Differences in Race and Ethnicity in Muscular Dystrophy Mortality Rates for Males under 40 Years of Age, 2006-2015.

BACKGROUND/AIMS: Duchenne Muscular Dystrophy (DMD) has childhood onset, primarily affects males, and is usually fatal before the age of 40 years. Previous studies have indicated that this X-linked condition is more prevalent in whites than in blacks, but those were based on active surveillance, and limited to smaller populations and younger ages. METHODS: US death data were used to calculate mortality rates by race and ethnicity, with MD as either the underlying or multiple cause of death (MCD). Poisson approximation was used for confidence intervals; chi-square was used to compare rates. RESULTS: From 2006 to 2015, there were 3,256 deaths in males <40 years with MD as MCD, and 71% of these were aged 15-29 years. For whites, the average annual death rate was 0.43/100,000, which was significantly higher (p < 0.0001) that that of blacks (0.28), American Indian/Alaska Natives (0.20), and Asian/Pacific Islanders (0.21). The rate for non-Hispanic whites (0.46) was significantly higher (p < 0.0001) than the rates for Hispanic whites (0.31), Hispanic blacks (0.07), and non-Hispanic blacks (0.29). CONCLUSION: Since DMD is the primary cause of deaths in young males with MD, mortality rates are a reasonable proxy for the relative difference in racial prevalence. It appears that DMD is significantly more common in white males than in males of other races.

Disparities in health care utilization by race among teenagers and young adults with muscular dystrophy.

BACKGROUND: For people with muscular dystrophy (MD) health care access is crucial and utilization is expected to be high. A multidisciplinary approach is needed for optimal management of symptoms of this rare condition. Regular primary care, specialty care, therapy, and medicine use can improve quality of care and reduce need for emergency treatment and hospitalization. We analyzed health insurance and administrative data to test for racial disparities in regular care use among teenagers and young adults with MD. METHODS: We used South Carolina Medicaid and other administrative data for individuals aged 15-24 years to determine annual health care utilization patterns for individuals with MD by race. We studied adolescents and young adults with MD because this age group represents a time when the condition is typically intensifying and the transition from pediatric to adult care is expected. We used Generalized Estimating Equation models to analyze longitudinal utilization data conditional on other factors that may lead to utilization differences. RESULTS: Race is correlated with health care utilization among adolescents and young adults with MD. Blacks have lower overall utilization, and less primary care, therapy, and specialist care use but higher incidence of hospitalization and emergency treatment use compared with whites and also to other races. The most striking disparity was the use of outpatient services. Blacks utilized these services 50% less compared with whites and 70% less compared with others. Even in regression analysis, where we take into account individual unobserved factors and allow clustering at the individual level, these differences remained and were in most cases statistically significant. CONCLUSIONS: Our results indicate that there are differences in health care utilization by race even when individuals have access to the same health care benefits. This means simply offering coverage to individuals with MD may not be sufficient in eliminating health disparities. Future studies will be needed to examine other possible sources of these racial disparities, such as resource awareness, health knowledge, or access barriers such as transportation.

Ethnically diverse causes of Walker-Warburg syndrome (WWS): FCMD mutations are a more common cause of WWS outside of the Middle East.

Walker-Warburg syndrome (WWS) is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations. Mutations in six genes involved in the glycosylation of á-dystroglycan (POMT1, POMT2, POMGNT1, FCMD, FKRP and LARGE) have been identified in WWS patients, but account for only a portion of WWS cases. To better understand the genetics of WWS and establish the frequency and distribution of mutations across WWS genes, we genotyped all known loci in a cohort of 43 WWS patients of varying geographical and ethnic origin. Surprisingly, we reached a molecular diagnosis for 40% of our patients and found mutations in POMT1, POMT2, FCMD and FKRP, many of which were novel alleles, but no mutations in POMGNT1 or LARGE. Notably, the FCMD gene was a more common cause of WWS than previously expected in the European/American subset of our cohort, including all Ashkenazi Jewish cases, who carried the same founder mutation.

A Roma founder BIN1 mutation causes a novel phenotype of centronuclear myopathy with rigid spine.

OBJECTIVE: To describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified. METHODS: Patients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed. RESULTS: Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma. CONCLUSION: We have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.

