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1.  Splicing biomarkers of disease severity in myotonic dystrophy 
Annals of neurology  2013;74(6):862-872.
To develop RNA splicing biomarkers of disease severity and therapeutic response in myotonic dystrophy type 1 (DM1) and type 2 (DM2).
In a discovery cohort we used microarrays to perform global analysis of alternative splicing in DM1 and DM2. The newly identified splicing changes were combined with previous data to create a panel of 50 putative splicing defects. In a validation cohort of 50 DM1 subjects we measured the strength of ankle dorsiflexion (ADF) and then obtained a needle biopsy of tibialis anterior (TA) to analyze splice events in muscle RNA. The specificity of DM-associated splicing defects was assessed in disease controls. The CTG expansion size in muscle tissue was determined by Southern blot. The reversibility of splicing defects was assessed in transgenic mice by using antisense oligonucleotides (ASOs) to reduce levels of toxic RNA.
Forty-two splicing defects were confirmed in TA muscle in the validation cohort. Among these, 20 events showed graded changes that correlated with ADF weakness. Five other splice events were strongly affected in DM1 subjects with normal ADF strength. Comparison to disease controls and mouse models indicated that splicing changes were DM-specific, mainly attributable to MBNL1 sequestration, and reversible in mice by targeted knockdown of toxic RNA. Splicing defects and weakness were not correlated with CTG expansion size in muscle tissue.
Alternative splicing changes in skeletal muscle may serve as biomarkers of disease severity and therapeutic response in myotonic dystrophy.
PMCID: PMC4099006  PMID: 23929620
2.  Patient Identification of the Symptomatic Impact of Charcot Marie Tooth Disease Type 1A 
The burden of Charcot Marie Tooth type 1A, the most common inherited peripheral neuropathy, including impact on patient quality of life is not well understood. This study aims to qualitatively describe the range of symptoms associated with Charcot Marie Tooth type 1A and impact on quality of life.
We performed qualitative interviews with 16 adult Charcot Marie Tooth type 1A patients. Each interview was analyzed using a qualitative framework technique to identify and index symptoms by theme.
Sixteen patients provided 656 quotes. One hundred and forty-five symptoms of importance were identified representing 20 symptomatic themes. Symptoms associated with difficulty with mobility and ambulation, specific activity impairment, and emotional distress were the most frequently mentioned.
Multiple symptoms contribute to Charcot Marie Tooth type 1A disease burden, some previously under-recognized. Improved recognition of under-recognized symptoms will optimize patient care and quality of life.
PMCID: PMC3752697  PMID: 23965405
Charcot Marie Tooth disease type 1A; quality of life; symptoms; inherited neuropathies
3.  Evoked myotonia can be “dialed-up” by increasing stimulus train length in Myotonic Dystrophy Type 1 
Muscle & nerve  2010;41(2):191-196.
It is unknown how evoked myotonia varies with stimulus frequency or train length, or how it compares to voluntary myotonia in myotonic dystrophy type 1 (DM1).
First dorsal interosseous (FDI) tetanic contractions evoked by trains of 10–20 ulnar nerve stimuli at 10–50 Hz were recorded in 10 DM1 patients and 10 normals. For comparison, maximum voluntary handgrip contractions were also recorded. An automated computer program placed cursors along the declining (relaxation) phase of the force recordings at 90 and 5% of peak force (PF) and calculated relaxation times (RTs) between these points.
For all stimulus frequencies and train lengths, evoked RTs were much shorter, and evoked PFs were much greater in normals than in DM1. In normals, evoked RT was independent of stimulus frequency and train length, while in DM1, RT was longer for train lengths of 20 stimuli (mean:9 seconds in DM1; 0.20 in normals) than for 10 stimuli (mean:3 seconds in DM1, 0.19 in normals), but it did not change with stimulus frequency. In both groups, PF increased greatly as stimulus frequency rose from 10 to 50 Hz but only slightly as train length rose from 10 to 20 stimuli. Voluntary handgrip RT (mean:1.9 seconds) was less than evoked FDI RT (mean:9 seconds).
In DM1, evoked RT can be “dialed up” by increasing stimulus train length. Evoked myotonia testing utilizing a stimulus paradigm of at least 20 stimuli at 30–50 Hz may be useful in anti-myotonic drug trials, particularly when grip RT is normal or equivocal.
PMCID: PMC4122294  PMID: 19750543
myotonia; myotonic dystrophy; handgrip; relaxation time
4.  Patient Identified Disease Burden in Facioscapulohumeral Muscular Dystrophy 
Muscle & nerve  2012;46(6):951-953.
The multitude of symptoms associated with facioscapulohumeral muscular dystrophy (FSHD) disease burden are of varying importance. The extent of these symptoms and their cumulative effect on the FSHD population is unknown.
We conducted interviews with adult FSHD patients to identify which symptoms have the greatest effect on their lives. Each interview was recorded, transcribed, coded, and analyzed using a qualitative framework technique, triangulation, and 3-investigator consensus approach.
