1. No category

21-09-2011
CMD Family Survey of Current Medical Care
 33 responders
 CMD subtypes represented: collagen 6, aDG, LAMA2
Related CMD, L-CMD and undiagnosed CMD
 Asked to identify their CMD subtype and top 3 care
issues
Congenital Muscular Dystrophy
CARE = Treatment



ANNE RUTKOWSKI, MD
CURE CMD CHAIRMAN
KAISER SCPMG


Medical: poor weight gain, managing contractures/scoliosis,
pulmonary function
Access to experts
Diagnostic odyssey
Ongoing emotional toll
Lack of reliable information organized as a strategic plan and
presented at diagnosis
CMD Diagnosis
CMD Comprehensive Care
Over 50% of CMD families may not carry
a molecular diagnosis.
Supportive and pro-active care can be
initiated in spite of a lack of molecular
diagnosis.
Diagnosis
“Living life takes precedence over finding my
diagnosis”
1. Does overdue emphasis on the classic
presentations or the CMD vs LGMD detract from
our ability to teach and recognize the spectrum?
2. When is it appropriate to “skip” the muscle biopsy
if genetic testing is available?
3. What CMD subtypes “suffer” from the highest
rates of under-diagnosis? Why?
4. What are recommendations for genetic
confirmation of disease?
Collagen 6 myopathy
 Phenotype spectrum: Ullrich CMD to intermediate
phenotype to Bethlem myopathy
 Classic signs: hyperflexible fingers, toes, progressive
contractures (elbow, knees, hips), skin findings
(keratosis pilaris, keloid), progressive respiratory
failure, round face, facial erythema, chatty
personality
 CK normal
 Genes: col6a1, col6a2, col6a3
1
21-09-2011
Collagen 6 Myopathy
LAMA2 Related CMD (Merosin, MDC1A)
 Phenotype: non-ambulant (complete) and ambulant
(partial)
 Classic findings: abnl white matter on brain MRI,
hypotonia at birth, bi-modal respiratory support
requirement, feeding/nutritional deficiency
 CK elevated
 LAMA2
LAMA2 Related CMD (Merosin)
Dystroglycanopathy
 Phenotype: broadest spectrum
 WWS like
 Fukuyama and MEB like
 CMD with cerebellar cysts
 CMD with MR
 CMD without MR
 LGMD with MR
 LGMD without MR
 Classic phenotype: muscle hypertrophy (UE/LE), brain MRI
findings, mild laxity of wrists and fingers, elevated CK,
myopia (eye findings), steroid responsive
 Genes: FKRP, fukutin, LARGE, POMT1, POMT2, POMGnT1,
DAG1, DPM1, DPM2, DPM3, col4 ?
 Clues- microcephaly (POMT1, POMT2)
macrocephaly/cerebellar cysts (POMGnT1)
SEPN1 related myopathy
L-CMD
 Phenotype: early and later onset
 Phenotype: L-CMD to EDMD
 Classic findings: pronounced axial weakness, rigid
 Classic phenotype: initial gains and then loss
spine with lateral deviation- s-shaped curve,
respiratory failure while ambulatory, underweight
 CK: nl to min elevation
 Gene: SEPN1
 Muscle biopsy: myopathic (multi-minicore) and
dystrophic
(infant/toddler), rigid spine, axial weakness, foot
drop (distal weakness), head drop, cardiac
arrhythmia, cardiomyopathy, resp failure
 CK: mild to mod elevated
 Gene: LMNA (Lamin A/C)
2
21-09-2011
L-CMD: Rigid Spine and Dropped Head
syndrome
Diagnostic Pearls
 “ Developmental delay, do a CK”
 This will diagnose aDGs
 CK normal –min elevated: does not exclude CMD
 Pattern recognition: Doing the muscle biopsy?
