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In pediatric health care there is increasing attention for a child-centered approach, also referred to as personalized care (Coyne, Hallstrom, & Soderback, 2016). In this care it is essential to assess personal relevant functioning, hence, to explore which activities are important for a child and to assess the quality of performance of these meaningful activities (Coster & Khetani, 2008; Rodger & Kennedy-Behr, 2017). Therefore, health care providers need to ask children what they do or want to do and then assess the performance in their own context. However, how can providers ask children with multiple disabilities how they feel on the meaningfulness of activities? To provide personalized care and plan interventions that focus on meaningful activities insight is needed into the performance of meaningful activities in the daily living environment. Therefore, this case report describes whether the combined use of Talking Mats® and the Perceive, Recall, Plan and Perform-Assessment of home videos in a child with limited communication and cognitive abilities is feasible.

CHEK2 is considered to be involved in homologous recombination repair (HRR). Individuals who have germline pathogenic variants (gPVs) in CHEK2 are at increased risk to develop breast cancer and likely other primary cancers. PARP inhibitors (PARPi) have been shown to be effective in the treatment of cancers that present with HRR deficiency—for example, caused by inactivation of BRCA1/2. However, clinical trials have shown little to no efficacy of PARPi in patients with CHEK2 gPVs. Here, we show that both breast and non-breast cancers from individuals who have biallelic gPVs in CHEK2 (germline CHEK2 deficiency) do not present with molecular profiles that fit with HRR deficiency. This finding provides a likely explanation why PARPi therapy is not successful in the treatment of CHEK2 -deficient cancers. [ABSTRACT FROM AUTHOR]

Background The first studies on patients with forkhead-box protein P1 (FOXP1) syndrome reported associated global neurodevelopmental delay, autism symptomatology, dysmorphic features and cardiac and urogenital malformations. The aim of this study was to assess the prevalence of congenital abnormalities in an unbiased cohort of patients with FOXP1 syndrome and to document rare complications. Methods Patients with FOXP1 syndrome were included, mostly diagnosed via whole-exome sequencing for neurodevelopmental delay. A parent-report questionnaire was used to assess medical signs and symptoms, including questions about features rated as most burdensome by patients and their family. Results Forty individuals were included, 20 females and 20 males. The mean age at assessment was 13.2 years (median 8.5 years; range 2-54 years; =18 years n = 7). Seven adults were included. All patients had developmental problems, including cognitive, communication, social-emotional and motor delays. The most prevalent medical signs and symptoms include delayed bladder control, sleeping problems, hypermetropia, strabismus, sacral dimple, undescended testes, abnormal muscle tone and airway infections. The most burdensome complaints for patients with FOXP1 syndrome, as perceived by parents, include intellectual disability, impaired communication, behaviour problems, lack of age-appropriate self-reliance, attention problems and anxiety. According to parents, patients have quite similar reported symptoms, although incontinence, obsessions and a complex sensory profile have a higher ranking. Conclusion The results of this study may be used to further guide medical management and identify patient priorities for future research targeted on those features of FOXP1 syndrome that most impair quality of life of patients and their families. [ABSTRACT FROM AUTHOR]

Background: Currently, paediatric health care aims to use a child‐centred tailor‐made approach. In order to design tailored occupational therapy, the implementation of personalised occupation‐based measurements that guide and evaluate goal setting and are responsive to change is necessary. Purpose: Primarily, this study explored the potential of the Perceive, Recall, Plan, and Perform (PRPP) assessment to measure the change in the performance of children with multiple disabilities. As a secondary evaluation, the feasibility of the PRPP‐Intervention in a home‐based program to enable activities was described. The overall aim is to show the potential of the PRPP‐Assessment as an outcome measure to use as a base for designing tailor‐made person‐centred care. Methods: An exploratory longitudinal multiple case series mixed‐methods design was used. The PRPP‐Assessment, scored by multiple raters, was conducted based on parent‐provided videos. The assessed activities were chosen by the child and/or parents. Responsiveness was evaluated by hypotheses formulated a priori and by comparing measured change with change on concurrent measures: Goal Attainment Scaling (GAS) and Canadian Occupational Performance Measure (COPM). Over a 6‐week period, children and their parents (or caregivers) participated in an online home‐based video coaching program where parents were coached in the implementation of the training, based on the PRPP‐Intervention, by paediatric occupational therapists on a weekly basis. The feasibility of the intervention was explored using semi‐structured interviews with children, parents, and the treating occupational therapists and was analysed by directed content analysis. Results: Three out of 17 eligible children agreed to participate and completed post‐intervention measurement, of which two completed the intervention. Quantitative results showed that eight out of nine activities improved on the PRPP‐Assessment and the COPM, and nine improved on the GAS. In total, 13 out of 15 hypotheses for responsiveness were accepted. Participants experienced the intervention as successful and acceptable. Facilitators and concerns over demand, implementation, practicality, integration, and adaptation were shared. Conclusion: The PRPP‐Assessment showed the potential to measure change in a heterogeneous group of children. The results indicated a positive tendency for the intervention and also provide directions for further development. [ABSTRACT FROM AUTHOR]

