Relative contribution of comorbid diseases to health-related quality of life in patients with Parkinson's disease.

BACKGROUND: Multimorbidity is common in elderly people, and one of the major consequences of multimorbidity is low health-related quality of life (HRQoL). The aim of this study was to investigate the frequency of comorbid diseases in patients with Parkinson's disease (PD) and to analyze their relative importance in HRQoL. The aim was also to examine agreement between the generic 15D questionnaire and the PD-specific Parkinson's Disease Questionnaire (PDQ-8) to further validate 15D in the evaluation of HRQoL in patients with PD. METHODS: Patients with PD (N = 551) filled a questionnaire on comorbid diseases, and the 15D questionnaire yielding a 15-dimensional health profile and a score representing the overall HRQoL. Self-organizing map was used for an unsupervised pattern recognition of the health profiles. Relative importance analysis was used to evaluate the contribution of 16 comorbid diseases to the 15D score. The agreement between 15D and PDQ-8 questionnaires was studied in a subset of 81 patients that were examined clinically. RESULTS: 533 patients (96.7%) reported comorbid diseases. The most affected dimensions in the 15D questionnaire were secretion, usual activities, discomfort and symptoms, and sexual activity. Self-organizing map identified three patterns of health profiles that included patients with high, low or transition HRQoL. The transition subgroup was similar to low HRQoL subgroup in non-motor dimensions. Sixteen comorbid diseases explained 33.7% of the variance in the 15D score. Memory deficit, depression, heart failure, and atrial fibrillation had the highest relative importance. The intraclass correlation coefficient between the generic 15D and the PD-specific PDQ-8 was 0.642 suggesting moderate reliability. CONCLUSIONS: The most marked differences in HRQoL were in the dimensions of secretion, usual activities, and sexual activity. Pattern detection of 15D health dimensions enabled the detection of a subgroup with disproportionately poor HRQoL in non-motor dimensions. The comorbid diseases affecting most to HRQoL were memory deficit and depression. The generic 15D questionnaire can be used in the evaluation of HRQoL in PD patients.

A severe neurodegenerative disease with Lewy bodies and a mutation in the glucocerebrosidase gene.

Several heterozygous variants of the glucocerebrosidase gene (GBA1) have been reported to increase the risk of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GBA1-associated PD has been reported to be more severe than idiopathic PD, and more deleterious variants are associated with more severe clinical phenotypes. We report a family with a heterozygous p.Pro454Leu variant in GBA1. The variant was associated with a severe and rapidly progressive neurodegenerative disease with Lewy bodies that were clinically and pathologically diverse. Pathogenicity prediction algorithms and evolutionary analyses suggested that p.Pro454Leu is deleterious.

Clinical spectrum and genotype-phenotype associations in Finnish patients with Wilson's disease.

Genotype-phenotype correlation data covering all ages of Wilson's disease onset in Caucasian patients are limited. We therefore analyzed genotype-phenotype correlations in a retrospective cohort of Finnish patients. Six homozygous (HoZ) and 11 compound heterozygous (CoHZ) patients were included. There were no differences in the presence/absence of hepatic, neurological, psychiatric or any symptoms at diagnosis (p > 0.30 for all) between HoZ and CoHZ patients, but HoZ patients had an earlier age of diagnosis (median 6.7 versus 34.5; p = 0.003). Severe liver affliction was almost exclusively associated with the p.H1069Q variant. Patients with p.H1069Q had a later mean age of diagnosis (30.2 ± 11.6 vs. 8.7 ± 4.9 years; p < 0.001) compared to those without. There were no differences in the presence/absence of hepatic, neurological, psychiatric or any symptoms at diagnosis between p.H1069Q-positive and p.H1069Q-negative patients (p > 0.54 for all). These results suggest that population-specific factors may partly explain the high clinical variability of Wilson's disease.

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.

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 Alzheimer'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.

Association between mitochondrial DNA haplogroups J and K, serum branched-chain amino acids and lowered capability for endurance exercise.

