Dystrophin analysis inthediagnosis ofmuscular dystrophy

Despite the fact Duchenne himself (back in 1861) noted that a proportion of young males affected by Duchenne muscular dystrophy (DMD) had some degree of intellectual impairment, it was not until a century later that this observation was confirmed by a number of investigators, who suggested that DMD affects not only the muscles but also the brain. Several early studies showed a great variation in cognitive deficits, which unlike muscular symptoms are not progressive. The reason for this variability was not understood until very recently. The literature on cognitive function in dystrophinopathies has recently expanded. In a meta-analysis of over 1000 patients with DMD and Becker muscular dystrophy (BMD), it was confirmed that the DMD/BMD mean IQ score is one standard deviation below population mean,1 ranging from severe learning disability to IQs above the mean and with a disproportionate effect on verbal working memory skills.2 Comorbid neuropsychiatric disorders including attention-deficit–hyperactivity disorder (11–20%), autism spectrum disorder (3–4%), and obsessive-compulsive behavioural problems (5–60%) have also been reported.3 This variation in cognitive and behavioural manifestations of DMD/BMD has fuelled the search for a genotype-phenotype correlation. A factor which complicated variability for decades is that the massive dystrophin gene contains a set of tightly regulated internal promoters that generate a range of protein isoforms. These isoforms are identical to each other at one end (the C-terminus), but differ as to where they start, often having unique N-termini. Thus mutations near the beginning of the gene will affect only the longest isoforms (Dp427M, Dp427B, and Dp427P, expressed mainly in skeletal and cardiac muscles and in minor amounts in the brain). Mutations progressively further along the gene affect more and more isoforms, disrupting in turn Dp260 (expressed in the retina), Dp140 (brain and kidneys), Dp116 (Schwann cells), and the shortest, Dp71 (expressed widely, but particularly in the brain where it is the most abundant isoform). The expression pattern of the shorter isoforms suggests that they might contribute to the preservation of cognitive function in DMD/BMD, depending where the mutation lies. Indeed, in patients with mutations affecting all isoforms (downstream of exon 63), there is a strong association with severe learning disability, with almost universal profound learning disability and IQ two standard deviations below the mean. In contrast, in individuals with mutations affecting only the full-length isoforms (upstream of exon 30), only a minimal frequency of intellectual impairment is observed.4,5 So what are these dystrophin isoforms doing in the brain? Their absence in DMD is not accompanied by obvious specific radiological or pathological features, and ultimately the role of dystrophin in the brain remains far from clear. In muscle it is proposed that it plays a role in resisting extreme mechanical stresses, but it is likely that in the brain a signalling role predominates. The full-length isoforms are largely neuronally expressed, and localize to punctate structures which seem to correspond to a subset of GABAergic synapses in the cortex, hippocampus, and cerebellum.6 Accordingly, lack of full-length dystrophin in the mdx mouse is associated with reduced GABAa receptor clustering, and enhanced defensive behaviour in response to danger. In contrast, most of the shorter isoforms appear to be expressed in glia, localizing to end-feet adjacent to capillaries; loss of these isoforms is associated with reduced levels of aquaporin-4, a protein involved in membrane permeability. The determining factor for poor cognitive outcomes in DMD/BMD, therefore, appears to be the differential cumulative loss of brain-expressed isoforms, determined by mutation position along the gene. Our current understanding suggests that it is the unknown glial role of brain dystrophin, rather than its GABAergic synaptic role, which is critical for cognitive function. We are, however, limited by lack of clarity regarding both the expression of some of the intermediate isoforms in the brain and the true core function of the dystrophin molecule. As well as addressing these biological questions, DMD/BMD-tailored neuropsychiatric inventories that embrace the range of the neurobehavioural phenotype need to be developed and validated, aiming to offer early identification of susceptible patients and thereby the application of appropriate management. This will help both to address the poorly acknowledged neurobehavioural phenotype in dystrophinopathies, and to provide outcome measures for future therapies.

10.1111/j.1469-8749.2010.03836.x

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Immunocytochemical analysis of dystrophin in congenital muscular dystrophy

恵理有川

Congenital muscular dystrophy

10.11501/3059884

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MUSCULAR DYSTROPHY

The Lancet (1993)

David Hilton‐Jones M. V. Squier