To investigate the reliability and validity of the Perceive, Recall, Plan and Perform System of Task Analysis (PRPP-Assessment) by parent-provided videos of children with mitochondrial disorders. Videos of 13 children performing 3–7 activities each were the subject of study, resulting in 65 activities. These were scored using the PRPP-Assessment by 11 raters. Internal consistency was calculated with Cronbach's alpha. Intra-rater reliability was evaluated by Bland-Altman Plots on 44 PRPP-Assessment scores. Inter-rater reliability was calculated with ICCAgreement on 128 PRPP-Assessment scores. Construct validity was assessed by comparing the PRPP-Assessment scores to the Canadian Occupational Performance Measure using Cohen's Kappa. PRPP-Assessments scores were evaluated with a multi-faceted Rasch Analysis. Internal consistency was high (0.92). Intra-rater reliability was sufficient to be good (92–96% within the 95%-Limits of the Agreement). The ICCAgreement for stage 1 Mastery Score showed acceptable inter-rater reliability (0.646). Stage 2 of the PRPP-Assessment showed low ICCs due to a lack of variability within the sample. Four out of six hypotheses on validity were accepted. Rasch's analysis demonstrated sound goodness-of-fit, and supported the validity of the PRPP-Assessment. The PRPP-Assessment by parent-provided videos in this heterogenic group showed sufficient to good psychometric properties. In practice, careful task selection and formulating criterion is recommended. PRPP-Assessment by parent-provided videos is reliable and valid in the complex, heterogenous group of children with mitochondrial disorders The PRPP-Assessment is suitable for children with mitochondrial disorders as it showed to contain familiar, functional and meaningful tasks and activities that fit with their level of functioning Professionals should be aware that parents might not be used to the criterium-based frame of reference of the PRPP-Assessment When applying the PRPP-Assessment, it is recommended to be careful in task selection and formulating the criterion. [ABSTRACT FROM AUTHOR]

Introduction: Uncovering the perspective of children with multiple disabilities is important in health care to enable person‐centred health care. For occupational therapists, uncovering the child perspective on meaningful activities is necessary to set appropriate goals for treatment. It is not always evident that children with multiple disabilities can express themselves in an interview. The interviewer should adapt his communication to the child. In literature, alternative communication is widely studied, but a clear algorithm for deciding what to use to successfully gain insight into the child perspective is missing. This study aims to identify helpful interview techniques and interviewer skills and how they can be used to effectively uncover the perspective of children. Methods: Videos of nine interviews with children with a mitochondrial disorder, conducted by an occupational therapist, were analysed by five researchers. The interviews were analysed to see how well the interviewee had obtained the child's perspectives followed by observation of communicative abilities of the child and the types of questions the interviewer asked. A qualitative directed content analysis of the semi‐structured interviews followed. Findings: An interview pattern was observed in the children's communication leading to six successful interviews. Children communicated verbally on four different levels and also used non‐verbal communication. The interviewer used five types of questions, which varied between and within the children. The content analysis resulted in two themes: parental influences and interviewer skills. Conclusion: Results show the importance of matching the type of questions to the verbal communication level of the child and revealed several interviewer skills and techniques. An overview to guide tailor‐made interviewing is presented. The interviewer has a major role in successful interviewing and thus in enabling the inclusion of the child perspective in research and care. [ABSTRACT FROM AUTHOR]

