RESEARCH THAT WILL BE PRESENTED IN AMERICAN ACADEMY OF NEUROLOGY MEETING - APRIL 2011
[P02.059] A Randomized, Placebo-Controlled, Multiple-Ascending Dose
Study of ACE-031 (ActRIIB-IgG1) in Duchenne Muscular Dystrophy (DMD)
Craig Campbell, London, ON, Canada, Kenneth Attie, Cambridge, MA,
Jean Mah, Calgary, AB, Canada, Mark Tarnopolsky, Hamilton, ON, Canada, Kathy
Selby, Vancouver, BC, Canada, Hugh McMillan, Ottawa, ON, Canada, Yijun Yang,
Wilson Dawn, Matthew Sherman, Cambridge, MA, Diana M. Escolar, McLean, VA
OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics (PK),
and pharmacodynamic (PD) effects of ACE-031 in DMD. BACKGROUND: DMD is
caused by dystrophin deficiency resulting in muscle weakness. ACE-031 is a
fusion protein comprised of the extracellular domain of activin receptor type
IIB and IgG1 Fc domain, which inhibits myostatin and other negative muscle
regulators. PRe-clinically, ACE-031 treatment resulted in increased muscle mass,
strength and utrophin expression, and decreased intramuscular fibrosis and CK
levels. DESIGN/METHODS: 36-48 ambulatory, steroid-treated DMD boys, age
4
years, will be randomized to escalating doses of ACE-031 or placebo (3:1), SC,
every 2-4 weeks for 12 weeks, with 12 weeks follow-up. Safety assessments
include adverse events, physical examination, laboratory and cardiac monitoring,
anti-drug antibodies. PD endpoints include body composition and bone density by
DXA, muscle and fat volumes by MRI, muscle strength and function, pulmonary
function, bone biomarkers, quality of life. RESULTS: Preliminary baseline
data for 24 patients are presented (all correlations p<0.0001 unless indicated).
Mean (SD)
age: 10.33.1
years; height z-score: -1.91.3;
total body %lean mass 65.811.5%;
%fat mass 31.511.8%.
Distances walked in 1, 2, or 3 minutes correlated with 6-minute walk distance
(6MWD) (r>0.92). 6MWD was inversely correlated with time to perform 10-meter
walk/run (10MWR) (r=-0.80) and 4-stair climb (4SC) (r=-0.78). 10MWR correlated
with 4SC (r=0.90) and Gower (r=0.86); 4SC correlated with Gower (r=0.68,
p=0.003, n=17). Lower extremity (LE) %lean mass correlated with LE strength
(r=0.62, p=0.003, n=20), 6MWD (r=0.60,p=0.003), 10MWR(r=-0.76), 4SC (r = -0.75),
and Gower (r=-0.73,p=0.001,n=16). Total body %fat mass correlated with time to
perform 10MWR (r=0.58,p=0.004) and 4SC (r=0.64,p=0.001). CONCLUSIONS: DMD
patients on steroids demonstrate baseline correlations of % lean and fat mass
with measures of muscle strength and function. This study will provide safety
and exploratory outcomes data for ACE-031 in boys with DMD.
[S34.004] Forty-Eight Week Follow-Up Data from a Phase I/IIa
Extension Study of PRO051/GSK2402968 in Subjects with Duchenne Muscular
Dystrophy
Nathalie Goemans, Leuven, Belgium, Mar Tulinius, Gothenburg, Sweden,
Rosamund Wilson, Marlborough, Wiltshire, United Kingdom, Judith van Deutekom,
Sjef de Kimpe, Giles Campion, Leiden, The Netherlands
OBJECTIVE: To evaluate the efficacy and safety of 48 weeks of treatment
with PRO051/GSK2402968 in boys with Duchenne muscular dystrophy (DMD).
BACKGROUND: DMD patients suffer from progressive muscle degeneration due to
mutations in the DMD gene and resulting absence of functional dystrophin in the
muscle cell wall. PRO051/GSK2402968 is an antisense oligonucleotide compound
which induces exon 51 skipping during pre-mRNA splicing and produces novel
dystrophin expression in a subpopulation of DMD patients. DESIGN/METHODS:
Twelve DMD patients with mutations correctable by skipping exon 51, (11
ambulatory, 1 non-ambulatory at study entry) completed a dose-escalation Phase
I/IIa study (Netherlands Trial Register #NTR124) and entered the open-label
extension study. Subjects were to receive weekly subcutaneous injections of
6mg/kg of PRO051/GSK2402968 in the extension study, regardless of earlier dose.
All subjects were at stable steroid doses during the study. Assessments were
performed at baseline and 4-week intervals thereafter. RESULTS: All boys
reported treatment-emergent AEs. The most common AEs were increased urinary
1-microglobulin
(100%), proteinuria (92%) and injection site reactions (100%). However, the
majority of AEs were considered to be mild; there were no severe
treatment-related AEs. There was some evidence of mild proteinuria, confirmed as
greater than the upper limit of normal range (>0.15g<0.3g/24hrs),
in four boys at subsequent 24-hr collection. Increases in some renal and hepatic
parameters were observed but none were considered progressive. Four serious AEs
(not related to treatment) were reported. There was an improvement in 6-minute
walking distance test (6MWD) from 12 weeks; this was maintained until week 48,
when the mean (SD) improvement in 6MWD was +29 (80)m. CONCLUSIONS: PRO051/GSK2402968
6mg/kg administered weekly by subcutaneous injection was generally well
tolerated across 48 weeks of treatment. Renal and hepatic function warrant
further monitoring. As 6MWD is expected to deteriorate over 48 weeks, the
improvements observed in this functional measurement are encouraging.
[S34.002] Safety, Pharmacokinetic and Exploratory Efficacy of AVI-4658
a Phosphorodiamidate Morpholino Oligomer (PMO) To Skip Exon 51 in Duchenne
Muscular Dystrophy Patients
Stephen B. Shrewsbury, Bothell, WA, Sebahattin Cirak, London, United
Kingdom, Michela Guglieri, Newcastle, United Kingdom, Kate Bushby, Newcastle
Upon Tyne, United Kingdom, Francesco Muntoni, London, United Kingdom
OBJECTIVE: This study investigated safety, pharmacokinetics (PK),
exploratory biological and clinical efficacy of the first systemic
administration of AVI-4658 over 12 weekly IV injections at 0.5, 1.0, 2.0, 4.0,
10.0 and 20.0 mg/kg. BACKGROUND: DMD is the commonest inherited muscular
dystrophy in children, affecting 1 in every 3,500 boys, presenting with muscle
weakness by age 5, wheelchair confinement by age 12; later respiratory
insufficiency requiring mechanical ventilation and cardiomyopathy, placing a
huge burden on patient (who rarely survive into their 30s) and parents/caregivers.
Out of frame exon deletions in the dystrophin gene are the commonest mutations.
DESIGN/METHODS: Open label, dose escalation study in ambulant DMD
patients aged 5-15 years; muscle biopsy to assess dystrophin expression at
baseline and 14 weeks. Clinical parameters were followed for 26 weeks: safety (adverse
events (AEs), physical examinations, laboratory tests), skeletal muscle,
pulmonary and cardiac function, PK at 1st, 6th and 12th
doses. RESULTS: All 219 doses of AVI-4658 were well tolerated; no dose
related increase in AEs, change in vital signs, laboratory tests (or other
investigations). PK showed expected short plasma half life, rapid renal
clearance. Biologically, dose related exon skipping demonstrated, with
consistent increase in dystrophin positive fibers in the higher two doses,
reaching 55% in one patient. Proper assembly of Dystroglycan Protein Complex
observed with reductions in various inflammatory T cell counts and no immune
response to new dystrophin. Clinically, general functional stability shown over
26 weeks. CONCLUSIONS: The first PMO for DMD was well tolerated at all
doses in all 19 patients; predictable PK with systemic delivery demonstrating
exon skipping, new dystrophin expression and resulting restoration of associated
proteins and reduction of inflammatory infiltrate. Clinical benefit remains to
be characterized in higher dose and/or longer duration studies.
[P02.066] Clinical and Preclinical Comparison of the Pharmacokinetic
Parameters of AVI-4658, a Phosphorodiamidate Morpholino Oligomer for the
Treatment of Duchenne Muscular Dystrophy
Peter Sazani, Stephen Shrewsbury, Bothell, WA
OBJECTIVE: Compare the pharmacokinetics of intravenous AVI-4658 in
Duchenne muscular dystrophy (DMD) patients (0.5 to 20mg/kg) with the
toxicokinetic parameters of intravenous dosing in, cynomolgus monkeys (5 to 320
mg/kg). BACKGROUND: DMD is a degenerative neuromuscular disease resulting
from dystrophin gene mutations, and affects 1 of 3500 male newborns. AVI-4658 is
a splice switching oligomer (SSO) designed to skip dystrophin exon 51, restore
the translation reading frame, and enable an internally truncated but functional
dystrophin protein. DESIGN/METHODS: Ambulant DMD patients were dosed
intravenously with AVI-4658 once weekly for 12 weeks with 0.5, 1.0, 2.0, 4.0,
10.0 or 20.0mg/kg. Following the 1st, 6th and 12th
doses, blood was taken between 5 minutes and 24 hours postdose. Cynomolgus
monkeys were dosed intravenously once weekly for 12 weeks at 0, 5, 40 or
320mg/kg, with blood taken from 0.25 to 36 hours postdose. All samples were
analyzed using a validated hybridization-based bioanalytical method.
