Validation of actigraphy sleep metrics in children aged 8 to 16 years: considerations for device type, placement and algorithms.

BACKGROUND: Actigraphy is often used to measure sleep in pediatric populations, despite little confirmatory evidence of the accuracy of existing sleep/wake algorithms. The aim of this study was to determine the performance of 11 sleep algorithms in relation to overnight polysomnography in children and adolescents. METHODS: One hundred thirty-seven participants aged 8-16 years wore two Actigraph wGT3X-BT (wrist, waist) and three Axivity AX3 (wrist, back, thigh) accelerometers over 24-h. Gold standard measures of sleep were obtained using polysomnography (PSG; Embletta MPRPG, ST + Proxy and TX Proxy) in the home environment, overnight. Epoch by epoch comparisons of the Sadeh (two algorithms), Cole-Kripke (three algorithms), Tudor-Locke (four algorithms), Count-Scaled (CS), and HDCZA algorithms were undertaken. Mean differences from PSG values were calculated for various sleep outcomes. RESULTS: Overall, sensitivities were high (mean ± SD: 91.8%, ± 5.6%) and specificities moderate (63.8% ± 13.8%), with the HDCZA algorithm performing the best overall in terms of specificity (87.5% ± 1.3%) and accuracy (86.4% ± 0.9%). Sleep outcome measures were more accurately measured by devices worn at the wrist than the hip, thigh or lower back, with the exception of sleep efficiency where the reverse was true. The CS algorithm provided consistently accurate measures of sleep onset: the mean (95%CI) difference at the wrist with Axivity was 2 min (-6; -14,) and the offset was 10 min (5, -19). Several algorithms provided accurate measures of sleep quantity at the wrist, showing differences with PSG of just 1-18 min a night for sleep period time and 5-22 min for total sleep time. Accuracy was generally higher for sleep efficiency than for frequency of night wakings or wake after sleep onset. The CS algorithm was more accurate at assessing sleep period time, with narrower 95% limits of agreement compared to the HDCZA (CS:-165 to 172 min; HDCZA: -212 to 250 min). CONCLUSION: Although the performance of existing count-based sleep algorithms varies markedly, wrist-worn devices provide more accurate measures of most sleep measures compared to other sites. Overall, the HDZCA algorithm showed the greatest accuracy, although the most appropriate algorithm depends on the sleep measure of focus.

Relationship of arsenic and chromium availability with carbon functional groups, aluminum and iron in Little Washita River Experimental Watershed Reservoirs, Oklahoma, USA.

Sediment from three reservoirs located in the Little Washita River Experimental Watershed (LWREW) in Oklahoma, USA with contrasting dominant land uses were analyzed for total and extractable concentrations of arsenic (As) and chromium (Cr), and the potential ecologic risk to benthic organisms. Extractable As ranged from 0.24 to 1.21 mg kg-1, in the order grazing>cropland>forest and 0.13-0.58 mg kg-1 for extractable Cr, in the order of forest>grazing>cropland. However, only approximately < 1.5% of total As and < 4% of total Cr were extractable. Total As ranged from 16.2 to 141 mg kg-1 and total Cr ranged from 5.06 to 40.1 mg kg-1 both in the order of cropland>grazing>forest. The sediment exhibited an alkaline pH (8.0-8.7). As sorption exhibited a positive relationship with Al (r = 0.9995; P = 0.0001), Fe (r = 0.9829; P = 0.0001), and C (r = 0.4090; P = 0.0017) and Cr correlated positively with Al (r = 0.9676 P = 0.0001), Fe (r = 0.9818; P = 0.0001), and C (r = 0.3368; P = 0.0111). In addition, both As and Cr exhibited positive relationships with carbon (C) functional groups in the order of O-alkyl C> methoxyl C> alkyl C> aromatic C> carboxyl C> phenolic C. The sediment concentration analysis results illustrated that As in all reservoirs exceeded their respective Threshold Effect Level (TEL) and/or Probable Effect Level (PEL) indicating that existing concentrations of metals in these sediments were sufficiently high to cause adverse effects. However, Cr concentrations in all reservoirs evaluated was lower compared to the TEL and PEL.