 Distal flexibility, proximal contractures, skin findings: collagen 6
 Elevated CK, enlarged calves, some joint laxity with or without
cognitive disability, myopia, with or without brain abnl on MRI:
aDG, consider telethonin (LGMD), col4 (WWS)
 Elevated CK, failure to thrive, “SMA look a like”, brain MRI
white matter change: LAMA2 Related CMD (Merosin)
 Axial weakness, s shaped scoliosis, respiratory insufficiency
while ambulatory: SEPN1 related myopathy
 Axial weakness, dropped head syndrome, foot drop: L-CMD
Diagnosis: Genetic Confirmation
Diagnosis: Goal and Resources
Golden years for diagnosis
Genetic confirmation is essential to:
1.
2.




Goal: Decrease cost and emotional toll of
diagnostic odyssey, improve rates of
genetic confirmation, initiate optimal proactive medical care early
 CMD Video Library: identify the pattern
 Soon to be published CMD Diagnostic Reviewalgorithms
 CMD Overview, Genetests.org
http://www.ncbi.nlm.nih.gov/books/NBK1291/
 CMD Consensus Care Guidelines
http://jcn.sagepub.com/content/25/12/1559
confirm disease subtype and guide management.
confirm disease inheritance and guide family planning decisions
(Col6 variable genetics: AD, AR, spontaneous dominant negative)
Genotype-phenotype correlations
CMD clinical trials
Genotype-phenotype correlation contributes to the
body of knowledge, eventually contributes to prognosis
counseling
4. Set expectations for what genetic testing will do (not
change what you do today) and time period to receive
feedback on testing
3.
CMD International Registry (CMDIR)
www.cmdir.org
 Patient and parent self report on care and outcomes
 Available in over 40 languages
 Over 25 countries registered and 475 participants
 Initially focused on registering CMD, now expanded to
register through limb girdle spectrum (LGMD)
 Expanded to include the congenital myopathies and
register through late onset congenital myopathy



Acts as a central hub for clinical study and trial information
Promotes diagnosis and genetic confirmation (where
available) through national centers of excellence
Linked to CMD BioBank and CMD GaP (Genotype and
Phenotype study)
3
21-09-2011
Respiratory Management: Care of Breathing
Respiratory Management: Care of Breathing
Respiratory insufficiency not “missed diagnosis” as the
driver of morbidity and mortality.
How to detect, manage and stabilize progressive
respiratory insufficiency.
4 special populations to consider:
a. The walking patient with severe respiratory
insufficiency
b. The cognitively impaired
c. The peri-operative scoliosis surgery patient
d. The CMD patient who desires pregnancy
Breathing Management: Respiratory
Insufficiency
Pulmonary Health
Test
Test
Test
Questionnaire
To identify and
trend respiratory
insufficiency
To identify
difficulty
coughing/exp
muscle strength
To identify need
for BIPAP
(noctural
hypoventilation
or daytime
hypercapnea)
To identify
symptoms of early
respiratory
insufficiency and
determine how well
managed
FVC (sitting and
supine)
Ulna length
% predicted FVC
sVC
PCF
Overnight pulse
oximetry
Essen Questionnaire
(diaphragmatic
weakness)
Sleep study
SRI ( adults)
ABG
Cough Assist
FVC is the 5th vital sign. Every parent, affected individual,
nurse, clinician needs to know and trend the FVC and %
predicted FVC over the course of several visits. It is the
trend that matters as well as very low values.
Similar to motor decline, respiratory decline is gradual. Endstage signs: breathlessness, restless sleep, daytime
headaches, mood change
Why catch respiratory insufficiency early?
 There is a treatment. Non invasive ventilation (BiPAP)
 It improves quality of life and survival.
 It prevents right sided heart failure
 Correct management decreases respiratory infections and
mortality.