Pharmacokinetic/toxicokinetic parameters were then calculated, including Cmax,
AUC, Tmax, Vss, Cl, and T.
RESULTS: Pharmacokinetically, AVI-4658 behaved in a manner consistent
with other PMO drugs, in both DMD patients and cynomolgus monkeys. Total
exposure, as well as the Cmax achieved in plasma, for AVI-4658
increased proportionally with dose, with no apparent saturation at higher doses.
In general, the plasma elimination half-life was short (up to 3.6hours), and
consistent across dose levels and species. In cynomolgus monkeys, increase in
total exposure was proportional with the instance and intensity of histological
findings in the kidney, which did not alter the function of the kidneys at any
dose. No dose limiting toxicities were observed in either patients or monkeys.
CONCLUSIONS: Across cynomolgus monkeys and DMD patients, AVI-4658
demonstrated a favorable pharmacokinetic profile, in which total exposure was
proportional to the dose administered, up to the maximum feasible dose of
320mg/kg in cynomolgus monkeys.
[P02.058] The Health-Related Needs of Patients and Families Affected
by Duchenne and Becker Muscular Dystrophy (DBMD): Data from the Muscular
Dystrophy Surveillance, Tracking and Research Network (MDSTARNet)
Alexis M. Smirnow, Shree Pandya, Helena Temkin-Greener, James Dolan,
Rochester, NY, Katherine Mathews, Christina Trout, Iowa City, IA, Christopher
Cunniff, Tucson, AZ, Charlotte Druschel, Troy, NY, Paul Romitti, Iowa City, IA,
Lisa Miller, Denver, CO, MDSTARnet, Rochester, NY
OBJECTIVE: To develop a profile of healthcare, psychosocial, and
information related needs of patients with DBMD and their caregivers.
BACKGROUND: Previous research exploring the experience of individuals
diagnosed with a chronic childhood illness, such as DBMD, and their families has
revealed a wide range of needs, many of which exceed the scope of traditional
medical care. DESIGN/METHODS: The MDSTARNet is a multistate collaboration
that conducts population-based surveillance for DBMD and annual surveys with
their caregivers. A Needs Assessment survey was conducted between September 2008
and June 2009 to evaluate the needs of patients with DBMD and their caregivers.
The survey included 76 questions related to 3 domains - healthcare services,
psychosocial issues and information related to DBMD care. RESULTS:
Responses were received from 53 adults with DBMD and 145 primary caregivers from
four states (Arizona, Colorado, Iowa and Western NY). At least one unmet need
was reported by 87% of affected adults and 96% of caregivers. Among affected
adults, the most frequent unmet needs reported were: making and maintaining
romantic adult relationships (36%), finding funding for vehicle modifications
(38%) and managing joint contractures and muscle weakness (17%). Among
caregivers, counseling to help emotional adjustment (39%), information about
jobs/future planning for the male with DBMD (49%) and accessing a nurse
coordinator/health team advocate (26%) were unmet needs most frequently reported.
Overall, among affected adults and caregivers, the number of unmet needs
reported for psychosocial issues and information exceeded those reported for
healthcare. CONCLUSIONS: The survey results demonstrate a broad range of
unmet needs for patients and families affected by DBMD. Developing a profile of
health-related needs for those affected by DBMD will help identify gaps in care
and guide the development of interventions to facilitate optimal health outcomes.
[P02.060] Health Care Services Received by Patients with Duchenne/Becker
Muscular Dystrophy (DBMD): Data from the Muscular Dystrophy Surveillance,
Tracking and Research Network (MDSTARNet)
Shree Pandya, Rochester, NY, Kim Campbell, Troy, NY, Jennifer
Andrews, John Meaney, Chris Cunniff, Tucson, AZ, Charlotte Druschel, Troy, NY,
Lisa Miller, Denver, CO, Paul Romitti, Iowa City, IA, MDSTARNet, Rochester, NY
OBJECTIVE: To document the type, frequency and setting of health care
services received by patients with DBMD in a population based surveillance
program covering four states. BACKGROUND: Anecdotal data from families
and health care providers suggests a wide variation in services received by
patients with DBMD. DESIGN/METHODS: The MDSTARNet is a multistate
collaboration that conducts population based surveillance for DBMD and annual
surveys with their primary caregivers. From April 2007-May 2008, 372 eligible
caregivers from four states (AZ, CO, IA and western NY) were identified. 200
(53.7%) completed a telephone interview. The interview included questions about
the type of provider seen (primary care, neuromuscular specialist, orthopedist,
pulmonologist, cardiologist, physical therapist (PT), occupational therapist(OT),
speech therapist (ST) and other) and the type of services received (respiratory,
dietary, mental health, social work, pain management, pastoral and case
management) over the past 12 months, and setting (clinic, school, home) for
these visits. Frequencies with which these services were received were compared
among states using Chi square tests. Statistical significance was set at p<0.05.
RESULTS: The care providers reported seeing primary care clinicians
(85%), neuromuscular specialists (86%), cardiologists (72%), pulmonologists
(55%), orthopedists (30%) and PT (72%), OT (39%), ST (17%) and other (17%).
Services received included case management (62%), social work (26%), respiratory
(27%), dietary (19%), mental health (16%), pastoral (16%) and pain management
(5%). There were significant differences among states in regards to the cardiac,
pulmonary, and orthopedic specialists seen and in the location of receipt of
physical therapy services. CONCLUSIONS: The results of this study support
the anecdotal data regarding the variation in services perceived by parents and
providers.
[S34.003] Safety and Feasibility of Transvenous Limb Perfusion with
Saline in Human Muscular Dystrophy
Zheng Fan, Keith Kocis, Robert Valley, James Howard, Manisha Chopra,
Hongyu An, Weili Lin, Joseph Muenzer, William Powers, Chapel Hill, NC
OBJECTIVE: Assess the safety and feasibility of the transvenous limb
perfusion gene delivery method in human muscular dystrophy. BACKGROUND:
High-pressure retrograde transvenous limb perfusion has been successfully used
to deliver gene therapies into skeletal muscles in experimental animals.
Translating this promising technique to humans with muscular dystrophy requires
addressing multiple safety and logistical aspects separate from the therapeutic
agent. DESIGN/METHODS: A dose escalation study of transvenous single limb
perfusion with 0.9% saline in adults with Becker or limb-girdle muscular
dystrophies starting with 5% of limb volume. Cardiac, vascular, renal, muscle
and nerve function were monitored. Anesthesia was provided with fentanyl,
midazolam and propofol. An 18 or 20 g intravenous catheter was inserted into the
distal great saphenous vein. A single cuff tourniquet was placed just above the
knee with pressure of 310 mmHg. Infusion of normal saline was carried out with a
Belmont FMS 2000 Rapid Infuser at a maximum line pressure of 300 mmHg with a
goal infusion rate of 80ml/min. RESULTS: Infusion volume was escalated
stepwise to 20% limb volume in six subjects. No subject complained of any post
procedure pain other than due to needle punctures. Safety warning boundaries
were exceeded only for transient depression of limb tissue oximetry and
transient elevation of muscle compartment pressures; these were not associated
with nerve, muscle or vascular damage within 72 hours post procedure. Muscle MRI
demonstrated fluid accumulation in muscles of the perfused leg at 20% limb
volume. CONCLUSIONS: High-pressure retrograde transvenous limb perfusion
with saline up to 20% of limb volume at these infusion parameters is safe and
feasible in human muscular dystrophy. These studies will serve as a basis for
future gene therapy clinical trials.
