From exercise intolerance to functional improvement: The second wind phenomenon in the identification of McArdle disease

McArdle disease is the most common of the glycogen storage diseases. Onset of symptoms is usually in childhood with muscle pain and restricted exercise capacity. Signs and symptoms are often ignored in children or put down to 'growing pains' and thus diagnosis is often delayed. Misdiagnosis is not uncommon because several other conditions such as muscular dystrophy and muscle channelopathies can manifest with similar symptoms. A simple exercise test performed in the clinic can however help to identify patients by revealing the second wind phenomenon which is pathognomonic of the condition. Here a patient is reported illustrating the value of using a simple 12 minute walk test.RSS is funded by Ciências sem Fronteiras/CAPES Foundation. The authors would like to thank the Association for Glycogen Storage Disease (UK), the EUROMAC Registry funded by the European Union, the Muscular Dystrophy Campaign, the NHS National Specialist Commissioning Group and the Myositis Support Group for funding

EUROMAC: A European registry for patients with McArdle disease and other very rare muscle glycogenoses

EUROMAC is a European registry of McArdle Disease patients and other very rare muscle glycogenosis (glycogenosis types 0, IV, VII, IX, X, XIII; phosphoglycerate kinase 1 deficiency and muscle lactate dehydrogenase deficiency) presenting with exercise intolerance as the key symptom. EUROMAC aims to promote awareness and understanding of McArdle disease and related conditions to harmonize standards of diagnosis and care and to promote research. EUROMAC was created and developed by a network of 15 partners from 7 EU countries, Turkey and US. Initially funded by the European Commission's Directorate General for Health and Consumers, the registry is currently supported by a grant received from the Fondo de Investigaciones Sanitarias (PI116/01492). Following informed consent from the participant, data (demographics, main clinical symptoms, comorbidities, age at diagnosis and genetic diagnosis) were uploaded onto a safe, encrypted web-based registry (https://www.registryeuromac.eu/en/). In parallel, education, training and dissemination activities were performed. EUROMAC is the largest international registry for patients with McArdle disease. As of March 2018, 313 patients from 10 different countries were recruited. The first Polish patient diagnosed with McArdle disease followed a EUROMAC teaching course, held in Warsaw. The implementation of the EUROMAC project and the setting-up of an international registry have significantly contributed to the effective dissemination of rare muscle GSDs, raising the awareness of these conditions. Additionally, it provided a unique insight into the co-comorbidities affecting people with McArdle disease that should lead to strategies to reduce and manage them in the future.Sin financiación3.115 JCR (2019) Q3, 76/204 Clinical Neurology1.177 SJR (2019) Q1, 85/378 Neurology (clinical)No data IDR 2019UE

Data from the European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC)

Background: The European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) was launched to register rare muscle glycogenoses in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases through workshops and websites. A network of twenty full and collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry. After approximately 3 years of data collection, the data in the registry was analysed. Results: Of 282 patients with confirmed diagnoses of muscle glycogenosis, 269 had McArdle disease. New phenotypic features of McArdle disease were suggested, including a higher frequency (51.4%) of fixed weakness than reported before, normal CK values in a minority of patients (6.8%), ptosis in 8 patients, body mass index above background population and number of comorbidities with a higher frequency than in the background population (hypothyroidism, coronary heart disease). Conclusions: The EUROMAC project and registry have provided insight into new phenotypic features of McArdle disease and the variety of co-comorbidities affecting people with McArdle disease. This should lead to better management of these disorders in the future, including controlling weight, and preventive screening for thyroid and coronary artery diseases, as well as physical examination with attention on occurrence of ptosis and fixed muscle weakness. Normal serum creatine kinase in a minority of patients stresses the need to not discard a diagnosis of McArdle disease even though creatine kinase is normal and episodes of myoglobinuria are absent.Sin financiación4.123 JCR (2020) Q2, 64/175 Genetics & Heredity1.274 SJR (2020) Q1, 365/2448 Medicine (miscellaneous)No data IDR 2019UE

Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: evidence for a founder effect

ABSTRACT Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation

Effectiveness of the Combined Recombinant Human Growth Hormone and Gonadotropin-Releasing Hormone Analog Therapy in Pubertal Patients with Short Stature due to SHOX Deficiency

Context: Isolated heterozygous SHOX defects are the most frequent monogenic cause of short stature, and combined therapy with recombinant human GH (rhGH) and GnRH analog (GnRHa) in pubertal patients has been suggested, but there are no data on final height

Genetic Predictors Of Long-term Response To Growth Hormone (gh) Therapy In Children With Gh Deficiency And Turner Syndrome: The Influence Of A Socs2 Polymorphism.

