Quantitative muscle ultrasound in adult spinal muscular atrophy. A pilot study.

INTRODUCTION/AIMS: Muscle ultrasound has been investigated in children with spinal muscular atrophy (SMA) and proposed as a potential biomarker of disease severity. We studied the ultrasound properties in adults with SMA to see whether they also have potential as markers of disease severity in older patients. METHODS: Thickness and quantitative echogenicity of muscle and subcutaneous tissue were compared between eight prospectively recruited adult patients with SMA and eight age, sex and body mass index-matched controls. Measurements were made in the dominant deltoid, biceps, triceps, forearm extensors, first dorsal interosseous, quadriceps, tibialis anterior, and gastrocnemius muscles. The muscle-to-subcutaneous (M:S) thickness and echogenicity ratios were also calculated. A mean value across all muscles as well as the individual values for each muscle were then calculated for each parameter in each subject and compared between the two groups. Significance was set at 0.05 after Bonferroni correction. RESULTS: In the SMA patients, mean muscle thickness was significantly smaller (1.3 vs. 1.9 cm), muscle echogenicity higher (106 vs. 67 on the grayscale level), and subcutaneous thickness larger (0.9 vs. 0.3 cm) than in controls; M:S echogenicity ratio was significantly increased and M:S thickness ratio reduced in the patients. The most abnormal scores were found in the nonambulatory patients and the least abnormal in the ambulatory patients. DISCUSSION: Ultrasound can detect and quantify the severity of muscle atrophy and structure in adult SMA, suggesting a potential role as a marker of disease severity, which will require validation by larger studies.

Mitochondrial disease in New Zealand: a nationwide prevalence study.

BACKGROUND: The complexities of mitochondrial disease make epidemiological studies challenging, yet this information is important in understanding the healthcare burden and addressing service and educational needs. Existing studies are limited to quaternary centres or focus on a single genotype or phenotype and estimate disease prevalence at 12.5 per 100 000. New Zealand's (NZ) size and partially integrated national healthcare system make it amenable to a nationwide prevalence study. AIM: To estimate the prevalence of molecularly confirmed and suspected mitochondrial disease on 31 December 2015 in NZ. METHODS: Cases were identified from subspecialists and laboratory databases and through interrogation of the Ministry of Health National Minimum Dataset with a focus on presentations between 2000 and 2015. Patient records were reviewed, and those with a diagnosis of 'mitochondrial disease' who were alive and residing in NZ on the prevalence date were included. These were divided into molecularly confirmed and clinically suspected cases. Official NZ estimated resident population data were used to calculate prevalence. RESULTS: Seven hundred twenty-three unique national health index numbers were identified. Five hundred five were excluded. The minimum combined prevalence for mitochondrial disease was 4.7 per 100 000 (95% confidence interval (CI): 4.1-5.4). The minimum prevalence for molecularly confirmed and suspected disease was 2.9 (95% CI 2.4-3.4) and 1.8 (95% CI 1.4-2.2) cases per 100 000 respectively. CONCLUSIONS: Within the limitations of this study, comparison to similar prevalence studies performed by specialist referral centres suggests mitochondrial disease is underdiagnosed in NZ. This highlights a need for improved education and referral pathways for mitochondrial disease in NZ.

Nerve ultrasound detects abnormally small nerves in patients with spinal and bulbar muscular atrophy.

INTRODUCTION/AIMS: Sensory impairment secondary to dorsal root ganglion neuronopathy is common, although often subclinical, in X-linked spinal and bulbar muscular atrophy (SBMA). We investigated the hypothesis that nerves of SBMA patients show the same morphological changes on ultrasound as other inherited sensory neuronopathies and that these changes are distinct from those in axonal neuropathy. METHODS: We compared the ultrasound cross-sectional areas (CSAs) of median, ulnar, sural, and tibial nerves of prospectively recruited SBMA patients with those of patients with acquired axonal neuropathy and healthy controls. We also compared the individual nerve CSAs of SBMA and neuropathy patients with our laboratory reference values. RESULTS: There were 7 SBMA patients, 18 neuropathy patients, and 42 healthy controls. The nerve CSAs of the SBMA patients were significantly smaller than those of patients in the other two groups. The changes were most prominent in the upper limbs (p < .001), with the nerves of the SBMA patients being on average approximately half the size of the controls and a third the size of the neuropathy patients. On individual analysis, the ultrasound abnormality was sufficiently characteristic to be detected in all but one SBMA patient. DISCUSSION: These ultrasound changes are similar to those reported in other inherited sensory neuronopathies and clearly different from the ultrasound findings in axonal neuropathy. Smaller nerves are possibly a distinctive finding in SBMA that may distinguish it from other motor neuron syndromes. Further studies are warranted to confirm this and determine the optimal sonographic protocol.