[P04.023] Systemic Gene Delivery for Therapy of Neuromuscular
Disorders
Jeffrey Chamberlain, Seattle, WA
OBJECTIVE: To develop pre-clinical methods for gene therapy of
neuromuscular disorders. BACKGROUND: We are developing methods for
systemic delivery of therapeutic genes to muscles throughout the body using
animal models of Duchenne muscular dystrophy (DMD), which lack dystrophin. We
have previously shown that adeno-associated virus type 6 (AAV6) vectors are able
to systemically deliver genes throughout the body of adult mice when injected
intravascularly, resulting in highly efficient gene expression that persists for
the lifespan of the mouse. However, the AAV shuttles have a limited carrying
capacity, and as a result we have also been developing functional yet truncated
versions of the dystrophin gene. A single injection of an AAV6/micro-dystrophin
vector into the vasculature of adult, dystrophic mice results in elimination of
dystrophic histopathology for the lifespan of the mouse. DESIGN/METHODS:
We have been exploring whether systemic gene transfer can be used in larger
animal models and whether AAV-mediated transfer of dystrophin elicits an immune
response. RESULTS: Delivery of AAV6 vectors into various veins and
arteries of the dog results in efficient gene transfer to downstream muscles,
but does not lead to whole body gene transfer. Instead, it appears that vector
will need to be delivered into multiple vascular sites to target muscles body
wide. Delivery of AAV vectors encoding micro-dystrophin in dogs results in a
cellular immune response against the AAV capsid. However, this immune response
can be blocked with transient immune suppression, resulting in dystrophin
expression for up to 2 years. To address concerns about whether dystrophin could
be immunogenic in patients with dystrophin null-alleles, we have developed a
micro-utrophin gene. When delivered to dystrophic mice, micro-utrophin is nearly
as effective as dystrophin in alleviating pathology. CONCLUSIONS:
Intravascular AAV delivery of micro-utrophin or micro-dystrophin coupled with
transient immune suppression could lead to an effective therapy for DMD or other
neuromuscular disorders.
[P04.022] Treatment with a Soluble Activin Receptor Type IIB Fusion
Protein Reduces Serum Creatine Kinase Levels in Treadmill-Exercised mdx
Mice
Jennifer Lachey, Abigail Pullen, Alan Koncarevic, Jasbir Seehra,
Cambridge, MA
OBJECTIVE: This study evaluates the potential benefit of treatment with a
soluble activin receptor type IIB (ActRIIB) on myofiber integrity in the mdx
model of Duchenne muscular dystrophy (DMD). BACKGROUND: DMD is
characterized by the absence of functional dystrophin protein which results in
reduced sarcolemmal integrity. Creatine kinase (CK), normally localized to
muscle cytoplasm, is found at high levels in serum of DMD patients and
considered a biomarker of myofiber integrity. Multiple ligands signal through
ActRIIB to negatively regulate muscle growth. Treatment with a soluble ActRIIB
fusion protein (RAP-031) to inhibit endogenous ActRIIB signaling increased
muscle mass and body weight, and restored muscle strength in mdx mice. To
determine possible benefits to myofiber stability, we assessed the effect of
RAP-031 on serum CK levels in treadmill-exercised mdx mice. DESIGN/METHODS:
Mdx mice were divided into 4 groups: unexercised for 4 weeks (Control),
exercised for 4 weeks (4 WEEK), exercised for 8 weeks/vehicle-treated (VEH) and
exercised for 8 weeks/RAP-031-treated (RAP; 10mg/kg s.c. twice weekly). The VEH
and RAP groups were exercised for 4 weeks without treatment, then dosed and
exercised for an additional 4 weeks. Serum CK was assayed after the last
exercise exposure. RESULTS: We have previously demonstrated that RAP-031
increased lean mass and body weight in mdx mice. Consistent with this,
the RAP cohort was significantly heavier than the VEH group (p<0.001) at study
termination. CK levels were elevated in the 4 WEEK group compared to the Control
group and further increased in the VEH group. In contrast, mice in the RAP group
had significantly lower CK values (p<0.05) compared to all other groups.
CONCLUSIONS: RAP-031 treatment prevented increases in CK due to exercise in
mdx mice. Furthermore, RAP-031 appeared to reverse the increases in CK
from pre-dose exercise. These data suggest that RAP-031 improves dystrophic
muscle by, at least in part, improving myofiber stability.
[P02.063] Assessment of Muscle Strength in Healthy Children and
Ambulant Boys with Duchenne Muscular Dystrophy at Ages 6 through 11 Years of Age
Richard Abresch, Davis, CA, Craig McDonald, Sacramento, CA, Jay J.
Han, Folsom, CA, Erik Henricson, Sacramento, CA
OBJECTIVE: To quantify the disease progression of knee and elbow extensor
and flexor muscles of ambulant boys with Duchenne muscular dystrophy (DMD) using
an isometric dynamometer and to develop predictive equations by comparing these
values to healthy controls (CTRL). BACKGROUND: The primary impairment
resulting from DMD is progressive loss of muscle tissue and strength. However,
the clinical significance of quantitative myometry data is not well understood.
DESIGN/METHODS: Isometric strength of knee and elbow extensor and flexor
muscles was obtained using a Lido dynamometer in 125 DMD and 61 CTRL boys, ages
6
11 years. RESULTS: Extension of the knee and elbow of the DMD (14.7 and
6.4NM, respectively) was 40% and 42% of CTRL (36.6 and 15.1 NM, respectively) at
age 6 years and decreased linearly to 15.8% and 10.3% of CTRL at age 11. Flexion
of the knee and elbow of the DMD (11.6 and 9.6 NM, respectively) was 52% and 62%
of CTRL (22.2 and 15.5 NM, respectively) at age 6 years and decreased linearly
to 25.8% and 33.4% of CTRL at age 10. CONCLUSIONS: This study quantifies
patterns of muscle weakness in DMD and compares them to percent predictive
strength equations of healthy controls using height, age, and weight as
predictors.
[P02.064] Impairment of Excitation-Contraction Coupling in Patients
with Duchenne Musclar Dystrophy
Takayasu Fukudome, Higashisonogigun, Nagasaki, Japan
OBJECTIVE: To investigate whether excitation-contraction (E-C) coupling
of muscle is impaired in patients with Duchenne muscular dystrophy (DMD).
BACKGROUND: The dystrophyn-associated glycoprotein complex is associated
with E-C coupling and abnormal E-C coupling has been reported in dystrophic
muscle fibers from mdx mouse. Impaired E-C coupling was assumed in
patients with DMD. DESIGN/METHODS: In 3 patients with Duchenne muscular
dystrophy (DMD), 2 patients with myotonic dystrophy (DM) and 10 normal subjects,
compound muscle action potentials (CMAPs) of the abductor pollicis brevis and
movement-related potentials using an accelerometer placed at the thumb tip were
simultaneously recorded after median nerve stimulation at the wrist. The E-C
coupling time (ECCT) was estimated by a latency difference between CMAP and
movement-related potential. RESULTS: The mean ECCT was 3.6
0.44 msec (mean
SEM) in normal controls (4 men and 6 women; mean age,37 years old, range, 24-49
years old). The ECCT in 3 patients with DMD (3 men; ages,15, 16 and 17 years
old) were 4.7 msec, 14.6 msec and 6.0 msec. The ECCT in 2 patients with DM (one
man; aged 61 years and one woman; aged 58 years old) were 6.6 msec and 5.0 msec.
CONCLUSIONS: ECCT was prolonged in both DMD and DM patients compared to
control subjects. For one of the patients with DMD, the ECCT was significantly
prolonged. To evaluate the relationship between the ECCT and muscle weakness,
impairment of motor function or gene mutation of the dystrophyn protein is
needed. ECCT may be useful for evaluating the effects of DMD genetic therapy
clinical trials.
[P02.062] A Canadian Survey on Lung Volume Recruitment (LVR) in
Children with Duchenne Muscular Dystrophy
Jean Mah, Calgary, AB, Canada, Douglas McKim, Lynda Hoey, Nick
Barrowman, Sherri Katz, Ottawa, ON, Canada
OBJECTIVE: (1) To describe the current respiratory management of children
with Duchenne Muscular Dystrophy (DMD); and (2) To compare the clinical practice
of Pediatric Respirologists and Neuromuscular specialists across Canada.
BACKGROUND: DMD is the most common muscular dystrophy of childhood. Recent
improvement in survival until the third or fourth decade of life is partly
related to early detection and management of respiratory complications. Previous
observational studies have indicated that regular LVR, a technique to increase
lung volumes and cough flows, may improve respiratory outcomes. DESIGN/METHODS:
A web-based survey was sent to all 56 practicing Pediatric Respirologists in
Canada and to all 24 Neuromuscular specialists of the Canadian Pediatric
Neuromuscular Group (CPNG), who follow children with neuromuscular diseases.
RESULTS: Responses were received from 38 (66%) Pediatric Respirologists and
17 (66%) CPNG members. Among 38 Respirologists, 33 see DMD patients under the
age of 18. Of these 33, only 6 (18%) practicing at 3 centers reported using LVR
in about one-third of their patients regularly during clinical stability. Among
17 CPNG members, all of whom see DMD patients under the age of 18, only 2 (12%)
practicing at a single center reported using LVR in about half of their patients
routinely. The majority of the Respirologists (61%) and Neuromuscular
specialists (64%) felt that manual LVR between respiratory exacerbations is an
intervention that warrants further study, with decline in forced vital capacity
(percent predicted) and health-related quality of life being important clinical
outcome measures. CONCLUSIONS: There is variability in the respiratory
management of pediatric DMD patients across Canada. Few Pediatric Respirologists
and Neuromuscular specialists use LVR at least twice daily during periods of
clinical stability. The majority believe that LVR should be the intervention for
a larger clinical trial in this population. Decline in forced vital capacity and
quality of life are considered the most important outcomes of interest.
