A call to introduce newborn screening for spinal muscular atrophy (SMA) in Scotland

Peer reviewedPublisher PD

Skeletal disproportion in glucocorticoid-treated boys with Duchenne muscular dystrophy

We aimed to compare body segment and bone lengths in glucocorticoid-treated boys with Duchenne muscular dystrophy (DMD) with healthy controls using dual-energy absorptiometry (DXA) images. Total height (Ht), sitting height (SH), leg length (LL) and bone lengths (femur, tibia) in boys with DMD and age-matched control boys were measured using DXA. Thirty boys with DMD (median age 10.0 years (6.1, 16.8)) were compared with 30 controls. SH in DMD was 3.3 cm lower (95% CI − 6.1, − 0.66; p = 0.016). LL in DMD was 7.3 cm lower (95% CI − 11.2, − 3.4; p < 0.0001). SH:LL of boys with DMD was higher by 0.08 (95% CI 0.04, 0.12; p < 0.0001). Femur length in DMD was 2.4 cm lower (95% CI − 4.6, − 0.12; p = 0.04), whereas tibial length in DMD was 4.8 cm lower (95% CI − 6.7, − 2.9; p < 0.0001). SH:LL was not associated with duration of glucocorticoid use (SH:LL β = 0.003, 95% CI − 0.01 to 0.002, p = 0.72). Conclusion: Glucocorticoid-treated boys with DMD exhibit skeletal disproportion with relatively shorter leg length and more marked reduction of distal long bones. As glucocorticoid excess is not associated with such disproportion, our findings raise the possibility of an intrinsic disorder of growth in DMD

Pathogenic Variants in MT-ATP6: A United Kingdom-Based Mitochondrial Disease Cohort Study

Distinct clinical syndromes have been associated with pathogenic MT-ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty-one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT-ATP6-related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310-31

Fractures and linear growth in a nationwide cohort of boys with Duchenne muscular dystrophy with and without glucocorticoid treatment

Importance: Based on studies with relatively small sample size, fragility fractures are commonly reported in glucocorticoid (GC)-treated boys with Duchenne muscular dystrophy (DMD). Objective: To determine the fracture burden and growth impairment in a large contemporary cohort of boys with DMD in the United Kingdom and in relation to GC regimen. Design, Setting, and Participants: A retrospective review of fracture morbidity and growth from 832 boys with DMD in the UK NorthStar database (2006-2015), which systematically captures information from 23 participating centers. A total of 564 boys had more than 1 visit. No numbers of boys who refused were collected, but informal data from 2 centers in London and from Scotland show that refusal is very low. Data were analyzed between October 2006 and October 2015. Main Outcomes and Measures: Fracture incidence rate per 10 000 person-years was determined. Cox regression analysis was used to identify factors associated with first fracture. Results: Median age at baseline was 6.9 years (interquartile range, 4.9-7.2 years). At baseline, new fractures were reported in 7 of 564 participants (1.2%). During a median follow-up of 4 years (interquartile range, 2.0-6.0 years), incident fractures were reported in 156 of 564 participants (27.7%), corresponding to an overall fracture incidence rate of 682 per 10 000 person-years (95% CI, 579-798). The highest fracture incidence rate was observed in those treated with daily deflazacort at 1367 per 10 000 person-years (95% CI, 796-2188). After adjusting for age at last visit, mean hydrocortisone equivalent dose, mobility status, and bisphosphonate use prior to first fracture, boys treated with daily deflazacort had a 16.0-fold increased risk for first fracture (95% CI, 1.4-180.8; P = .03). Using adjusted regression models, change in height standard deviation scores was −1.6 SD lower (95% CI, −3.0 to −0.1; P = .03) in those treated with daily deflazacort compared with GC-naive boys, whereas there were no statistical differences in the other GC regimen. Conclusions and Relevance: In this large group of boys with DMD with longitudinal data, we document a high fracture burden. Boys treated with daily deflazacort had the highest fracture incidence rate and the greatest degree of linear growth failure. Clinical trials of primary bone protective therapies and strategies to improve growth in boys with DMD are urgently needed, but stratification based on GC regimen may be necessary

The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P

No abstract available

Recessive desmin-null muscular dystrophy with central nuclei and mitochondrial abnormalities

No abstract available

Expanding the FDXR-Associated Disease Phenotype: Retinal Dystrophy Is a Recurrent Ocular Feature.

PurposeThe purpose of this study was to report retinal dystrophy as a novel clinical feature and expand the ocular phenotype in patients harboring biallelic candidate FDXR variants.MethodsPatients carrying biallelic candidate FDXR variants were identified by whole genome sequencing (WGS) as part of the National Institute for Health Research BioResource rare-disease and the UK's 100,000 Genomes Project (100KGP) with an additional case identified by exome sequencing. Retrospective clinical data were collected from the medical records. Haplotype reconstruction was performed in families harboring the same missense variant.ResultsTen individuals from 8 unrelated families with biallelic candidate variants in FDXR were identified. In addition to bilateral optic atrophy and variable extra-ocular findings, 7 of 10 individuals manifested retinal dystrophy comprising dysfunction and degeneration of both rod and cone photoreceptors. Five of 10 subjects had sensorineural hearing loss. The previously unreported missense variant (c.1115C > A, p.(Pro372His)) was found in 5 of 8 (62.5%) study families. Haplotype reconstruction using WGS data demonstrated a likely ancestral haplotype.ConclusionsFDXR-associated disease is a phenotypically heterogeneous disorder with retinal dystrophy being a major clinical feature observed in this cohort. In addition, we hypothesize that a number of factors are likely to drive the pathogenesis of optic atrophy, retinal degeneration, and perhaps the associated systemic manifestations

Expanding the FDXR-Associated Disease Phenotype: Retinal Dystrophy Is a Recurrent Ocular Feature

International audiencePurpose: The purpose of this study was to report retinal dystrophy as a novel clinical feature and expand the ocular phenotype in patients harboring biallelic candidate FDXR variants.Methods: Patients carrying biallelic candidate FDXR variants were identified by whole genome sequencing (WGS) as part of the National Institute for Health Research BioResource rare-disease and the UK's 100,000 Genomes Project (100KGP) with an additional case identified by exome sequencing. Retrospective clinical data were collected from the medical records. Haplotype reconstruction was performed in families harboring the same missense variant.Results: Ten individuals from 8 unrelated families with biallelic candidate variants in FDXR were identified. In addition to bilateral optic atrophy and variable extra-ocular findings, 7 of 10 individuals manifested retinal dystrophy comprising dysfunction and degeneration of both rod and cone photoreceptors. Five of 10 subjects had sensorineural hearing loss. The previously unreported missense variant (c.1115C > A, p.(Pro372His)) was found in 5 of 8 (62.5%) study families. Haplotype reconstruction using WGS data demonstrated a likely ancestral haplotype.Conclusions: FDXR-associated disease is a phenotypically heterogeneous disorder with retinal dystrophy being a major clinical feature observed in this cohort. In addition, we hypothesize that a number of factors are likely to drive the pathogenesis of optic atrophy, retinal degeneration, and perhaps the associated systemic manifestations