There is great interindividual variability in the response to GH therapy. Ascertaining genetic factors can improve the accuracy of growth response predictions. Suppressor of cytokine signaling (SOCS)-2 is an intracellular negative regulator of GH receptor (GHR) signaling. The objective of the study was to assess the influence of a SOCS2 polymorphism (rs3782415) and its interactive effect with GHR exon 3 and -202 A/C IGFBP3 (rs2854744) polymorphisms on adult height of patients treated with recombinant human GH (rhGH). Genotypes were correlated with adult height data of 65 Turner syndrome (TS) and 47 GH deficiency (GHD) patients treated with rhGH, by multiple linear regressions. Generalized multifactor dimensionality reduction was used to evaluate gene-gene interactions. Baseline clinical data were indistinguishable among patients with different genotypes. Adult height SD scores of patients with at least one SOCS2 single-nucleotide polymorphism rs3782415-C were 0.7 higher than those homozygous for the T allele (P < .001). SOCS2 (P = .003), GHR-exon 3 (P= .016) and -202 A/C IGFBP3 (P = .013) polymorphisms, together with clinical factors accounted for 58% of the variability in adult height and 82% of the total height SD score gain. Patients harboring any two negative genotypes in these three different loci (homozygosity for SOCS2 T allele; the GHR exon 3 full-length allele and/or the -202C-IGFBP3 allele) were more likely to achieve an adult height at the lower quartile (odds ratio of 13.3; 95% confidence interval of 3.2-54.2, P = .0001). The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with TS and GHD after long-term rhGH therapy. Polymorphisms located in GHR, IGFBP3, and SOCS2 loci have an influence on the growth outcomes of TS and GHD patients treated with rhGH. The use of these genetic markers could identify among rhGH-treated patients those who are genetically predisposed to have less favorable outcomes.99E1808-1

Genetic predictors of long-term response to growth hormone (GH) therapy in children with GH deficiency and turner syndrome: The influence of a SOCS2 polymorphism

Design and Patients: Genotypes were correlated with adult height data of 65 Turner syndrome (TS) and 47GHdeficiency (GHD) patients treated with rhGH, by multiple linear regressions. Generalized multifactor dimensionality reduction was used to evaluate gene-gene interactions. Background: There is great interindividual variability in the response to GH therapy. Ascertaining genetic factors can improve the accuracy of growth response predictions. Suppressor of cytokine signaling (SOCS)-2 is an intracellular negative regulator of GH receptor (GHR) signaling. Copyright. Objective: The objective of the study was to assess the influence of a SOCS2 polymorphism (rs3782415) and its interactive effect with GHR exon 3 and -202 A/C IGFBP3 (rs2854744) polymorphisms on adult height of patients treated with recombinant human GH (rhGH). Results: Baseline clinical data were indistinguishable among patients with different genotypes. Adult height SD scores of patients with at least one SOCS2 single-nucleotide polymorphism rs3782415-C were 0.7 higher than those homozygous for the T allele (P < .001). SOCS2 (P = .003), GHR-exon 3 (P=.016) and-202 A/C IGFBP3 (P=.013) polymorphisms, together with clinical factors accounted for 58% of the variability in adult height and 82% of the total height SD score gain. Patients harboring any two negative genotypes in these three different loci (homozygosity for SOCS2 T allele; the GHR exon 3 full-length allele and/or the -202C-IGFBP3 allele) were more likely to achieve an adult height at the lower quartile (odds ratio of 13.3; 95% confidence interval of 3.2-54.2, P = .0001). Conclusion: The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with TS andGHDafter long-term rhGH therapy. Polymorphisms located inGHR, IGFBP3, and SOCS2 loci have an influence on the growth outcomes of TS and GHD patients treated with rhGH. The use of these genetic markers could identify among rhGH-treated patients those who are genetically predisposed to have less favorable outcomes999E1808E1813CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP307922/2013–8; 301339/2008–9; 304678/2012–0sem informaçã

STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability.

Context and objective: GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessivecondition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mildheight reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations.Methods: We genotyped and performed clinical and laboratory evaluations in 52 relatives of two previously describedBrazilian brothers with homozygous STAT5B c.424_427del mutation (21 heterozygous). Additionally, we obtained heightdata and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional familiesharboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data fromfirst-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data fromheterozygous individuals and non-carriers were compared.Results: Individuals carrying heterozygous STAT5B c.424_427del mutation were 0.6 SDS shorter than their non-carrierrelatives (PZ0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (PZ0.028) andIGFBP3 (PZ0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygousSTAT5B mutations had an average height SDS of K1.4G0.8 when compared with population-matched controls (P! 0.001).Conclusions: STAT5B mutations in the heterozygous state have a significant negative impact on height (w3.9 cm). This effectis milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support thehypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability.Fil: Scalco, Renata C.. Universidade de Sao Paulo; BrasilFil: Hwa, Vivian. Cincinnati Center for Growth Disorders; Estados UnidosFil: Domene, Horacio Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Jasper, Hector Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Marino, Roxana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Pereira, Alberto M.. Leiden University Medical Center; Países BajosFil: Tonelli, Carlos A.. Universidade do Extremo Sul Catarinense; BrasilFil: Wit, Jan M.. Leiden University Medical Center; Países BajosFil: Rosenfeld, Ron G.. Oregon Health and Science University; Estados UnidosFil: Jorge, Alexander A. L. . Universidade de Sao Paulo; Brasi