1375 quotes were obtained through 20 patient interviews. 251 symptoms of importance were identified representing 14 themes of FSHD disease burden. Symptoms associated with mobility impairment, activity limitation, and social role limitation were most frequently mentioned by participants.
There are multiple themes and symptoms, some previously under-recognized, that play a key role in FSHD disease burden.
PMCID: PMC4097080  PMID: 23225386
Facioscapulohumeral muscular dystrophy; quality of life; disease burden; neuromuscular disorders; symptoms
5.  Teaching Video NeuroImages: Trapezius myotonia percussion sign in myotonic dystrophy type 2 
Neurology  2013;80(24):e251.
Myotonic dystrophy type 2 (DM2) is an autosomal dominant disorder with proximal weakness, muscle pain, and early-onset cataracts.1 In comparison with myotonic dystrophy type 1 (DM1), myotonia is less symptomatic, more proximal, and harder to detect during clinical and electrodiagnostic testing.2 Here we document the presence of trapezius myotonia in patients with DM2 (video on the Neurology® Web site at In our experience, similar proximal percussion does not produce as marked a response in DM1 or nondystrophic myotonic disorders. This sign demonstrates a mechanism to test for proximal myotonia, and in at-risk patients, may be suggestive of an underlying diagnosis of DM2.
PMCID: PMC3721102  PMID: 23751923
6.  Reevaluating Measures of Disease Progression in Facioscapulohumeral Muscular Dystrophy 
Neuromuscular disorders : NMD  2013;23(4):306-312.
Recent advances in the understanding of the molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) have identified potential therapeutic targets. Consequently, an accurate understanding of disease progression in FSHD is crucial for the design of future clinical trials. Data from 228 subjects in 3 clinical trials and 1 natural history study were compared to examine disease progression in FSHD. All studies utilized the same techniques for manual muscle testing and maximum voluntary isometric contraction testing. Both techniques yield a total strength score that can be followed over time as an indicator of disease progression. Whereas natural history data showed a decrease in strength over 1 year, there was an apparent increase in strength at 6 months in 2 of the 3 clinical trials in both the placebo and treatment groups, that persisted for up to 1 year for maximum voluntary isometric contraction testing. Variability estimates from the clinical trial data were consistent with those seen in the natural history data. Patients in clinical trials in FSHD may have better outcomes than those in natural history studies, regardless of treatment assignment, emphasizing the importance of placebo groups and the need for caution when interpreting the strength results of controlled and uncontrolled trials.
PMCID: PMC3602208  PMID: 23406877
1. All neuromuscular disease; 2. Muscle disease; 3. Outcome research; 4. All clinical trials; 5. Clinical trials methodology/study design
7.  Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1) 
Neurology  2012;79(4):348-357.
To determine the most critical symptoms in a national myotonic dystrophy type 1 (DM1) population and to identify the modifying factors that have the greatest effect on the severity of these symptoms.
We performed a cross-sectional study of 278 adult patients with DM1 from the national registry of patients with DM1 between April and August 2010. We assessed the prevalence and relative significance of 221 critical DM1 symptoms and 14 disease themes. These symptoms and themes were chosen for evaluation based on prior interviews with patients with DM1. Responses were categorized by age, CTG repeat length, gender, and duration of symptoms.
Participants with DM1 provided symptom rating survey responses to address the relative frequency and importance of each DM1 symptom. The symptomatic themes with the highest prevalence in DM1 were problems with hands or arms (93.5%), fatigue (90.8%), myotonia (90.3%), and impaired sleep or daytime sleepiness (87.9%). Participants identified fatigue and limitations in mobility as the symptomatic themes that have the greatest effect on their lives. We found an association between age and the average prevalence of all themes (p < 0.01) and between CTG repeat length and the average effect of all symptomatic themes on participant lives (p < 0.01).
There are a wide range of symptoms that significantly affect the lives of patients with DM1. These symptoms, some previously underrecognized, have varying levels of importance in the DM1 population and are nonlinearly dependent on patient age and CTG repeat length.
PMCID: PMC3400095  PMID: 22786587
8.  Plasma Exchange vs. Intravenous Immunoglobulin for Myasthenia Gravis Crisis: An Acute Hospital Cost Comparison Study 
To compare the short term financial costs of treating a patient in myasthenia gravis crisis (MGC) with intravenous immunoglobulin (IVIG) versus plasma exchange (PLEX).
An itemized comparative cost-minimization analysis of IVIG vs. plasma exchange for MGC was performed. Calculations were based on each therapy’s implementation cost, associated hospitalization times, and predicted cost to treat known complications. A cost superiority determination was proposed based on the total cost profile of each therapy.
The difference in total cost favored IVIG over PLEX with an average savings of $22,326 per patient. Sensitivity analysis demonstrated that overall costs are highly dependent on IVIG dosing, hospital lengths of stay, and the number of plasma exchange days required.