Noninvasive
ventilation
% Predicted FVC
Measuring Ulna Length
 A more sensitive indicator of change
 Calculation involves FVC and height
 Obtaining height in people with CMD can be challenging



Standing height
Arm span
Ulna Length
 Baseline testing at age 6 years in those with normal
cognition
 Serial testing- neuromuscular respiratory management is
all about TRENDS, respiratory insufficiency is insidious
4
21-09-2011
Measuring Ulna Length Video
www.curecmd.org
Where can I find references to calculate height
and % predicted FVC based on ulna length?
 Gauld LM, Kappers J, Carlin JB, Robertson CF.
Height Prediction from ulna length. Dev Med Child
Neurol. 2004 Jul: 46 (7): 475-80.
 Gauld LM, Kappers J, Carlin JB, Robertson CF.
Prediction of childhood pulmonary function using
ulna length. Am J Respir Crit Care Med. 2003 Oct
1:168 (7):804-9. Epub 2003 Jul 17
Parallel progressive loss of ambulation and onset of
ventilatory support in Col6 Myopathy
Nadeau A, Kinali M, Main M, Jimenez-Mallebrera C, Aloysius A, Clement E, North
B, Manzur AY, Robb SA, Mercuri E, Muntoni F. Natural history of Ullrich congenital
muscular dystrophy. Neurology. 2009 Jul 7;73(1):25-31 )
Respiratory Management: LAMA2 Related CMD
Geranmayeh et al. Neuromus Dis 2010
Decrease in % predicted FVC with age in Col6
Myopathy
Nadeau A, Kinali M, Main M, Jimenez-Mallebrera C, Aloysius A, Clement E, North
B, Manzur AY, Robb SA, Mercuri E, Muntoni F. Natural history of Ullrich congenital
muscular dystrophy. Neurology. 2009 Jul 7;73(1):25-31 )
Serial Pulmonary Testing
It’s the trending that matters.
Pulmonary Function Testing: Make every visit
count!
 FVC sitting and supine, pulse ox, ulna length
performed at each clinic visit
 Calculate % predicted FVC
 FVC starting at age 5 years
 Consider starting FVC at age 4 if no cognitive
impairment to train child to perform FVC annually
 Endtidal C02 for all patients on noninvasive
ventilation
5
21-09-2011
Pulmonary Function Tests: Using Handheld Device
for FVC
Serial Pulmonary Testing:
It’s the Trending that Matters
Overnight Pulse Oximetry Indications:
 Increased work of breathing, tachypnea, retractions,
restless sleep, decreased functioning during the day,
morning headache
 Recurrent chest infections
 Poor weight gain
 Forced vital capacity <60% predicted, sleep study
unavailable
 >20% difference between sitting and supine % FVC if
sitting forced vital capacity <80%, sleep study unavailable
Abnormal:
1. <90% on room air for >5min with a low of at least 85%
OR
2. >30% of total sleep time at <90% saturation
Serial Pulmonary Testing:
It’s the Trending that Matters
Blood gas
 Acute onset of respiratory distress
 Noninvasive CO2 monitoring is not available
 If using transcutaneous CO2 or end-tidal CO2, correlate with
PaCO2
Polysomnography- sleep study (includes CO2
monitoring):
 Identify apnea, hypopneas, seizures, and gas exchange
abnormalities
 Obtain if abnormal overnight oximetry
 Obtain if symptomatic in spite normal overnight oximetry
recording.
 To titrate best settings for noninvasive ventilation
Hypoventilation is present if >25% of the total sleep time is
spent with CO2 >50 torr
Nutrition and Bone Health
Peri-operative Respiratory management
10 CMD patients with and without cognitive disability with
average % predicted FVC 30%
 Inclusion criteria: pain secondary to posture, not on
daytime ventilatory support, no evidence of cardiac failure
 6 week pre-operative inspiratory resistance training, using
a simple device that improved % predicted from 30-34%
 During surgery, used short acting anesthetic agents:
sufentanyl and propofol, extubated in recovery room to
noninvasive ventilation (use of cough assist)
 Post operatively- stabilization of % predicted FVC for one
year and then decline
Takaso et al. Surgical correction of spinal deformity in
patients with congenital muscular dystrophy. J Ortho Sci
2010 (15): 493-501
Nutritional Status
 Does improved nutrition improve quality of life?