Do differences in compositional time use explain ethnic variation in the prevalence of obesity in children? Analyses using 24-hour accelerometry.

BACKGROUND/OBJECTIVES: Whether variation in sleep and physical activity explain marked ethnic and socioeconomic disparities in childhood obesity is unclear. As time spent in one behaviour influences time spent in other behaviours across the 24-hour day, compositional analyses are essential. The aims of this study were to determine how ethnicity and socioeconomic status influence compositional time use in children, and whether differences in compositional time use explain variation in body mass index (BMI) z-score and obesity prevalence across ethnic groups. METHODS: In all, 690 children (58% European, 20% Maori, 13% Pacific, 9% Asian; 66% low-medium deprivation and 34% high deprivation) aged 6-10 years wore an ActiGraph accelerometer 24-hours a day for 5 days yielding data on sedentary time, sleep, light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA). Height and weight were measured using standard techniques and BMI z-scores calculated. Twenty-four hour movement data were transformed into isometric log-ratio co-ordinates for multivariable regression analysis and effect sizes were back-transformed. RESULTS: European children spent more time asleep (predicted difference in minutes, 95% CI: 16.1, 7.4-24.9) and in MVPA (6.6 min, 2.4-10.4), and less time sedentary (-10.2 min, -19.8 to -0.6) and in LPA (-12.2 min, -21.0 to -3.5) than non-European children. Overall, 10% more sleep was associated with a larger difference in BMI z-score (adjusted difference, 95% CI: -0.13, -0.25 to -0.01) than 10% more MVPA (-0.06, -0.09 to -0.03). Compositional time use explained 35% of the increased risk of obesity in Pacific compared with European children after adjustment for age, sex, deprivation and diet, but only 9% in Maori and 24% in Asian children. CONCLUSIONS: Ethnic differences in compositional time use explain a relatively small proportion of the ethnic differences in obesity prevalence that exist in children.

Correction: Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

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A case-comparison study of pregnant women with mitochondrial disease - what to expect?

OBJECTIVE: Mitochondrial disease is a disorder of energy metabolism that affects 1 in 4300 adults in the UK. Pregnancy is associated with physiological demands that have implications for energy metabolism. We were interested to know how pregnancy was affected in women with mitochondrial disease, particularly those with the most common pathogenic mutation m.3243A>G. DESIGN: Retrospective case-comparison study. POPULATION/SETTING: Sixty-seven women with genetically confirmed mitochondrial disease from the UK Mitochondrial Diseases Cohort and 69 unaffected women participated. METHODS: Participants answered questionnaires regarding each of their pregnancies. Patients were divided into two groups according to genetic mutation, with those harbouring m.3243A>G comprising a single group. MAIN OUTCOME MEASURES: Pregnancy-related complications, mode of delivery, gestational age and birthweight of newborns. RESULTS: Of 139 live births in the comparison group, 62 were in the m.3243A>G group and 87 were in the 'all other mutations' group. Pregnancies of women with the m.3243A>G mutation had significantly more gestational diabetes (odds ratio [OR] = 8.2, 95% CI 1.3-50.1), breathing difficulties (OR = 7.8, 95% CI 1.0-59.1) and hypertension (OR = 8.2, 95% CI 3.1-21.5) than the comparison group. Only half of the pregnancies in the m.3243A>G group had normal vaginal delivery, with emergency caesarean section accounting for 24.2% of deliveries. Babies were born significantly earlier to mothers harbouring m.3243A>G with 53.3% of them preterm (<37 weeks). These babies were also more likely to require resuscitation and admission. CONCLUSION: Women who carried the m.3243A>G mutation appeared to be at higher risk of complications during pregnancies, caesarean section and preterm delivery than the unaffected women or those with other forms of mitochondrial disease. TWEETABLE ABSTRACT: Pregnant women with mitochondrial disease - m.3243A>G mutation - are at greatly increased risk of complications and preterm delivery.

Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause Levodopa-responsive infantile-onset Parkinsonism.

