Distribution of genetic variants and cognitive profile in cases with Becker muscular dystrophy

INTRODUCTION

Becker’s muscular dystrophy (BMD) is an X-linked neuromuscular disease associated with in-frame variants in the Duchenne muscular dystrophy (DMD) gene with partially expressing dystrophin protein and resulting in a milder phenotype compared to DMD.^[1] The birth incidence of BMD is 1/18,450 male live births in contrast to 1 in 5618 live male births for DMD.^[2] DMD gene spans 79 exons and consists of seven isoforms expressed in a tissue-specific manner. Distil dystrophin isoforms, exhibiting developmental, regional, and cell type specificity within the central nervous system, have earlier been shown to have an association with intellectual disability and working memory alterations in DMD^[3] in a non-progressive manner.^[4] Variable degrees of cognitive and neuropsychiatric alterations have been reported in DMD. Although a milder phenotype, BMD males still experience a notable incidence of learning difficulties, as well as issues with attention and behavior.^[5] Despite BMD and DMD sharing the same genetic loci, cognitive deficits are less common in BMD, indicating a crucial role of dystrophin protein in neurological processes. Studies report difficulties in spelling, arithmetic, and reading, along with behavioral problems.^[6] It is also reported that 15% and 7% of DMD and BMD cases exhibit mild mental retardation, respectively. Conversely, 31% of DMD cases and 38% of BMD cases are assessed as having normal intelligence levels. However, variants associated with the Dp140 isoform increase susceptibility to decreased intelligence quotient (IQ) when compared to subjects with an intact Dp140 isoform.^[7] The current study aimed to examine the copy number variations (CNVs) in BMD and the associated intelligence profile to map the position-specific impact on the development of cognitive status.

MATERIALS AND METHODS

RESULTS

Distribution of CNVs in BMD

Table 1 indicates that 67% of BMD cases harbored deletions in DMD gene [Figure 1A]. Among the BMD cases with identified CNVs, 79% had in-frame deletions. The remaining 21% BMD cases were predicted to have out-of-frame CNVs [Figure 1B]. However, the phenotypes were similar to BMD and further breakpoint assessment was required to validate the findings. In 79% of BMD cases, CNVs were present near the Dp140 isoform promoter location and predicted to be preserved due to in-frame nature of CNVs [Figure 1C].

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Figure 1:

Distribution of copy number variations (CNVs) in Becker’s muscular dystrophy (BMD) (n = 21). Pie diagram showing (A) Frequency of CNVs. (B) Predicted proportion of cases with outof-frame or in-frame CNVs according to Leiden Databases. (C) Predicted frequency of CNVs at the Dp140 short isoform promoter region indicating in BMD cases.

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DISCUSSION

BMD is a milder form of the fatal DMD phenotype. We earlier reported that distil DMD gene CNVs are associated with altered but non-progressive cognitive and neuropsychological functioning in the cases with DMD primarily as a function of working memory alterations.^[3,4,9] We report frequency and distribution of DMD gene copy number status along with general intelligence in the cases with BMD. Our BMD cohort predominantly included deletions. Majority of these cases were predicted to have in-frame deletion indicating that the distal short isoform including Dp140 which is associated with cognitive alterations could be intact. Dp140 is transcribed upstream exon 45 having 1kb 5’UTR region and has first initiation codon at exon 51 location.^[10] In CNS, dystrophin protein is expressed as full length as well as short dystrophin isoforms using alternate promoter regions.^[11] Several studies have shown that mutations leading to the loss of Dp140 dystrophin isoform result in more cognitively impaired phenotype.^[3] A study has reported that exon 52 deletion is associated with cognitive decline in around 70% of the patients;^[12] however, other mechanisms of cognitive alterations have also been proposed.^[13]

Recent meta-analysis conducted in BMD revealed IQ of 89.92 with VIQ score of 85.84 and PIQ score of 94.0.^[14] Young et al. reported a higher IQ score of 95.6 in BMD.^[5] However, similar to our study, small sample size could have affected the results. It also indicates population-specific variabilities in the cognition profile affected by demographic variables including socioeconomic status. Another study from North India reported an IQ of 90.6 in BMD group with a significantly decreased IQ of 82.5 in DMD.^[15] In contrast, Ferrero and Rossi in their systematic review reported high rates (range 7–25%) of intellectual disability in BMD.^[16] These studies clearly indicate cognitive variability between DMD and BMD, an imperative need for neuropsychological rehabilitation in DMD, poor verbal span in DMD, and an association of cognitive impairment with DMD gene loci. Neuropsychological analysis in BMD has also revealed a poor performance in executive functioning, verbal memory, and processing compared to healthy individuals despite having sufficient educational backgrounds.^[17] Moreover, BMD boys might have higher susceptibility to attention-deficit hyperactivity disorders, behavioral and emotional abnormalities, and speech deficits, indicating a need for early neuropsychological screenings.^[16] A poor working memory hypothesis in DMD has been well documented,^[9] hence, the integrative rehabilitation programs may also be proposed for BMD boys.

Subsequent studies have revealed that rather than the direct association with cognitive decline, deletions in the distal part of the gene were more associated with cognitive decline than those in the proximal part of the gene.^[11] BMD subjects have reduced cognitive decline in comparison to DMD, as evident from our analysis. Individuals with BMD have average cognitive function when compared to general population.^[18] Studies have shown that the mutations in DMD/BMD are most commonly found in the distal hotspot portion of the gene located between exons 45 and 55.^[19] A study conducted in India has also reported a higher prevalence of mutations in the hotspot distal part of the gene, i.e., 45–55.^[19]

For the management of these fatal diseases, corticosteroids are generally considered a first-line treatment although it cannot totally reverse the disease, it slows the progression of the disease.^[20,21] Although glucocorticoids are considered a standard of care in DMD/BMD management yet dose regimens have not been optimized and side effects of certain glucocorticoids have been observed.^[22] It is also important to understand the cognitive profile in BMD as exon skipping therapy in DMD could potentially resemble that of BMD. This change in phenotype includes muscular as well as cognitive phenotypes. No study has yet appeared showing its impact on cognitive profile.

A study on the quality of life (QoL) of muscular dystrophy subjects of different age groups has revealed concerns pertaining to poor health and social stigma among the adolescent and young DMD; however, patients with BMD are associated with a better QoL on several scales in comparison to DMD subjects.^[23] However, the current study also necessitates a domain-wise assessment in BMD subjects. One of the limitations of this study was a reduced sample size, screening of breakpoints for CNVs, and sequencing-based identification of variants in cases where CNVs could not be identified.

CONCLUSION

Most commonly mutated region was found to be 45–55 exon region in BMD subjects. The Dp140 region was predicted to be in-frame and it could be a reason that the cognitive profile of BMD was comparable to controls.