Congenital muscular dystrophy in Arab children.

The congenital muscular dystrophies are autosomal recessive disorders with different clinical phenotypes, the spectrum of which varies between different ethnic communities. We report our findings in 21 Arab children with congenital muscular dystrophy. All 21 cases were of the pure type, with normal mental status, except 1 case with perinatal hypoxic-ischemic insult. Fourteen were laminin alpha2 (merosin) deficient, and six were laminin alpha2 positive; laminin alpha2 status was not determined in one patient. None of the laminin alpha2-deficient patients achieved independent ambulation, whereas three of the laminin alpha2-positive patients were able to walk. The elevated levels of serum creatine kinase did not differentiate the two groups and tended to decrease after the age of 5 years. Radiologic evaluation demonstrated an abnormal central white-matter signal in 11 of 13 laminin alpha2-deficient and in 1 of 5 laminin alpha2-positive patients; none had evidence of brain dysplasia. Nerve conduction velocities were normal in 5 of 5 laminin alpha2-positive patients, whereas in the laminin alpha2-deficient patients, it was slow in 9 of 11 for the motor nerves and normal in 8 of 9 for the sensory nerve. Two of the laminin alpha2-positive patients had pseudohypertrophy of the calves, and two of the laminin alpha2-deficient ones had seizures. The patient in whom the laminin alpha2 status was not determined had a severe course, an abnormal central white-matter signal, and epilepsy and resembled more the laminin alpha2-deficient group.

Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population.

BACKGROUND: Mutations in the dysferlin (DYSF) gene cause 3 different phenotypes of muscular dystrophies: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal anterior compartment myopathy. OBJECTIVE: To present the results of clinical and molecular analysis of 8 patients with dysferlinopathy from 5 unrelated families. DESIGN: Clinical assessment was performed with a standardized protocol. A muscle biopsy specimen was obtained and studied by immunohistochemistry. Genetic analysis was performed using single-stranded conformation polymorphism and direct sequencing of genomic DNA. RESULTS: All the patients presented the R1905X mutation in the DYSF gene in homozygosity, and the haplotype analysis at the DYSF locus revealed that it was a novel and founder mutation. A C-to-T transition at nucleotide position 6086 changes an arginine into a stop codon, leading to premature termination of translation. This mutation was expressed as 3 different clinical phenotypes (limb-girdle muscular dystrophy type 2B, Miyoshi distal myopathy, and distal anterior dysferlinopathy), but only 1 phenotype was found in the same family. CONCLUSIONS: The new R1905X DYSF founder mutation produced the 3 possible dysferlinopathy phenotypes without intrafamilial heterogeneity. This homogeneous population in Sueca, Spain, should be helpful in studying the modifying factors responsible for the phenotypic variability.

Severe limb girdle muscular dystrophy in Spanish gypsies: further evidence for a founder mutation in the gamma-sarcoglycan gene.

Limb-girdle muscular dystrophy type 2C (LGMD2C) is an autosomal recessive muscular dystrophy with primary gamma-sarcoglycan deficiency, generally associated with a severe clinical course. gamma-sarcoglycan, a 35kDa dystrophin-associated protein, is encoded by a single gene on chromosome 13q12. Six different mutations have been described in that gene, and it has been proved they are the origin of the disease. One of these mutations (C283Y), a G-->A transition in codon 283, was recently and exclusively identified in Gypsy patients from different European countries. We report the study of 11 LGMD2C unrelated Gypsy families (nine Spanish and two Portugese). The muscle biopsies of these patients showed a drastically decreased immunostaining with alpha and gamma-sarcoglycan antibodies. All the patients were homozygous for C283Y missense mutation, and all affected chromosomes (patients and heterozygous relatives) carried the allele 5 (112 bp) of the intragenic microsatellite D13S232. Unexpectedly, this allele is most frequent in the Caucasian population but not in the normal Gypsy population. The clinical severity of all patients demonstrates that the C283Y missense mutation in a homozygous state causes a severe LGMD2C (DMD-like). The elevated number of families ascertained let us assume that LGMD2C is prevalent in the Gypsy population, and that all the families have inherited a founding mutation.