[P02.065] Use of Optical Coherence Tomography for Idiopathic
Intracranial Hypertension in Boys with Duchenne Muscular Dystrophy
Jean K. Mah, Fiona Costello, Calgary, AB, Canada
OBJECTIVE: (1) To report the association between idiopathic intracranial
hypertension (IIH) and Duchenne muscular dystrophy (DMD); (2) To describe the
use of optical coherence tomography (OCT) for the detection of IIH in DMD.
BACKGROUND: DMD is an X-linked recessive form of muscular dystrophy, with
progressive weakness leading to quadriparesis, cardiomyopathy, respiratory
insufficiency, and death around the third decade of life. Corticosteroid is
often used as a disease-modifying therapy to prolong the duration of independent
ambulation and to delay the onset of secondary complications. Side effects of
corticosteroid include weight gain, behavioral change, short stature, and
increase risk of infection or fractures. To our knowledge, there has been no
reported association between IIH and DMD. DESIGN/METHODS: This was a
retrospective case review from a tertiary paediatric neuromuscular center in
Calgary. RESULTS: Two boys (age 11 and 15 years, BMI>95% for age) with
DMD on long-term deflazacort treatment developed IIH. The first boy had
asymptomatic papilloedema found during routine eye exam; the second boy
presented with a two-week history of severe bifrontal pulsatile headache with
bilateral sixth nerve palsy. Fundoscopic exam in both cases confirmed bilateral
papilloedema, and lumbar puncture revealed elevated opening pressure without any
evidence of infection or inflammation. Cerebral sinovenous thrombosis was
excluded by brain MRI/MRV or cranial CTV. Treatment with lumbar puncture,
acetozolamide, and weight control measures resulted in complete resolution of
symptoms. OCT showed marked thickening of the retinal nerve fiber layer
thickness consistent with papilloedema in both eyes acutely, which improved in
follow-up. CONCLUSIONS: IIH is a rare complication of boys with DMD.
Potential risk factors include young age, use of corticosteroid, obesity, and
physical inactivity due to underlying weakness. Early recognition, exclusion of
other secondary causes of IIH, and prompt treatment is needed to avoid permanent
visual loss. OCT is useful for detecting IIH and monitoring the response to
treatment.
[S34.006] Predictors of Ambulation Loss in Boys with Duchenne
Muscular Dystrophy
Richard Abresch, Davis, CA, Craig McDonald, Sacramento, CA, Jay Han,
Folsom, CA
OBJECTIVE: The purpose of this study was to predict which variables could
predict loss of ambulation and reduction in walking velocity in ambulant boys
with Duchenne muscular dystrophy (DMD) over a one-year time period.
BACKGROUND: The FDA has recently specified that clinical trials conducted in
support of drug approvals must incorporate a primary endpoint that objectively
measures a clinically meaningful
life-changing
milestones. DMD clinical trials need short-term surrogate outcome measures that
are predictive of alterations of these life-changing milestones. DESIGN/METHODS:
Height, weight, timed motor performance, strength, and functional grade were
assessed at baseline and approximately one-year time later in 63 ambulatory DMD
subjects, ages 5 -13 years. Stepwise discriminant analysis was used to identify
the significant predictors of (a) loss of ambulation and (b) a minimum 40%
reduction in walking velocity. RESULTS: Age, weight, and time to stand
from supine at the initial evaluation were significant predictors of one-year
ambulation status (Wilks'
= 0.573, F=19.36, p<0.0001). Age and time to stand from supine at initial
evaluation were significant predictors of reduction in walking velocity and
ambulation approximately one-year later (Wilks'
= 0.753, F=4.93, p<0.005). No other variables significantly entered into the
equation. Baseline assessment of age, weight and time to stand correctly
classified one-year post-baseline ambulation status 78% of the time, and
non-ambulating status 89% of the time. Baseline assessment of age and time to
stand correctly classified patients who exhibited a 40% reduction in walking
speed and those who did not 73% and 89% of the time, respectively.
CONCLUSIONS: Findings from this study suggests that time to rise from supine
and age can effectively predict ambulation status and reductions in walking
speed in boys with DMD. This information will be useful for anticipatory
guidance, development of outcome measures, and translational studies of DMD.
[P02.067] Novel Pointmutation in R1 Domain of Dystrophin Gene Causes
Missfolding of Dystrophin and Becker's Muscular Dystrophy
Gyula Acsadi, Detroit, MI, Steven A. Moore, Iowa City, IA, Angélique
Cheron, Rennes, France, Lindsey Bennett, William Kupsky, Detroit, MI, Elisabeth
Le Rumeur, Jean-François Hubert, Rennes, France
OBJECTIVE: To determine structural and functional characteristics of the
mutant dystrophin protein found in mild Becker's muscular dystrophy (BMD).
BACKGROUND: Dystrophin provides a structural link between the sarcolemma and
cytoskeletal f-actin. Missense mutations in the dystrophin gene often lead to
BMD but a genotype/phenotype correlation is difficult to establish. Depending on
the mutation locus, a disruption of various binding capacities even in the
repeat region may have a major impact on the functionality of dystrophin.
DESIGN/METHODS: We have identified a family with two young brothers having
very mild proximal weakness, recurrent abdominal pain and moderately elevated
serum creatine kinase levels (3,000 IU). An immunostaining approach to
evaluating dystrophin expression was performed on a muscle biopsy. After
determining the mutation in the dystrophin gene, we carried out in vitro
biophysical analysis of a two-repeat portion of the dystrophin rod domain
bearing the mutation. RESULTS: Dystrophin immunofluorescence showed
absent to weak staining for dystrophin regions encoded by exons 7 to 9. A T>C
transition at codon 427 causing a Leu>Pro amino acid change in the first
spectrin-like repeat (R1) was identified as a novel mutation. There was no
change in the lipid binding capacity of R1, R2 dystrophin peptides containing
the patient's mutation. However, significant alteration in thermal and chemical
folding behavior was observed. CONCLUSIONS: In frame mutations in the R1
spectrin-like domain can affect the folding and binding properties of dystrophin
protein and lead to a mild forms of BMD.
[P06.268] Prevalence and Characteristics of Pain in Myotonic
Dystrophy Type 2: A Postal Survey in Finland
Aki J. Hietaharju, Kimmo I. Suokas, Tampere, Finland, Maija Haanpaa,
Espoo, Finland, Bjarne Udd, Vasa, Finland
OBJECTIVE: The objective of this study was to assess the prevalence and
clinical characteristics of pain in Finnish myotonic dystrophy type 2 (DM2)
patients. BACKGROUND: DM2 is an autosomal dominant multisystem disease
caused by the expansion of tetranucleotide repeats (CCTG) in the zinc finger
protein 9 gene. In addition to muscle weakness and myotonia, fluctuating or
episodic musculoskeletal pain is regarded as one of the key symptoms of DM2.
However, only a few studies have addressed the occurrence of pain and its
clinical features in this disorder. DESIGN/METHODS: Postal survey was
carried out for all patients with genetically confirmed DM2 and available
contact information (n=132). The cohort was estimated to represent 85 % of
Finnish DM2 patients. The respondents (n=93) answered a specific questionnaire
including pain charts, 11-point pain intensity numerical rating scale (PI-NRS)
and Brief Pain Inventory (BPI). Health-related quality of life was assessed by
using a Finnish validated version of the RAND 36-Item Short Form Health Survey (RAND-36).
Depression was screened using the short form of Beck Depression Inventory (RBDI).
RESULTS: Prevalence of pain at the time of the survey was 53,8 %. In
addition, 22,6 % had experienced pain previously. Majority of the patients (48,0
%) reported daily pain at the time of the survey, and in 14 % of the responders
pain was constant. Pain was increased by exercise in 57, 9 % and by cold in 56,1
% of the responders. Quality of life scores were significantly lower in DM2
patients reporting pain than in those with no pain (p< 0.01). In 18,3 % of the
responders, the RBDI score was suggestive of moderate or severe depression.
CONCLUSIONS: Pain is a very common feature of DM2 and is experienced on a
daily basis by most of the patients. It significantly reduces quality of life
and is related with depression.