BACKGROUND: Endurance exercise training promotes the catabolism of branched-chain amino acids (BCAAs) in skeletal muscles. We have previously shown that mitochondrial DNA (mtDNA) haplogroups J and K are markers of low responders in endurance training. In this paper, we hypothesize that BCAA catabolism is a surrogate marker of lower respiratory chain activity attributed to these haplogroups. We evaluated whether exercise-induced changes in amino acid concentrations differ between subjects harbouring mtDNA haplogroups J or K and those with non-JK haplogroups. METHODS: Finnish male conscripts (N = 633) undertook the 12-min Cooper running test at the beginning and end of their military service. The intervention during the service mainly included endurance aerobic exercise and sports-related muscle training. Concentrations of seven amino acids were analysed in the serum using a high-throughput 1H NMR metabolomics platform. Total DNA was extracted from whole blood, and restriction fragment analysis was used to determine mtDNA haplogroups J and K. RESULTS: The concentrations of the seven amino acids were higher following the intervention, with the exception of phenylalanine; interestingly, the increase in the concentrations of three BCAAs was larger in subjects with haplogroup J or K than in subjects with non-JK haplogroups (p = 0.029). MtDNA haplogroups J and K share two common nonsynonymous variants. Structural analysis based on crystallographic data on bovine complexes I and III revealed that the Leu18 variant in cytochrome b encoded by m.14798T > C may interfere with ubiquinone binding at the Qi site in complex III. CONCLUSIONS: The increase in the concentrations of serum BCAAs following exercise intervention differs between subjects harbouring mtDNA haplogroup J or K and those harbouring non-JK haplogroups. Lower response in endurance training and difference in exercise-induced increase in the concentrations of serum BCAAs suggest decreased respiratory chain activity. Haplogroups J and K share m.14798T > C in MT-CYB, which may hamper the function of complex III.

NDUFA1 p.Gly32Arg variant in early-onset dementia.

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.

Biallelic expansion in RFC1 as a rare cause of Parkinson's disease.

An intronic expansion (AAGGG)exp in the RFC1 gene has recently been shown to cause recessively inherited cerebellar ataxia, neuropathy, and vestibular areflexia syndrome and, furthermore, a few patients with ataxia and parkinsonism have been reported. We investigated 569 Finnish patients with medicated parkinsonism for RFC1 and found biallelic (AAGGG)exp in three non-consanguineous patients with clinically confirmed Parkinson's disease without ataxia suggesting that RFC1-related disorders include Parkinson's disease as well.

Molecular epidemiology of hereditary ataxia in Finland.

BACKGROUND: The genetics of cerebellar ataxia is complex. Hundreds of causative genes have been identified, but only a few cause more than single cases. The spectrum of ataxia-causing genes differs considerably between populations. The aim of the study was to investigate the molecular epidemiology of ataxia in the Finnish population. PATIENTS AND METHODS: All patients in hospital database were reviewed for the diagnosis of unspecified ataxia. Acquired ataxias and nongenetic ataxias such as those related to infection, trauma or stroke were excluded. Sixty patients with sporadic ataxia with unknown etiology and 36 patients with familial ataxia of unknown etiology were recruited in the study. Repeat expansions in the SCA genes (ATXN1, 2, 3, 7, 8/OS, CACNA1A, TBP), FXN, and RFC1 were determined. Point mutations in POLG, SPG7 and in mitochondrial DNA (mtDNA) were investigated. In addition, DNA from 8 patients was exome sequenced. RESULTS: A genetic cause of ataxia was found in 33 patients (34.4%). Seven patients had a dominantly inherited repeat expansion in ATXN8/OS. Ten patients had mitochondrial ataxia resulting from mutations in nuclear mitochondrial genes POLG or RARS2, or from a point mutation m.8561C > G or a single deletion in mtDNA. Interestingly, five patients were biallelic for the recently identified pathogenic repeat expansion in RFC1. All the five patients presented with the phenotype of cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS). Moreover, screening of 54 patients with Charcot-Marie-Tooth neuropathy revealed four additional patients with biallelic repeat expansion in RFC1, but none of them had cerebellar symptoms. CONCLUSIONS: Expansion in ATXN8/OS results in the majority of dominant ataxias in Finland, while mutations in RFC1 and POLG are the most common cause of recessive ataxias. Our results suggest that analysis of RFC1 should be included in the routine diagnostics of idiopathic ataxia and Charcot-Marie-Tooth polyneuropathy.

Association of mitochondrial DNA haplogroups J and K with low response in exercise training among Finnish military conscripts.

BACKGROUND: We have previously suggested that some of the mutations defining mitochondrial DNA (mtDNA) haplogroups J and K produce an uncoupling effect on oxidative phosphorylation and thus are detrimental for elite endurance performance. Here, the association between haplogroups J and K and physical performance was determined in a population-based cohort of 1036 Finnish military conscripts. RESULTS: Following a standard-dose training period, excellence in endurance performance was less frequent among subjects with haplogroups J or K than among subjects with non-JK haplogroups (p = 0.041), and this finding was more apparent among the best-performing subjects (p < 0.001). CONCLUSIONS: These results suggest that mtDNA haplogroups are one of the genetic determinants explaining individual variability in the adaptive response to endurance training, and mtDNA haplogroups J and K are markers of low-responders in exercise training.

Mutation Analysis of the Genes Associated with Parkinson's Disease in a Finnish Cohort of Early-Onset Dementia.