A large inbred Palestinian family with two forms of muscular dystrophy.

This paper reports the results of a clinical, genetic and histopathological study of 19 patients belonging to a large inbred Palestinian family living in Um-El-Fahem, a town located in Israel, which is solely inhabited by Arabs. Their custom of marrying only among relatives has kept the genetic homogeneity of the families intact. There were ten cases of congenital muscular dystrophy (CMD) and nine cases of adult limb-girdle muscular dystrophy (LGMD) belonging to two generations of the same family. Both forms showed autosomal recessive inheritance. The patients with congenital muscular dystrophy had generalized muscular weakness and hypotonia at birth without arthrogryposis or CNS involvement and then had a relatively benign evolution with stabilization of the clinical picture at different ages and variable degree of severity. Muscle biopsy showed a dystrophic pattern. The other nine patients presented with the picture of adult limb-girdle muscular dystrophy but with an unusual tendency to the stabilization of symptoms.

Limb girdle muscular dystrophy in Manitoba Hutterites does not map to any of the known LGMD loci.

Limb girdle muscular dystrophy (LGMD) is a heterogeneous group of disorders affecting primarily the shoulder and pelvic girdles. Autosomal dominant and recessive forms have been identified; 8 have been mapped and 1 more has been postulated on the basis of exclusion of linkage. An autosomal recessive muscular dystrophy was first described in 1976 in the Hutterite Brethren, a North American genetic and religious isolate [Shokeir and Kobrinsky, 1976; Clin Genet 9:197-202]. In this report, we discuss the results of linkage analysis in 4 related Manitoba Hutterite sibships with 21 patients affected with a mild autosomal recessive form of LGMD. Because of the difficulties in assigning a phenotype in some asymptomatic individuals, stringent criteria for the affected phenotype were employed. As a result, 7 asymptomatic relatives with only mildly elevated CK levels were assigned an unknown phenotype to prevent their possible misclassification. Two-point linkage analysis of the disease locus against markers linked to 7 of the known LGMD loci and 3 other candidate genes yielded lod scores of < or = -2 at theta = 0.01 in all cases and in most cases at theta = 0.05. This suggests that there is at least 1 additional locus for LGMD.

Are there ethnic differences in deletions in the dystrophin gene?

We studied 160 cases of Duchenne muscular dystrophy (DMD) drawn from all parts of India, using multiplex PCR of 27 exons. Of these, 103 (64.4%) showed intragenic deletions. Most (69.7%) of the deletions involved exons 45-51. The phenotype of cases with deletion of single exons did not differ significantly from those with deletion of multiple exons. The distribution of deletions in studies from different countries was variable, but this was accounted for either by the small number of cases studied, or by fewer exons analyzed. It is concluded that there is likely to be no ethnic difference with respect to deletions in the DMD gene.

Seven autosomal recessive limb-girdle muscular dystrophies in the Brazilian population: from LGMD2A to LGMD2G.

The autosomal recessive limb-girdle muscular dystrophies (AR-LGMDs) are a heterogeneous group of disorders of progressive weakness of the pelvic and shoulder girdle musculature. The clinical course is characterized by great variability, ranging from severe forms with onset in the first decade and rapid progression resembling clinically Xp21 Duchenne muscular dystrophy (DMD) to milder forms with later onset and slower course. Eight genes are mapped for the AR-LGMDs; they are: LGMD2A (CAPN3) at 15q, LGMD2B (dysferlin) at 2p, LGMD2C (gamma-SG) at 13q, LGMD2D (alpha-SG) at 17q, LGMD2E (beta-SG) at 4q, LGMD2F (6-SG) at 5q, LGMD2G at 17q, and more recently LGMD2H at 9q. The LGMD2F (delta-SG) and LGMD2G genes were mapped in Brazilian AR-LGMD families. Linkage analysis in two unlinked families excluded the eight AR-LGMD genes, indicating that there is at least one more gene responsible for AR-LGMD. We have analyzed 140 patients (from 40 families) affected with one of seven autosomal recessive LGMD loci, that is, from LGMD2A to LGMD2G. The main observations were: 1) all LGMD2E and LGMD2F patients had a severe condition, but considerable inter- and intra-familial clinical variability was observed among patients from all other groups; 2) serum CK activities showed the highest values in LGMD2D (alpha-SG) patients among sarcoglycanopathies and LGMD2B (dysferlin) patients among nonsarcoglycanopathies; 3) comparison between LGMD2A (CAPN3) and LGMD2B (dysferlin) showed that the first have on average a more severe course and have calf hypertrophy more frequently (86% versus 13%); and 4) inability to walk on toes was observed in approximately 70% of LGMD2B patients.

