Ocular and neurodevelopmental features of Duchenne muscular dystrophy: a signature of dystrophin function in the central nervous system

Abstract

Multiple isoforms of dystrophin (Dp427, Dp260, Dp140, Dp71) are expressed differentially in the central nervous system (CNS) including the retinal layers. Disruption of these protein products is responsible for cognitive dysfunction, electroretinogram (ERG) abnormalities and behavioural disorders in Duchenne muscular dystrophy (DMD). We studied the ocular characteristics and neuropsychiatric profile of 16 DMD boys. The ISCEV standard, full-field flash ERGs were assessed. Intellectual ability and behavioural disturbances were measured. All genotypes were associated with mildly abnormal photopic ERG a:b-wave amplitude ratios. In addition, we identified the following genotype/phenotype correlations: boys with mutations upstream of exon 30 (ie, isolated Dp427 altered expression) showed normal scotopic a:b ratios, abnormal photopic oscillatory potential OP2 and normal scotopic OP2. Conversely, all boys with DMD mutations downstream of exon 30 showed profoundly 'negative' scotopic ERGs (a:b ratios 41). In these patients, the involvement of Dp260 isoform resulted in the absence of slow rod pathway signalling in15 Hz scotopic flicker ERGs. These boys had abnormal scotopic OP2 and normal photopic OP2. Finally, children with mutations also affecting Dp71 were associated with more pronounced electronegative ERGs. When correlating ERGs to neurodevelopmental outcome, we found a positive correlation between negative scotopic ERGs and neurodevelopmental disturbances, and the most severe findings were in boys with Dp71 disruption. These findings suggest a strong association between DMD mutations affecting different DMD isoforms with characteristically abnormal scotopic ERGs and severe neurodevelopmental problems. The role of the ERG as a potential biomarker for dystrophin function in the CNS and response to novel genetic therapies warrants further exploration.

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

“…The virtual lack of Dp260 and Dp116 expression confirms earlier hypotheses on the exclusive expression of these isoforms in the retina and peripheral nerves, respectively, despite a recent report indicating that Dp260 may be expressed in brain as well 44 . Based on the BrainSpan data, Dp140 is expressed mainly during the foetal stages of life across the brain, and at middle adulthood in few samples from the cerebellum and cortex.…”

Dystrophin Dp116: A yet to Be Investigated Product of the Duchenne Muscular Dystrophy Gene

“…Although the expression of Dp71 is ubiquitous in cells, the expression of other dystrophin isoforms is tissue-specific, with Dp427m expressed in skeletal and cardiac muscles, Dp427c in neurons of the cortex, Dp427p in cerebellar Purkinje neurons, Dp260 in retina, Dp140 in brain and kidney tissues, and Dp116 in Schwann cells [7]. Dp260 deficiency is associated with electroretinogram abnormalities [8,9]; Dp140 is involved in cerebral development and blood flow regulation [10,11]; and Dp71 has multiple physiological roles in cellular processes, including cell adhesion and cell division [12]. …”

Asymmetrical Functional Deficits of ON and OFF Retinal Processing in the mdx3Cv Mouse Model of Duchenne Muscular Dystrophy

“…14,15 These more severe functional manifestaiovs.arvojournals.org j ISSN: tions are characteristic of~80% of DMD patients, who exhibit dmd mutations in the central region or in the 3 0 end of the gene. 5,16 In comparison to other mdx strains (mdx, mdx 2Cv , mdx 4Cv , and mdx 5Cv ), 17 mdx 3Cv is currently the only mouse model that exhibits statistically smaller and slower scotopic bwave and OPs comparable to the ERG phenotype of DMD patients. As such, the mdx 3Cv mouse has been touted to be an important model for understanding retinal anomalies in the human disease.…”