Impact and predictors of quality of life in adults diagnosed with a genetic muscle disorder: a nationwide population-based study.

OBJECTIVES: To determine the impact of genetic muscle disorders and identify the sociodemographic, illness, and symptom factors influencing quality of life. METHODS: Adults (aged 16-90 years) with a confirmed clinical or molecular diagnosis of a genetic muscle disorder identified as part of a nationwide prevalence study were invited to complete an assessment of the impact of their condition. Quality of life was measured using the World Health Organization Quality of Life questionnaire. Impact was measured via the prevalence of symptoms and comparisons of quality of life against New Zealand norms. Multivariate regression models were used to identify the most significant predictors of quality of life domains. RESULTS: 490/596 participants completed the assessment (82.2% consent rate). Quality of life was lower than the general population on physical (t = 9.37 p < 0.0001, d = 0.54) social (t = 2.27 p = 0.02, d = 0.13) and environmental domains (t = 2.28 p = 0.02, d = 0.13), although effect sizes were small. No difference was found on the psychological domain (t = - 1.17 p = 0.24, d = 0.07). Multivariate regression models (predicting 42%-64% of the variance) revealed personal factors (younger age, being in employment and in a relationship), symptoms (lower pain, fatigue, and sleep difficulties), physical health (no need for ventilation support, fewer activity limitations and no comorbidities), and psychosocial factors (lower depression, anxiety, behavioural dyscontrol and higher self-efficacy, satisfaction with health care and social support) contributed to improved quality of life. CONCLUSIONS: A range of factors influence the quality of life in adults diagnosed with a genetic muscle disorder and some may serve as targets for multi-faceted intervention.

A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele.

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative disease with onset in mid- to late adulthood. The genetic basis for a large proportion of Caucasian patients was recently shown to be the biallelic expansion of a pentanucleotide (AAGGG)n repeat in RFC1. Here, we describe the first instance of CANVAS genetic testing in New Zealand Maori and Cook Island Maori individuals. We show a novel, possibly population-specific CANVAS configuration (AAAGG)10-25(AAGGG)exp, which was the cause of CANVAS in all patients. There were no apparent phenotypic differences compared with European CANVAS patients. Presence of a common disease haplotype among this cohort suggests this novel repeat expansion configuration is a founder effect in this population, which may indicate that CANVAS will be especially prevalent in this group. Haplotype dating estimated the most recent common ancestor at ∼1430 ce. We also show the same core haplotype as previously described, supporting a single origin of the CANVAS mutation.

A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel RFC1 repeat expansion motif, (ACAGG)exp, in three affected individuals. This motif was associated with additional clinical features including fasciculations and elevated serum creatine kinase. These features have not previously been described in individuals with genetically-confirmed CANVAS. Haplotype analysis showed our patients shared the same core haplotype as previously published, supporting the possibility of a single origin of the RFC1 disease allele. We analysed data from >26 000 genetically diverse individuals in gnomAD to show enrichment of (ACAGG) in non-European populations.

Strategies for identifying pollution sources in a headwater catchment based on multi-scale water quality monitoring.