BACKGROUND: Alzheimer's disease, frontotemporal lobar degeneration, dementia with Lewy bodies, and Parkinson's disease (PD) overlap in clinical characteristics, neuropathology, and genetics. OBJECTIVE: The aim of this study was to evaluate the role of pathogenic mutations and rare variants in genes associated with PD among early-onset dementia (EOD) patients. METHODS: Rare non-synonymous variants (MAF < 0.01) in ten genes (SNCA, PARK2, PARK7, LRRK2, PINK1, ATP13A2, UCHL1, HTRA2, GBA, and SNCAIP) and low-frequency (MAF < 0.05) GBA variants were screened using a targeted next-generation sequencing panel in a strictly defined cohort of 37 early-onset (age at onset (AAO) <65 years) dementia patients presenting with atypical features (e.g., myoclonia or spasticity), rapidly progressive course of the disease or with a family history of dementia. The identified variations were further screened in a larger cohort of EOD (n = 279, mean AAO 57, range 36-65) patients. RESULTS: No pathogenic mutations were found, but we identified seven possible risk variants for neurodegeneration (LRRK2 p.Arg793Met, PARK2 p.Ala82Glu, SNCAIP p.Arg240Gln, SNCAIP p.Phe369Leu, GBA p.Asn409Ser, GBA p.Glu365Lys, GBA p.Thr408Met). DISCUSSION: Altogether, the frequency of these variants was two times higher in the first selected cohort compared to the whole cohort. This suggests that specific rare variants in the genes associated with PD might play a role also especially in familial EOD.

Mitochondrial DNA variation in sudden cardiac death: a population-based study.

Cardiomyopathy and cardiac conduction defects are common manifestations of mitochondrial disease. Previous studies suggest that clinically asymptomatic individuals harbouring pathogenic mitochondrial DNA (mtDNA) mutations in the cardiac muscle may have sudden cardiac death (SCD) as the first manifestation of mitochondrial disease. We investigated the contribution of pathogenic mtDNA point mutations and mtDNA haplogroups in cardiac muscle in a cohort of 280 Finnish subjects that had died from non-ischaemic SCD with the median age of death at 59 years and in 537 population controls. We did not find any common or novel pathogenic mutations, but the frequency of haplogroup H1 was higher in the SCD subjects than that in 537 population controls (odds ratio: 1.76, confidence interval 95%: 1.02-3.04). We conclude that, at the population level, pathogenic point mutations in mtDNA do not contribute to non-ischaemic SCD, but natural variation may modify the risk.

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.

Analysis of functional variants in mitochondrial DNA of Finnish athletes.

BACKGROUND: We have previously reported on paucity of mitochondrial DNA (mtDNA) haplogroups J and K among Finnish endurance athletes. Here we aimed to further explore differences in mtDNA variants between elite endurance and sprint athletes. For this purpose, we determined the rate of functional variants and the mutational load in mtDNA of Finnish athletes (n = 141) and controls (n = 77) and determined the sequence variation in haplogroups. RESULTS: The distribution of rare and common functional variants differed between endurance athletes, sprint athletes and the controls (p = 0.04) so that rare variants occurred at a higher frequency among endurance athletes. Furthermore, the ratio between rare and common functional variants in haplogroups J and K was 0.42 of that in the remaining haplogroups (p = 0.0005). The subjects with haplogroup J and K also showed a higher mean level of nonsynonymous mutational load attributed to common variants than subjects with the other haplogroups. Interestingly, two of the rare variants detected in the sprint athletes were the disease-causing mutations m.3243A > G in MT-TL1 and m.1555A > G in MT-RNR1. CONCLUSIONS: We propose that endurance athletes harbor an excess of rare mtDNA variants that may be beneficial for oxidative phosphorylation, while sprint athletes may tolerate deleterious mtDNA variants that have detrimental effect on oxidative phosphorylation system. Some of the nonsynonymous mutations defining haplogroup J and K may produce an uncoupling effect on oxidative phosphorylation thus favoring sprint rather than endurance performance.

Mutation Analysis of the Genes Linked to Early Onset Alzheimer's Disease and Frontotemporal Lobar Degeneration.

A lot of effort has been done to unravel the genetics underlying early-onset Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). However, many familial early-onset dementia (EOD) cases still show an unclear genetic background. The aim of this study was to evaluate the role of the known causative mutations and possible pathogenic variants associated with AD and FTLD in a Finnish EOD cohort. The cohort consisted of 39 patients (mean age at onset 54.8 years, range 39-65) with a positive family history of dementia or an atypical or rapidly progressive course of the disease. None of the patients carried the C9orf72 hexanucleotide repeat expansion. Mutations and variants in APP, PSEN1, PSEN2, MAPT, GRN, VCP, CHMP2B, FUS, TARDBP, TREM2, TMEM106B, UBQLN2, SOD1, PRNP, UBQLN1, and BIN1 were screened by using a targeted next generation sequencing panel. Two previously reported pathogenic mutations (PSEN1 p.His163Arg and MAPT p.Arg406Trp) were identified in the cohort. Both patients had familial dementia with an atypical early onset phenotype. In addition, a heterozygous p.Arg71Trp mutation in PSEN2 with an uncertain pathogenic nature was identified in a patient with neuropathologically confirmed AD. In conclusion, targeted investigation of the known dementia-linked genes is worthwhile in patients with onset age under 55 and a positive family history, as well as in patients with atypical features.

