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Natural history of a cohort of Duchenne muscular dystrophy children seen between 1998 and 2014: An observational study from South India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.222881
Keywords: Duchenne muscular dystrophy, India, natural history
Duchenne muscular dystrophy (DMD) is an X-linked recessive muscular dystrophy and affects 1 in 3600 live male births.[1] It results from mutations in the dystrophin gene at the short arm (locus 21.2) of X chromosome.[2] Its diagnosis is by genetic testing using either multiplex polymerase chain reaction (mPCR) or multiplex ligation-dependent probe amplification (MLPA) techniques to identify exon deletions/duplications. Next generation sequencing (NGS) is helpful in identifying deletion/duplication negative patients, while muscle biopsy with immunohistochemistry or western blot still remains the gold standard technique for genetically unconfirmed cases. The majority of patients are diagnosed around 5 years of age when their physical ability starts differing significantly from their peers.[3] Muscle weakness, due to ongoing loss of skeletal muscle, results in loss of ambulation at around 10 years of age. As the disease progresses, respiratory, orthopedic, and cardiac complications ensue. Without intervention, the mean age at death is 19 years.[3] There are no long-term follow-up studies from India to describe the course of the disease and the survival pattern in this population. The present work was an attempt to study the natural history of the disease and its survival pattern in a large cohort of DMD population from India.
Study design, patient selection, and data collection This was an observational study with retrospective and prospective patient recruitment from the neuromuscular clinic of a quaternary care university hospital. Patients were identified retrospectively by retrieving case records of those diagnosed with DMD either genetically (mPCR/MLPA or both) or by muscle immunohistochemistry (biceps or quadriceps biopsy) between March 1998 and February 2013. Prospective inclusion was from March 2013 to April 2014. The study protocol was approved by the institutional ethics committee. All patients or their legal representatives provided written informed consent for participation in the study. A total of 500 patients who had furnished details of postal address were sent a simple questionnaire in English and local language along with return paid post. The clinical details were collected till April 2014 and entered in a pre-designed proforma. Outcome analysis Primary outcome measures included age at onset of attaining wheelchair status (loss of ambulation), bedbound (additional truncal weakness) stage, and age at death. Secondary outcome included correlation of severity of intellectual disability, cardiac dysfunction, and degree of spine deformity with the primary outcome measures. Intelligence was assessed by a qualified neuropsychologist using the Binet-Kamat scale.[4] Statistical analysis The demographic data is expressed using descriptive statistics {mean ± standard deviation [SD] (range)}. When the data was skewed, median and range are provided. The presenting clinical features at initial evaluation are presented as the number of patients demonstrating individual clinical features. Primary outcome is expressed as the number and percentage of patients with age as mean ± SD (range). Univariate analysis was used for correlating a variable with the primary outcome measure. Wilcoxon log rank test was used for group differences of nonparametric data. Kaplan Meir survival curves are presented for primary outcome measures. The statistical analysis was done using the Statistical Package for the Social Sciences for Windows version 16.0 (SPSS, Chicago, IL, USA). The significance level was fixed at α = 0.05.
Demographic and clinical characteristics of the Duchenne muscular dystrophy population Among 500 patients, 275 responded or came for follow-up, 31% by completing the questionnaire, and 69% by completing both the questionnaire and attending the outpatient clinic. The demographic features are shown in [Table 1].
The mean age at onset of symptoms was 3.7 ± 1.9 (range, 1 to 8) years; 41% of the children had an age of onset less than 3 years. A delay in acquisition of milestones was seen in 57%, and a delay in mental milestones in 14% of the children. The mean age at presentation was 8.1 ± 2.5 (2–15) years. The mean duration of symptoms was 4.3 ± 2.5 years, and the mean duration of follow up was 2.6 ± 2.8 years. All the cases had lower limb symptoms; more than one-third had associated truncal weakness with difficulty in rising from the supine position, and approximately one-third had upper limb weakness with difficulty in raising arms above the head [Figure 1].
Calf hypertrophy was present in 93.3% and tendoachilles contractures in 70% of the patients. Winging of scapula was seen in 34.5% of the patients and kyphoscoliosis in 13.5% of them. Intelligence assessment revealed average intelligence in 37 (42.0%), dull normal intelligence in 27 (30.6%), borderline intelligence in 14 (15.9%), and mild mental retardation in 9 (10.2%) of the patients. One (1.1%) patient was classified as bright normal. Cardiac evaluation done in 127/275 patients showed an abnormal electrocardiogram (ECG) and/or two-dimensional echocardiogram in 2.9% of the cases. Primary outcome measures During the study period of 15 years, 155/275 (56.3%) children had attained at least one of the primary outcome measures [Table 2]. Wheelchair bound status was attained by 124 children at a mean age of 10.3 ± 1.6 years [Figure 2]; and bedbound status was attained by 24 children at a mean age of 11.8 ± 2.1 years [Figure 3]. In 7 patients who died, the mean age at death was 15.2 ± 2.4 (12–19) years. The exact cause of death was unclear as the patients had died at home/local hospital with no clinical details being available.
