Overview of Research in DMD I: Clinical Studies. Abstracts from 10th International Congress of World Muscle Society - 28 September to 1 October/ 2005 Foz do Iguassu Brazil
T.P.1.01
Long term daily prednisone therapy delays decline in pulmonary function and improves survival in patients with Duchenne dystrophy
S. Pandya, D. Guntrum, R.T. Moxley – New York - USA
We have previously reported that daily prednisone prolongs independent walking in Duchenne dystrophy (DD) to an average age of 14.5 years in patients who have received treatment for up to 15 years. We now describe the beneficial effect of long term daily prednisone on pulmonary function in the same cohort of patients who began prednisone between 1986 and 1989. Patients have received 0.75 mg/kg/d of prednisone unless side effects required a reduction in dosage. Patients have returned for follow-up evaluations twice a year. We have measured vital signs, height, weight, forced vital capacity (FVC) and side effects. We have routinely offered noninvasive nasal ventilation when the FVC drops below a liter (L)or earlier if symptoms of respiratory insufficiency/nocturnal hypoventilation are reported. The average age of the cohort (N=30) at initiation of prednisone was 10.5 years (range 5–15) and at last visit was 24.1 years (range 12–33).The average dosage of prednisone at the last visit was 0.35 mg/kg/d. The main reason for reduction in dosage was weight gain. Nine patients have died (average age 25.5 years). Five are ventilator dependent (average age 31.5 years). We continue to follow the remaining cohort whose average age is 26.3 years and FVC is 1.5L. The age at which FVC dropped below a liter in patients who passed that milestone was 21.6 years. Patients receiving daily prednisone therapy have shown a higher peak FVC, a slower decline in pulmonary function and longer survival compared to natural history controls and patients treated with noninvasive nasal ventilation as reported in the literature.
T.P.1.02
Burden of care in the childhood neuromuscular diseases: parental issues and concerns in Duchenne dystrophy
R. Gellman, C. Shields, S. Pandya – New York - USA
We reviewed the literature to determine the burden of care on families of boys with Duchenne dystrophy (DD). We found that there are almost no large-scale comprehensive studies on this topic. Prior to beginning work on a detailed instrument to document burden of care and family needs, we organized an idea generating focus group with parents of boys with DD. Five parents (4 mothers, 1 father) of 6 boys (ages 5–15) participated in the 90 min open ended conversation. Two of the authors took notes (RG,CS), which were later transcribed, analyzed and organized into categories based on similarity of content. The themes that emerged can be grouped into the following categories: (1) Health services (i.e. access to and coordination among multiple services), (2) Financial issues (i.e. cost of services, equipment etc) (3) Family stress (i.e. inadequate time as a couple, insufficient time for other children, ability to maintain jobs and careers etc)
(4) Physical burdens of caring for a child with limited abilities, (5) Developmental issues related to the child as well as siblings (i.e. age appropriate social options for the child, discipline issues, siblings having to mature fast etc) (6) Coping mechanisms used by the families (i.e. support groups, church, friends, extended family etc). Information gathered from the focus group discussions will allow us to expand on the themes and issues that have emerged and develop a questionnaire that identifies in a clear and comprehensive fashion the burden on families raising a child with DD and their needs.
T.P.1.03
Which dose of steroids is necessary to treat DMD?