[P06.275] Myotonic Dystrophy Type-2 (DM2): Patient-Reported
Highest-Impact Symptoms and Issues
Chad Heatwole, Rochester, NY, Rita Bode, Elmwood Park, IL, Nicholas
Johnson, Christine Quinn, William Martens, Richard Moxley, Rochester, NY,
Barbara Vickrey, Los Angeles, CA, David Victorson, Evanston, IL
OBJECTIVE: To identify, quantify, and analyze the symptoms and issues
most relevant to DM2 patients. BACKGROUND: DM2 is an autosomal dominant
multisystemic disease capable of impairing the physical, mental, and social
health of patients. Patient-centered studies identifying the symptoms and issues
of greatest importance to this population are currently limited. DESIGN/METHODS:
We conducted structured interviews with fifteen genetically confirmed adult DM2
patients. Each interview focused on identifying the symptoms and issues that
exert the most critical impact on patients' health related quality-of-life (HRQOL).
We recorded, transcribed, coded, and analyzed each interview using a qualitative
framework technique and three investigator approach. RESULTS: Results: We
coded 943 participant quotes which were sorted into 244 themes and 19 subdomains
that represent the physical, mental, social, and disease-specific HRQOL of DM2
patients. We designed a disease-specific HRQOL model. Categories in this model
include: 1) mobility and ambulation; 2) proximal leg weakness; 3) fine motor and
upper extremity dysfunction; 4) proximal upper extremity and shoulder
limitations; 5) truncal weakness; 6) activity impairment specific to DM2; 7)
emotional distress; 8) cognitive impairment; 9) impaired body image specific to
DM2; 10) social role dissatisfaction; 11) social role limitations; 12) offspring
and genetic issues; and DM2 specific symptoms of: 13) sleep disturbance; 14)
fatigue; 15) pain; 16) myotonia; 17) gastrointestinal dysfunction; 18) vision/hearing
impairment; and 19) communication difficulties. CONCLUSIONS: There are
multiple themes, some previously under-recognized, that impact DM2 HRQOL.
Obtaining the patient's point of view is a critical first step in the future
development of valid patient-reported outcome measures and functional rating
scales for this population.
[P06.270] Test-Retest Reliability of Strength Measurements of the
Long Finger Flexors (LFF) in Patients with Myotonic Dystrophy Type 1 (DM1)
Katy Eichinger, Nuran Dilek, Jeanne Dekdebrun, William Martens, Chad
Heatwole, Charles Thornton, Richard Moxley, Shree Pandya, Rochester, NY
OBJECTIVE: To document the test-retest reliability of strength
measurements of the LFF in patients with DM1. BACKGROUND: Patients with
DM1 have distal upper extremity weakness which begins in the long finger flexors.
Grip strength using a Jamar dynamometer has been used in the past to document
hand strength. Grip strength however, is a measure of intrinsic and extrinsic
hand muscle strength and does not isolate the LFF. Testing procedures to
specifically examine the LFF have not been established. DESIGN/METHODS:
Strength of the LFF was measured by manual muscle testing (MMT) and quantitative
muscle testing (QMT) in 22 patients with DM1. MMT was performed on the LLF of
the thumb, first and second digits using standard MRC procedures and grading.
QMT was performed using a Jamar hand dynamometer and a pinch gauge (B&L
Engineering). The LFF were tested using the Jamar hand dynamometer on the last
setting, and the palmar pinch was measured using the pinch gauge. These testing
procedures were performed twice in a 24 hour period. RESULTS: The
interclass correlation coefficient (ICC) for MMT of the LFF for the right and
left hands were .971 and .943 respectively. The ICC for the LFF using the Jamar
dynamometer was .919 for the right hand and.847 for the left hand. The ICC for
palmar pinch was .957 and .954 for the right and left hands respectively.
CONCLUSIONS: Strength testing of the LFF demonstrated excellent test-retest
reliability over a 24 hour period. Tests of sensitivity to change over longer
periods of time will need to be performed prior to using these tests as outcome
measures for clinical trials.
[P06.260] Cardiomyopathy in Limb Girdle Muscular Dystrophy 2B and 2I
Xiomara Q. Rosales, Sean J. Moser, Tam Tran, Beth McCarthy, Nicholas
Dunn, Philip Habib, Orlando P. Simonetti, Jerry R. Mendell, Subha V. Raman,
Columbus, OH
OBJECTIVE: To characterize the myocardium in LGMD2I and 2B patients using
cardiac magnetic resonance (CMR). BACKGROUND: Limb girdle muscular
dystrophies (LGMD) are inclusive of 7 autosomal dominant and 14 autosomal
recessive disorders featuring progressive muscle weakness and atrophy. Two of
the most common forms of LGMD include deficiencies of dysferlin (LGMD2B) and
fukutin related protein (LGMD2I). Considering the importance of cardiac function
as a predictor of prognosis, we used CMR as highly sensitive measure of cardiac
function to define systolic dysfunction, myocardial fibrosis, and diastolic
dysfunction. DESIGN/METHODS: Consecutive patients with genetically-proven
LGMD types 2I (n= 7) and 2B (n=9) were enrolled. All subjects underwent cardiac
magnetic resonance (CMR) on a standard 1.5 Tesla clinical scanner with cine
imaging for left ventricular (LV) volume and ejection fraction (EF) measurement,
vector velocity analysis of cine data to calculate myocardial strain, and late
post-gadolinium enhancement imaging (LGE) to assess for myocardial fibrosis.
RESULTS: Sixteen LGMD patients (7 LGMD2I, 9 LGMD2B), and 8 control subjects
completed CMR. All but one patient had normal LV size and systolic function; one
(type 2I) had severe dilated cardiomyopathy. Of 15 LGMD patients with normal
systolic function, LGE imaging revealed myocardial fibrosis in 7 (47%).
Peak systolic circumferential and radial strain rates were similar in patients
vs. controls. Five of 7 LGE-positive patients had mild diastolic dysfunction (3
type 2B, 2 type 2I) that was not present in any LGE-negative patients or
controls. CONCLUSIONS: The prevalence of advanced cardiomyopathy in
patients with LGMD2I and LGMD2B appears to be limited, but subclinical fibrosis
and diastolic dysfunction do occur and may warrant consideration of
cardioprotective therapies. Longitudinal studies will be necessary to define the
natural history of cardiomyopathy in LGMD2B and 2I.
[P06.278] Diminished PGC-1
Contributes to Mitochondrial Dysfunction and Elevated Oxidative Stress in
Myotonic Dystrophy Type 1 (DM1)
Xiang Fang, Rui Gao, Qinghua Liang, Galveston, TX, Analisa Botta,
Rome, Italy, Robert Smith, Partha Sarkar, Galveston, TX
OBJECTIVE: To understand the molecular basis of mitochondrial dysfunction
and oxidative stress in DM1 skeletal muscle. BACKGROUND: DM1 is an
autosomal dominant dystrophic muscle disease caused by the expansion of CTG
repeats in the 3' UTR of the DMPK gene. Massive expansion of CTG repeats within
the 3' UTR results in dystrophic and degenerative skeletal muscle defects and
associated mitochondrial dysfunction. The mechanism by which expanded CTG
repeats leads to mitochondrial abnormalities is not yet established. Because PGC-1
is a key regulator of mitochondrial biogenesis/respiration and oxidative stress,
we tested whether PGC-1
is involved in dysregulation of mitochondrial function and oxidative stress in
DM1 skeletal muscle. DESIGN/METHODS: DNA and protein from control and DM1
patient skeletal muscle were isolated and extracted. The expression of PGC-1
and genes regulating mitochondrial biogenesis, oxidative phosphorylation and
reactive oxygen species (ROS) detoxification were assessed by Western-blot and
real-time quantitative PCR analyses. RESULTS: Steady-state mRNA levels of
PGC-1
were significantly down-regulated in DM1 skeletal muscle. Similarly, expression
of PGC-1
target genes regulating mitochondrial OXPHOS was significantly decreased in DM1
skeletal muscle. TFA1, 2, ATP5A1, COX2, 3, and 4, and TFAM expression was
decreased by 40-75% from DM1 muscle samples as compared with those of controls.
Consistent with these findings, levels of the ROS detoxifying genes e.g.
superoxide dismutase, glutathione peroxidase and catalase were also markedly
decreased in DM1 skeletal muscle, concomitantly associated with elevated tissue
ROS levels. CONCLUSIONS: PGC-1
plays a critical role in the pathogenesis of DM1, altering mitochondrial
function and oxidative stress.