Molecular and histological characteristics of the Duchenne muscular dystrophy cohort The genetic data was available in 206/275 boys. Both mPCR and MLPA techniques were used; however, the current hospital policy is only to perform MLPA testing. Gene deletion was present in 204 patients and duplication in 2 patients. Of the 206 boys with gene deletion, 36 had proximal, 158 had distal, and 10 had proximal and distal deletions. Among the 2 duplications, one each had proximal and distal duplication [Table 3]. The type of deletion/duplication had no bearing on any of the primary outcome measures. Immunohistochemical confirmation with total absence of dystrophin antibody staining for all 3 domains was available for 114 patients (in some children, subsequent genetic confirmation was done for genetic counseling).
Treatment and clinical improvement Around 54.5% of the children were on a regular oral prednisolone dose of 0.75 mg/kg/day whereas others did not agree to take steroids or chose to take alternate forms of therapy/medicines (ayurveda, homeopathy, yoga, etc.), or stopped their medication without medical consultation. In the subgroup of patients on steroids, 50% showed reduction and 5.3% showed stabilization in the frequency of falls. Approximately 37.3% showed improvement in the speed of walking, whereas stabilization of walking difficulty was observed in 11.3% of the children. Approximately 13.3% showed improvement in their ability to run and 10% maintained a stable disability. Improvement in their ability to climb stairs was observed in 12% children, and this symptom stabilized in 12.6% of the children. 6% of the patients improved in their ability to rise from the floor and 12% had clinically stable deficit. Correlation analysis Correlation analysis [Table 4] showed a significant effect of older age at presentation, longer duration of illness, late toe walking, and intellectual disability, on early loss of ambulation. These factors were identified as significant predictors among the bedbound patients. Cardiac abnormality, kyphoscoliosis, and the gene deletion/duplication pattern did not show any significant effect on the time-to-loss of ambulation. No significant correlation was observed with other parameters. Correlation analysis was not possible between the expired patients and other groups due to the small number of patients present in each of the subgroups. Hence, only their descriptive parameters are presented.
Demography and diagnostic delay In our cohort, the onset of symptoms was approximately at 3.7 years of age, which is consistent with other studies published from India and elsewhere.[5],[6],[7] The duration from the symptom onset-to-diagnosis was 4.3 years, which is also similar to the studies published in the Western literature.[8],[9],[10] This could be due to a lack of awareness of the existence of the disease by the parents, or due to a diagnostic delay by the primary care physicians/pediatricians, especially when the phenotype of the patients is skewed toward mental or language delay. Mohamed et al., reported the presence of nonmotor phenotype as an important contributor to the late diagnosis of the disease.[11] Recent reports also highlight an unchanged pattern of diagnostic delay over the last 2 decades.[12],[13] In addition, lack of testing for creatine kinase (CK) levels in children with motor/developmental delay also contributed to the diagnostic delay.[9],[10] We encountered a few patients who underwent exhaustive diagnostic work-up for liver pathology due to raised alanine transaminase (ALT) and asparate transaminase [AST] levels (one patient even underwent liver biopsy twice). Similar instances have been reported in literature resulting in delayed diagnosis.[10] To circumvent this issue, neonatal screening for DMD has been proposed; however, at present, establishing the utility of these approaches and their implications need further studies.[14],[15] Our cohort consisted mainly of children hailing from a lower socioeconomic status and usually residing in rural areas. They had less access to medical facilities and neurologists, which could be the main reason for the delayed diagnosis. In addition, the low literacy rate among parents and caretakers might have led to the delay in seeking medical advice. On instances, we have observed poor clinical suspicion by the primary care physicians resulting in delayed referral/diagnosis. They tend to consider the delay in motor milestones as a constitutional delay or ascribe it to other nonspecific causes unless there is an affected child in the family. Clinical features The history of developmental delay was observed in 57% of the children, and this frequency is similar to an earlier study from India wherein 62.3% children had delayed milestones.[5] In a study by Cyrulnik et al., the authors reported developmental delay in nearly two-third of the children with DMD, which is similar to the findings of the present series.[16] Lower limb symptoms dominated in our cohort, with gait change, running difficulty, frequent falls, and difficulty in rising from squatting position being the most common symptoms. Squatting on the floor is a common practice in Indian culture, often bringing the motor problem into focus. Lower limb predominant phenotype is well in line with the earlier published literature.[7] The majority of patients with DMD exhibit pseudohypertrophy of the calf muscles. Reporting on calf hypertrophy can be subjective, resulting in variable rates in different studies. In our study, calf hypertrophy was observed in 93.3% of the patients, which is comparable to the study by Pradhan et al., who observed this sign in 94% of the DMD patients.[17] Beenakar et al., used ultrasound as an objective tool for measuring calf circumference and found a very low prevalence of this finding, which was present in only one-third of the patients.