Evaluation of immunoregulatory cells in Duchenne muscular dystrophy and spinal muscular atrophy among African and Indian patients.

Suppressor cells were assayed by numerical and functional tests in Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) among African and Indian children in order to contribute to an understanding of the pathogenesis of these neurological disorders. Peripheral blood mononuclears (PBM) were classified as total T cells and T cell subsets by the OKT series of monoclonal antibodies and as B cells by the presence of surface immunoglobulin. The suppressive effects of PBM pretreated with concanavalin A (Con A) on normal homologous phytohaemagglutinin (PHA) transformation of mononuclear cells was determined. PBM stimulation by PHA was also assessed. Patients with DMD had a significant increase (P = 0.0353) in the number of T suppressor/cytotoxic cells (1218 +/- 142 cells/mm3, mean +/- SE) as compared to controls (815 +/- 95 cells/mm3) and a significant reduction (P = 0.0282) in OKT4+ cells expressed as a percentage of OKT3+, 50% +/- 3 compared to 61% +/- 3. No differences were detected in any of the numerical assays employed in SMA as compared to controls, or within SMA patients according to severity of disease. Suppressor function and PHA transformation were normal in both groups of patients. No significant correlations were detected between numerical and functional assays of suppression. The implication of the results obtained for the role of immunoregulatory cells in the pathogenesis of DMD in these children is discussed.

Analysis of dystrophin gene deletions in patients from the Mexican population with Duchenne/Becker muscular dystrophy.

Forty unrelated Mexican patients with Duchenne/Becker muscular dystrophy were analyzed for intragenic DMD gene deletions, using the multiplex amplification of 15 deletion-prone exons described by Chamberlain et al. and Beggs et al. The percentage of deletions was 52.5%, and the majority of them (86.3%) were located at the hot spot deletion region which encompasses exons 44-55. This frequency is higher than that found in American and European populations. There were no correlations between deletion size, location and clinical severity.

Nuclear inclusions in oculopharyngeal muscular dystrophy in Quebec.

Seven French-Canadian cases of clearcut oculopharyngeal muscular dystrophy (OPMD) had their muscle studied for the presence of intranuclear inclusions, and they were all positive. Inclusions of both "mature" and "immature" types were seen in our material. The presence of such intranuclear structures should be added to the criteria of the clinical picture and the family history for diagnosis of a case and inclusion of a family in further genetic studies. Reverse genetic studies of large families and biochemical studies of these intranuclear structures may help to understand the pathogenesis of this common disease in Quebec.

Autosomal recessive, fatal infantile hypertonic muscular dystrophy among Canadian Natives.

We describe eleven mid-western Canadian aboriginal infants with a unique, progressive muscle disorder. All except one had muscle biopsy and/or autopsy. The infants were normal newborns who rapidly developed rigidity of all skeletal muscles, with early, respiratory insufficiency. Death occurred before 18 months of age. Electromyography showed increased insertion activity and profuse fibrillation potentials; motor unit potentials and interference pattern are normal until late in the course. Pathologic features include progressive, granular to powdery Z-band transformation, myofibrillar loss, and muscle regeneration. SDS-gel electrophoresis of one muscle sample revealed increased 54kDa and reduced 80kDa protein fractions. This disease differs from other conditions with Z-band alterations because of continuous muscle activity and relentless clinical progression. The clinical features, elevated serum creatine kinase, electromyographic and muscle biopsy findings suggest a dystrophic process. The recognition of this condition as an autosomal recessive disorder allows appropriate genetic counselling.

A variant of Fukuyama congenital muscular dystrophy in a non-Japanese child.