[P06.267] Steroid Response in Patients with Dystroglycanopathy
Katherine D. Mathews, Carrie M. Stephan, Karla S. Laubenthal, Steven
A. Moore, Iowa City, IA
OBJECTIVE: Retrospective review of response to corticosteroids in cohort
of patients with dystroglycanopathies. BACKGROUND: The
dystroglycanopathies are a group of autosomal recessive disorders that share a
deficiency in glycosylation of a-dystroglycan. Mutations in six genes are known
to result in disease. There is a wide range of clinical severity from
Walker-Warburg syndrome, a severe form of congenital muscular dystrophy, to limb
girdle muscular dystrophy. Case reports and anecdotal clinical experience
suggest that some individuals respond to steroids. DESIGN/METHODS: All
patients participating in a natural history study of genetically confirmed
dystroglycanopathies were included. Information about current and previous
medications used for muscular dystrophy, along with their responses to the
medications was systematically collected. Medical records were reviewed when
possible. RESULTS: Thirteen of 32 (40.6%) participants have used
corticosteroids due to muscle disease. Nine patients with mutations in FKRP,
FKTN, or POMT2 remain on steroids at varied doses due to reported beneficial
clinical response. Four discontinued steroids due to lack of effect or
side-effects. Steroids were started in five patients prior to their
dystroglycanopathy diagnoses, in three for suspicion of myositis and in two for
presumed Duchenne muscular dystrophy. In two families, younger affected siblings
are on steroids due to the dramatic response seen in the older sibling. Four
patients resumed steroids due to worsening weakness after discontinuation and
they remain on steroids. CONCLUSIONS: This is the first systematic report
of steroid use in a cohort of dystroglycanopathy patients. The reason for
steroid responsiveness is not clear, but modulation of inflammation has been
suggested. While retrospective, these data together with published case reports
suggest that corticosteroid treatment modifies the course of disease in some
individuals with dystroglycanopathy, and provide support for proceeding with a
prospective trial in this patient group.
[P06.265] Psychometric Evaluation of Manual Muscle Testing in Adult
Patients with Muscular Dystrophies
Reza Sadjadi, West Vancouver, BC, Canada, Michael Rose, London,
United Kingdom
OBJECTIVE: To investigate psychometric properties of Manual Muscle
Testing in Muscular Dystrophies. BACKGROUND: There is an increased
interest in psychometric evaluation and validation of outcome measures (OM) in
different diseases. Rasch analysis allows us to compare psychometric properties
of items in an outcome measure and for MMT it could tell us which muscles are
the most informative and how well any expanded MRC gading scale works. We
investigated psychometric properties of the Manual Muscle Testing (MMT) protocol
used during a clinical trial investigating the safety and efficacy of the
myostatin inhibitor MYO-029 in the treatment of three types of muscular
dystrophy. DESIGN/METHODS: 86 patients with Becker, Limb-Girdle or
Facio-Scapulo-Humeral Muscular Dystrophy had 345 MMT assessments. A total of 24
muscle groups (22 pairs and neck flexion/extension) were rated using an expanded
10 level Medical Research Council (MRC) scale (0,1,2,3-,3,3+,4-,4,4+,5). We used
Rasch model to compare item fit, separation and difficulty for different muscle
groups and for the expanded MRC scale. RESULTS: Overall, MMT showed
relatively reliable psychometric properties (Outfit MNSQ 1.03 Reliability 0.91).
Relative distributions of item and person location estimates showed a relatively
good coverage of muscle strength by continuous MMT items. Most muscle groups had
disordered category thresholds and reducing detailed MRC scale to less detailed
6-level scale (0,1,2,3,4,5) improved psychometric properties of MMT. Hip muscle
group form a small sub-dimension behaving slightly different from other muscle
groups in MMT. CONCLUSIONS: Overall, most muscle groups were useful for
reliable differentiation between different levels of overall muscle strength in
muscular dystrophies. The original MRC scale (6-points) has better measurement
properties than the expanded (10-point) MRC scale for MMT. Hip muscle group MMT
sub-scores may need to be analysed as a potentially independent outcome measure
in future trials.
[P06.273] Natural History of DM2/PROMM in Italy: Neuromuscular and
Multisystem Progression over Time in 88 Patients
Alice Zanolini, Valeria A. Sansone, Enrico Bugiardini, Barbara
Fossati, San Donato Milanese (Milan), Italy, Rosanna Cardani, Milan, Italy,
Luigi De Ambroggi, Giovanni Meola, San Donato Milanese (Milan), Italy
OBJECTIVE: Quantify progression of muscle weakness, myotonia and
multiorgan involvement in a cohort of Italian patients with myotonic dystrophy
type 2 (DM2-PROMM phenotype) over time. BACKGROUND: Progression of muscle
weakness and multisystem involvement in DM2 is thought to be slower and less
severe than that of myotonic dystrophy type 1 (DM1). However, history data in
DM2 are still limited. DESIGN/METHODS: Muscle involvement (MegaMRC,
clinical and EMG myotonia tests, biceps muscle biopsy), cardiac (AV/IV blocks,
RR interval, ejection fraction, PM/ICD implantation) and respiratory involvement
(daytime sleepiness, sleep apnoeas, NIV support) were retrospectively analyzed
in 88 patients with DM2 (56 males, 32 females) admitted from January 1994 to
September 2010, mean follow-up 8.3
2.1. RESULTS: Age at onset was in the 3rd and 4th
decade (65%, mean age 39.3
11.1); 15% developed symptoms over 60 (range 5-15 years). Progression of muscle
weakness (mean MMRC from 139.7 to 137.2, p=0.002) occurred at a rate of 0.4 MRC
points/year. 12% of patients became wheelchair bound during observation (all
after age 70); 3% required PM implantation and 4% NIV support. Clinical and EMG
myotonia was detectable in 25% of patients at onset and in an additional 20% at
follow-up EMG. Muscle biopsy showed type II atrophy, ribonuclear and
muscle-blind inclusions at baseline and with a size increase over time in repeat
muscle biopsy (6 patients). CONCLUSIONS: Progression of muscle, cardiac
and respiratory involvement occur in DM2 although at a later age and with less
frequency than in DM1. Respiratory insufficiency seems rarer in DM2. EMG may
fail to detect myotonia at onset whereas immunohistochemistry and FISH are
abnormal at the very onset of symptoms. This suggests that muscle biopsy rather
than EMG may be of greater support to the clinical diagnosis of DM2.
[P06.276] Myotonic Dystrophy Type-1: Patient Validation Study of the
Highest-Impact Symptoms and Issues
Chad Heatwole, Rochester, NY, Rita Bode, Elmwood Park, IL, Nicholas
Johnson, Christine Quinn, William Martens, Richard Moxley, Rochester, NY,
Barbara Vickrey, Los Angeles, CA, David Victorson, Evanston, IL
OBJECTIVE: To determine the prevalence and relative impact of the
symptoms and issues most important to the myotonic dystrophy type-1 (DM1)
population's heath related quality-of-life (HRQOL). BACKGROUND: DM1 is an
autosomal dominant multisystemic disease capable of impairing the physical,
mental, and social health of patients. A previous pilot study of 20 DM1 patients
identified 221 high priority symptoms and issues to DM1 patients. The relative
importance and frequency of these themes in an extended DM1 population is not
known. DESIGN/METHODS: 550 DM1 patients from the National Registry of
Myotonic Dystrophy Patients and Family Members were sent a survey designed to
identify the most critical DM1-specific HRQOL issues. Participants were asked to
identify the relative impact on their lives of 221 previously identified
high-impact themes. A relative impact score for each theme was determined (0=no
impact on DM1 patients; 100=severe impact on all DM1 patients). RESULTS:
278 DM1 participants completed the surveys. Prevalence and relative impact of
all 221 themes were determined. Problems with hands or arms (93.5%), fatigue
(90.8%), myotonia (90.4%), impaired sleep (87.9%), and limitations in mobility
(85%) were the subdomains with the highest prevalence. Fatigue (62.3),
limitations in mobility (60.6), inability to do specific activities (58.7), and
impaired sleep (56.2) were the subdomains with the highest relative impact
scores. Participant responses varied based on age, CTG repeat length, employment,
education, and time since symptom onset. CONCLUSIONS: DM1-specific HRQOL
is defined by multiple themes of varying importance and prevalence. Identifying
the most important issues for patients is a critical step in selecting optimal
therapeutic targets and for the development of a valid, DM1-specific,
patient-reported outcome measure for use in clinical trials. Supported by: NIH,
MDA, Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy
Patients and Family Members.
[P06.262] Infantile Muscular Dystrophy in Canadian Aboriginals Is an
B-Crystallinopathy
Duygu Selcen, Rochester, MN, Marc R. Del Bigio, Albert E. Chudley,
Winnipeg, MB, Canada, Harvey Sarnat, Seattle, WA, Craig Campbell, Sharan Goobie,
London, ON, Canada, Bernard N. Chodirker, Winnipeg, MB, Canada
OBJECTIVE: To determine the genetic basis of a recessively transmitted
fatal infantile muscular dystrophy. BACKGROUND: A recessively transmitted
fatal infantile muscular dystrophy associated with hypertonia has been described
in Canadian Aboriginals. The affected infants present with progressive limb and
axial muscle stiffness, develop severe respiratory insufficiency, and most die
in the first year of life. DESIGN/METHODS: We performed histochemical,
immunocytochemical, electron microscopy and molecular genetic studies in a
cohort of 12 patients affected by this disease. RESULTS: Conventional
histochemical and electron microscopy studies suggested myofibrillar myopathy (MFM).
Therefore we searched for ectopic expression of multiple proteins typical of MFM.