 Does improved nutrition decrease rate of
respiratory infections?
 Does improved nutrition improve survival?
 How does bone health correlate with nutrition,
vitamin D and mobility?
6
21-09-2011
Nutrition in LAMA2 Related CMD
Assessed feeding difficulties in 14 children:
 12/14 <3% for weight
 14/14 difficulty chewing
 6/14 recurrent chest infection
Intervention: 5/6 had gastrostomy placed with
decrease in rate of chest infection and improved
weight gain to 10%
Philpot et al. Feeding problems in MDC1A. Arch Dis Child.
1999
Gastrostomy placement in peds neuromuscular disease
Ramelli GP et al. Dev Med & Child Neuro
Retrospective chart review of pediatric neuromuscular patients with
gastrostomy at Hammersmith Hospital
Total: 32 patients- 15 patients (CMD), 11 patients (CM), other (6)
Two main qualitative reasons for placing gastrostomy:
1. Swallowing difficulties (feeding problems- dysphagia, weak suck,
aspiration, coughing/choking with meals, frequent chest infection,
vomiting, GERD)
2. Problems with growth and nutrition (poor appetite, fussy eating,
long mealtimes >30 min, inadequate weight gain, inadequate oral
intake, failure to thrive, vomiting, GERD)
Videofluroscopy performed in 25/31 patients, 21 had abnormal VF,
13/21 had aspiration.
17 patients had tried oral supplementation for an average of 2 years and
2 months. 15/17 had static weight.
Post gastrostomy: weight improved in 17/22 patients. Height
improved in 9/14. 26/32 patients had reduced chest infections. No
significant complications noted.
Nutrition and Bone Health
Test
Questionnaire
Test
To assess body
mass index
(BMI), weight
longitudinally
Constipation and To assess bone
Hydration
health
• Standard
protocol for
standing
height,
weight, ulna
length
• Assess on
every visit
• Develop
treatment
plan for static
weight
• Diet
modification
• Increase
supported
movement
(swimming)
• Life context:
limiting
factors to
hydration
• Treatment:
miralax
Nutrition: Key Screening Issues
Questionnaire
Children: 0-3 yrs,
identify aspiration,
ability to eat
Teenagers to adults:
functionally able to
eat, independent?
• 1,25
• Time to eat
dihydroxy
• Referral to
vitamin D
dietician
level
• Abnormal report by
• Calcium and
parents and
• Vitamin D
concern for
supplementati
aspiration: VF
on
• Role for
DEXA
• Role for
bisphosphona
tes?
Nutrition CMD
Goal: Decrease frequency of respiratory infections,
quality of life, fatigue
 Known
 Trending weight and BMI are important
 Being underweight likely multifactorial: respiratory
insufficiency, difficulty eating (jaw contractures, oral
motor weakness), difficulty swallowing, increased
metabolic demand
 Being overweight may cause an earlier loss of ambulation
 Unknown
 Target weight and BMI for individual subtypes is
unknown
 Is there a cachexia phenotype that contributes to weight
issues?
 Length of mealtimes: more than 30 minutes per
meal is considered to be prolonged
 Frequency of meals
 Frequency of pulmonary infections
 Difficulties chewing; choking and coughing
 Food texture modification
 Family stress or enjoyment of mealtimes for the
child and parents
 The ability to feed independently
 Position for feeding
Motor Function: What is a Research and what
is part of routine clinical visit?
