 40–48 years and their disease course had been unremarkable apart from the early onset. Conclusions: Our results suggest that (AAGGG)exp in RFC1 is a rare cause of early-onset PD. Other populations should be examined in order to determine whether our findings are specific to the Finnish population.publishedVersionPeer reviewe

Genetic causes and risk factors associated with phenotypes occurring in mitochondrial disorders

Abstract Finding the genetic causes leading to phenotypes of mitochondrial diseases is challenging because of heterogeneity of the disorders and variety of the underlying biochemical defects. In adults, many of the manifestations of mitochondrial diseases cannot be distinguished from the neurodegenerative processes associated with old age. A single mutation or mutations within the same gene can result in a broad range of disorders. Conversely, clinically similar, monogenic disorders may be caused by genes which are governing entirely different cellular pathways. This study investigated the genetic etiology underlying certain symptoms which are characteristic for mitochondrial syndromes, or mimics of the mitochondrial ones. In the first project, we presented the contribution of genetic variation in the Wolfram Syndrome 1 gene to the risk of diabetes mellitus and sensorineural hearing impairment. We also estimated the frequency of a rare pathogenic variation in WFS1. The second project detected a link between the complex phenotype of age-related hearing impairment and the WFS1 gene. Monogenic forms of ARHI are extremely rare and we succeeded in recognizing one Mendelian form of the trait. The third project confirmed the Mitofusin 2 gene causality in the outlier phenotype of Charcot-Marie-Tooth disease. The fourth project described a Finnish family with two affected siblings with adult-onset ataxia, diabetes mellitus, and hypergonadotropic hypogonadism. The found novel mutation in mtDNA, m.8561C>G, was located in the overlapping region of two mitochondrial genes and resulted in an impaired assembly and dysfunctional energy production of mitochondrial ATP synthase. This thesis expands our knowledge about complex neurological phenotypes and identifies not only some causative genes but also outlier phenotypes, which should be noted in clinical practice.Tiivistelmä Perintötekijät mitokondriaalisten ja niiden kaltaisten tautien taustalla ovat vaikeasti tunnistettavissa. Tautien kirjo on valtava, ja niihin johtavat biokemialliset syyt ovat moninaisia. Aikuisten mitokondriotaudit voivat jäädä diagnosoimatta, koska oireet voivat peittyä vanhenemiseen liittyviin neurodegeneratiivisiin prosesseihin. Sama mutaatio tai eri mutaatiot samassa geenissä voivat johtaa kliinisesti täysin erilaisiin ilmiasuihin. Toisaalta, kliinisesti samankaltaiset taudit voivat olla geneettisesti ja solubiologiallisesti kirjavia. Tässä tutkimuksessa selvitetään geneettistä etiologiaa tiettyjen mitokondriaalisille ja niiden kaltaisille taudeille tyypillisten oireiden taustalla. Ensimmäisessä osajulkaisussa tunnistetaan geneettisiä riskivariantteja Wolfram Syndrome 1 -geenissä diabeteksen ja kuulonaleneman taustalta. Lisäksi tutkimuksessa estimoidaan harvinaisen tautia aiheuttavan variaation määrää kyseisessä geenissä. Toinen projekti esittelee suomalaisen perheen, jossa myöhään alkaneen kuulonaleneman, ikäkuulon, geneettinen syy paljastuu WFS1-geenistä, jota ei aiemmin ole liitetty kyseiseen ilmiasuun. Yhden geenin aiheuttamat ikäkuulotapaukset ovat todella harvinaisia, koska ikäkuulo on monimutkainen kokonaisuus, johon ympäristötekijöillä on suuri vaikutus. Kolmas osajulkaisu kuvaa potilastapauksia, joiden ilmiasu on epätyypillinen Charcot-Marie-Toothin neuropatia. Tautigeeni on tunnettu Mitofusin 2, mutta sen aiheuttaman taudinkuvat ovat yleensä vakavampia ja varhain alkaneita. Viimeinen osajulkaisu kuvaa suomalaisen perheen, jonka kahden oireisen sisaruksen taustalta löytyy mitokondriaalisen DNA:n uusi mutaatio, joka sijaitsee kahden geenin alueella muuttaen niiden molempien lopputuotetta. Mutaation, m.8561C>G, osoitetaan vaikuttavan mitokondriaalisen ATP-syntaasin rakentumiseen ja energiatuotantoon. Tämä väitöskirja laajentaa geneettistä tietoisuutta neurologisten tautien taustalla ja esittelee uusia geneettisiä syitä ja ilmiasuja, jotka tulisi huomioida kliinisessä työssä terveydenhuollossa