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.

A nonsynonymous mutation in the WFS1 gene in a Finnish family with age-related hearing impairment.

Wolfram syndrome (WS) is caused by recessive mutations in the Wolfram syndrome 1 (WFS1) gene. Sensorineural hearing impairment (HI) is a frequent feature in WS and, furthermore, certain mutations in WFS1 cause nonsyndromic dominantly inherited low-frequency sensorineural HI. These two phenotypes are clinically distinct indicating that WFS1 is a reasonable candidate for genetic studies in patients with other phenotypes of HI. Here we have investigated, whether the variation in WFS1 has a pathogenic role in age-related hearing impairment (ARHI). WFS1 gene was investigated in a population sample of 518 Finnish adults born in 1938-1949 and representing variable hearing phenotypes. Identified variants were evaluated with respect to pathogenic potential. A rare mutation predicted to be pathogenic was found in a family with many members with impaired hearing. Twenty members were recruited to a segregation study and a detailed clinical examination. Heterozygous p.Tyr528His variant segregated completely with late-onset HI in which hearing deteriorated first at high frequencies and progressed to mid and low frequencies later in life. We report the first mutation in the WFS1 gene causing late-onset HI with audiogram configurations typical for ARHI. Monogenic forms of ARHI are rare and our results add WFS1 to the short list of such genes.

Molecular Epidemiology of Charcot-Marie-Tooth Disease in Northern Ostrobothnia, Finland: A Population-Based Study.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuromuscular disorder with a population prevalence of 9.7-82.3/100,000. In this study, we have estimated the prevalence of CMT and its subtypes in Finland and examined the frequency of molecular etiologies. METHODS: A population-based survey included adult patients with peripheral neuropathy from the province of Northern Ostrobothnia, Finland. Secondary causes of peripheral polyneuropathy were excluded and patients with clinical and neurophysiological features pertinent with CMT were included. Molecular diagnostics was carried out when DNA was available. RESULTS: We found 107 subjects with CMT yielding a prevalence 34.6/100,000 in Northern Ostrobothnia. The heterozygous point mutation p.His123Arg in ganglioside induced differentiation associated protein 1 (GDAP1) was found in 31.5% and peripheral myelin protein 22 (PMP22) duplication in 16.9% of the affected. Point mutations in myelin protein zero, mitofusin 2, and gap junction protein beta 1 accounted for 6.7% of the cases. In addition, 18 persons had hereditary neuropathy with liability to pressure palsies and 15 of them carried the PMP22 deletion. CONCLUSIONS: The prevalence of CMT in Northern Ostrobothnia, Finland, seems to be slightly higher than those in previous studies in European populations. Founder mutation in the GDAP1 gene accounts for a large part of the genetically defined CMT2 in Finland.

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.

A novel MTTT mutation m.15933G > A revealed in analysis of mitochondrial DNA in patients with suspected mitochondrial disease.

BACKGROUND: Mitochondrial diseases present with variable multi-organ symptoms. Common disease-causing mutations in mitochondrial DNA (mtDNA) are regularly screened in diagnostic work-up, but novel mutations may remain unnoticed. METHODS: Patients (N = 66) with a clinical suspicion of mitochondrial disease were screened for their mtDNA coding region using conformation sensitive gel electrophoresis and sequencing. Long-PCR was used to detect deletions followed by POLG1 sequencing in patients with multiple deletions. RESULTS: We discovered three novel mtDNA variants that included m.8743G > C, m.11322A > G and m.15933G > A. The novel MTTT variant m.15933G > A is suggested to be pathogenic. Analysis revealed also multiple mtDNA deletions in two patients and five nonsynonymous variants that were putatively pathogenic according to in-silico prediction algorithms. In addition, a rare haplogroup H associated m.7585_7586insT variant was discovered. CONCLUSIONS: Among patients with a suspected mitochondrial disease, a novel MTTT variant m.15933G > A was discovered and is suggested to be pathogenic. In addition, several putatively pathogenic nonsynonymous variants and rare variants were found. These findings highlight the importance of coding region mtDNA screening among patients with clinical features suggesting a mitochondrial disease, but who lack the common mitochondrial disease mutations.