Rural headwater catchments are important to describe the connectivity of pollution sources to water bodies. Strategies to optimize water quality monitoring networks, as parameter definition, sampling, and statistical approach, have been widely discussed. The objectives of this study were to describe the spatial and temporal dynamics (intra- and inter-events) of water quality and to establish its implications for environmental monitoring programs. The monitoring was carried out in a rural headwater catchment (1.2 km2) with shallow soils, high slopes, and intense agricultural activity in Southern Brazil. To better describe the impact of agriculture on water resources, the monitoring strategy was based on definition of the best set of parameters and different sampling frequency to incorporate intra- and inter-event variability and statistical analysis approach. We also analyzed parameters in different sub-basins with physiographic traits. Three hydrological compartments were analyzed: surface flow, groundwater, and base flow. Physico-chemical parameters, the concentration of elements associated with agricultural activity, and biological parameters were evaluated. Total phosphorus and turbidity were the parameters most affected by agricultural activity. They reflected on the inter- and intra-events, the impacts of soil and water degradation by agricultural activity, and the precarious rural sanitation conditions. Spatiotemporal variability of the parameters characterizes the different mechanisms for transferring pollutants from diffuse sources to water bodies. Spatial and temporal patterns in water quality changes were used to discuss environmental monitoring strategies, such as parameter and sampling frequency definition, to improve soil and water conservation programs at the catchment scale.

A Nationwide, Population-Based Prevalence Study of Genetic Muscle Disorders.

BACKGROUND: Previous epidemiological studies of genetic muscle disorders have relied on medical records to identify cases and may be at risk of selection biases or have focused on selective population groups. OBJECTIVES: This study aimed to determine age-standardised prevalence of genetic muscle disorders through a nationwide, epidemiological study across the lifespan using the capture-recapture method. METHODS: Adults and children with a confirmed clinical or molecular diagnosis of a genetic muscle disorder, resident in New Zealand on April 1, 2015 were identified using multiple overlapping sources. Genetic muscle disorders included the muscular dystrophies, congenital myopathies, ion channel myopathies, GNE myopathy, and Pompe disease. Prevalence per 100,000 persons by age, sex, disorder, ethnicity and geographical region with 95% CIs was calculated using Poisson distribution. Direct standardisation was applied to age-standardise prevalence to the world population. Completeness of case ascertainment was determined using capture-recapture modelling. RESULTS: Age standardised minimal point prevalence of all genetic muscle disorders was 22.3 per 100,000 (95% CI 19.5-25.6). Prevalence in Europeans of 24.4 per 100,000, (95% CI 21.1-28.3) was twice that observed in NZ's other 3 main ethnic groups; Maori (12.6 per 100,000, 95% CI 7.8-20.5), Pasifika (11.0 per 100,000, 95% CI 5.4-23.3), and Asian (9.13 per 100,000, 95% CI 5.0-17.8). Crude prevalence of myotonic dystrophy was 3 times higher in Europeans (10.5 per 100,000, 9.4-11.8) than Maori and Pasifika (2.5 per 100,000, 95% CI 1.5-4.2 and 0.7 per 100,000, 95% CI 0.1-2.7 respectively). There were considerable regional variations in prevalence, although there was no significant association with social deprivation. The final capture-recapture model, with the least deviance, estimated the study ascertained 99.2% of diagnosed cases. CONCLUSIONS: Ethnic and regional differences in the prevalence of genetic muscle disorders need to be considered in service delivery planning, evaluation, and decision making.

Spinocerebellar ataxia type 2-neuronopathy or neuropathy?

INTRODUCTION: Use of peripheral nerve ultrasound alongside standard electrodiagnostic tests may help to gain insight into the pathophysiology of peripheral nerve involvement in type 2 spinocerebellar ataxia (SCA2). METHODS: Twenty-seven patients with SCA2 underwent ultrasound cross-sectional area (CSA) measurement of median, ulnar, sural and tibial nerves, and motor (median, ulnar, tibial) and sensory (median, ulnar, radial, sural) nerve conduction studies. RESULTS: Twenty patients had pathologically small-nerve CSAs, suggestive of sensory neuronopathy. In these patients, electrophysiology showed non-length-dependent sensory neuropathy (14 of 20), "possible sensory neuropathy" (1 of 20), or normal findings (5 of 20). Four different patients had length-dependent sensory neuropathy on electrophysiology, and 1 had enlarged nerve CSAs. Regression analysis showed an inverse relationship between ataxia scores and upper limb nerve CSA (P < 0.03). DISCUSSION: Our findings suggest that a majority of patients with SCA2 (74%) have a sensory neuronopathy and this correlates with disability. A minority of patients have findings consistent with axonal neuropathy (18%). Muscle Nerve, 2019.