Mutation m.15923A>G in the MT-TT gene causes mild myopathy – case report of an adult-onset phenotype

Abstract Background: Only five patients have previously been reported to harbor mutations in the MT-TT gene encoding mitochondrial tRNA threonine. The m.15923A > G mutation has been found in three severely affected children. One of these patients died within days after birth and two had a phenotype of myoclonic epilepsy with ragged red fibers (MERRF) in early childhood. We have now found the mutation in an adult patient with mild myopathy. Case presentation: The patient is a 64-year-old Finnish man, who developed bilateral ptosis, diplopia and exercise intolerance in his fifties. Family history was unremarkable. Muscle histology showed cytochrome c-oxidase (COX) negative and ragged red fibres. The m.15923A > G mutation heteroplasmy was 33% in the skeletal muscle and 2% in buccal epithelial cells. The mutation was undetectable in the blood. Single-fibre analysis was performed and COX-negative fibres had a substantially higher heteroplasmy of 92%, than the normal fibres in which it was 43%. Conclusions: We report the fourth patient with m. 15923A > G and with a remarkably milder phenotype than the previous three patients. Our findings and recent biochemical studies suggest that the mutation m.15923A > G is a definite disease-causing mutation. Our results also suggest that heteroplasmy of the m.15923A > G mutation correlates with the severity of the phenotype. This study expands the catalog of the phenotypes caused by mutations in mtDNA

The m.7510T>C mutation:hearing impairment and a complex neurologic phenotype

Abstract Objectives: Mutations in mitochondrial DNA cause a variety of clinical phenotypes ranging from a mild hearing impairment (HI) to severe encephalomyopathy. The MT-TS1 gene is a hotspot for mutations causing HI. The m.7510T>C mutation in MT-TS1 has been previously associated with non-syndromic HI in four families from different ethnic backgrounds. Materials and Methods: We describe the clinical, genetic, and histopathological findings in a Finnish family with the heteroplasmic m.7510T>C mutation in mitochondrial DNA. Results: The family proband presented with a progressive mitochondrial disease phenotype including migraine, epilepsy, mild ataxia, and cognitive impairment in addition to HI. One young adult presented with HI only. Other family members had a mild phenotype comprising ataxia and tremor in addition to HI. Mutation heteroplasmy was 90% in the blood of maternal grandmother and ≥99% in the muscle and blood of the three other family members. Muscle histology was consistent with mitochondrial myopathy in three family members. The mitochondrial haplogroup of the family was a different branch of the haplogroup H than in the previous reports of this mutation. Conclusion: Our results suggest that, in addition to sensorineural HI, the m.7510T>C mutation is associated with a spectrum of mitochondrial disease clinical features including migraine, epilepsy, cognitive impairment, ataxia, and tremor, and with evidence of mitochondrial myopathy

NDUFA1 p.Gly32Arg variant in early-onset dementia

Abstract Early-onset dementia (EOD) is highly heritable. However, in many EOD cases the genetic etiology remains unknown. Mitochondrial dysfunction is associated with neurodegeneration and the complex I (CI) deficiency is the most common enzyme deficiency in diseases related to oxidative phosphorylation. The X-chromosomal NDUFA1 gene is essential for the activity of CI. Mutations in NDUFA1 are associated with mitochondrial diseases especially with Leigh syndrome. CI deficiency is also associated with neurodegenerative diseases, such as Alzheimer’s disease (AD). The aim of this study was to evaluate the role of NDUFA1 variants in EOD patients. Next-generation sequencing panel was used to screen NDUFA1 variants in a cohort of 37 EOD patients with a family history of dementia or an atypical or rapidly progressive course of disease. We identified a hemizygous p.Gly32Arg variant in two brothers with AD. Subsequent screening of the variant in a larger cohort of EOD patients (n = 279) revealed three additional variant carriers (one male and two heterozygote females), suggesting that NDUFA1 variant p.Gly32Arg may play a role in neurodegenerative dementia