Mitochondrial aminoacyl-tRNA synthetases (mtARSs) are essential, ubiquitously expressed enzymes that covalently attach amino acids to their corresponding tRNA molecules during translation of mitochondrial genes. Deleterious variants in the mtARS genes cause a diverse array of phenotypes, many of which involve the nervous system. Moreover, distinct mutations in mtARSs often cause different clinical manifestations. Recently, the gene encoding mitochondrial tryptophanyl tRNA synthetase (WARS2) was reported to cause 2 different neurological phenotypes, a form of autosomal recessive intellectual disability and a syndrome of severe infantile-onset leukoencephalopathy. Here, we report the case of a 17-year-old boy with compound heterozygous mutations in WARS2 (p.Trp13Gly, p.Ser228Trp) who presented with infantile-onset, Levodopa-responsive Parkinsonism at the age of 2 years. Analysis of patient-derived dermal fibroblasts revealed decreased steady-state WARS2 protein and normal OXPHOS content. Muscle mitochondrial studies suggested mitochondrial proliferation without obvious respiratory chain deficiencies at the age of 9 years. This case expands the phenotypic spectrum of WARS2 deficiency and emphasizes the importance of mitochondrial protein synthesis in the pathogenesis of Parkinsonism.

The effect of increasing risk and challenge in the school playground on physical activity and weight in children: a cluster randomised controlled trial (PLAY).

BACKGROUND: To investigate whether changing the play environment in primary schools to one that includes greater risk and challenge increases physical activity and reduces body mass index (BMI). SUBJECTS/METHODS: A 2-year cluster randomised controlled trial was undertaken in 16 New Zealand schools (years 1-8). Intervention schools (n=8) redesigned their play environments to encourage imaginative and independent free play by increasing opportunities for risk and challenge (for example, rough-and-tumble play), reducing rules and adding new playground components (for example, loose parts). Control schools (n=8) were asked to not change their play environment. A qualified playworker rated all school play environments at baseline and 1 year. Primary outcomes were moderate-to-vigorous physical activity (7-day accelerometry) and BMI z-score, collected in 840 children at baseline, 1 and 2 years. Data were analysed using generalised estimating equations. RESULTS: Multiple changes were made to the school play environments resulting in a significant difference in overall play evaluation score between intervention and control schools of 4.50 (95% confidence interval: 1.82 to 7.18, P=0.005), which represents a substantial improvement from baseline values of 19.0 (s.d. 3.2). Overall, schools liked the intervention and reported many benefits, including increased physical activity. However, these beliefs did not translate into significant differences in objectively measured physical activity, either as counts per minute (for example, 35 (-51 to 120) during lunch break) or as minutes of moderate-to-vigorous physical activity (0.4, -1.1 to 2.0). Similarly, no significant differences were observed for BMI, BMI z-score or waist circumference at 1 or 2 years (all P>0.321). CONCLUSIONS: Altering the school play environment to one that promoted greater risk and challenge for children did not increase physical activity, nor subsequently alter body weight. Although schools embraced the concept of adding risk and challenge in the playground, our findings suggest that children may have been involved in different, rather than additional activities.

A novel de novo STXBP1 mutation is associated with mitochondrial complex I deficiency and late-onset juvenile-onset parkinsonism.

Mutations in STXBP1 have recently been identified as a cause of infantile epileptic encephalopathy. The underlying mechanism of the disorder remains unclear and, recently, several case reports have described broad and progressive neurological phenotypes in addition to early-onset epilepsy. Herein, we describe a patient with early-onset epilepsy who subsequently developed a progressive neurological phenotype including parkinsonism in her early teens. A de novo mutation in STXBP1 (c.416C>T, p.(Pro139Leu)) was detected with exome sequencing together with profound impairment of complex I of the mitochondrial respiratory chain on muscle biopsy. These findings implicate a secondary impairment of mitochondrial function in the progressive nature of the disease phenotype.

Diquat causes caspase-independent cell death in SH-SY5Y cells by production of ROS independently of mitochondria.