Performing the Perceive, Recall, Plan and Perform (PRPP)-Assessment, using video material of everyday life, seems sensible to lower the patient burden, enhance ecological validity, and provide care at a distance. However, receipt of adequate video material is not self-evident and assessing videos can be challenging. Therefore, this study aims to optimize the process of gaining video material and to optimize the PRPP-Assessment based on parent-provided videos. An action design research method was used, focusing on implementation of the PRPP-Assessment based on parent-provided videos within the care of children with a mitochondrial disorder or similar symptoms. Five cycles were conducted. To receive input, the cycles used videos of nine children performing activities, written feedback, and semi-structured interviews and focus groups comprising parents (n = 13), a teacher (n = 1), occupational therapists (n = 16), and other professionals (n = 2). This led to successful implementation of the PRPP-Assessment. General lessons were learned on (1) instructing parents; (2) handling video material; (3) PRPP-Assessment based on parent-provided videos; and (4) PRPP-Assessment of children (with limited functional abilities). Lessons learned should be implemented in practice and are incorporated into a manual to guide the implementation of video-based observations with PRPP-Assessment in practice. [ABSTRACT FROM AUTHOR]

Haplo‐insufficiency of the TGFβ‐activated kinase 1 binding protein 2 (TAB2) gene is associated with short stature, facial dysmorphisms, connective tissue abnormalities, hearing loss, and cardiac disease. Skeletal dysplasia and sacral dimples are also found in a minority of patients. Here, we describe a 3‐generation family with caudal appendage, other sacral anomalies, and skeletal abnormalities including hypoplasia of the iliac wings and scapulae, fusion of the carpal bones and stenosis of the spinal canal, as well as a remarkable course of prenatally‐detected cardiomyopathy with characteristics changing over time. Genetic analysis showed a heterozygous nonsense variant in the TAB2 gene. [ABSTRACT FROM AUTHOR]

Clark–Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the TRIP12 (Thyroid Hormone Receptor Interactor 12) gene. TRIP12 encodes an E3 ligase in the ubiquitin pathway. The ubiquitin pathway includes activating E1, conjugating E2 and ligating E3 enzymes which regulate the breakdown and sorting of proteins. This enzymatic pathway is crucial for physiological processes. A significant proportion of TRIP12 variants are currently classified as variants of unknown significance (VUS). Episignatures have been shown to represent a powerful diagnostic tool to resolve inconclusive genetic findings for Mendelian disorders and to re-classify VUSs. Here, we show the results of DNA methylation episignature analysis in 32 individuals with pathogenic, likely pathogenic and VUS variants in TRIP12. We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic TRIP12 variants, establishing its utility as a clinical biomarker for Clark–Baraitser syndrome. In addition, we performed analysis of differentially methylated regions as well as functional correlation of the TRIP12 genome-wide methylation profile with the profiles of 56 additional neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Previously, mutations in the AMMECR1 gene have been described in six males with developmental delay, sensorineural hearing loss (SNHL) and/or congenital abnormalities, including fetal nuchal edema, fetal pericardial effusion, talipes, congenital hip dysplasia, elliptocytosis and cleft palate. In this report, we present three female relatives of a male fetus with an intragenic deletion in this X‐linked gene. All three women reported hearing loss and one was born with a soft cleft palate and hip dysplasia. The audiograms showed mild to moderate SNHL with a variable pattern of the affected frequencies. Immunohistochemical analysis of fetal cochlea was performed confirming the expression of AMMECR1 in the human inner ear. Since hearing loss, cleft palate and congenital hip dysplasia were reported before in male AMMECR1 point mutation carriers and AMMECR1 is expressed in fetal inner ear, we suggest that female carriers may display a partial phenotype in this X‐linked condition. [ABSTRACT FROM AUTHOR]

Context Natriuretic peptide receptor-C (NPR-C, encoded by NPR3) belongs to a family of cell membrane–integral proteins implicated in various physiological processes, including longitudinal bone growth. NPR-C acts as a clearance receptor of natriuretic peptides, including C-type natriuretic peptide (CNP), that stimulate the cGMP-forming guanylyl cyclase-coupled receptors NPR-A and NPR-B. Pathogenic variants in CNP , NPR2 , and NPR3 may cause a tall stature phenotype associated with macrodactyly of the halluces and epiphyseal dysplasia. Objective Here we report on a boy with 2 novel biallelic inactivating variants of NPR3. Methods History and clinical characteristics were collected. Biochemical indices of natriuretic peptide clearance and in vitro cellular localization of NPR-C were studied to investigate causality of the identified variants. Results We identified 2 novel compound heterozygous NPR3 variants c.943G>A p.(Ala315Thr) and c.1294A>T p.(Ile432Phe) in a boy with tall stature and macrodactyly of the halluces. In silico analysis indicated decreased stability of NPR-C, presumably resulting in increased degradation or trafficking defects. Compared to other patients with NPR-C loss-of-function, the phenotype seemed to be milder: pseudo-epiphyses in hands and feet were absent, biochemical features were less severe, and there was some co-localization of p.(Ile432Phe) NPR-C with the cell membrane, as opposed to complete cytoplasmic retention. Conclusion With this report on a boy with tall stature and macrodactyly of the halluces we further broaden the genotypic and phenotypic spectrum of NPR-C-related tall stature. [ABSTRACT FROM AUTHOR]

