Interest in muscle MRI has been largely stimulated in the last few years by the recognition of an increasing number of genetic defects in the field of inherited neuromuscular disorders. Muscle ultrasound (US) and computed tomography (CT) have been used to detect the presence of muscle involvement in patients affected by these disorders, but until recently the use of muscle MRI has been, with a few exceptions, limited to detecting inflammatory forms. The aim of this review is to illustrate how muscle MRI, in combination with clinical evaluation, can contribute to the selection of appropriate genetic tests and more generally in the differential diagnosis of genetically distinct forms of neuromuscular disorders. Possible future applications of muscle MRI are also discussed.

ABBREVIATIONS 3Di-svDevelopmental, Diagnostic and Dimensional Interview -short version ASD Autistic spectrum disorder CBCL Child Behavior Checklist DMD Duchenne muscular dystrophy SCDC Social Communication Disorder Checklist AIM Duchenne muscular dystrophy (DMD) is associated with neuropsychiatric disorders. The aim of the study was to characterize the DMD neuropsychiatric profile fully and to explore underlying genotype/phenotype associations.METHOD One hundred and thirty males with DMD (mean age 9y 10mo, range 5-17y) in four European centres were included and completed IQ assessment and a neurodevelopmentalscreening questionnaire. Of these, 87 underwent comprehensive neuropsychiatric assessment using structured diagnostic interview and parent-reported questionnaires. RESULTSThe overall mean score on the neurodevelopmental questionnaire was significantly abnormal compared with the general population of children (p<0.001). On average, intelligence was below the population mean, with intellectual disability observed in 34 males (26%). Autistic spectrum disorder was identified in 18 (21%), hyperactivity in 21 (24%), and inattention in 38 (44%). Clinical levels of internalizing and externalizing problems were observed in 21 (24%) and 13 (15%) respectively. Over a third of males scored more than two measures of emotional, behavioural, or neurodevelopmental problems. Males with mutations at the 3 0 end of the DMD gene affecting all protein isoforms had higher rates of intellectual disability and clusters of symptoms.INTERPRETATION Males with DMD are at very high risk of neuropsychiatric disturbance, and this risk appears to increase with mutations at the 3 0 end of the gene. Patterns of symptom clusters suggest a DMD neuropsychiatric syndrome, which may require prompt evaluation and early intervention.Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder affecting one in 5000 live male births, which causes progressive muscle weakness leading to loss of ambulation in the mid-adolescent years. Affected males generally present in the first few years of life with motor symptoms and enlarged calves. However, neurodevelopmental disorders are increasingly recognized features and can be the initial presenting symptoms. 1,2 DMD occurs as a result of mutations in the dystrophin gene. The large dystrophin gene contains 79 exons plus seven promoters. These tightly regulated internal promoters generate a range of different protein isoforms, with diverse expression in tissues. Mutations in the 5 0 end of the gene (i.e. mutations from exons 1-31) only affect the three longest isoforms, Dp427M, Dp427C, and Dp427P, which are expressed in skeletal and cardiac muscles, in the neurons in the cortex, and in cerebellar Purkinje cells respectively. However, mutations progressively further along the gene affect increasingly more isoforms. Mutations between exons 31 and 44, in addition to disrupting expression of the long isoforms, will also disrupt Dp260 (expressed mostly in the retina); mutations between exons 4...

This study provides longitudinal data of NSAA and 6MWT over a 12-month period. These data can be useful when designing a clinical trial.

The motor skills of patients with spinal muscular atrophy, type I (SMA-I) are very limited. It is difficult to quantify the motor abilities of these patients and as a result there is currently no validated measure of motor function that can be utilized as an outcome measure in clinical trials of SMA-I. We have developed the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (“CHOP INTEND”) to evaluate the motor skills of patients with SMA-I. The test was developed following the evaluation of 26 infants with SMA-I mean age 11.5 months (1.4–37.9 months) with the Test of Infant Motor Performance and The Children’s Hospital of Philadelphia Test of Strength in SMA, a newly devised motor assessment for SMA. Items for the CHOP INTEND were selected by an expert panel based on item mean and standard deviation, item frequency distribution, and Chronbach’s alpha. Intra-rater reliability of the resulting test was established by test–retest of 9 infants with SMA-I over a 2 month period; Intraclass correlation coefficient (ICC) (3,1) = 0.96. Interrater reliability was by video analysis of a mixed group of infants with neuromuscular disease by 4 evaluators; ICC (3,4) = 0.98 and in a group of 8 typically developing infants by 5 evaluators ICC (3,5) = 0.93. The face validity of the CHOP INTEND is supported by the use of an expert panel in item selection; however, further validation is needed. The CHOP INTEND is a reliable measure of motor skills in patients with SMA-I and neuromuscular disorders presenting in infancy.

Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG.

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Our data broaden the clinical spectrum associated with mutations in glycosyltransferases and provide data on their prevalence in the Italian population.

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