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Muscle magnetic resonance imaging (MRI) and ultrasound (US) are emerging tools to assist in the diagnosis of children with genetic muscle disease. Increasing number of studies demonstrate that these imaging techniques can identify selective patterns of muscle atrophy, fatty degeneration, and muscle edema that help to distinguish between different early-onset genetic myopathies and muscular dystrophies. Recognizing patterns of pathology by muscle imaging can help to guide genetic testing and avoid the more invasive procedure of a muscle biopsy. Conversely, since massive parallel sequencing is now more commonly used as the initial step in diagnostic testing, imaging techniques can help to confirm or exclude if a variant of uncertain significance is indeed disease causing and compatible with a pattern of pathology as detected by muscle imaging. Whereas for diagnostic purposes and pattern recognition, muscle pathology does not need to be quantified, measuring disease progression is increasingly supported by quantitative muscle imaging, which is critical given the recent increment in rare disease therapeutic trials. Here, we discuss the value of muscle imaging techniques in pediatricmuscle disease and summarize data identifying specific patterns of involvement in muscle MRI and US in some of the more common genetic myopathies and muscular dystrophies. [ABSTRACT FROM AUTHOR]

In 1987 Fitzsimmons and Guilbert described identical male twins with progressive spastic paraplegia, brachydactyly with cone shaped epiphyses, short stature, dysarthria, and 'low-normal' intelligence. In subsequent years, four other patients, including one set of female identical twins, a single female child, and a single male individual were described with the same features, and the eponym Fitzsimmons syndrome was adopted (OMIM #270710). We performed exome analysis of the patient described in 2009, and one of the original twins from 1987, the only patients available from the literature. No single genetic etiology exists that explains Fitzsimmons syndrome; however, multiple different genetic causes were identified. Specifically, the twins described by Fitzsimmons had heterozygous mutations in the SACS gene, the gene responsible for autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS), as well as a heterozygous mutation in the TRPS1, the gene responsible in Trichorhinophalangeal syndrome type 1 (TRPS1 type 1) which includes brachydactyly as a feature. A TBL1XR1 mutation was identified in the patient described in 2009 as contributing to his cognitive impairment and autistic features with no genetic cause identified for his spasticity or brachydactyly. The findings show that these individuals have multiple different etiologies giving rise to a similar phenotype, and that 'Fitzsimmons syndrome' is in fact not one single syndrome. Over time, we anticipate that continued careful phenotyping with concomitant genome-wide analysis will continue to identify the causes of many rare syndromes, but it will also highlight that previously delineated clinical entities are, in fact, not syndromes at all. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Peripheral nervous system axons and myelin have unique potential protein, proteolipid, and ganglioside antigenic determinants. Despite the existence of a blood–nerve barrier, both humoral and cellular immunity can be directed against peripheral axons and myelin. Molecular mimicry may be triggered at the systemic level, as was best demonstrated in the case of bacterial oligosaccharides. The classification of immune neuropathy has been expanded to take into account specific syndromes that share unique clinical, electrophysiological, prognostic and serological features. Guillain-Barré syndrome encompasses a classical syndrome of acute demyelinating polyradiculoneuropathy and many variants: axonal motor and sensory, axonal motor, Miller-Fisher, autonomic, and sensory. Similarly, chronic immune neuropathy is composed of classic chronic inflammatory demyelinating polyradiculoneuropathy and variants characterized as multifocal (motor or sensorimotor), sensory, distal symmetric, and syndromes associated with monoclonal gammopathy. Among putative biomarkers, myelin associated glycoprotein and several anti-ganglioside autoantibodies have shown statistically significant associations with specific neuropathic syndromes. Currently, the strongest biomarker associations are those linking Miller-Fisher syndrome with anti-GQ1b, multifocal motor neuropathy with anti-GM1, and distal acquired symmetric neuropathy with anti-MAG antibodies. Many other autoantibody associations have been proposed, but presently lack sufficient specificity and sensitivity to qualify as biomarkers. This field of research has contributed to the antigenic characterization of motor and sensory functional systems, as well as helping to define immune neuropathic syndromes with widely different clinical presentation, prognosis and response to therapy. Serologic biomarkers are likely to become even more relevant with the advent of new targeted forms of immunotherapy, such as monoclonal antibodies. [ABSTRACT FROM AUTHOR]