Objective: Dravet syndrome (DS) is a severe and intractable form of epilepsy with prolonged seizures which may evolve to other seizure types and associated with mild‐to‐severe intellectual disabilities. Fibroblast growth factor 21 (FGF‐21) is a stress hormone mediating metabolic and oxidative stress and circulating level of FGF‐21 had been shown to increase in some patients with impairment of oxidative phosphorylation in muscles. In DS, FGF‐21 is of interest for further study as mitochondrial oxidative stress was identified previously in patients. Methods: Plasma FGF‐21 levels were compared between 22 DS patients and 22 normal controls, and their clinical characteristics of DS patients at the time of plasma sampling were studied retrospectively. Besides, the relationships of FGF‐21 level with intellectual development, seizure frequency, valproate treatment, and types of SCN1A mutations were analyzed. Logarithmic transformation of FGF‐21 levels was performed before comparison and statistical analysis. Results: Mean of log10 FGF‐21 level was significantly higher in DS patients when comparing with normal controls (P =.0042). Mean of log10 FGF‐21 level was significantly higher in DS patients with normal‐to‐mild ID versus mild‐to‐severe ID (P =.0193) and with valproate treatment versus without valproate treatment (P =.015). No significant difference was shown in FGF‐21 level in DS patients with missense versus truncating SCN1A variants, and no correlation could be demonstrated between seizure frequency and FGF‐21 level. Significance: Significantly higher level of plasma FGF‐21 was identified in DS patients. The high FGF‐21 levels were shown to be associated with developmental outcome and valproate treatment. These results support further investigation on the relationship of FGF‐21 with the clinical outcomes of DS and other related mechanism which is important for possible therapeutic development for this epileptic encephalopathy. [ABSTRACT FROM AUTHOR]

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage‐sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi‐faceted complications due to haploinsufficiency of BPTF. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage is rare in term born neonates. Besides several non‐genetic risk factors, pathogenic variants in COL4A1 and COL4A2 have been described to play a role in the pathophysiology of neonatal intracerebral hemorrhage. To the best of our knowledge, no intragenic COL4A2 duplications have been reported in humans to date. We report a neonate with intracerebral hemorrhage and a de novo intragenic COL4A2 duplication. Although it is not clear yet whether this genetic factor fully explains the clinical phenotype, it may have contributed at least as a risk factor for cerebral hemorrhage. Screening for intragenic COL4A1 and COL4A2 duplications as part of collagen IV diagnostics should be considered as part of the fetal and neonatal work‐up for unexplained cerebral hemorrhages and to collect more evidence of the pathogenicity of this genetic mechanism. [ABSTRACT FROM AUTHOR]

Background The mitochondrial DNA (mDNA) 3243A>G variant is the most common pathogenic variant of the mDNA. To interpret results of clinical trials in mitochondrial disease, it is important to have a clear understanding of the natural course of disease. To obtain more insight into the disease burden and the progression of disease in carriers of the mDNA 3243 A>G variant, we followed a cohort of 151 carriers from 61 families prospectively for up to 6 years. Methods The disease severity was scored using the Newcastle Mitochondrial Disease Adult Scale (NMDAS), including SF-36 quality of life (QoL) scores. Heteroplasmy levels were measured in urinary epithelial cells (UEC), leucocytes and saliva. The progression of the disease was studied using linear mixed model analysis. Results One hundred twenty-four carriers (out of 151) were symptomatic. Four clinical groups were identified: 1) classical mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (n=7), 2) maternally inherited diabetes deafness syndrome (n=60), 3) 'other' (n=57) and 4) dormant carriers (n=27). A yearly increase of NMDAS score of 0.47 point was measured in the total group. Heteroplasmy levels in both leucocytes and UEC were only weakly correlated with disease severity. Physical QoL declined with age. The most important determinants of QoL decline were hearing loss, speech problems, exercise intolerance, gait instability, psychiatric problems and gastrointestinal involvement. Conclusion The mDNA 3243 A>G variant causes a slowly progressive disease, with a yearly increase of NMDAS score of ~0.5 point overall with the clinical phenotype being the only determinant of disease progression. [ABSTRACT FROM AUTHOR]