A. Dubrovsky, A. Lautre, L. Mesa, J. Corderi, D. Flores, L. Pirra – Buenos Aires - Argentina
Introduction: Steroids are effective in slowng down the progression of DMD, but adverse effects (AE) limit their use. AE of steroids are dependant on the dose and length of treatment. It has been established that 0.75 mg/Kg/day for Prednisone, and 0.9 mg/Kg/day for Deflazacort are the appropriate doses for starting treatment. It is known that starting with lower doses is less effective, but there are no studies, nor is there a consensus, on whether it is necessary to maintain the starting dose during long-term treatment (years). Objective: To compare efficacy of chronic
steroid treatment given at different doses. Methods: A retrospective analysis of motor performance in three groups of DMD patients (diagnosis confirmed by muscle biopsy or DNA test) under chronic Deflazacort treatment with a stable dose in relation to body weight was performed over a period of 12–18 months. The first six months of treatment were excluded from the analysis. Doses ranged between 0.50–0.74 mg/kg (18 patients) X=101.2 months of age (a), 0.75–0.90 mg/kg (11patients) X=96.4 (a) and 0.91–1 mg/kg (18 patients) X=95.3(a). Motor assessments included the timed Gowers (TG) maneuver and the Scott motor ability score (SS). Body weight as well as TG and SS showed no statistical differences between groups at the beginning of the analysis (Kruskal–Wallis Test). Results No statistically significant (ns) differences (Kruskal–Wallis Test) were observed among groups in the loss of motor function or in body weight variation. Calculated ‘monthly loss’ for both motor tests was ns as well. Conclusions: This study suggests that the dose needed to maintain the benefits achieved with steroids in DMD is not necessarily the starting dose, as is the case in many steroid treated diseases. The maintenance dose of steroids has not been established yet, this is a crucial issue in relation with long term AE. A prospective randomized trial to determine which is the minimal necessary maintenance dose is urged.
T.P.1.04
C.Angelini, D.M.Bonifati, M.Ermani, R. Padoan, E.P. Hoffman, E. Pegoraro – Padova – Italy and Washington -USA
The variables that play a role in determining steroid response in DMD have not so far been analyzed: we here, study the glucocorticoid receptor N363S polymorphism and age of onset in therapy. Forty-eight DMD patients treated either with prednisone or deflazacort were analyzed retrospectively. Clinical data included age of onset in steroid therapy, GSCG (Gait, Stairs, Chair, Gowers) functional score, MRC score, and monitoring of side effects. The mean change in functional score at 12 months was =7.4 with values ranging from = 55% to +50%. Half of the patients showed improvement (negative scores). There was a significant correlation between functional score and age of onset of treatment (P<0.001) with younger patients tending to improve and older patients tending to deteriorate. Treated patients showed variable incidence cushingoid appearance, increased appetite, and hirsutism during therapy but none dropped out. Fractures were not more frequent than in the untreated patients. We further screened by PCR/SSCP/ direct sequencing of the entire glucocorticoid receptor (GRL) gene to verify if mutations in the GRL gene may be associated with a better or worse response to steroid. Mutation studies revealed an heterozygous A–G mutation at GRL cDNA position 1220 in three DMD patients, resulting in an asparagine to serine amino acid change at aminoacid position 363 (N363S). Frequency of the N363S polymorphism was about 6% in our patient population, since we found three N363S positive DMD. N363S carriers DMD patient did not show any difference in shortterm evaluation of muscle strength and functional score in comparison with the GRL non-carrier patients. However, when long-term effect of the N363S polymorphism was considered, N363S carrier DMD showed a significant difference towards a later age of loss of ambulation. In fact, wheel-chair bound (WCB) age was after 12 years in all 3 carriers, respectively at age 12, 14 and 14.5 years. The mean age of WCB was in N363S carriers 162+15.9 months versus 130+21.7 months in non carrier DMD (P<0.016). Our data suggest that the N363S GRL polymorphism may be implicated in the long-term response to glucocorticoids. These data point to the GRL gene as a candidate factor in the clinical response to exogenously administered glucocorticoid. However, it is also evident that other variables such as age of onset therapy are involved in clinical response to steroid in DMD. Our data suggest a better response to steroid treatment when started early.
