ABSTRACT
Pain is prevalent in individuals with limb-girdle muscular dystrophy (LGMD) R9, but impact on daily living and correlation with fatigue remain unknown. Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference and fatigue short forms were completed annually by 23 children and 54 adults with biallelic fukutin-related protein (FKRP) variants for up to six years. Concurrent motor and pulmonary function were evaluated. Pain interference T-scores were near the normal mean of 50 by linear mixed model analysis (48.5 in children, 51.6 in adults). 58% of participants experienced pain interference levels greater than the general population on at least one assessment. Fatigue T-scores were elevated in adults but not children (49.0 in children, 55.1 in adults), and 75% had at least one elevated fatigue score. Of participants with at least two visits, serial scores were not consistent across visits, without a clear pattern. Pain interference and fatigue were positively correlated (r = 0.55). Both increased with older age (r = 0.21 and 0.41 respectively). Neither differed by sex or ambulation status. Motor (r=-0.32) and pulmonary (r=-0.25) function correlated with fatigue in adults, not children. Results suggest that pain in those with LGMDR9 is variable and episodic, limiting impact on daily life, while fatigue increases over time.
Subject(s)
Muscular Dystrophies, Limb-Girdle , Adult , Humans , Muscular Dystrophies, Limb-Girdle/complications , Pain/etiology , Fatigue/etiology , PentosyltransferasesABSTRACT
Diagnostic journey for people with FKRP mutations participating in a dystroglycanopathy natural history study (nâ¯=â¯68; NCT00313677) was analyzed. Earliest symptoms and age at muscular dystrophy diagnosis were abstracted from subject-reported medical history and record review. Initial signs/symptoms were classified as chronic motor dysfunction (e.g., delayed motor milestones, weakness, falling; nâ¯=â¯40, 59%), elevated transaminases (nâ¯=â¯7, 10%), or acute/intermittent symptoms (myoglobinuria, myalgia, febrile illness-associated acute weakness; nâ¯=â¯21, 31%). Median time from sign/symptom onset to diagnosis was 6.5 years and differed by symptom group: 7.5 years for motor group, 9 years for acute/intermittent group, and 4 years for elevated transaminases group. The sign/symptom category that most commonly resulted in a diagnosis was chronic motor dysfunction (nâ¯=â¯45). Of those without clear weakness as first symptom (nâ¯=â¯55), 36.4% were not diagnosed with MD until weakness became apparent. Median time to diagnosis was shortest for those with febrile illness-associated acute weakness (0.25 years). Median time from first sign/symptom to MD diagnosis has decreased incrementally from 18.8 years for those with onset in the 1970s to < 10 years for symptom onset occurring after 2000. Awareness of disease presentation variability will aid in earlier diagnosis, which is increasingly important with treatments in development.
Subject(s)
Muscular Dystrophies/diagnosis , Muscular Dystrophies/physiopathology , Adolescent , Adult , Aged , Child , Delayed Diagnosis , Female , Humans , Male , Middle Aged , Muscle Weakness/etiology , Muscle Weakness/physiopathology , Muscular Dystrophies/complications , Muscular Dystrophies/genetics , Myoglobinuria/etiology , Pentosyltransferases/genetics , Young AdultABSTRACT
INTRODUCTION: Published information about the experiences of pregnancy in limb girdle muscular dystrophy (LGMD) is limited and does not specify LGMD type, limiting utility. We describe the experience and outcomes of pregnancy in a cohort of women with LGMD type R9 (LGMDR. METHODS: All women 18 y of age or older with a genetic and clinical diagnosis of LGMDR9 who are enrolled in the University of Iowa Wellstone dystroglycanopathy natural history study (clinicaltrials.gov NCT00313677) were invited to complete a questionnaire about their pregnancy experiences, including questions about pregnancy complications, muscle symptoms experienced during pregnancy, and post-partum course. RESULTS: A total of 22 women responded to the survey. Thirteen women reported 26 live births. The majority of pregnancies that resulted in a live birth were uncomplicated (n = 19, 73%), and most infants had no complications (n = 25, 96%). The rates of assisted vaginal delivery (n = 9, 35%) and induction of labor (n = 18, 70%) were both significantly higher than the national average. Almost half of pregnancies (n = 11, 42%) resulted in increased weakness during pregnancy; only one returned to pre-pregnancy baseline. DISCUSSION: The data presented here suggest that women with LGMDR9 who are considering a pregnancy should be counseled that they might have a higher likelihood of assisted vaginal delivery and could experience progression of weakness. These results are generally consistent with previous reports, but future studies of pregnancy in defined subtypes of LGMD will be required to confirm these findings and determine if risks vary by genotype.