• Migraine is a frequent reported complaint in patients with mitochondrial disease. • Migraine shows major impact on quality of life of patients with mitochondrial disease. • More specific treatment on the metabolic pathway may enhance quality of life for these patients. Mitochondrial respiratory chain dysfunction may be predisposing for the development of migraine, reflected in high migraine prevalence in patients with mitochondrial disease. Prevalence and impact of migraine in patients with proven mitochondrial disease and the current treatment efficacy were studied using online questionnaires. Patients were selected at the Internal Medicine Department. Headache was reported by 34 (55%) out of 62 patients. Migraine-criteria were met by 85% of them. Efficacy of migraine treatment was achieved in 4 patients. Given the high prevalence of migraine and current treatment insufficiency, migraine is a major threat of quality of life patients with mitochondrial disease. [ABSTRACT FROM AUTHOR]

KH176 is a potent intracellular reduction–oxidation‐modulating compound developed to treat mitochondrial disease. We studied tolerability, safety, pharmacokinetics, pharmacodynamics, and efficacy of twice daily oral 100 mg KH176 for 28 days in a double‐blind, randomized, placebo‐controlled, two‐way crossover phase IIA study in 18 adult m.3243A>G patients without cardiovascular involvement. Efficacy parameters included clinical and functional outcome measures and biomarkers. The trial was registered within ClinicalTrials.gov (NCT02909400), the European Clinical Trials Database (2016‐001696‐79), and ISRCTN (43372293) (The KHENERGY study). Twice daily oral 100 mg KH176 was well tolerated and appeared safe. No serious treatment‐emergent adverse events were reported. No significant improvements in gait parameters or other outcome measures were obtained, except for a positive effect on alertness and mood, although a coincidence due to multiplicity cannot be ignored. The results of the study provide first data on safety and efficacy of KH176 in patients with mitochondrial disease and will be instrumental in designing future clinical trials. [ABSTRACT FROM AUTHOR]

Mitochondrial disorders are multisystem conditions that can potentially affect gait in many ways. The aim of this study was to select the optimal protocol to quantify the spatiotemporal parameters of gait in ambulatory children with mitochondrial disorders based on feasibility, test-retest reliability, and the difference between patients and controls. Gait at self-selected pace was quantified in ambulatory children with a genetically confirmed primary mitochondrial disease using the GAITRite electronic walkway. Three protocols were tested: pre-exercise, post-exercise (after a 3-min walking test), and recovery. In 14 ambulatory patients, we showed good to perfect reliability for velocity, cadence, step length, step time, step time variability, and step width in the recovery condition. The difference between patients and 70 individually age- and gender matched healthy controls only became apparent in the post-exercise protocol. In conclusion, measuring spatiotemporal parameters of gait using the GAITRite in ambulatory children with mitochondrial disease is feasible and reliable for most of the parameters measured. When using gait analysis in future studies in children with mitochondrial disease, we advise i) to use an exercise test prior to the gait analysis, ii) to let children practice the test before the actual data collection, and iii) not to use symmetry parameters. [ABSTRACT FROM AUTHOR]

