Distrofia miotónica tipo 1: 13 años de experiencia en un hospital terciario. Estudio clínico y epidemiológico. Correlación genotipo-fenotipo / Myotonic dystrophy type 1: 13 years of experience at a tertiary hospital. Clinical and epidemiological study and genotype-phenotype correlation

Introducción: Se desconoce la incidencia de la distrofia miotónica tipo 1 (DM1), enfermedad con gran variedad fenotípica, en nuestra región. El objetivo de nuestro trabajo es estimar la incidencia de DM1 en nuestro centro (referencia en Aragón) e identificar las características propias de nuestra población (correlación genotipo-fenotipo). Métodos: Estudio descriptivo retrospectivo de 459 pacientes clasificados según número de repeticiones CTG en: normal (5-35), premutado (36-50), protomutado (51-80), pequeñas expansiones (81-150), intermedias (151-1.000) y grandes (> 1.000). Además, según el fenotipo mostrado, se categorizaron como: no afectos (5-50 CTG), forma leve o asintomática (51-150 CTG), clásica (151-1.000 CTG) y severa (> 1.000 CTG). Resultados: La incidencia de DM1 fue de 20,61 (IC 95%: 19,59-21,63) casos por millón de individuos-año. Se evidenció una correlación inversa entre el número de CTG y la edad al diagnóstico genético (ρ = −0,547; IC 95%: −0,610 a −0,375; p < 0,001). El CTG5 fue el alelo polimórfico más frecuente en sanos. Del total de afectos, el 28,3% presentaron la forma leve o asintomática, el 59,1% la forma clásica y el 12,6% la forma severa. El 35,1% presentaron herencia materna, el 59,4% herencia paterna y el 5,5% herencia incierta. En las formas leves la calvicie frontal en varones fue el rasgo fenotípico más prevalente, junto con miotonía y cataratas, mientras que en la clásica predominó la ptosis palpebral, la debilidad facial, las alteraciones en la voz y la pronunciación, la miotonía y la sensación de cansancio/somnolencia. Conclusiones: La incidencia de DM1 es relevante en Aragón. La revisión multidisciplinar del fenotipo de pacientes con DM1 es clave para un diagnóstico precoz y medicina personalizada.(AU)

Introduction: The incidence of myotonic dystrophy type 1 (DM1), a disease with great phenotypic variety, in our region is unknown. This study aims to estimate the incidence of DM1 at our hospital (a reference centre in Aragon, Spain) and to identify the characteristics of our population (genotype-phenotype correlation). Methods: Retrospective, descriptive study of 459 patients classified according to the number of CTG repeats, as follows: normal (5-35), premutation (36-50), protomutation (51-80), small expansions (81-150), intermediate expansions (151-1000), and large expansions (> 1000). Furthermore, according to clinical phenotype, patients were categorised as unaffected (5-50 CTG repeats), mild form or asymptomatic (51-150), classical form (151-1000), and severe form (> 1000). Results: The incidence of DM1 was 20.61 cases per million person-years (95% CI: 19.59-21.63). An inverse correlation was observed between the number of CTG repeats and the age at genetic diagnosis (ρ = −0.547; 95% CI: −0.610 to −0.375; P < .001). CTG5 was the most frequent polymorphic allele in healthy individuals. Of all patients with DM1, 28.3% presented the mild or asymptomatic form, 59.1% the classical form, and 12.6% the severe form. Inheritance was maternal in 35.1% of cases, paternal in 59.4%, and uncertain in 5.5%. In mild forms, frontal balding in men was the most prevalent phenotypic trait, as well as myotonia and cataracts, while in the classical form, ptosis, facial weakness, voice and pronunciation alterations, myotonia, and fatigue/sleepiness were most frequent. Conclusions: The incidence of DM1 in Aragon is significant. Multidisciplinary study of the phenotype of patients with DM1 is key to early diagnosis and personalised management.(AU)

Myotonic dystrophy type 1: 13 years of experience at a tertiary hospital. Clinical and epidemiological study and genotype-phenotype correlation.

