Functional abilities, respiratory and cardiac function in a large cohort of adults with Duchenne muscular dystrophy treated with glucocorticoids.

BACKGROUND AND PURPOSE: The transition to adult services, and subsequent glucocorticoid management, is critical in adults with Duchenne muscular dystrophy. This study aims (1) to describe treatment, functional abilities, respiratory and cardiac status during transition to adulthood and adult stages; and (2) to explore the association between glucocorticoid treatment after loss of ambulation (LOA) and late-stage clinical outcomes. METHODS: This was a retrospective single-centre study on individuals with Duchenne muscular dystrophy (≥16 years old) between 1986 and 2022. Logistic regression, Cox proportional hazards models and survival analyses were conducted utilizing data from clinical records. RESULTS: In all, 112 individuals were included. Mean age was 23.4 ± 5.2 years and mean follow-up was 18.5 ± 5.5 years. At last assessment, 47.2% were on glucocorticoids; the mean dose of prednisone was 0.38 ± 0.13 mg/kg/day and of deflazacort 0.43 ± 0.16 mg/kg/day. At age 16 years, motor function limitations included using a manual wheelchair (89.7%), standing (87.9%), transferring from a wheelchair (86.2%) and turning in bed (53.4%); 77.5% had a peak cough flow <270 L/min, 53.3% a forced vital capacity percentage of predicted <50% and 40.3% a left ventricular ejection fraction <50%. Glucocorticoids after LOA reduced the risk and delayed the time to difficulties balancing in the wheelchair, loss of hand to mouth function, forced vital capacity percentage of predicted <30% and forced vital capacity <1 L and were associated with lower frequency of left ventricular ejection fraction <50%, without differences between prednisone and deflazacort. Glucocorticoid dose did not differ by functional, respiratory or cardiac status. CONCLUSION: Glucocorticoids after LOA preserve late-stage functional abilities, respiratory and cardiac function. It is suggested using functional abilities, respiratory and cardiac status at transition stages for adult services planning.

Myotonic dystrophy type 1: palliative care guidelines.

Palliative care for adults with neuromuscular conditions is an emerging field. Previous guidelines regarding myotonic dystrophy and palliative care have only mentioned end-of-life care and little else. The following guidelines have been written using national experts as a description of best practice as part of the Dystrophia Myotonica National Care Guidelines Consortium.

Respiratory involvement in ambulant and non-ambulant patients with facioscapulohumeral muscular dystrophy.

Understand the occurrence and predictors of respiratory impairment in FSHD. Data from 100 FSHD patients was collected regarding demographics, genetics, respiratory status and pulmonary function tests, clinical manifestations and Clinical Severity Scale (CSS) scores. Patients were assigned to two severity groups using CSS: mild (scores <3.5) and moderate/severely affected (scores ≥3.5). Forced Vital Capacity (FVC) was classified as severely impaired if less than 50% of the predicted. Statistical analysis was performed using IBM SPSS Statistics 23, tests were two-tailed and the level of significance set at 5%. Spirometry was available for 94 patients; 41.5% had abnormal results with a restrictive pattern in 38.3% patients. There was a correlation between FVC; CSS score and D4Z4 fragment length with a higher probability of severe respiratory involvement in the early onset group, moderate/severe disease and D4Z4 fragments <18 kb. Patients with severe respiratory involvement showed a high prevalence of sleep-disordered breathing. FVC decline over time was indicative of three progression groups. Respiratory involvement for both ambulant and non-ambulant patients with FSHD is more frequent and severe than previously suggested. Sleep-disordered breathing is frequent and negatively influences the respiratory status. Annual screening of the respiratory status with spirometry and clinical assessment is thus warranted in FSHD patients, even while ambulant.

Whole exome sequencing and the clinician: we need clinical skills and functional validation in variant filtering.

Whole exome sequencing (WES) is a recently developed technique in genetics research that attempts to identify causative mutations in complex, undiagnosed genetic conditions. Causative mutations are usually identified after filtering the hundreds of variants on WES from an individual's DNA selected by the phenotype. We investigated a patient with a slowly progressive chronic axonal distal motor neuropathy and extrapyramidal syndrome using WES, in whom common genetic mutations had been excluded. Variant filtering identified potentially deleterious mutations in three known disease genes: DCTN1, KIF5A and NEFH, which have been all associated with similar clinical presentations of amyotrophic lateral sclerosis, Parkinsonism and/or hereditary spastic paraplegia. Predicting the functional effect of the mutations were analysed in parallel with detailed clinical investigations. This case highlights the difficulties and pitfalls of applying WES in patients with complex neurological diseases and serves as an instructive tale.