Evidence indicates that Parkinson's disease (PD), in addition to having a genetic aetiology, has an environmental component that contributes to disease onset and progression. The exact nature of any environmental agent contributing to PD is unknown in most cases. Given its similarity to paraquat, an agrochemical removed from registration in the EU for its suspected potential to cause PD, we have investigated the in vitro capacity of the related herbicide Diquat to cause PD-like cell death. Diquat showed greater toxicity towards SH-SY5Y neuroblastoma cells and human midbrain neural cells than paraquat and also MPTP, which was independent of dopamine transporter-mediated uptake. Diquat caused cell death independently of caspase activation, potentially via RIP1 kinase, with only a minor contribution from apoptosis, which was accompanied by enhanced reactive oxygen species production in the absence of major inhibition of complex I of the mitochondrial respiratory chain. No changes in α-synuclein expression were observed following 24-h or 4-week exposure. Diquat may, therefore, kill neural tissue by programmed necrosis rather than apoptosis, reflecting the pathological changes seen following high-level exposure, although its ability to promote PD is unclear.

Characterization of short root anomaly in a Mexican cohort--hereditary idiopathic root malformation.

OBJECTIVE: The purpose of this study was to systematically characterize individuals with short root anomaly (SRA) without any history of orthodontic treatment. The long-term objective of the study was to improve diagnosis and treatment planning and determine risk factors for developing SRA. SETTING AND SAMPLE POPULATION: Twenty-seven patients including two families and 16 unrelated individuals from (9-48 years) reported to orthodontic and/or dental practitioners within the USA. MATERIALS AND METHODS: Digital panoramic and periapical films were analyzed to document pattern and frequency of SRA-affected teeth. Crown-to-root (CR) ratios of the affected teeth were used to characterize the extent of malformation. Pedigree analysis by inspection was completed for one family to determine pattern of inheritance. RESULTS: Twenty-six of the twenty-seven individuals were of Latino descent, and one was of Filipino descent. Hard tissues including enamel, dentin, pulp chambers and canals, and surrounding soft tissues were normal. We found that 25 of 27 individuals had localized SRA and two Latino individuals had generalized SRA. Teeth were affected bilaterally with maxillary central incisors (~63%) and mandibular second premolars most commonly involved (~33%). Affected teeth had a distinct, similar radiographic appearance; in the generalized cases, there was a more severe affection with larger (~twice) CR ratios. Ninety-four percent of affected individuals did not show a significant difference in the CR ratios at different ages. Pedigree analysis suggests an autosomal dominant inheritance pattern in one family. CONCLUSION: This is the first report to show that SRA occurs more frequently in Latino individuals and has a predilection for anterior teeth. The occurrence of SRA in two families further confirms a hereditary component and supports a distinct nosology and nomenclature, hereditary idiopathic root malformation (HIRM) and warrants further investigation.

Selection on female behaviour fluctuates with offspring environment.

Temporal variation in selection has long been proposed as a mechanism by which genetic variation could be maintained despite short-term strong directional selection and has been invoked to explain the maintenance of consistent individual differences in behaviour. We tested the hypothesis that ecological changes through time lead to fluctuating selection, which could promote the maintenance of variation in female behavioural traits in a wild population of North American red squirrels. As predicted, linear selection gradients on female aggression and activity significantly fluctuated across years depending on the level of competition among juveniles for vacant territories. This selection acted primarily through juvenile overwinter survival rather than maternal fecundity. Incorporating uncertainty in individual measures of behaviour reduced the magnitude of annual selection gradients and increased uncertainty in these estimates, but did not affect the overall pattern of temporal fluctuations in natural selection that coincided with the intensity of competition for vacant territories. These temporal fluctuations in selection might, therefore, promote the maintenance of heritable individual differences in behaviour in this wild red squirrel population.

Mitochondrial DNA deletions and depletion within paraspinal muscles.