Background Despite remarkable advances in genetic testing, many adults with syndromic epilepsy remain without a molecular diagnosis. The challenge in providing genetic testing for this patient population lies in the extensive genetic heterogeneity associated with epilepsy. Even for the subset of epilepsy patients that present with a defining feature, such as microcephaly, the number of possible genes that would require interrogation by Sanger sequencing is extensive and often prohibitively expensive. Case presentation We report a family of French Canadian descent with four adult children affected with severe intellectual disability, epilepsy and microcephaly born to consanguineous parents and evaluated by the Genetics Service to provide informed genetic counseling to unaffected family members regarding possible recurrence risks. We used whole-exome sequencing (WES) of DNA from one affected sibling as a first-line diagnostic tool and compared the prioritization of variants using two strategies: 1) focusing on genes with homozygous variants; and, 2) focusing on genes associated with microcephaly. Both approaches prioritized the same homozygous novel frameshift mutation (p.Arg608Serfs"26) in WDR62, a gene known to cause autosomal recessive primary microcephaly. Sanger sequencing confirmed the presence of the homozygous mutation in the other three affected siblings. Conclusions WES and subsequent filtering of the rare variants in a single affected family member led to the rapid and cost-effective identification of a novel homozygous frameshift mutation in WDR62, thereby explaining the severe neurodevelopmental disorder in this family and facilitating genetic counseling. Our findings support WES as an effective first-line diagnostic tool in families presenting with rare genetically heterogeneous neurological disorders. [ABSTRACT FROM AUTHOR]

ABSTRACT Ataxia demonstrates substantial phenotypic and genetic heterogeneity. We set out to determine the diagnostic yield of exome sequencing in pediatric patients with ataxia without a molecular diagnosis after standard-of-care assessment in Canada. FORGE (Finding Of Rare disease GEnes) Canada is a nation-wide project focused on identifying novel disease genes for rare pediatric diseases using whole-exome sequencing. We retrospectively selected all FORGE Canada projects that included cerebellar ataxia as a feature. We identified 28 such families and a molecular diagnosis was made in 13; a success rate of 46%. In 11 families, we identified mutations in genes associated with known neurological syndromes and in two we identified novel disease genes. Exome analysis of sib pairs and/or patients born to consanguineous parents was more likely to be successful (9/13) than simplex cases (4/15). Our data suggest that exome sequencing is an effective first line test for pediatric patients with ataxia where a specific single gene is not immediately suspected to be causative. [ABSTRACT FROM AUTHOR]

This study was conducted to examine the validity and the intra-rater and inter-rater reliability of the Physiotherapy functional mobility profile (PFMP) questionnaire. It was administered to 48 in-patients in an acute care hospital. The patients' past functional mobility status was evaluated utilizing the PFMP questionnaire to examine the value of this information for present physiotherapy goals. A very good intra-rater and inter-rater reliability for patient and for the significant other was found. The intraclass Correlation Coefficient (ICC) ranged from 0.83-0.99. The sensitivity of the PFMP questionnaire was found to be very good, ranging from to 0.82-1.00 for individual items and for the total score. The specificity was also excellent, ranging from 0.50-1.00 for individual items and for the total score. A high correlation was found between direct observation and the questionnaire of patient. High correlations also were obtained by comparing the total score of completed the PFMP questionnaire from the patient to the total score collected from the significant other for the 1-week time frame. However, lower correlations were observed for the 1-month and 6-month time frames prior to hospitalization. The PFMP is a reliable instrument in establishing recent past functional mobility level using information provided by either the patient or the patient's significant other. Prehospitalization functional mobility status is of interest to physiotherapists in establishing a baseline reference for treatment and to set out functional goals for discharge in an acute care hospital. The significant other can provide a valid substitute for recent patient's prehospitalization functional mobility status. [ABSTRACT FROM AUTHOR]