Family communication following a diagnosis of myotonic dystrophy: To tell or not to tell?

Family communication about genetic information enables informed medical and reproductive decision-making. The literature suggests that a significant proportion of genetically at-risk family members remain uninformed about genetic risk information as a result of non-disclosure. This study explored the experiences of New Zealand families communicating about a diagnosis of type 1 myotonic dystrophy (DM1). Eligible individuals were identified and recruited from the New Zealand (NZ) MD Prev study, a nationwide study which aimed to determine the prevalence, impact, and costs of genetic muscle disorders across the lifespan. Twelve qualitative semi-structured interviews were conducted with 17 participants. The findings demonstrate diversity among and within families, with several distinct family narratives described. Most participants reported a motivation to tell relatives about their diagnosis to promote autonomy. Women were pivotal throughout communication processes and this was often tied to the concept of maternal responsibility and a desire to promote relatives' reproductive autonomy. The diagnosis of DM1 and the subsequent family communication decisions altered relationships for many, with both positive and negative impacts described. The findings demonstrate that individuals require time to explore the impact of a diagnosis of DM1 on self, family and intimate partner relationships to anticipate unique communication challenges. Genetic counselors can use these findings to inform their approach to counseling families with DM1. Longitudinal genetic counseling may be beneficial as a way to provide individuals with life stage specific support as they communicate with their relatives about a diagnosis of DM1.

Peripheral nerve ultrasound in Friedreich ataxia.

INTRODUCTION: Sensory impairment in Friedreich ataxia (FRDA) is generally accepted as being due to a ganglionopathy. The degree of contribution from axonal pathology remains a matter of debate. Nerve ultrasound may be able to differentiate these processes. METHODS: The ultrasound cross-sectional area of median, ulnar, tibial, and sural nerves of 8 patients with FRDA was compared with 8 age- and gender-matched healthy controls and with reference values in our population. RESULTS: The nerves of the patients with FRDA were significantly larger than those of healthy controls at all upper limb sites (P < 0.05) but not significantly different in the lower limbs. DISCUSSION: Our findings add additional weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are also likely to play a role. Muscle Nerve 57: 852-856, 2018.

Load dissipation by corn residue on tilled soil in laboratory and field-wheeling conditions.

Crop residues may partially dissipate applied loads and reduce soil compaction. We evaluated the effect of corn residue on energy-applied dissipation during wheeling. The experiment consisted of a preliminary laboratory test and a confirmatory field test on a Paleaudalf soil. In the laboratory, an adapted Proctor test was performed with three energy levels, with and without corn residue. Field treatments consisted of three 5.1 Mg tractor wheeling intensities (0, 2, and 6), with and without 12 Mg ha(-1) corn residue on the soil surface. Corn residue on the soil surface reduced soil bulk density in the adapted Proctor test. By applying energy of 52.6 kN m m(-3) , soil dissipated 2.98% of applied energy, whereas with 175.4 kN m m(-3) a dissipation of 8.60% was obtained. This result confirms the hypothesis that surface mulch absorbs part of the compaction effort. Residue effects on soil compaction observed in the adapted Proctor test was not replicated under subsoiled soil field conditions, because of differences in applied pressure and soil conditions (structure, moisture and volume confinement). Nevertheless, this negative result does not mean that straw has no effect in the field. Such effects should be measured via stress transmission and compared to soil load-bearing capacity, rather than on bulk deformations. Wheeling by heavy tractor on subsoiled soil increased compaction, independently of surface residue. Two wheelings produced a significantly increase, but six wheelings did not further increase compaction. Reduced traffic intensity on recently tilled soil is necessary to minimize soil compaction, since traffic intensity show a greater effect than surface mulch on soil protection from excessive compaction. © 2015 Society of Chemical Industry.

The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations.

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).

Prevalence of muscular dystrophies: a systematic literature review.