Test
Functional Scale
Handout
Assess Maximal and
Current Motor
Functiion
PEDI
Explain difference
between contracture
and weakness
Myometry
Physical therapy:
stretching
Goniometry
Timed Tests
(ambulatory)
Composite motor scales
CHOP Intend,
Hammersmith,
MFM 32,
North Star
7
21-09-2011
Mental Health
Heart Health: L-CMD, aDG, LAMA2 Related CMD
Cardiomyopathy
Arrhythmia
Echo
EKG
Holter monitor
Depression Screening in Caregiver and
Affected Individual
PHQ2, PHQ9
Reduce “disease burden” for
families where heart not
implicated, institute
surveillance for CMD
subtypes where
cardiomyopathy is prevalent
Cognition
No cognitive
impairment
Encourage placement of
child in regular education
with appropriate support.
Cognitive impairment
Referral to state services for
people with cognitive
impairment
Early PT/OT/Speechintegrate program
Seizure control
Emotional support for
families
An emphasis on
communication not
ambulation as key to quality of
life.
Treatment: LGMD ? Case reports
Reference
Patient cases
Godfrey et al. Ann Neurol. 2006
Fukutin mutation
Patient 1: hypotonia during first few
months, 10 months with febrile illness,
paralyzed, slow recovery
Patient 2: 4 months Coxsackie
(herpangina), hypotonic, lost head ability,
resolved except unable to roll, with
persistent gross motor developmental
delay
Patient 3: 4 months truncal weakness,
hypotonia with CK, 13,000. 1 year unable
to roll or sit
Darin et al, Eur J Paediatr Neurol 2007
FKRP mutation
Patient 1: 1year URI, transient loss of neck
muscle/head control, 2 yrs of age URIwaddling gait
Patient 2: 16 months URI, ptosis, neck
control and walking.
Treatment
Case reports of steroid responsive children with aDG
labeled as LGMD who in case report have congenital
onset of symptoms.
Anecdotal reports of steroid responsive CMD/LGMD MR
ambulatory children with dystroglycanopathy
Recent report of steroid responsive L-CMD: 4/9 patients,
ambulatory cohort, initiated between age 10 months-3
years (average length of treatment= 8 years)
Komaki H et al. Inflammatory changes in infantile-onset
LMNA-associated myopathy. Neuromuscular Dis 2011
Key Messages
For the majority of CMD subtypes, there is NO
treatment, outside of optimization of medical care.
Optimization of medical care may have a bigger
treatment effect than any potential therapeutic target
currently under preclinical investigation.
Improved nutrition, pulmonary management and good
orthopedic/rehab follow up may have the greatest
impact on quality of life and survival.
Trending nutrition, respiratory involvement and muscle
strength is key.
8
21-09-2011
Interventions
Consider interventions where appropriate:
 oral supplementation or ngtube: initial
plateau/decline in weight/height
 gastrostomy: plateau or decline in weight/height,
aspiration, recurrent chest infection
 respiratory resistance training or hyperinsufflation
(peri-operative period)
 noninvasive ventilation: night-time hypoventilation
and/or hypercapnea
 prednisone: ambulatory aDG and L-CMD
Developing Meaningful CMD Clinical
Research
 Highlight the key care parameters that impact CMD
quality of life and survival: nutrition, respiratory care,
scoliosis management, contracture management
 Define clinical hypotheses to answer key unknowns:
what is target BMI for patients with LAMA 2 related
CMD
 Develop studies to create evidence based guidelines:
two cohorts, children with LAMA 2 CMD below 5%
randomization to gastrostomy versus nutritional
support, outcomes: resp infection, hospitalization,
QoL
 Define local and national resources: subspecialty
service, equipment, access
Develop Meaningful CMD Clinical Research
 Define a core set of care parameters: what is
reasonable given local resources
 Define and implement a clinic checklist: implement
“the reasonable” across each patient visit
 Use implementation to test hypothesis regarding
efficacy of specific care parameters: does
implementing reasonable measures improve
survival, rate of hospitalization compared to
retrospective data?
 Setting up collaborative sites: strength in numbers
9