B-crystallin
(BC)
expression was absent from all fibers using a monoclonal antibody raised against
the entire protein. However, a monoclonal antibody directed against the first 10
residues of
BC
immunostained portions of abnormal fibers. Pursuing this clue, we searched for
mutations in the gene for
BC
(CRYAB) in available DNA samples of 8 patients. All harbor a homozygous
deletion, c.60C, predicting a Ser to Ala change at codon 21 and a stop codon
after 23 missense residues (p.Ser21AlafsX24). Clinically unaffected parents are
heterozygous for this mutation. CONCLUSIONS: The homozygous c.60delC in
CRYAB pinpoints the genetic basis of the fatal infantile hypertonic
muscular dystrophy of Canadian Aboriginals. MFMs are typically transmitted by
dominant inheritance but in this disease the parental phenotype is rescued by
limited expression of the highly truncated nonfunctional mutant gene product.
The severe patient phenotype is due to homozygosity for the markedly hypomorphic
allele
[P06.277] Bent Spine Syndrome as an Early Manifestation of Myotonic
Dystrophy Type 1
Vivek Krishna, William Arnold, Columbus, OH, Victoria Lawson, Lewis
Center, OH
OBJECTIVE: To describe two cases of myotonic dystrophy type 1 exhibiting
early weakness of spinal extensor muscles. BACKGROUND: Bent spine
syndrome (BSS) is a posture of forward flexion of the trunk or neck, commonly
associated with dystonia of the axial muscles in extrapyramidal disease. The
syndrome may additionally result from spinal extensor muscle weakness. A variety
of muscle diseases are associated with BSS including fascioscapulohumeral
dystrophy, nemaline rod myopathy, inflammatory myopathies, and proximal myotonic
myopathy (PROMM), but only a few reports exist describing BSS in association
with type 1 myotonic dystrophy (DM1). We report two cases with early, prominent
spinal extensor weakness. DESIGN/METHODS: A chart review was performed.
RESULTS: Case 1: A 63 year-old female presented with flexed posture,
immobility, and back pain, prompting her evaluation 10 years after the onset of
symptoms. Examination showed nearly 90 degrees of forward flexion of the
thoracic spine with standing and walking. She had mild facial and limb weakness
with no apparent grip or percussion myotonia. Genetic testing revealed 130
trinucleotide repeats in the dystrophia myotonicaprotein
kinase (DMPK) gene. Case 2: A 66 year-old female presented with a 13-year
history of progressive proximal weakness and forward flexion of the spine.
Examination showed facial, distal upper and proximal lower limb weakness, grip
myotonia, and marked forward flexion of the upper thoracic spine and nearly
complete head drop. Genetic testing revealed 283 CTG repeats in the DMPK
gene. CONCLUSIONS: Patients presenting with spinal extensor muscle
weakness present a diagnostic challenge. BSS has rarely been reported as an
early or distinctive feature of DM1. These cases emphasize the phenotypic
heterogeneity of DM1 and underscore the importance of considering DM1 in the
differential diagnosis of BSS.
[P04.255] Sleep Apnea and Other Sleep Dysfunction in Myotonic
Dystrophy Type 2
Amtul Farheen, Woodbridge, NJ, Sudhansu Chokroverty, Edison, NJ,
Howard Sander, New York, NY, Raji Grewal, Cranbury, NJ, Qi Rui Yang, West Orange,
NJ, Kamran Kabolizadeh, Edison, NJ, Sombabu Maganti, Metuchen, NJ, David Rosen,
Edison, NJ, Vinay Chaudhry, Baltimore, MD
OBJECTIVE: To describe sleep dysfunction in myotonic dystrophy type 2 (DM2).
BACKGROUND: DM2 is a recently described hereditary myotonic dystrophy
which is differentiated from myotonic dystrophy type 1 (DM1) by different
genetic mutations. Sleep apnea has been described in DM1 but is a novel finding
in four of our six patients with DM2. DESIGN/METHODS: Four women (51, 53,
62, 63) and two men (57, 63) presented with difficulty raising their shoulders
and climbing stairs. Major sleep complaints included chronic insomnia, snoring,
and excessive daytime somnolence. One patient (63 F) also gave a history of
dream-enacting behavior. Examination revealed diffuse symmetric muscle weakness
involving proximal more than distal muscles and thenar eminence percussion
myotonia. EMG/NCV and polysomnographic (PSG) studies were performed. RESULTS:
Genetic testing was consistent with a CCTG expansion in the ZNF9 gene on
chromosome 3. Two sisters (51, 53) had normal chromosome 19 CTG repeat size
which excluded DM1 and the DM2 genetic testing was not available when they were
investigated. EMG revealed myotonia with myopathic findings. PSG results in four
patients (57M, 63M, 63 F, 62 F) were consistent with obstructive sleep apnea (OSA).
One patient (63 F) during CPAP titration had a dream-enacting behavior (someone
was trying to strangle her) and PSG showed REM without atonia and excessive
phasic muscle bursts (consistent with REM behavior disorder). In two sisters
(51, 53) PSG findings showed absent REM sleep in one (51) and alpha-REM-spindle
mixture in the other who also showed paradoxical movements in the effort
channels suggesting increased upper airway resistance. CONCLUSIONS: These
sleep abnormalities including REM behavior disorder in one and sleep apnea in
four patients with DM2 are unique observations and to our knowledge have not
been described before.
[S34.005] Systemic Delivery of Targeted RNA Interference as a
Treatment for Myotonic Dystrophy
Joel R. Chamberlain, Eva Stepniak, Seattle, WA
OBJECTIVE: To develop a treatment for dominantly inherited disorders.
BACKGROUND: Therapy for dominant genetic disease requires elimination of the
disease causing entity. We have chosen to target the trinucleotide
repeat-expanded mRNA that causes myotonic dystrophy (DM1) through coercion of
the RNA interference pathway. DM1 is the most common adult form of muscular
dystrophy and is characterized by an inability of skeletal muscles to relax
after contraction (myotonia), as well as the seemingly unrelated manifestations
of hyperinsulinemia, somnolence, endocrine disturbances, and cognitive deficits.
Evidence relating the varied effects of expressing the repeat-expanded mRNA
emerged from studies showing that proteins involved in splicing were disrupted
in their ability to dictate the adult splicing pattern of a subset of genes in
the muscle cell. Reversion to the fetal pattern of splicing of certain genes
appears to be related to particular phenotypic disturbances in DM. A mouse model
of DM1, the HSALR mouse, was created by placing 250 CTG
repeats in the 3'UTR of the human HSA gene and displays the characteristic
myotonia and defects in splicing as observed in the human disease. DESIGN/METHODS:
Artificial expression cassettes were designed and constructed to direct sequence
specific degradation of HSALR mRNA using the mouse U6 promoter
driving expression of short hairpin RNAs. Knockdown of HSALR
mRNA was assayed in vitro and effective expression cassettes to trigger RNA
interference (RNAi) were selected for use in adeno-associated virus (AAV)
shuttles, which were used to carry the RNAi expression cassettes to the muscles
of the HSALRmice. RESULTS: Systemic injection of the
AAV6 RNAi cassettes targeting the HSALR mRNA showed
wide-spread transduction of muscles. We assayed quadriceps muscle for changes in
the splicing pattern of the SERCA1 gene and observed a reversion in splicing in
a population of mRNAs after injection of select HSALR mice.
CONCLUSIONS: Further development of targeted RNAi could lead to therapy for
myotonic dystrophy and other dominant diseases of muscle.
[P06.271] Laboratory Abnormalities in Patients with Myotonic
Dystrophy Type 2
Nicholas Johnson, Chad Heatwole, Rochester, NY, Bradley S. Goldberg,
Tel Aviv, Israel, William Martens, Richard Moxley, Rochester, NY
OBJECTIVE: To study, identify, and describe the clinical laboratory
abnormalities common to myotonic dystrophy type-2 (DM2). BACKGROUND:
Myotonic dystrophy type 2, similar to myotonic dystrophy type-1, is an autosomal
dominant, multi-system disorder. Patients commonly experience progressive
weakness, early onset cataracts, and clinical myotonia; however, other body
systems are frequently involved including the brain, endocrinologic, hematologic,
hepatic, and renal systems. Although clinical laboratory abnormalities are
frequently observed in DM2, large scale studies of these abnormalities in this
relatively rare disease are limited. DESIGN/METHODS: 83 DM2 patients
previously evaluated through a university medical center were identified.
Laboratory results from this population were compiled, averaged, and compared to
university standard reference ranges. RESULTS: 1442 total DM2 studies
representing sixty-eight different types of laboratory tests were evaluated.
Results for 359 (24.9%) of these studies were outside of their standard
reference range. The relative frequency of abnormally elevated laboratory values
was greater than 50% in several tests, including creatine kinase, total
cholesterol, lipase, alanine aminotransferase (ALT), and lactate dehydrogenase.