BACKGROUND: Determining the prevalence of neuromuscular disorders for the general population is important to identify the scope of burden on society and enable comparisons with other health conditions. This systematic review aims to identify and collate the findings of studies published between 1960 and 2013 on the prevalence of all types of muscular dystrophies. SUMMARY: Relevant articles were identified through electronic database searches and manual searches of reference lists. There were 38 articles from across 19 countries that met the inclusion criteria. The total combined prevalence for all muscular dystrophies for studies classified as having a low risk of bias ranged between 19.8 and 25.1 per 100,000 person-years. Myotonic dystrophy (0.5-18.1 per 100,000), Duchenne muscular dystrophy (1.7-4.2) and facioscapulohumeral muscular dystrophy (3.2-4.6 per 100,000) were found to be the most common types of disorder. There was wide variation in study methodology, case ascertainment, and verification procedures and populations studied, all of which may contribute to the wide prevalence range, in addition to the likely variation in prevalence by country. Key Messages: Greater consistency in the conduct and reporting of neuroepidemiological studies is urgently needed to enable comparisons to be made between studies, countries, and over time.

The TREAT-NMD Duchenne muscular dystrophy registries: conception, design, and utilization by industry and academia.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.

RFC1 in an Australasian neurological disease cohort: extending the genetic heterogeneity and implications for diagnostics.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome is a progressive, generally late-onset, neurological disorder associated with biallelic pentanucleotide expansions in Intron 2 of the RFC1 gene. The locus exhibits substantial genetic variability, with multiple pathogenic and benign pentanucleotide repeat alleles previously identified. To determine the contribution of pathogenic RFC1 expansions to neurological disease within an Australasian cohort and further investigate the heterogeneity exhibited at the locus, a combination of flanking and repeat-primed PCR was used to screen a cohort of 242 Australasian patients with neurological disease. Patients whose data indicated large gaps within expanded alleles following repeat-primed PCR, underwent targeted long-read sequencing to identify novel repeat motifs at the locus. To increase diagnostic yield, additional probes at the RFC1 repeat region were incorporated into the PathWest diagnostic laboratory targeted neurological disease gene panel to enable first-pass screening of the locus for all samples tested on the panel. Within the Australasian cohort, we detected known pathogenic biallelic expansions in 15.3% (n = 37) of patients. Thirty indicated biallelic AAGGG expansions, two had biallelic 'Maori alleles' [(AAAGG)exp(AAGGG)exp], two samples were compound heterozygous for the Maori allele and an AAGGG expansion, two samples had biallelic ACAGG expansions and one sample was compound heterozygous for the ACAGG and AAGGG expansions. Forty-five samples tested indicated the presence of biallelic expansions not known to be pathogenic. A large proportion (84%) showed complex interrupted patterns following repeat-primed PCR, suggesting that these expansions are likely to be comprised of more than one repeat motif, including previously unknown repeats. Using targeted long-read sequencing, we identified three novel repeat motifs in expanded alleles. Here, we also show that short-read sequencing can be used to reliably screen for the presence or absence of biallelic RFC1 expansions in all samples tested using the PathWest targeted neurological disease gene panel. Our results show that RFC1 pathogenic expansions make a substantial contribution to neurological disease in the Australasian population and further extend the heterogeneity of the locus. To accommodate the increased complexity, we outline a multi-step workflow utilizing both targeted short- and long-read sequencing to achieve a definitive genotype and provide accurate diagnoses for patients.

STRling: a k-mer counting approach that detects short tandem repeat expansions at known and novel loci.

Expansions of short tandem repeats (STRs) cause many rare diseases. Expansion detection is challenging with short-read DNA sequencing data since supporting reads are often mapped incorrectly. Detection is particularly difficult for "novel" STRs, which include new motifs at known loci or STRs absent from the reference genome. We developed STRling to efficiently count k-mers to recover informative reads and call expansions at known and novel STR loci. STRling is sensitive to known STR disease loci, has a low false discovery rate, and resolves novel STR expansions to base-pair position accuracy. It is fast, scalable, open-source, and available at: github.com/quinlan-lab/STRling .