T.P.1.05
Deflazacort in Duchenne muscular dystrophy (DMD): results in a Brazilian series
M.B.D. Resende, S.L. Parreira, M.D.C. Peduto, C. Carvalho, M.R. Rodrigues, M.S. Carvalho, M. Scaff, S.K.N. Marie, U.C. Reed – São Paulo – Brazil
Objective: To evaluate the results concerning efficacy and long-term side effects of deflazacort therapy for Duchenne Muscular Dystrophy (DMD). Methods: From 1997 to 2005, 98 boys with DMD have received steroids therapy and among them 78 were treated with deflazacort, 1 mg/kg/day. Results: Five patients were lost to follow-up. Six, aged 7–12 years (y) are completing the first year of treatment and manifest stabilization with no functional deterioration. Sixty-seven boys, among which 59 are up to 10 y, have been treated from 13 months to 8 y: 35 maintained ambulation and 24 lost it (9 at 10y, 6 at 11y, 4 at 12y, 3 at 13y and 2 at 14y). Among these 24, five had started therapy when they were already manifesting great decrease of muscular strength and two were considered unresponsive to deflazacort. Among the eight under 10 y, three lost independent walking at 8 y, after one year of treatment. Among the 78 patients treated, one manifested serious gastrointestinal troubles and depression, and treatment was interrupted. Seven boys developed incipient cataracts that are being periodically evaluated. Growth retardation occurred in nine. One or more side-effects of a minor importance (weight gain, slight ‘Cushing face’, gastrointestinal disturbances, excessive hair growth and hyperactivity) were found in all. Among the patients with 12–18 months of the treatment, we did not find significant side-effects. Conclusion: Most of DMD patients benefit from deflazacort therapy by improving muscular strength,
prolonging independent walking and manifesting few side-effects.
T.P.1.06
Assessment of muscle function in boys with Duchenne muscular dystrophy (DMD) treated with steroids
S.L. Parreira, M.B.D. Resende, M.D.C. Peduto, M.S. Carvalho, S.K.N. Marie, U.C. Reed – São Paulo - Brazil
Objective: To select practical methods for assessing muscle function of boys with DMD treated with steroids, we evaluated 32 boys using a standard protocol for testing functional abilities and muscle strength. Methods: MRC (Medical Research Council), Hammersmith motor ability score; record of time for walking 9 m and getting up from the floor; lifting of load weights adjusted individually. The assessment was repeated at intervals of one month during the first 6 months and 2
months until completing 15 months of follow-up. Results: Twelve patients maintained independent walking, 7 lost it and 6 were excluded by irregular medication or surgical procedures. Statistical analyses was performed for each test in the two groups of patients (for those who lost walking we considered data from the last examination before loosing ambulation) and did not indicate any significant changes along the follow-up, therefore, demonstrating trend for stability, even in
patients who lost the ambulation. In these, such lost was probably associated to the already advanced muscle deterioration at the onset of the treatment or to other variable intercurrences. Conclusion: The first and second examination after starting steroid therapy can follow a
three-months interval: after that, a six-months interval is sufficient for an objective evaluation. The tests can be simplified using MRC only for lower limbs and trunk, Hammersmith motor ability score and the record of time for getting up from the floor. We hope that in Brazil, these tests may be useful for assess individual patients or groups and can be employed for evaluating the results of eventual non-palliative treatments.
T.P.1.07
The impact of corticosteroids on forced vital capacity in Duchenne muscular dystrophy
M. Eagle, M. McCallum, S. Blyth, V. Straub, K. Bushby – Newcastle – UK
Purpose of Study: Steroids are increasingly used in ambulant boys with DMD as they are likely to walk for longer, have improved respiratory function, may avoid the need for spinal surgery and might have better heart function than untreated boys. Benefits of starting steroids in DMD
boys who have already lost ambulation are not yet established. We have evaluated the medium term impact of steroids (18 months) on FVC in ambulant boys and the effect of 6 months treatment in a non-ambulant population. Methods: Two different groups were studied. FVC was monitored 6 monthly in 39 ambulant boys prescribed steroids according to the UK steroid consensus and 26 age matched boys who did not take steroids. In the second group 14 non-ambulant boys agreed to participate in an open trial of prednisolone (0.75 mg/kg/day). A pre-treatment assessment period of three months was followed by 6 months on steroids and three further months on no treatment. Results: Ten ambulant patients had used steroids for at least 18 months. Their mean age was 8.42 years and the mean FVC was 1.36 l (87% predicted). The mean age of the 26 untreated ambulant boys was 8.57 years, mean FVC was 1.29 l (70%predicted). There was no significant difference in age or in actual FVC although there was a trend towards higher FVC in the treated group. Percentage FVC was significantly higher in the treated group (P=0.0052). Mean age in the non-ambulant group was 15.7 years, mean age at loss of ambulation was 9.5 years. In the 7 patients who have so far completed 6 months treatment the mean FVC has risen from 1.4–1.53 l. Conclusions: Steroid treatment in ambulant boys significantly increases percentage FVC and there is also a trend towards improved actual measures. Preliminary data in non-ambulant patients suggests that there is an improvement in FVC with use of steroids.