We report a case of Fukuyama congenital muscular dystrophy with inflammatory infiltrate on muscle biopsy in an American girl of non-Japanese ancestry. The child was hypotonic, had decreased muscle strength in all extremities, and poor head control. Her mental and motor development were delayed. She developed generalized seizures at 19 months of age. Her muscle enzymes were abnormal; cranial computed tomography demonstrated hypoplasia of the cerebellum. Electromyogram was normal. Deltoid muscle biopsy documented scattered basophilic regenerating myofibers and focal atrophic fibers with focal increases of endomysial connective tissue, small endomysial foci of inflammatory cells, and occasional perimysial, perivenular lymphocytic infiltrates. Prednisone therapy produced some decrease in serum muscle enzyme levels.

[Gamma-sarcoglycanopathy: clinico-pathological and genetic study of 11 cases]. / Gamma-sarcoglicanopatía: estudio clinicopatológico y genético de 11 casos.

INTRODUCTION: Limb Girdle Muscular Dystrophy type 2C (LGMD2C) is an autosomal recessive dystrophy due to the deficit of gamma-sarcoglycan, one of the proteins of the dystrophin-associated proteins complex (DAP). A new mutation in the gamma-sarcoglycan gene, 13q12, has been described recently and is exclusive of the gypsy community. OBJECTIVE: To describe the clinicopathological and the genetic findings of eleven cases from a Spanish gypsy family with LGMD2C and the mutation C283Y. MATERIAL AND METHODS: We describe a large gypsy family with the C283Y mutation and eleven affected patients. We have performed an extensive clinical and pathological study with immunohistochemistry and Western blot analyses in the eleven patients and a genetic study of a total of twenty-seven members of the family. RESULTS: The patients presented a severe muscular dystrophy with a dystrophic pattern in the muscle biopsy, normal immunolabeling for dystrophin, very weak for alpha-, beta- and delta-sarcoglycan and absent for gamma-sarcoglycan. These eleven patients were found to be homozygous for the mutation and twelve other members of the family, heterozygous. CONCLUSIONS: The clinical picture and the evolution of the disease herein described is similar to that observed in DMD. Two fundamental differences were found: the autosomal recessive mode of inheritance, and the normal immunohistochemistry and immunoblot for dystrophin in the skeletal muscle.

Novel ancestral Dysferlin splicing mutation which migrated from the Iberian peninsula to South America.

Primary dysferlinopathies are a group of recessive heterogeneous muscular dystrophies. The most common clinical presentations are Miyoshi myopathy and LGMD2B. Additional presentations range from isolated hyperCKemia to severe functional disability. Symptomatology begins in the posterior muscle compartment of the calf and its clinical course progresses slowly in Miyoshi myopathy whereas LGMD2B involves predominantly the proximal muscles of the lower limbs. The age of onset ranges from 13 to 60years in Caucasians. We present five patients that carry a novel mutation in the exon12/intron12 boundary: c.1180_1180+7delAGTGCGTG (r.1054_1284del). We provide evidence of a founder effect due to a common ancestral origin of this mutation, detected in heterozygosity in four patients and in homozygosity in one patient.

Fukutin mutations in non-Japanese patients with congenital muscular dystrophy: less severe mutations predominate in patients with a non-Walker-Warburg phenotype.

Six genes including POMT1, POMT2, POMGNT1, FKRP, Fukutin (FKTN) and LARGE encode proteins involved in the glycosylation of α-dystroglycan (α-DG). Abnormal glycosylation of α-DG is a common finding in Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), Fukuyama congenital muscular dystrophy (FCMD), congenital muscular dystrophy types 1C and 1D and some forms of autosomal recessive limb-girdle muscular dystrophy (LGMD2I, LGMD2K, LGMD2M), and is associated with mutations in the above genes. FCMD, caused by mutations in Fukutin (FKTN), is most frequent in Japan, but an increasing number of FKTN mutations are being reported outside of Japan. We describe four new patients with FKTN mutations and phenotypes ranging from: severe WWS in a Greek-Croatian patient, to congenital muscular dystrophy and cobblestone lissencephaly resembling MEB-FCMD in two Turkish patients, and limb-girdle muscular dystrophy and no mental retardation in a German patient. Four of the five different FKTN mutations have not been previously described.