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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 A mutation. These data will help to guide surveillance and management.

ObjectiveTo test the hypothesis that we will be able to detect change in motor outcome measures over time in a cohort with mutations in FKRP.MethodsIndividuals 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 (ResultsSixty-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.ConclusionsThere 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).

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.

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.

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 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.Clinicaltrials.gov identifier:NCT00313677.

Objective: To describe the hearing loss in facioscapulohumeral muscular dystrophy (FSHD) and examine the relationship to genotype. Methods: Medical records of all individuals with FSHD seen at the University of Iowa neuromuscular clinic between July 2006 and July 2012 (n = 59) were reviewed. Eleven had significant hearing loss and no non-FSHD cause. All available audiology records for these individuals were analyzed. The relationship between the FSHD mutation (EcoRI/BlnI fragment size) and hearing loss was evaluated using a logistic regression analysis. Results: In patients with hearing loss, recalled age at onset of facial weakness ranged from birth to 5 years and shoulder weakness was 3 to 15 years. The age at diagnosis of hearing loss ranged from birth to 7 years. Only 2 were identified by newborn hearing screen. Most audiograms demonstrated a bilateral, sloping, high-frequency sensorineural hearing loss. Of the 4 patients with more than 5 years of data, 3 had progression of hearing loss. Logistic regression showed statistically significant negative association between the presence of hearing loss and EcoRI/BlnI fragment size ( p = 0.0207). Conclusions: FSHD with a small EcoRI/BlnI fragment is associated with a bilateral, progressive, sloping, high-frequency hearing loss with onset in childhood. Patients with FSHD and small EcoRI/BlnI fragment sizes should have hearing screened, even if the child passed newborn hearing screening.

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.Twenty-four dystrophinopathy heterozygotes and 24 normal women each underwent standard exercise stress echocardiography.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 demonstratedor = 1 of the following: abnormal resting LVEF, abnormal LVEF response to exercise, or exercise-induced wall motion abnormality.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.

Fukutin-related protein ( FKRP; OMIM #606596) is critical for the appropriate glycosylation of α-dystroglycan, a component of the dystrophin-glycoprotein complex. The 12-kb FKRP gene is composed of 3 noncoding exons and 1 exon encompassing the entire open reading frame.1 Mutations in FKRP cause autosomal recessive muscular dystrophy with a wide range of clinical severity. A common missense mutation, c.826C>A (p.L276I), has been identified. Generally, individuals homozygous for this mutation have a mild form of limb-girdle muscular dystrophy (LGMD) 2I, compound heterozygotes with 1 c.826C>A allele have a more severe form of LGMD 2I, and those with 2 unique alleles are most severely affected, including some with congenital muscular dystrophy.1,2 We report a high incidence of myoglobinuria and muscle pain in a retrospective study of patients with LGMD 2I. ### Methods. #### Standard protocol approvals, registrations, and patient consents. Institutional Review Board approval was obtained for all recruitment and data collection. Written informed consent was obtained from all participants or their legal guardians. This study was posted on clinicaltrials.gov (NCT00313677). All patients with FKRP mutations were eligible for enrollment from 2006 to the present. #### Genetic testing. FKRP mutations were confirmed in the University of Iowa …

Mutations in FKRP, critical for normal glycosylation of alpha-dystroglycan, result in clinically heterogeneous muscular dystrophy. Purpose: Describe the clinical phenotype and progression in a cohort of patients with FKRP mutations who were followed with annual standardized assessments. Methods: IRB approval was obtained. Subjects are enrolled in an ongoing Dystroglycanopathy natural history study. The current report includes all patients with FKRP mutations. Data collection included MMT, myometry, timed function tests, mutation analysis and historical information. Forty-three participants, ages 1–51years, have been followed for p