T.P.1.08
Bone density in patients with Duchenne muscular dystrophy (DMD)
M. Eagle, D. Rawlings, V. Straub, K. Bushby – Newcastle - UK
Purpose of Study: Steroids are now widely used in ambulant patients with DMD and are being considered for use in non-ambulant patients to maintain respiratory function. Steroids are thought to have a deleterious effect on bone density and long-term use is possibly associated with vertebral fractures. In our study, we wanted to look at bone mineral density in DMD boys by Dual Energy X-ray absorptiometry (DEXA) scans before and after steroid treatment. Methods: Fifty-eight patients with DMD had pre-steroid DEXA scans of whom 39 were ambulant and 19 were nonambulant. Thirteen ambulant patients that were started on steroids after the first DEXA scan had follow-up scans (mean follow up time 1.5 years). Two scans per patient visit were performed, adult lumbar spine (fast array) and adult whole body (fan beam). Bone edges were manually adjusted as appropriate. All scans were performed on a HOLOGIC 4500 A scanner subject to recommended quality control. Mean age of patients in the ambulant population was 8 years at baseline, and in the non-ambulant 14.8. Results: For all boys, bone density at baseline was below the age adjusted population mean, and in many instances fell below the normal range. Results for non-ambulant boys at baseline were generally poorer, particularly for the whole body. Follow-up on ambulant boys indicated no significant changes in bone density at any site, contrary to what would be expected in a normal group. Conclusions: DMD boys, whether ambulant or non-ambulant, show low bone density even before the treatment with steroids.
T.P.1.09
Improved pulmonary function in boys with Duchenne muscular dystrophy when deflazacort treatment is started in the second decade
W.D Biggar,*, V.A. Harris, K.A. Campbell, J. Vajsar – Toronto – Canada
Objective: We compared the pulmonary function for three groups of boys between 10 and 15 years of age with DMD: (a) boys treated with daily deflazacort (starting dose 0.9 mg/kg) since 5–7 years of age, (b) boys treated with daily deflazacort since 10–11 years of age and (c) steroid-naive
boys. Design: Twenty-eight boys were in group (a), 11 boys were in group (b) and had been treated with deflazacort for at least 2 years and 20 boys in group (c). All boys were followed by the same multidisciplinary team and clinical protocol every 4–6 mos. Main results: FVC-pp began to decline after 9 years of age in steroid-naive boys (c). At 10 years, their FVC-pp was 65+13% compared to 94+13% boys in group (a) (P<0.005). By 15 years of age, FVC-pp for boys in group (c) was significantly reduced to 47+19% compared to 82+17% for boys in group (a) (P<0.005). For boys in group (b) who started deflazacort at 10–11 years of age, their FVC-pp improved
after starting deflazacort and remained so after knd 2 years of treatment. After 1 year of treatment when they were 11–12 years old, their FVC-pp was 83+7% compared to 66+16% for boys in group (c) (P<0.002) After 2 years of treatment, their FVC-pp was 80+9% compared to 59+18% for
boys in group (c) (P<0.002). By 15 years, 6 boys in group (c) required nighttime ventilation and had had at least one respiratory tract infection requiring hospitalization. No boys treated with deflazacort, early or late, required night-time ventilation. Other infections were not more common in
boys treated with deflazacort. Three additional boys started on deflazacort when they were 19–22 years old and showed some improved pulmonary function (5–10%) and fewer symptoms of dyspnea. Conclusion: Pulmonary function benefits from daily deflazacort even when treatment is started after 10 years of age when most boys are using a wheelchair full-time. It will be important to treat more steroid-naý¨ve boys, for example when they are 15– 20 years of age, to determine if they have improved pulmonary function and fewer respiratory tract infections requiring hospitalization when treated with deflazacort.