In addition, serum levels of immunoglobulin G (IgG) and absolute lymphocyte
count were found to be low in 75% and 54% of all DM2 patients tested.
CONCLUSIONS: There is a high frequency of laboratory abnormalities in DM2.
These abnormalities are referable to multiple organ systems, indicating the
widespread pathological manifestations of DM2. These abnormalities may provide a
foundation for clinical monitoring and disease screening in this population.
[S24.004] Reducing Bodies and Myofibrillar Myopathy Features in FHL1
Dystrophy
Duygu Selcen, Rochester, MN, Mark Bromberg, Steven S. Chin, Salt
Lake City, UT, Andrew G. Engel, Rochester, MN
OBJECTIVE: To search for mutations in FHL1 in patients with
myofibrillar myopathy (MFM). BACKGROUND: Mutations in the FHL1
have been associated with a diverse chronic myopathies including late onset
X-linked axial and scapuloperoneal myopathy with bent spine syndrome, reducing
body (RB) myopathy, X-linked dominant scapuloperoneal muscular dystrophy, rigid
spine syndrome, and contractures and cardiomyopathy mimicking Emery-Dreifuss
muscular dystrophy. MFMs are morphologically distinct but genetically
heterogeneous muscular dystrophies in which disintegration of Z-disks and then
of myofibrils is followed by ectopic accumulation of multiple proteins. Because
some pathologic features of the FHL1-muscular dystrophies and the MFMs overlap,
we searched for mutations in FHL1 in 50 MFM patients. DESIGN/METHODS:
Histochemical, immunocytochemical, and ultrastructural studies; mutation
analysis. RESULTS: We detected two novel and one previously identified
missense mutation in 5 MFM patients. Two mutations are in the second LIM domain
and one outside the LIM domains of FHL1. The age of onset was 6-75 years
and the age at diagnosis 10-77 years. All but one patient presented with
progressive muscle weakness; one had hypertrophied muscles, rigid spine, and
joint contractures, and one also had peripheral neuropathy. Patients harboring
LIM2 domain mutations had typical MFM features and also displayed menadione-NBT
positive RBs whereas the patient with the mutation outside LIM domains had no
RBs. High resolution EM showed the RBs composed of 13 nm tubulofilaments that
emanated from Z-disks. This was followed by myofibrillar disintegration,
accumulation of myriad RBs in cytoplasm and many nuclei and of cytoplasmic
degradation products, and aggregation of endoplasmic reticulum and sarcotubular
profiles. CONCLUSIONS: Light microscopy of FHL1 dystrophies can show MFM
features with or without RBs. Presence of RBs points to a mutation in LIM2
domain of FHL1. Mutation outside the LIM domains resulted in a milder
phenotype with late onset.
[P06.274] Factors Related to Quality of Life in Patients with
Myotonic Dystrophy Type 1
Stojan Peric, Vidosava Rakocevic Stojanovic, Sanja Pavlovic, Ivana
Basta, Zorica Tasic, Dragana Lavrnic, Belgrade, Serbia, Serbia and Montenegro
OBJECTIVE: To assess potentially treatable factors that might influence
self-reported QoL in patients with adult form of DM1. BACKGROUND:
Health-related quality of life (QoL) measures obtained through patient-oriented
tools are now considered essential in the evaluation of neurological diseases,
especially in those that may affect the general health status of patients such
as myotonic dystrophy type 1 (DM1). Quality of life assessments contribute to
greater understanding of disease's consequences, the effects of its treatment
and palliative care. DESIGN/METHODS: A cross-sectional study was applied
in 114 consecutively recruited DM1 patients. The severity of muscular
involvement in DM1 was measured by MIRS scale. Multisystemic affection was
thoroughly investigated in all patients. The following assessment instruments
were also used: The Fatigue Severity Scale (FSS), The Daytime Sleepiness Scale (DSS),
The Hamilton Depression Scale, Visual Pain Scale and The SF-36 questionnaire.
RESULTS: The mean total SF-36 score was 45.423.9
indicating that QoL was significantly affected in patients with DM1. Considering
demographic features, younger patients (p<0.01), married patients and patients
without children had better QoL (p<0.05). Duration of disease and severity of
muscular involvement significantly affected QoL in DM1 patients (p<0.01). Among
multisystemic affections, we found constipation and snoring (p<0.05), as well as
presence of fainting and gallstones (p<0.01) to have a significant influence on
QoL. Central symptoms of DM1 including depression, anxiety and fatigue
significantly affected QoL (p<0.01), while daytime sleepiness did not show
correlation with QoL (p>0.05). QoL was also affected by presence and intensity
of pain (p<0.01). CONCLUSIONS: QoL was significantly affected in patients
with DM1. We identified potentially treatable factors that influenced QoL in DM1
patients, including constipation, snoring, cardiac abnormalities, gallstones,
depression, anxiety, fatigue and pain. We assume that treatment of these
symptoms may significantly improve palliative care and QoL in patients with DM1.
[P06.269] Test-Retest Reliability of the Purdue Pegboard Test and the
Jebsen-Taylor Hand Function Test in Patients with Myotonic Dystrophy Type 1 (DM1)
Katy Eichinger, Nuran Dilek, Jeanne Dekdebrun, William Martens, Chad
Heatwole, Charles Thornton, Richard Moxley, Shree Pandya, Rochester, NY
OBJECTIVE: To document the test-retest reliability of Purdue Pegboard
Test and the Jebsen -Taylor Hand Function Test in patients with DM1.
BACKGROUND: Hand weakness has been well documented in patients with DM1;
however hand function using standardized tests like the Purdue Pegboard Test and
the Jebsen-Taylor Hand Function Test has not been examined in patients with DM1.
Reliable and sensitive measures of hand function are essential for therapeutic
trials in DM-1. DESIGN/METHODS: The Purdue Pegboard Test and the
Jebsen-Taylor Hand Function Test were performed twice within a 24 hour period in
22 patients using standardized instructions. The Purdue Pegboard Test consists
of having the patient place as many pegs as they can in the board in 30 seconds.
The Jebsen-Taylor Hand Function Test consists of 7 subtests: writing, picking up
small objects, turning cards over, simulated feeding, stacking checkers, lifting
light cans, and lifting heavy cans. The tests were performed sequentially.
RESULTS: The intraclass correlation coefficient (ICC) for the Purdue
Pegboard Test was .835. The ICC for the overall Jebsen-Taylor Hand Function Test
was .896, with ICC's ranging from .394 to .931 on the subtests. The subtests of
writing had excellent test-retest reliability with the majority of the other
subtests demonstrating moderate test-retest reliability. CONCLUSIONS:
These tests of hand function demonstrate good reliability in patients with DM-1
when repeated over a 24 hour time period. Tests of sensitivity to change over
longer periods of time will need to be performed prior to using these tests as
outcome measures for clinical trials.
[S34.001] A Phase I Dose-Escalating Study of AAV1-Gamma-Sarcoglycan
Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C
Olivier Benveniste, Paris, France, Faycal Hentati, Tunis, Tunisia,
Bruno Eymard, Paris, France, Didier Caizergues, Evry, France, Thomas Voit, Serge
Herson, Paris, France
OBJECTIVE: Safety of dose-escalating AAV1-gamma-sarcoglycan gene therapy
(Phase I) for Limb Girdle Muscular Dystrophy type 2C (LGMD 2C). BACKGROUND:
Gamma-sarcoglycanopathy or LGMD 2C is an as yet untreatable disease caused by
autosomal recessively inherited mutations of the gamma-sarcoglycan gene (SGC).
DESIGN/METHODS: Nine non-ambulant LGMD 2C patients (2 M, 7 F, age 27 y
[16 to 38]), with a del525t homozygous mutation on the
SGC
gene and absence of
SGC
immunostaining in muscle biopsy were enrolled. They were divided into 3 groups
to receive 3 escalating doses of an AAV1 vector expressing human
SGC
gene under the control of the desmin promoter, by local intramuscular injection
into the extensor carpi radialis muscle. The first group received
a single injection of 3x109 viral genome (vg) in 100
l,
the second a single injection of 1.5x1010 vg in 100
l
and the third group received 3 concomitant 100
l
injections at the same site (a total of 4.5x1010 vg). RESULTS:
No serious side effects were observed. All patients became seropositive for AAV1
and one developed a cytotoxic response again AAV1 capsid. In biopsy specimens
taken 30 days after the injection, immunohistochemistry showed
SGC
expression in 5/9 patients, with 4.7 to 10.5% of positively stained fibers and
detection of
SGC
mRNA by RT-PCR in the 3 patients who received the highest dose. The
SGC
protein became also detectable by Western blot in one patient. CONCLUSIONS:
Exogenous
SGC
expression can be obtained in LGMD2C patients following AAV1 gene transfer,
without adverse effects, paving the way for future developments in gene therapy
of hereditary muscle diseases.