AIMS: Although mitochondrial abnormalities have been reported within paraspinal muscles in patients with axial weakness and neuromuscular disease as well as with ageing, the basis of respiratory deficiency in paraspinal muscles is not known. This study aimed to determine the extent and basis of respiratory deficiency in paraspinal muscles from cases undergoing surgery for degenerative spinal disease and post mortem cases without a history of spinal disease, where age-related histopathological changes were previously reported. METHODS: Cervical and lumbar paraspinal muscles were obtained peri-operatively from 13 patients and from six post mortem control cases (age range 18-82 years) without a neurological disease. Sequential COX/SDH (mitochondrial respiratory chain complex IV/complex II) histochemistry was performed to identify respiratory-deficient muscle fibres (lacking complex IV with intact complex II activity). Real-time polymerase chain reaction, long-range polymerase chain reaction and sequencing were used to identify and characterize mitochondrial DNA (mtDNA) deletions and determine mtDNA copy number status. Mitochondrial respiratory chain complex subunits were detected by immunohistochemistry. RESULTS: The density of respiratory-deficient fibres increased with age. On average, 3.96% of fibres in paraspinal muscles were respiratory-deficient (range 0-10.26). Respiratory deficiency in 36.8% of paraspinal muscle fibres was due to clonally expanded mtDNA deletions. MtDNA depletion accounted for further 13.5% of respiratory deficiency. The profile of immunohistochemically detected subunits of complexes was similar in respiratory-deficient fibres with and without mtDNA deletions or mtDNA depletion. CONCLUSIONS: Paraspinal muscles appeared to be particularly susceptible to age-related mitochondrial respiratory chain defects. Clonally expanded mtDNA deletions and focal mtDNA depletion may contribute towards the development of age-related postural abnormalities.

Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids.

Mitochondrila DNA (mtDNA) is the only extrachromosomal DNA in humans. It is a small (16.5 kb) genome which encodes 13 essential peptides of the respiratory chain, two rRNAs and 22 tRNAs. Defects of this genome are now recognized as important causes of disease and may take the form of point mutations or rearrangements. There is no effective treatment for patients with mtDNA mutations. In the majority of patients with mtDNA defects, both mutant and wild-type molecules are present in the same cell-a phenomenon known as intracellular heteroplasmy. In addition, in the presence of heteroplasmy there is a threshold whereby a certain level of mutant mtDNA is necessary before the disease becomes biochemically and clinically apparent. Based on the presence of heteroplasmy and the recessive nature of these mutations, we believe it will be possible to treat patients by selectively inhibiting the replication of the mutant mtDNA, thereby allowing propagation of only the wild-type molecule. To confirm the validity of such an approach we synthesised peptide nucleic acids (PNAs) complementary to human mtDNA templates containing a deletion breakpoint or single base mutation, both mutations well documented to cause disease. Using an in vitro replication run-off assay under physiological conditions, the antigenomic PNAs specifically inhibited replication of mutant but not wild-type mtDNA templates. Furthermore, we have shown uptake of these PNAs into cultured human myoblasts. We believe that we have therefore established the potential value of antigenomic PNA therapy for patients with heteroplasmic mtDNA disorders.

Axin2+ PDL Cells Directly Contribute to New Alveolar Bone Formation in Response to Orthodontic Tension Force.

Wnt-ß-catenin signaling plays a key role in orthodontic tooth movement (OTM), a common clinical practice for malocclusion correction. However, its targeted periodontal ligament (PDL) progenitor cells remain largely unclear. In this study, we first showed a synchronized increase in Wnt-ß-catenin levels and Axin2+ PDL progenitor cell numbers during OTM using immunostaining of ß-catenin in wild-type mice and X-gal staining in the Axin2-LacZ knock-in line. Next, we demonstrated time-dependent increases in Axin2+ PDL progenitors and their progeny cell numbers within PDL and alveolar bones during OTM using a one-time tamoxifen-induced Axin2 tracing line (Axin2CreERT2/+; R26RtdTomato/+). Coimmunostaining images displayed both early and late bone markers (such as RUNX2 and DMP1) in the Axin2Lin PDL cells. Conversely, ablation of Axin2+ PDL cells via one-time tamoxifen-induced diphtheria toxin subunit A (DTA) led to a drastic decrease in osteogenic activity (as reflected by alkaline phosphatase) in PDL and alveolar bone. There was also a decrease in new bone mass and a significant reduction in the mineral apposition rate on both the control side (to a moderate degree) and the OTM side (to a severe degree). Thus, we conclude that the Axin2+ PDL cells (the Wnt-targeted key cells) are highly sensitive to orthodontic tension force and play a critical role in OTM-induced PDL expansion and alveolar bone formation. Future drug development targeting the Axin2+ PDL progenitor cells may accelerate alveolar bone formation during orthodontic treatment.