T.P.2.01
Phase 1 multiple-dose safety and PK study of PTC124 for nonsense mutation suppression therapy of Duchenne muscular dystrophy (DMD)
S. Hirawat, V.J. Northcutt, E.M. Welch, G.L. Elfringa, S. Hwang, N.G. Almstead, W. Ju, L.L. Miller - USA
Purpose: PTC124 is a novel, orally bioavailable, nonantibiotic, small molecule that promotes ribosomal readthrough of mRNA containing a nonsense mutation (premature stop codon). PTC124 induces full-length dystrophin protein production and decreased muscle injury in mdx mice harboring a nonsense mutation in the dystrophin gene. This Phase 1 singlesite, escalating multiple-dose study assessed the safety, PK, and nonspecific stop codon readthrough effects of PTC124 as a prelude to Phase 2 studies in patients with DMD. Methods: Healthy volunteers (18–30 years of age) were enrolled in 2 stages. In Stage 1, 24 subjects were treated with an oral suspension of PTC124 at doses of 10-, 20-, 30-, or 50-mg/kg BID with meals for 7 consecutive days; in Stage 2, 6 additional subjects were treated with 50- mg/kg BID for 14 days. Results:Nodrug-related adverse events were evident at any dose level. Reversible, asymptomatic elevations in AST and ALT to
!2 times the upper limit of normal were observed among 9 of the 30 subjects enrolled in the study. PTC124 administration safely achieved target trough plasma concentrations exceeding the 2- to 10-mcg/mL values that were associated with activity in preclinical models. Western blots evaluating for elongation of reference proteins (cystatin C, C-reative protein and a2 microglobulin) in PBMCs collected from subjects treated at 50 mg/kg BID for 14 days revealed no nonspecific readthrough of normal stop codons. Conclusions: These data support evaluation of PTC124 as a treatment for patients with DMD in a planned Phase 2 study.
T.P.2.02
E.E. Cedillo Rosa, B. Montes de Oca, A. Miranda Duarte, G. Martinez Castro, R. Rodriguez Jurado, A. Gomez, S. Lona Pimentel – Mexico DF - Mexico
Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder; it causes progressive muscular weakness and wheelchair dependency before 13 years of age. No treatment exists and several studies have shown that drugs as prednisone improve the strength and function of patients, however, with secondary effects. Carnitine has a role in mitochondrial energy metabolism and has been hypothesized to improve exercise performance in healthy subjects. Objective: The aim of this study was to improve resistance to muscular fatigue with the administration of carnitine in DMD patients. Patients and methods: A double blind randomized controlled trial was conducted; two groups of ten DMD subjects were included. Carnitine and placebo solutions had the same presentation and the doses were 50 mg/kg/day. Clinical muscular
evaluation and superficial electromyography (SEMG) were evaluated at the beginning, 1, 4, and 12 months. Statistical analysis was done with ANOVA for repeated measures. Results: No statistical significant differences in SEMG parameters were found. However, differences in 10 of 14 muscles clinically evaluated in upper limbs and 8 of 24 in lower limbs were found. Conclusions: To our knowledge there are no previous studies that evaluate carnitine as an alternative in the management of DMD patients. There are no differences in SEMG, however, at the end of the
study, an improvement in resistance fatigue in carnitine group was subjectively observed. Although this could not be evaluated with the methods employed. We propose spectroscopy to evaluate resistance to muscular fatigue, and increase carnitine dose.