Subject(s)
Delivery, Obstetric , Live Birth , Muscular Dystrophies, Limb-Girdle , Pregnancy Outcome , Adult , Female , Health Surveys , Humans , Middle Aged , Pregnancy , Young AdultABSTRACT
INTRODUCTION: Reported frequencies of cardiomyopathy in limb girdle muscular dystrophy R9 (LGMDR9) vary. We describe the frequency and age at onset of cardiomyopathy in an LDMDR9 cohort. METHODS: Echocardiograms from 56 subjects (157 echocardiograms) with LGMDR9 were retrospectively reviewed. The cumulative probability of having an abnormal echocardiogram as a function of age was assessed by survival analysis for interval-censored data by genotype. Correlations between cardiac and clinical function were evaluated. RESULTS: Twenty-five (45%) participants had cardiomyopathy. The median age at first abnormal echocardiogram for subjects homozygous for the c.826C>A variant was 54.2 y compared to 18.1 y for all other fukutin-related protein (FKRP) genotypes (P < .0001). There was a weak correlation between ejection fraction and 10-Meter Walk Test speed (r = 0.25), but no correlation with forced vital capacity (r = 0.08). DISCUSSION: Cardiomyopathy is prevalent among those with LGMDR9 and occurs later in subjects homozygous for the c.826C>A mutation. These data will help to guide surveillance and management.
Subject(s)
Cardiomyopathies/epidemiology , Cardiomyopathies/genetics , Muscular Dystrophies, Limb-Girdle/epidemiology , Adolescent , Adult , Age of Onset , Cardiomyopathies/complications , Female , Genotype , Humans , Male , Middle Aged , Muscular Dystrophies, Limb-Girdle/complications , Pentosyltransferases , Retrospective Studies , Survival AnalysisABSTRACT
OBJECTIVE: To test the hypothesis that we will be able to detect change in motor outcome measures over time in a cohort with mutations in FKRP. METHODS: Individuals with documented FKRP mutations were evaluated annually with a battery of established motor outcome measures including limited quantitative myometry and timed function measures. Results were analyzed using random coefficient regression to determine annual change in each measure. Due to the nonlinear progression through the lifespan of the study participants, pediatric (<19 years) and adult (≥19 years) cohorts were analyzed separately. Effect of genotype was evaluated in each cohort. RESULTS: Sixty-nine participants (30 pediatric, 44 adult) with at least 2 evaluations were included. There was a small but statistically significant decline in timed motor function measures in both pediatric and adult cohorts. Genotype significantly affected rate of decline in the pediatric but not the adult cohort. Some pediatric patients who are homozygous for the c.826C>A mutation showed improving motor performance in adolescence. Performance on the 10-meter walk/run was highly correlated with other timed function tests. CONCLUSIONS: There is a slow annual decline in motor function in adults with FKRP mutations that can be detected with standard motor outcome measures, while the results in the pediatric population were more variable and affected by genotype. Overall, these analyses provide a framework for development of future clinical trials. The dystroglycanopathies natural history study (Clinical Trial Readiness for the Dystroglycanopathies) may be found on clinicaltrials.gov (NCT00313677).