The use of IVIG for MGC may be a short term cost minimizing therapy compared to PLEX. Additional prospective studies are required to evaluate the extended cost profile and efficacy of these therapies.
PMCID: PMC3291869  PMID: 22361692
9.  Laboratory Abnormalities in Patients with Myotonic Dystrophy Type 2 
Archives of neurology  2011;68(9):1180-1184.
Myotonic dystrophy type-2 (DM2) is a recently discovered adult muscular dystrophy. Similar to DM1, this disease causes progressive debilitating weakness, clinical myotonia, and early cataracts, and is thought to cause widespread physiologic dysfunction of multiple organ systems.
To analyze and compile the laboratory abnormalities of patients with DM2.
Baseline DM2 laboratory data were compiled representing 68 different types of laboratory tests and 1442 total studies.
University Medical Center.
Eighty-three adults with genetically confirmed or clinically probable DM2 were identified. Of these patients, 49 had documented baseline laboratory screening.
Main Outcome Measures
The individual frequencies of abnormal values in the population with DM2 studied.
Of the 1442 studies, results for 359 (24.9%) were outside of their standard reference ranges. Of the 68 types of laboratory tests studied, 43 had values from fifteen or more different patients with DM2. The relative frequency of an abnormally elevated laboratory value was greater than 50% in several tests, including the levels of creatine kinase, total cholesterol, lactate dehydrogenase, and alanine aminotransferase (ALT). In addition, serum levels of immunoglobulin G (IgG) were low in 75% of all DM2 patients tested and absolute lymphocyte counts were low in 54% of all DM2 patients tested.
There is a high frequency of laboratory abnormalities in patients with DM2. These abnormalities provide insight into the widespread pathologic manifestations of DM2 and may form a basis for clinical monitoring and disease screening.
PMCID: PMC3429333  PMID: 21911698
10.  An Open-Label Trial of Recombinant Human Insulin-Like Growth Factor-I/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 (rhIGF-1/rhIGFBP-3) in Myotonic Dystrophy Type 1 
Archives of Neurology  2010;68(1):37-44.
To evaluate the safety and tolerability of recombinant human insulin-like growth factor-1 (rhIGF-1) complexed with IGF binding protein-3 (rhIGF-1/rhIGFBP-3) in patients with myotonic dystrophy type 1 (DM1).
Open-label dose-escalation clinical trial.
University medical center.
Fifteen moderately affected ambulatory participants with genetically-proven DM1.
Participants received escalating dosages of subcutaneous rhIGF-1/rhIGFBP-3 over 24 weeks followed by a 16 week washout period.
Outcome Measures
Serial assessments of safety, muscle mass, muscle function, and metabolic state were performed. The primary outcome variable was the ability of participants to complete 24 weeks on rhIGF-1/rhIGFBP-3 treatment.
All participants tolerated rhIGF-1/rhIGFBP-3. There were no significant changes in muscle strength or functional outcomes measures. Lean body muscle mass measured by dual energy x-ray absorptiometry increased by 1.95 kg (p=0.0007) after treatment. Participants also experienced a mean reduction in triglyceride levels of 47 mg/dL (p=0.002), a mean increase in HDL levels of 5.0 mg/dL (p=0.03), a mean reduction in HbA1c of 0.15% (p=0.03), and a mean increase in testosterone level (in men) of 203 ng/dL (p=0.002) while on rhIGF-1/rhIGFBP-3. Mild reactions at the injection site occurred (n=9 participants), as did mild transient hypoglycemia (n=3), lightheadedness (n=2), and transient papilledema (n=1).
rhIGF-1/rhIGFBP-3 treatment was generally well tolerated in DM1. rhIGF-1/rhIGFBP-3 was associated with increased lean body mass and improvements in metabolism, but not with increased muscle strength or function. Larger randomized controlled trials would be needed to further evaluate the efficacy and safety of this medication in patients with neuromuscular disease.
PMCID: PMC3374954  PMID: 20837825
11.  Mycophenolate mofetil for myasthenia gravis: a clear and present controversy 
Mycophenolate mofetil (MMF) has been used to treat myasthenia gravis (MG) for over 10 years. MMF’s use in the MG population stems from its theoretical mechanism of action and the medical literature that supports its benefit in MG patients. Recently, two large, double-blinded, placebo-controlled, randomized clinical trials were initiated to study the effectiveness of MMF for MG. One of these studies found no benefit in taking MMF with 20 mg of prednisone as compared to taking prednisone alone, while the other study demonstrated no advantage in taking MMF against placebo during a 36-week prednisone taper. This article critically reviews the medical literature on MMF’s use in MG and suggests further research avenues on this topic.
PMCID: PMC2646649  PMID: 19337460
myasthenia gravis; mycophenolate mofetil; CellCept

Results 1-11 (11)