T.P.2.04
Functional ability and respiratory capacity in non-ambulatory individuals with Duchenne muscular dystrophy (DMD) or spinal muscular atrophy before and after spinal stabilization
B.F. Steffensen, B. Klefbeck, A. Wennstro¨m-Nilsson – Denmark and Sweden
This study aimed at evaluating functional ability and respiratory capacity after spinal surgery in subjects with Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy type II (SMA II). Methods: All subjects in Denmark and parts of Sweden (five with DMD and five with SMA II) who
were candidates to spinal surgery during the year 2001 were included in the study. The subjects were assessed before intervention and 12 months after. The assessments comprised Cobb angle, muscle strength, ROM, spirometry and functional ability measured with the EK scale. Results: Scoliosis was corrected 64% (28–92%) in DMD and 62% (28–100%) in SMA. Muscle strength and ROM did not decrease significantly. Functional ability decreased significantly among subjects with DMD, but not with SMA. FVC decreased significantly among subjects with DMD, but not with SMA. Among subjects with DMDt here was a close relationship between degrees of correction of scoliosis and loss of FVC (rs=0.9), indicating that the more the scoliosis was corrected the more the FVC deteriorated. Among subjects with SMA there was an inverse relationship between degrees of correction of scoliosis and loss of FVC (rs=0.7) indicating that the more the scoliosis was corrected the better the FVC was preserved. These findings suggest disease specific changes secondary to spinal surgery. However, they need to be studied in a larger population to be confirmed.
T.P.2.05
Medical care and habilitation of DMD in Norway in view of the Scandinavian protocol
R. Melsom, I. Lund-Pettersen – Oslo - Norway
A Scandinavian consensus programme for Duchenne Muscular Dystrophy (DMD) was made during spring 2003. The consensus programme has recommendation for quality regarding diagnosis, treatment and follow up. To obtain indicators regarding the follow up of DMD in
Norway, a study was carried out in two counties in Norway Material and methods 17 boys/men from Buskerud and Akershus county with the diagnosis DMD participated in the study. Three lived in their own flat while the rest were staying with their parents. Results and interpretation Age at
diagnosis had decreased from 5.7 to 4.5 years in the period 1970–1990 (group 1) compared to period 1990–2000 (group 2). Both physiotherapy and occupational therapy were started earlier in the group born after 1989. Lung function tests were started earlier in boys born after 1989. Start of
cardiac evaluation did not show any difference in the two groups. Cardiac evaluation was not done regularly in any of the two groups. The recommendations in the consensus programme was not well followed in aspects regarding inheritance, nutrition, oral care, education, orthopaedic treatment, and rehabilitation of adults with DMD functioned poorly. It is therefore a need for evaluation of the hospital services and the services from the local communities in several counties and local communities to secure optimal follow-up and care for boys and men with DMD.
T.P.2.06
N. Dlamini, S. Messina, D.L. Padua, M. Main, R. Knight, A. Manzur, E. Mercuri, F. Muntoni, M. Kinali - UK and Italy
Most boys with Duchenne Muscular Dystrophy (DMD) lose independent ambulation leading to complete wheelchair dependence by 13 years of age. Prior to this rehabilitation in knee–ankle–foot orthoses (KAFOs) is often proposed to promote ambulation and protect from scoliosis. Quality
of life issues are important to consider when discussing treatment options with individuals with chronic, life-long illnesses. However, there has been no formal study to assess patient/family quality of life following rehabilitation in KAFOs. Our aim was to assess patient/parent perceptions
of quality life following KAFO rehabilitation and use this information to improve our practice. We developed a disease specific health related quality of life (HRQoL) questionnaire for DMD children, and their parents, that underwent rehabilitation in KAFOs. 66 patient/parent questionnaires were sent out and 40 were returned. Almost 50% of the boys perceived improved
quality of life following KAFO rehabilitation. The remaining 40% of the boys perceived their quality of life to be worse after KAFO rehabilitation. Forty percent of the parents perceived improved quality of life and 40 percent perceived a poorer quality of life, for their child—following KAFO
rehabilitation. There was a positive correlation between the length of time walking in KAFOs and total quality of life score in the boys but not in their parents. These results indicate that despite the difficulties around the loss of ambulation and the surgical procedure necessary for fitting of KAFOs, half of the DMD boys perceived an improved quality of life following rehabilitation. Some children and parents complained of the scarcity of written information available to them. As a result we have now developed a leaflet in which relevant information is provided.