INTRODUCTION: The incidence of myotonic dystrophy type 1 (DM1), a disease with great phenotypic variety, in our region is unknown. This study aims to estimate the incidence of DM1 at our hospital (a reference centre in Aragon, Spain) and to identify the characteristics of our population (genotype-phenotype correlation). METHODS: Retrospective, descriptive study of 459 patients classified according to the number of CTG repeats, as follows: normal (5-35), premutation (36-50), protomutation (51-80), small expansions (81-150), intermediate expansions (151-1000), and large expansions (> 1000). Furthermore, according to clinical phenotype, patients were categorised as unaffected (5-50 CTG repeats), mild form or asymptomatic (51-150), classical form (151-1000), and severe form (> 1000). RESULTS: The incidence of DM1 was 20.61 cases per million person-years (95% CI, 19.59-21.63). An inverse correlation was observed between the number of CTG repeats and the age at genetic diagnosis (ρ = -0.547; 95% CI, -0.610 to -0.375; P < .001). CTG5 was the most frequent polymorphic allele in healthy individuals. Of all patients with DM1, 28.3% presented the mild or asymptomatic form, 59.1% the classical form, and 12.6% the severe form. Inheritance was maternal in 35.1% of cases, paternal in 59.4%, and uncertain in 5.5%. In mild forms, frontal balding in men was the most prevalent phenotypic trait, as well as myotonia and cataracts, while in the classical form, ptosis, facial weakness, voice and pronunciation alterations, myotonia, and fatigue/sleepiness were most frequent. CONCLUSIONS: The incidence of DM1 in Aragon is significant. Multidisciplinary study of the phenotype of patients with DM1 is key to early diagnosis and personalised management.

CYB5R3 homozygous pathogenic variant as a rare cause of cyanosis in the newborn.

Detailed below is a very illustrative case of a rare pathology of recessive congenital methemoglobinemia. The patient, a newborn female, was homozygous for c.535G > A, p.(Ala179Thr) a pathogenic variant in the CYB5R3 gene. The reported population frequency of the allele is 0.853%, demonstrating why it is remarkable to find both parents are heterozygous carriers without consanguinity. A brief review of previously published cases is also presented.

Myotonic dystrophy type1: 13years of experience at a tertiary hospital. Clinical and epidemiological study and genotype-phenotype correlation. / Distrofia miotónica tipo1: 13años de experiencia en un hospital terciario. Estudio clínico y epidemiológico. Correlación genotipo-fenotipo.

INTRODUCTION: The incidence of myotonic dystrophy type1 (DM1), a disease with great phenotypic variety, in our region is unknown. This study aims to estimate the incidence of DM1 at our hospital (a reference centre in Aragon, Spain) and to identify the characteristics of our population (genotype-phenotype correlation). METHODS: Retrospective, descriptive study of 459 patients classified according to the number of CTG repeats, as follows: normal (5-35), premutation (36-50), protomutation (51-80), small expansions (81-150), intermediate expansions (151-1000), and large expansions (>1000). Furthermore, according to clinical phenotype, patients were categorised as unaffected (5-50 CTG repeats), mild form or asymptomatic (51-150), classical form (151-1000), and severe form (>1000). RESULTS: The incidence of DM1 was 20.61 cases per million person-years (95%CI: 19.59-21.63). An inverse correlation was observed between the number of CTG repeats and the age at genetic diagnosis (ρ=-0.547; 95%CI: -0.610 to -0.375; P<.001). CTG5 was the most frequent polymorphic allele in healthy individuals. Of all patients with DM1, 28.3% presented the mild or asymptomatic form, 59.1% the classical form, and 12.6% the severe form. Inheritance was maternal in 35.1% of cases, paternal in 59.4%, and uncertain in 5.5%. In mild forms, frontal balding in men was the most prevalent phenotypic trait, as well as myotonia and cataracts, while in the classical form, ptosis, facial weakness, voice and pronunciation alterations, myotonia, and fatigue/sleepiness were most frequent. CONCLUSIONS: The incidence of DM1 in Aragon is significant. Multidisciplinary study of the phenotype of patients with DM1 is key to early diagnosis and personalised management.

[Early infantile epileptic encephalopathy due to ITPA mutation]. / Encefalopatía epiléptica infantil precoz por mutación en ITPA.

TITLE: Encefalopatía epiléptica infantil precoz por mutación en ITPA.

[Infant with intracranial calcifications and retinopathy]. / Lactante con calcificaciones intracraneales y retinopatia.

INTRODUCTION: Intracranial calcifications can have a number of different causes, and the distribution and characteristics they present in neuroimaging can orient the specialist towards one or another. It is important to rule out the most frequent entities that are accompanied by intracranial calcifications, but other more remote genetic causes, such as Coats plus syndrome, should not be overlooked. CASE REPORT: Ex-premature female Infant with a gestational age of 34 weeks, diagnosed with retinopathy at 9 months after presenting strabismus. At 2 years of age, an MRI scan was performed for right hemiparesis, in which an image suggestive of a neoplasm was initially observed. Upon completion of the study with a cranial computed tomography scan, extensive calcifications were observed predominantly in the basal ganglia along with cystic lesions. After ruling out the most frequent causations of intracranial calcifications, the association between the retinopathy and the neurological features was established, and Coats plus syndrome was confirmed by a genetic study that revealed the presence of two hitherto unreported variants in heterozygosis in the CTC1 gene. CONCLUSION: Coats plus syndrome is an extraordinarily rare autosomal recessive disease, caused by mutations in the CTC1 gene, which involves the appearance of retinal telangiectasias, brain cysts, calcifications in deep nuclei and leukoencephalopathy, as well as other bone and gastrointestinal conditions. Treatment is symptomatic and the disease has a poor prognosis.