Organic matter composition and thermal stability influence greenhouse gases production in subtropical peatland under different vegetation types.

Peatlands are a major carbon (C) sink globally. Organic matter quality influence greenhouse gases production. However, little is known about how organic matter from different vegetation types, influences C composition and resultant greenhouse gases production in subtropical peatland. Anoxic incubation experiments were conducted using two types of peats with different botanical origin to assess C composition, CO2 and CH4 production. First peat had cypress dominance and the second knotted spikerush and water lily (spike + lily). Solid-state CPMAS 13C NMR determined C chemical stability, MESTA determined C thermal stability, stable isotopes for C source and gas chromatograph for carbon dioxide (CO2) and methane (CH4). The results indicated dominance of autochthonous C as indicated by δ13C signatures. Low thermal stable C (LTSC) dominated in litter, FL (fermentation layer) and spike + lily sediment, high thermal stable C was dominant in cypress peat. O-alkyl C strongly correlated with LTSC whereas aromatic C correlated negatively with R400 (LTSC:total C ratio). Generally, O-alkyl decreased and alkyl increased along litter-FL-peat continuum. Spike + lily peat exhibited initial stage of decomposition. Indicated by increased alkyl C, aromatic C and aromatic:O-alkyl ratio with increasing peat depth. Also, exhibited 3 times more CH4 and CO2 production compared to cypress peat that dominantly exhibited second stage of decomposition. O-alkyl C exhibited positive relationship with CH4 (P = 0.012, r2 = 0.57) and CO2 (P = 0.047, r2 = 0.41) production whereas R400 related positively with CH4 (P = 0.05, r2 = 0.40). Organic matter thermal and chemical composition varied between the peat types and thermally and chemically labile C influenced CO2 and CH4 production.

Multi-system neurological disease is common in patients with OPA1 mutations.

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.

Waist-to-height ratios in relation to BMI z-scores in three ethnic groups from a representative sample of New Zealand children aged 5-14 years.

Waist-to-height ratio (WHtR) is purported to offer a simpler index of health risk than body mass index (BMI) in children as it requires no adjustment for age or sex. Little is known regarding the usefulness of WHtR in different ethnic groups. The aim of this study was to compare the WHtR cutpoints associated with BMI definitions of overweight and obesity in a nationally representative sample of New Zealand children. Height, weight and waist circumference were measured in 3006 children (51.5% male) aged 5-14 years (n=1107 Maori, n=985 Pacific and n=924 New Zealand European and Others (NZEO)). A WHtR >0.5 was more common in Pacific (43.4%) and Maori (33.1%) children than in NZEO children (20.8%, P<0.001), with 25.6% of children overall being above this cutoff. Although ethnicity influenced the relationship between BMI and WHtR (P<0.01), differences were clinically insignificant as illustrated by the similarity in WHtR values for a given BMI (WHtR of 0.47 in Maori, 0.46 in Pacific and 0.48 in European boys at the 85th BMI percentile). The present results suggest that having WHtR values >0.5 should be equally useful in evaluating cardiovascular health risks in groups of Maori, Pacific and NZEO children.

Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children.

BACKGROUND: The POLG1 gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA replication and repair. Mutations in POLG1 have been linked to a spectrum of clinical phenotypes, and may account for up to 25% of all adult presentations of mitochondrial disease. METHODS AND RESULTS: We present 14 patients, with characteristic features of mitochondrial disease including progressive external ophthalmoplegia (PEO) and Alpers-Huttenlocher syndrome and laboratory findings indicative of mitochondrial dysfunction, including cytochrome c oxidase (COX) deficiency and multiple deletions or depletion of the mitochondrial DNA. Four novel POLG1 missense substitutions (p.R597W, p.L605R, p.G746S, p.A862T), are described, together with the first adult patient with a recently described polymerase domain mutation (p.R1047W). All novel changes were rare in a control population and affected highly conserved amino acids. CONCLUSION: The addition of these substitutions-including the first report of a dinucleotide mutation (c.1814_1815TT>GC)-to the growing list of defects further confirms the importance of POLG1 mutations as the underlying abnormality in a range of neurological presentations.