[18] A late presentation allowing for an easier clinical detection of pseudohypertrophy of the calf muscles may be the reason for a better diagnosis of this sign in a larger percentage of patients in our cohort. Kyphoscoliosis was seen in 13.5% of patients at the time of evaluation in the present study. The age of onset of scoliosis in boys with DMD is related to the age at which they lose their ability to ambulate, which is generally between 10 and 14 years. When they are wheelchair bound, the spinal curves are known to progress and evolve to include the entire thoracic and lumbar spine with potentially dangerous increases in the pelvic obliquity.[19],[20] Some studies suggest no beneficial effect of scoliosis surgery on declining respiratory function and no increased life expectancy.[21] None of our patients underwent scoliosis surgery as it is not widely practiced in India. Cardiac disease in DMD most often manifests as a cardiomyopathy and/or cardiac arrhythmias. Cardiac involvement was seen in a small number of children in our study. Approximately 2.9% had abnormalities detectable either on electrocardiogram (ECG) and/or echocardiography. All these children had hypertrophied cardiomyopathy and abnormal ECG findings. In the present cohort, none had cardiac failure or was on a pacemaker. Gulati et al., studied 30 patients of DMD for evidence of cardiac involvement, and noted that the onset of cardiac dysfunction was usually seen after the age of 10 years.[22] Cognitive impairment is an important manifestation of dystrophinopathies, especially DMD, and might present challenges while managing these children. Fortunately, severe cognitive impairment is not common in DMD. The mean intelligence quotient (IQ) score in our cohort was 86, which is comparable with the mean score of 83.2 as reported by Magri et al.[23] Among the Egyptian DMD children, the average IQ was more than 80.[24] Emery et al., in their analysis of 721 children reported that the mean IQ score was 82, which is similar to our findings.[25] Motor milestones Among the primary outcome measures, the mean age at wheelchair bound stage was 10 years. Despite ethnic variability, DMD patients lose the ability to walk at a median age of 10 years with some losing this ability either earlier than 10 years or after 12 years of age.[26] Kohler et al., studied 43 patients with DMD, and the mean age at which the patients lost their ambulation was 9.4 years.[27] They became dependent on a wheelchair at 14.6 years and had a median survival of 35 years. Parker et al., in their report on patients surviving into adulthood also reported similar observations, with the median age at loss of ambulation of approximately 10 years and wheelchair dependency at 11 years of age.[28] In a study by Rao et al., from India, 38 of 81 patients were wheelchair bound at 13 years of age.[6] Treatment and course The most common cause of death in DMD children is respiratory infection.[28],[29] Seven patients in our cohort died. with their age ranging between 12 and 19 (median: 15.2) years. However, the cause of death could not be ascertained because they died either at home or at a local hospital and medical details of the cause of death were not available. The follow-up was particularly difficult in our cohort (as is seen in most of the progressive neuromuscular disorders without definitive treatment), as most of the patients hailed from distant places and villages from where regular communication was difficult. In 1974, Drachman et al., reported a positive outcome in DMD using steroid medication, which were subsequently confirmed in other studies and meta-analyses.[30],[31],[32] Approximately 54.5% of our children received oral daily regimen of prednisolone at 0.75 mg/kg. There was significant improvement in clinical parameters with a good outcome as well as reduction in the frequency of falls, improvement in walking, running, climbing stairs, and ability to rise from the floor.[33] Survival analysis showed an improvement in the survival pattern with steroid therapy along with prolongation of the period of ambulation and delay in the attainment of bedbound status by approximately 21 and 36 months, respectively. These findings are similar to those reported by Desilva and Mendell.[34],[35] Griggs showed the dose response and time course of improvement where DMD children with 0.75 mg/kg of prednisolone were significantly stronger at follow-up than those treated with 0.3 mg/kg.[33] Many of the parents/caregivers preferred only physiotherapy or alternative medicine because of personal preferences, local beliefs, cultural biases, and an undue apprehension towards the adverse effects of medications, and the lack of efficacy of majority of medicines utilized in treating this disease. Predictors of motor progression The age at presentation of symptoms, duration of illness, delay in mental milestones, toe walking, and intellectual ability all showed significant impact on the ambulatory status, though no significant association was observed with age at onset, cardiac abnormality, scoliosis, and genotype. Mirski et al., found that delay in the onset of walking in boys with DMD is strongly associated with a cognitive delay; however, the impact of the latter on loss of ambulation was not discussed.[36]
In conclusion, this is the first study from India describing the natural history of DMD in a large cohort of genetically and/or immunohistochemically confirmed cases. The patterns of major DMD milestones, including the age at onset, age at loss of ambulation and death in our cohort is comparable to that of the Western cohort despite variability in the medical care. The genotype also parallels global trends suggesting a more homogeneous geno-phenotypic presentation of DMD. Oral steroids delay the loss of ambulation and probably add quality years to the life of the patients suffering from DMD. This study also highlights the current scenario of obstacles involved in establishing the diagnosis of DMD and its management. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]
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