Background. Engagement in everyday activities is important for the health and wellbeing of children. Children with mitochondrial disorders have impaired energy production leading to limitations in activity. It is unknown which activities these children perform and if the nature of activities of low-functioning children differs from average-functioning children. Therefore, this pilot study explored the activities reported in patient records of a heterogeneous group of children with genetically confirmed mitochondrial disorders. Methods. A retrospective qualitative directed content analysis by health care professionals reported activities (as part of their professional reasoning obligations) in hospital patient records of children with mitochondrial disorder. Results. Seventeen patient records, presenting notes on capacities and performed activities, showed an overview of everyday activities that covered the categories: self-care, house chores, therapy, school, computing, hobby, play, sports, and mobility/transport. The activity categories of low-functioning children did not differ from average-functioning children, although descriptions of specific activities differed between groups. Conclusion. This pilot exploration indicates that the types of activities that children with mitochondrial disorders perform are not necessarily linked to the child’s impairments. However, differences in levels of independence, assistive device usage, and energy costs seem to exist. Future research should address the child’s perspective on, and meaning of, activity performances. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial disorders are a clinically, biochemically and genetically heterogeneous group of multi-system diseases, with an unmet medical need for treatment. KH176 is an orally bio-available small molecule under development for the treatment of mitochondrial(-related) diseases. The compound is a member of a new class of drugs, acting as a potent intracellular redox-modulating agent essential for the control of oxidative and redox pathologies. The aim of this randomized, placebo controlled, double-blinded phase 1 study was to test safety, tolerability and pharmacokinetics of single and multiple doses of KH176 in healthy male volunteers. Putative effects on redox related biomarkers were explored.Results: KH176 was well tolerated up to and including a single dose of 800 mg and multiple doses of 400 mg b.i.d. for 7 Days. However, when the QT interval was corrected for heart rate, administration of single doses of 800 and 2000 mg and at a multiple dose of 400 mg KH176 had marked effects. Post-hoc analysis of the ECGs showed clear changes in cardiac electrophysiology at single doses of 800 and 2000 mg and multiple doses of 400 mg b.i.d.. At lower doses, detailed ECG analysis showed no changes in electrophysiology compared to placebo. Exposure-response modelling of the cardiac intervals revealed an exposure range of KH176 without effects on cardiac conduction and provided a threshold of 1000 ng/mL above which changes in intervals could occur. After single- and multiple-dose administration, the pharmacokinetics of KH176 was more than dose proportional. KH176 accumulated to a small extent and food only slightly affected the pharmacokinetics of KH176, which was considered clinically irrelevant. Renal excretion of unchanged KH176 and its metabolite represents a minor pathway in the elimination of KH176. As expected in healthy volunteers no effects on redox biomarkers were observed.Conclusion: The study deemed that KH176 is well tolerated up to single doses of 800 mg and multiple doses of 400 mg b.i.d. and has a pharmacokinetic profile supportive for a twice daily dosing. Only at high doses, KH176 causes clinically relevant changes in cardiac electrophysiology, including prolonged QTc interval and changes in T wave morphology. A Phase 2 clinical trial (100 mg b.i.d., orally) has been conducted recently of which the final results are expected Q1 2018.Trial Registration: NCT02544217 . Registered. ISRCTN43372293 . Retrospectively registered. [ABSTRACT FROM AUTHOR]

Background: More than half of the patients harbouring the m.3243A > G mutation were found to have trouble maintaining balance when walking in a recent study by our group. Others demonstrated that these patients had an abnormal gait pattern, as quantified by gait analysis. Gait analysis is an emerging method to quantify subtle changes in walking pattern, also during therapeutic interventions. Therefore, we aimed to test the reliability and reproducibility of gait analysis and select the most suitable protocol for this group of patients using a GAITRite electronic walkway. Four different protocols were tested: normal walking, dual task, post exercise and after a ten minutes of rest.Results: In total 36 patients with the m.3243A > G mutation and 50 healthy controls were enrolled in this study. Overall high intra class correlation coefficients were found in all experimental conditions for both patients and healthy controls indicating good reproducibility. Marked differences in gait between patients and controls were observed and were in line with the only available exploratory study performed. There was a good correlation between both the overall NMDAS score, NMDAS subscale scores, both markers for disease severity, and specific gait parameters.Conclusions: The observed reliability of the test makes GAITRite a suitable instrument for intervention studies in patients with mitochondrial disease. [ABSTRACT FROM AUTHOR]