TITLE: Lactante con calcificaciones intracraneales y retinopatia.Introduccion. Las calcificaciones intracraneales pueden tener multiples etiologias, y la distribucion y las caracteristicas que presenten en la neuroimagen pueden orientar hacia unas u otras. Es importante descartar las entidades mas frecuentes que cursan con calcificaciones intracraneales, pero no deben olvidarse otras causas geneticas mucho mas remotas, como el sindrome de Coats plus. Caso clinico. Lactante exprematura de 34 semanas de edad gestacional, diagnosticada de retinopatia a los 9 meses al presentar estrabismo. A los 2 años de edad se realizo una resonancia magnetica por hemiparesia derecha, en la que se observo una imagen sugestiva inicialmente de neoplasia. Al completar el estudio con una tomografia computarizada craneal, se observaron extensas calcificaciones de predominio en los ganglios basales y lesiones quisticas. Tras descartarse las etiologias mas frecuentes de calcificaciones intracraneales, se llego a la asociacion de la retinopatia y la clinica neurologica y se confirmo el sindrome de Coats plus mediante estudio genetico, que revelo la presencia de dos variantes en heterocigosis no documentadas hasta la fecha en el gen CTC1. Conclusion. El sindrome de Coats plus es una enfermedad autosomica recesiva extraordinariamente infrecuente, provocada por mutaciones en el gen CTC1, que supone la aparicion de telangiectasias retinianas, quistes cerebrales, calcificaciones en los nucleos profundos y leucoencefalopatia, ademas de otras afecciones oseas y gastrointestinales. El tratamiento es sintomatico y la enfermedad tiene un mal pronostico.

Nueva variante probablemente patogénica c.1249A>C en el exón 7 del gen GAA asociada a la enfermedad de Pompe del adulto / Novel probable pathological variant c.1249A>C in exon 7 of the GAA gene associated with Pompe disease in adults

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Clinical implication of FMR1 intermediate alleles in a Spanish population.

FMR1 premutation carriers (55-200 CGGs) are at risk of developing Fragile X-associated primary ovarian insufficiency as well as Fragile X-associated tremor/ataxia syndrome. FMR1 premutation alleles are also associated with a variety of disorders, including psychiatric, developmental, and neurological problems. However, there is a major concern regarding clinical implications of smaller CGG expansions known as intermediate alleles (IA) or gray zone alleles (45-54 CGG). Although several studies have hypothesized that IA may be involved in the etiology of FMR1 premutation associated phenotypes, this association still remains unclear. The aim of this study was to provide new data on the clinical implications of IA. We reviewed a total of 17 011 individuals: 1142 with primary ovarian insufficiency, 478 with movement disorders, 14 006 with neurodevelopmental disorders and 1385 controls. Similar IA frequencies were detected in all the cases and controls (cases 1.20% vs controls 1.39%, P = .427). When comparing the allelic frequencies of IA ≥ 50CGGs, a greater, albeit not statistically significant, number of alleles were detected in all the cohorts of patients. Therefore, IA below 50 CGGs should not be considered as risk factors for FMR1 premutation-associated phenotypes, at least in our population. However, the clinical implication of IA ≥ 50CGGs remains to be further elucidated.

The impact of exercise duration and intensity on the release of cardiac biomarkers.

Numerous studies have observed cardiac biomarker release with prolonged exercise. Despite this, we are unsure as to the constituent aspects of any given exercise bout that may be important in promoting cardiac biomarker release. This study examined the influence of exercise duration and intensity on the appearance of cardiac biomarkers. Twenty-one subjects ran for 45, 90 and 180 min at 85% and 95% of their individual anaerobic threshold on six different days randomized. Cardiac troponin I (cTnI) and N-terminal pro-brain natiuretic peptide (NT-proBNP) were assayed from blood samples collected before, 30 min and 3 h post-exercise. NT-proBNP was elevated after all exercise trials (range before: 21-32; range post: 38-67 ng/L). Peak post-exercise concentrations of NT-proBNP were associated with exercise duration (P=0.049), but not exercise intensity (P=0.451). cTnI was elevated after all exercise trials (range before: 0.007-0.011; range post: 0.008-0.021 µg/L). Peak post-exercise concentrations of cTnI were associated with exercise duration (P=0.003) and intensity (P=0.037). Data suggest that while both cTnI and NT-proBNP increased after all exercise trials, the mediating effect of duration influenced both NT-proBNP and cTnI while intensity influenced only cTnI.