T.P.2.07
Rehabilitation of walking in KAFO’s in Duchenne muscular dystrophy: can surgical release of the TA be avoided?
M. Main, G. Haliloglu, M. Kinali, E. Mercuri, F. Muntoni, R. Baker – UK and Italy
Background: Knee–ankle–foot orthoses (KAFO’s) are used to prolong ambulation in Duchenne Muscular Dystrophy (DMD). In our centre 90% of DMD have rehabilitation and 85% need surgical release of the tendoachilles (TA) for KAFO’s fitting. This requires a 10 days rehabilitation
program. Serial casting using Plaster of Paris (POP) is used to improve range of movement in joints in several neurological disorders. We undertook two pilot studies in DMD to assess the efficacy of this procedure in: (1) reducing contractures in ambulant kids; (2) avoiding surgery to allow the fitting of KAFO’s. In the first study, we serially cast seven ambulant DMD boys who had lost more than 20o of dorsiflexion. Range of movement improved past plantargrade in all but two boys (one with > 40o tightness; the other with marked pes cavus). In the second study we serially plastered 8 boys who were losing ambulation. The boys had 20–35o loss of ankle range. All children were able to achieve independent ambulation in KAFO’s without needing surgery and only one day of gait re-education. Serial casting can therefore, be used to reduce TA tightness in children with DMD; this procedure can be an alternative to surgery when TA contractures
are less than 40o.
T.P.2.08
V. Cuccurullo, L.I. Comi, L. Politano, P.F.Rambaldi, A. Palladino, F. De Luca, P. Sannino, R. Russo, L. Mansi, G. Nigro – Naples - Italy
Myocardial involvement is very often described in Becker dystrophy. The ECG and ECHO findings are similar to those observed in Duchenne Dystrophy, but the echocardiographic evidence of a dilated cardiomyopathy is delayed but more frequent. The evolution of Becker cardiomyopathy
presents a preclinical stage, an intermediate stage and an advanced stage with features of dilated cardiomyopathy. In order to evaluate the severity of the transition period toward a patent cardiomyopathy, we studied 20 Becker patients monitoring their left ventricular (LV) function
using an ambulatory nuclide system (Vest, Capintec, Inc., Ramsey, NJ, USA), which provides a reliable, continuous and non-invasive assessment of LV function during different activities. All patients underwent equilibrium radionuclide angiography (MUGA) after in vivo labelling of
red blood cells with 555 MBq Tecnetium-99m, to acquire basal data and permit a correct allocation of the VEST main detector. Few, but new interesting changes were found during the different activities (rest, walking, eating). In particular, the decrease in the LV ejection fraction observed during meals appears as a marker of initial dilated cardiomyopathy.
G.P.3.01
M.G. D’Angelo, F. Civati, M.L. Lorusso, A.M. Russo, R. Virgilio, A. Tavano, F. Fabbro, A.C. Turconi, N. Bresolin - Italia
Background: Duchenne Muscular Dystrophy (DMD) is a fatal recessive X-linked muscular disease caused by the absence of dystrophin. Dystrophin isoforms are also expressed in the cerebral neocortex and in the cerebellum. The presence of mental retardation in DMD patients is well recognised since 1992 (Emery), 1/3 of DMD children show reduction of Intelligent Quotient (IQ), associated with specific deficit in Verbal rather than Performance IQ. The cognitive impairment is not progressive and not correlated with the severity of muscle disease. Wicksell et al. (2004) showed that short-term memory deficits might play a critical role in the cognitive impairment and intellectual development seen in those with DMD. Some studies revealed that intellectual impairment is more frequent in patients carrying deletions in the distal part of the gene (including exons 45–54). The aim of the present study was to describe the neuropsychological profile in a group of DMD children. Patients: 18 children (aged from 4 to 12 years) with DMD were diagnosed according to international standard criteria. Methods: Intellectual level was assessed by means of
Wechsler Intelligence Scales (WISC-R). The following subtests of the NEPSY (Developmental Neuropsychological Assessment) were also administered: auditory attention and response set, visual attention, list learning and memory for names; further, the visual abstract memory subtest from the TEMA battery (Italian version of the TOMAL, Test of Memory and Learning). Results: On average, the children showed slight deficits in tests tapping the visual modality, particularly in visual attention. If IQ level is taken into consideration, it can be observed that auditory attention and verbal learning are relatively strong in DMD children, while performances in visual attention and visual memory tests are more strongly related to general intellectual functioning, with a subgroup of
DMD children clearly performing below expected levels. Discussion: The result of relative deficits in attention and memory in the visual rather than in the auditory modality is not obvious, given the general cognitive profile of DMD subjects, with better scores on visual-spatial tests and lower
scores in linguistic tests. Since attention and memory skills can play an important role in the planning and in the effectiveness of rehabilitative intervention, it could be advisable to include specific tests of these functions in the cognitive assessment of DMD.