Subject(s)
Disease Progression , Motor Disorders/genetics , Mutation , Pentosyltransferases/genetics , Adolescent , Adult , Child , Disability Evaluation , Female , Genotype , Humans , Longitudinal Studies , Male , Middle Aged , Young AdultABSTRACT
OBJECTIVE: To describe the phenomenon of acute illness-associated weakness (AIAW) in patients with dystroglycanopathy (DG), determine the frequency of this phenomenon in DGs, and compare it to the frequency in Duchenne-Becker muscular dystrophy (DBMD). METHODS: Patients enrolled in a DG natural history study provided medical history, including major illnesses or hospitalizations, at enrollment and annually. We noted a recurring syndrome of profound transient weakness in the setting of febrile illness. To determine the frequency of this phenomenon in the DG cohort and compare it to a cohort with another membrane-related muscular dystrophy, DBMD, we surveyed patients (e-survey tool), collecting demographics and information about episodes of sudden progression of weakness and events surrounding the episodes. RESULTS: Surveys were completed by 52 (56.6%) patients with DG and 51 (27.3%) patients with DBMD. AIAW was reported in 12 (23%) patients with DG and 2 (4%) patients with DBMD (odds ratio 7.35; 95% confidence interval 1.55, 34.77; p = 0.005). Altogether (history or survey), 21 patients with DG, with mutations in FKRP, FKTN, POMT1, POMT2, or POMGNT1, reported AIAW. These events typically occurred in children <7 years old, and the preceding illness usually included respiratory symptoms. In 10 (47.6%) patients with DG, AIAW preceded the diagnosis of muscular dystrophy. CONCLUSIONS: People with DG, across genotypes, can experience acute, transient weakness associated with a febrile illness, a phenomenon that rarely occurs in DBMD. The physiologic basis of this phenomenon is unknown. CLINICALTRIALSGOV IDENTIFIER: NCT00313677.
Subject(s)
Dystroglycans/genetics , Muscle Weakness/etiology , Adolescent , Adult , Age of Onset , Child , Child, Preschool , Cohort Studies , Cross-Sectional Studies , Female , Fever/complications , Genotype , Humans , Infant , Male , Muscle Proteins/genetics , Muscle Weakness/epidemiology , Muscle Weakness/genetics , Muscular Dystrophy, Duchenne/complications , Muscular Dystrophy, Duchenne/epidemiology , Young AdultABSTRACT
OBJECTIVE: To describe the spectrum of brain MRI findings in a cohort of individuals with dystroglycanopathies (DGs) and relate MRI results to function. METHODS: All available brain MRIs done for clinical indications on individuals enrolled in a DG natural history study (NCT00313677) were reviewed. Reports were reviewed when MRI was not available. MRIs were categorized as follows: (1) cortical, brainstem, and cerebellar malformations; (2) cortical and cerebellar malformations; or (3) normal. Language development was assigned to 1 of 3 categories by a speech pathologist. Maximal motor function and presence of epilepsy were determined by history or examination. RESULTS: Twenty-five MRIs and 9 reports were reviewed. The most common MRI abnormalities were cobblestone cortex or dysgyria with an anterior-posterior gradient and cerebellar hypoplasia. Seven individuals had MRIs in group 1, 8 in group 2, and 19 in group 3. Language was impaired in 100% of those in MRI groups 1 and 2, and degree of language impairment correlated with severity of imaging. Eighty-five percent of the whole group achieved independent walking, but only 33% did in group 1. Epilepsy was present in 8% of the cohort and rose to 37% of those with an abnormal MRI. CONCLUSIONS: Developmental abnormalities of the brain such as cobblestone lissencephaly, cerebellar cysts, pontine hypoplasia, and brainstem bowing are hallmarks of DG and should prompt consideration of these diagnoses. Brain imaging in individuals with DG helps to predict outcomes, especially language development, aiding clinicians in prognostic counseling.