Introduction: The 6-minute walk test (6MWT) is frequently used as an outcome measure for clinical trials in neuromuscular disease. Because this submaximal endurance test is not feasible for nonambulatory patients, the motor-assisted 6-minute cycling test (A6MCT) was developed.Methods: Nineteen children with neuromuscular disorders and children with OXPHOS-dysfunction performed the a6MCT and the 6MWT to explore feasibility and construct validity. Test-retest reproducibility was evaluated within 3 weeks.Results: The assisted 6-minute cycling test was feasible in 90% and 78% of the patients with a neuromuscular disorder and OXPHOS-dysfunction, respectively. The A6MCT for legs correlated with the 6MWT in both patient groups. The assisted 6-minute cycling showed good reproducibility for both legs and arms.Conclusions: This exploratory study indicates that the assisted 6-minute cycling test is a promising outcome measure for patients with a neuromuscular disorder and patients with OXPHOS-dysfunction. Muscle Nerve, 2015. Muscle Nerve 54: 232-238, 2016. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial disorders belong to the most prevalent inherited metabolic diseases with the m.3243A > G mutation reflecting being one of the most common mutations in mitochondrial DNA. Previous studies showed little relationship between mitochondrial genetics and disease manifestation. Relationship between genotype and disease manifestation with patient reported quality of life and other patient reported outcomes is still unexplored.Methods: Seventy-two out of the 122 invited adult patients with m.3243A > G mutation completed online standardized questionnaires on quality of life, functional impairment, fatigue and mental health as assessed by the RAND-SF36, the Sickness Impact Profile (SIP), the Checklist Individual Strength (CIS) and the Hospital Anxiety and Depression scale (HADS). Data were related to clinical manifestation reflected by the Newcastle Mitochondrial Disease Adult Scale (NMDAS) score and heteroplasmy levels of the mutation in urine epithelial cells.Results: Patients reported impaired quality of life. Sixty percent showed severe levels of fatigue, and 37% showed clinical relevant mental health problems, which was significantly more than healthy norms. These patient reported health outcomes showed negligible relationship with levels of heteroplasmy (r = <.30) and weak (.30 < r < .50) to moderate (.50 < r < .70) relationship with clinical manifestation.Conclusions: Patient reported outcomes on quality of life, fatigue and mental health problems, are only partly reflected by clinical assessments. In order to support patients more effectively, integration of patient reported outcomes, alongside symptoms of their disease, in clinical practice is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Since some drug intervention effects are only experienced by the patient, organizations such as the Food and Drug Administration prefer clinically meaningful outcome measures. Here, we evaluated which symptoms and limitations in daily life are most burdensome to pediatric patients with mitochondrial disorders and their parents, using two questionnaires. In a study of 78 patients, the most burdensome complaints included fatigue, behavior and speech disturbances, epilepsy and muscle weakness and a high degree of limitations in daily activities was found. Importantly, there was a discrepancy between what symptoms metabolic pediatricians estimated would be most burdensome compared to the patients''/caretakers'' opinion. To include feasible and relevant outcome measures in intervention studies, the experience and opinions of patients and caretakers should therefore be heard. [Copyright &y& Elsevier]

The m.3243A > G mutation has become known as the MELAS mutation. However, many other clinical phenotypes associated with this mutation have been described, most frequently being maternally inherited diabetes and deafness (MIDD). The m.3243A > G mutation, can be detected in virtually all tissues, however heteroplasmy differs between samples. Recent reports indicate, a preference to perform mutation analysis in urinary epithelial cells (UEC). To test this, and to study a correlation between the mutational load in different tissues with two mitochondrial scoring systems (NMDAS and NPMDS) we investigated 34 families carrying the m.3243A > G mutation. Heteroplasmy was determined in three non-invasively collected samples, namely leucocytes, UEC and buccal mucosa. We included 127 patients, of which 82 carried the m.3243A > G mutation. None of the children (n = 11) had specific complaints. In adults (n = 71), a median NMDAS score of 15 (IQR 10-24) was found. The most prevalent symptoms were hearing loss(48%), gastro-intestinal problems(42%), exercise intolerance(38%) and glucose intolerance(37%). Ten patients had neurologic involvement. Buccal mucosa had the best correlation with the NMDAS in all adults (r = 0.437,p < 0.001), whereas UEC had the strongest correlation with the NMDAS in severely affected patients (r = 0.593,p = 0.002). Heteroplasmy declined significantly with increasing age in all three samples (leucocytes r = -0.705 (p < 0.001), UEC r = -0.374(p = 0.001), buccal mucosa r = -0.460(p < 0.001). In our cohort of 82 patients, the m.3243A > G mutation causes a wide variety of signs and symptoms, MIDD being far more prevalent than MELAS. Looking at the characteristics of the three non-invasively available tissues for testing heteroplasmy we confirm that UEC are the preferred sample to test. [ABSTRACT FROM AUTHOR]