T.I.5
Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy
D. Duboc, C. Meune, G. Lerebours, J.-Y. Devaux, G. Vaksmann, H.M. Becane - France
Objective: To assess the cardiac preventive effect of perindopril in Duchenne Muscular disease (DMD). Background: DMD, an inherited X-linked disease, is characterized by progressive muscle weakness and myocardial involvement. Forty percent of the patients develop life threatening heart failure. Methods: In phase I, 57 children with DMD and LV ejection fraction (EF) > 55% (mean=65.0+5.4), between the ages of 9.5 and 13 years (10.7+1.2), were enrolled in a 3-year multicenter, randomized, double-blind trial of perindopril, 2–4 mg/day (group 1), versus placebo (group 2). In phase II, all the patients received open-label perindopril for 24 more months. LVEF was measured at 0, 36 and 60 months. Results: Phase I was completed by 56 (27 in group 1 and 29 in group 2) and phase II by 51 patients (24 and 27 in groups 1 and 2, respectively). There was no difference in baseline characteristics between the treatment groups. At the end of phase I, LVEF was 60.7+7.6% in group 1 versus 64.4+9.8% in group 2, and was <45% in a single patient in each group (ns). At 60 months, LVEF was 58.6+8.1% in group 1 versus 56.0+ 15.5% in group 2 (n.s.). A single patient had a LVEF <45% in group 1 versus 8 patients in group 2 (P=0.02). Conclusions: Early treatment with perindopril delayed the onset of prognostic relevant decrease in LVEF in children with DMD. On the base, of these results we recommend the treatment by perindopril in each child suffering from Duchenne muscular dystrophy in order to improve the vital prognostic of this disease.
This study was supported by a grant from the AFM (French association against myopathies) and from Servier Laboratories.
T.O.4
Adult life with Duchenne muscular dystrophy (DMD)
J. Rahbek, B. Werge, A. Madsen, J. Marquardt, B.F. Steffensen,J. Jeppesen - Denmark
Since 1990 practically all persons in Denmark with Duchenne muscular dystrophy (DMD) have had home mechanical ventilation when needed for survival. As a consequence the adult population of
DMD is growing. Knowledge on the physical and social consequences of a prolonged life with DMD remains sparse. The purpose of this study was to describe participatory and quality of life profiles in adults with DMD in Denmark. Methods: Sixty-five subjects with DMD (aged 18–42 years) were included in the study. The study was performed as interviews based on a semi-structured questionnaire comprising 197 items. Each subject was interviewed once in his home. Results: Seventy one percent use invasive ventilation, 19% use non-invasive ventilation and 10% do not use assisted ventilation, but use CPAP for mobilising secretions. Despite heavy immobilization, the ordinary adult person with DMD states his quality of life as excellent; he is neither worried about his disease nor the future. His assessment of income, hours of personal
assistance, housing, years spent in school, and ability to participate in desired activities are positive. He is still capable of functioning in a variety of activities that are associated with normal life. However, he lacks qualifying education and is in painful need of a love life. The frequency of pains is high; nearly 40% have pain daily. It should be anticipated that the boy with DMD grows up to manhood and will need competences for adult social life in all respects.