Exome sequencing in undiagnosed inherited and sporadic ataxias.

Inherited ataxias are clinically and genetically heterogeneous, and a molecular diagnosis is not possible in most patients. Having excluded common sporadic, inherited and metabolic causes, we used an unbiased whole exome sequencing approach in 35 affected individuals, from 22 randomly selected families of white European descent. We defined the likely molecular diagnosis in 14 of 22 families (64%). This revealed de novo dominant mutations, validated disease genes previously described in isolated families, and broadened the clinical phenotype of known disease genes. The diagnostic yield was the same in both young and older-onset patients, including sporadic cases. We have demonstrated the impact of exome sequencing in a group of patients notoriously difficult to diagnose genetically. This has important implications for genetic counselling and diagnostic service provision.

Gait impairment precedes clinical symptoms in spinocerebellar ataxia type 6.

BACKGROUND: Spinocerebellar ataxia type 6 (SCA6) is an inherited ataxia with no established treatment. Gait ataxia is a prominent feature causing substantial disability. Understanding the evolution of the gait disturbance is a key step in developing treatment strategies. METHODS: We studied 9 gait variables in 24 SCA6 (6 presymptomatic; 18 symptomatic) and 24 controls and correlated gait with clinical severity (presymptomatic and symptomatic). RESULTS: Discrete gait characteristics precede symptoms in SCA6 with significantly increased variability of step width and step time, whereas a more global gait deficit was evident in symptomatic individuals. Gait characteristics discriminated between presymptomatic and symptomatic individuals and were selectively associated with disease severity. CONCLUSIONS: This is the largest study to include a detailed characterization of gait in SCA6, including presymptomatic subjects, allowing changes across the disease spectrum to be compared. Selective gait disturbance is already present in SCA6 before clinical symptoms appear and gait characteristics are also sensitive to disease progression. Early gait disturbance likely reflects primary pathology distinct from secondary changes. These findings open the opportunity for early evaluation and sensitive measures of therapeutic efficacy using instrumented gait analysis which may have broader relevance for all degenerative ataxias.

Behr's Syndrome is Typically Associated with Disturbed Mitochondrial Translation and Mutations in the C12orf65 Gene.

BACKGROUND: Behr's syndrome is a classical phenotypic description of childhood-onset optic atrophy combined with various neurological symptoms, including ophthalmoparesis, nystagmus, spastic paraparesis, ataxia, peripheral neuropathy and learning difficulties. OBJECTIVE: Here we describe 4 patients with the classical Behr's syndrome phenotype from 3 unrelated families who carry homozygous nonsense mutations in the C12orf65 gene encoding a protein involved in mitochondrial translation. METHODS: Whole exome sequencing was performed in genomic DNA and oxygen consumption was measured in patient cell lines. RESULTS: We detected 2 different homozygous C12orf65 nonsense mutations in 4 patients with a homogeneous clinical presentation matching the historical description of Behr's syndrome. The first symptom in all patients was childhood-onset optic atrophy, followed by spastic paraparesis, distal weakness, motor neuropathy and ophthalmoparesis. CONCLUSIONS: We think that C12orf65 mutations are more frequent than previously suggested and screening of this gene should be considered not only in patients with mitochondrial respiratory chain deficiencies, but also in inherited peripheral neuropathies, spastic paraplegias and ataxias, especially with pre-existing optic atrophy.

Prominent sensorimotor neuropathy due to SACS mutations revealed by whole-exome sequencing.

OBJECTIVE: To determine the genetic basis of an unexplained multisystem neurological disorder affecting 2 siblings. DESIGN: Case reports and whole-exome DNA sequencing. SETTING: Neurogenetics clinic, Institute of Genetic Medicine, Newcastle upon Tyne, England. PATIENTS: Two adult siblings with a sensorimotor neuropathy, ataxia, and spasticity. MAIN OUTCOME MEASURES: Clinical, neurophysiological, imaging, and genetic data. RESULTS: Novel compound heterozygous frameshift mutations were detected in the SACS gene of both siblings, predicted to drastically truncate the sacsin protein. CONCLUSIONS: Whole-exome sequencing rapidly defined the genetic cause of the disorder, expanding the clinical phenotype associated with SACS mutations to include a severe sensorimotor neuropathy.