Subject(s)
Brain/diagnostic imaging , Language , Magnetic Resonance Imaging , Motor Activity , Muscular Dystrophies/diagnostic imaging , Muscular Dystrophies/physiopathology , Adolescent , Brain/abnormalities , Child , Child, Preschool , Epilepsy/diagnostic imaging , Epilepsy/physiopathology , Epilepsy/psychology , Female , Humans , Infant , Language Development Disorders/diagnostic imaging , Language Development Disorders/physiopathology , Language Tests , Male , Muscular Dystrophies/psychology , Retrospective StudiesABSTRACT
Limb girdle muscular dystrophy 2I is a slowly progressive muscular dystrophy due to mutations in the Fukutin-related protein ( FKRP) gene. Clinicians are frequently asked if physical activity is harmful for pediatric patients with limb girdle muscular dystrophy 2I. The primary objective of this study was to determine if there is a relationship between self-reported childhood activity level and motor function and respiratory function in older children and adults with limb girdle muscular dystrophy 2I. We compared retrospective self-reported middle school activity level and sport participation with age at onset of weakness, 10-meter walk test, and forced vital capacity later in life in 41 participants with FKRP mutations. We found no relationship between activity level in childhood and disease course later in life, suggesting that self-directed physical activity in children with limb girdle muscular dystrophy 2I does not negatively affect disease progression and outcome.
Subject(s)
Exercise , Muscular Dystrophies, Limb-Girdle/physiopathology , Sports , Adolescent , Adult , Age of Onset , Aged , Child , Disease Progression , Humans , Middle Aged , Muscular Dystrophies, Limb-Girdle/genetics , Pentosyltransferases , Proteins/genetics , Retrospective Studies , Self Report , Vital Capacity , Walk Test , Young AdultABSTRACT
BACKGROUND: Mutations in the X-linked gene encoding dystrophin cause skeletal and cardiac muscle diseases in men. Female "carriers" also can develop overt disease. The purpose of this study was to ascertain the prevalence of cardiac contractile abnormalities in dystrophinopathy carriers. METHODS: Twenty-four dystrophinopathy heterozygotes and 24 normal women each underwent standard exercise stress echocardiography. RESULTS: Heterozygotes demonstrated mildly lower left ventricular ejection fractions (LVEFs) at rest compared with controls (0.56 + or - 0.10 vs 0.62 + or - 0.07, P = .02). After exercise, the mean LVEF fell to 0.53 + or - 0.14 in heterozygotes but rose to 0.73 + or - 0.07 in controls (P < .001). Twenty-one of 24 dystrophinopathy heterozygotes demonstrated > or = 1 of the following: abnormal resting LVEF, abnormal LVEF response to exercise, or exercise-induced wall motion abnormality. CONCLUSIONS: Women heterozygous for dystrophinopathy demonstrate significant left ventricular systolic dysfunction, which is unmasked by exercise. This finding has mechanistic implications for both inherited and acquired cardiac disease states.
Subject(s)
Dystrophin/genetics , Heterozygote , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/genetics , Adult , Echocardiography , Exercise Test , Female , Humans , Loss of Heterozygosity/genetics , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
Mutations in the DMD gene, encoding the dystrophin protein, are responsible for the dystrophinopathies Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X-linked Dilated Cardiomyopathy (XLDC). Mutation analysis has traditionally been challenging, due to the large gene size (79 exons over 2.2 Mb of genomic DNA). We report a very large aggregate data set comprised of DMD mutations detected in samples from patients enrolled in the United Dystrophinopathy Project, a multicenter research consortium, and in referral samples submitted for mutation analysis with a diagnosis of dystrophinopathy. We report 1,111 mutations in the DMD gene, including 891 mutations with associated phenotypes. These results encompass 506 point mutations (including 294 nonsense mutations) and significantly expand the number of mutations associated with the dystrophinopathies, highlighting the utility of modern diagnostic techniques. Our data supports the uniform hypermutability of CGA>TGA mutations, establishes the frequency of polymorphic muscle (Dp427m) protein isoforms and reveals unique genomic haplotypes associated with "private" mutations. We note that 60% of these patients would be predicted to benefit from skipping of a single DMD exon using antisense oligonucleotide therapy, and 62% would be predicted to benefit from an inclusive multiexonskipping approach directed toward exons 45 through 55.