Clinicopathological correlates in the frontotemporal lobar degeneration-motor neuron disease spectrum.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology.

Paraplegia Following Type B Acute Aortic Dissection Can Spare the Spinal Cord.

Ischemic lumbosacral plexopathy secondary to an acute aortic dissection is a rare condition that is usually unilateral and frequently accompanied by a simultaneous spinal cord infarction. The functional prognosis relies on the severity of the nervous system involvement being usually worse when the spinal cord is involved. We present a case of a 46-year-old man who suffered an acute type B aortic dissection presenting as acute paraplegia due to bilateral ischemic lumbosacral plexopathy treated with thoracic endovascular aortic repair. An up-to-date review of the literature on ischemic lumbosacral plexus injury is provided.

A DM1 family with interruptions associated with atypical symptoms and late onset but not with a milder phenotype.

Carriage of interruptions in CTG repeats of the myotonic dystrophy protein kinase gene has been associated with a broad spectrum of myotonic dystrophy type 1 (DM1) phenotypes, mostly mild. However, the data available on interrupted DM1 patients and their phenotype are scarce. We studied 49 Spanish DM1 patients, whose clinical phenotype was evaluated in depth. Blood DNA was obtained and analyzed through triplet-primed polymerase chain reaction (PCR), long PCR-Southern blot, small pool PCR, AciI digestion, and sequencing. Five patients of our registry (10%), belonging to the same family, carried CCG interruptions at the 3'-end of the CTG expansion. Some of them presented atypical traits such as very late onset of symptoms ( > 50 years) and a severe axial and proximal weakness requiring walking assistance. They also showed classic DM1 symptoms including cardiac and respiratory dysfunction, which were severe in some of them. Sizes and interrupted allele patterns were determined, and we found a contraction and an expansion in two intergenerational transmissions. Our study contributes to the observation that DM1 patients carrying interruptions present with atypical clinical features that can make DM1 diagnosis difficult, with a later than expected age of onset and a previously unreported aging-related severe disease manifestation.

Correction to: Manifesting heterozygotes in McArdle disease: a myth or a reality-role of statins.

Unfortunately the name of one of the authors was spelled incorrectly in the published original article. The correct name is Alejandro Santos-Lozano. The original article got updated.

Manifesting heterozygotes in McArdle disease: a myth or a reality-role of statins.

McArdle disease is an autosomal recessive condition caused by deficiency of the PYGM gene-encoded muscle isoform of glycogen phosphorylase. Some cases of "manifesting" heterozygotes or carriers (i.e., patients who show some McArdle-like symptoms or signs despite being carriers of only one mutated PYGM allele) have been reported in the literature but there is controversy, with misdiagnosis being a possibility. The purpose of our study was to determine if there are actually "manifesting" heterozygotes of McArdle disease and, if existing, whether statin treatment can trigger such condition. Eighty-one relatives of McArdle patients (among a total of 16 different families) were studied. We determined whether they were carriers of PYGM mutations and also collected information on exercise tests (second wind and modified Wingate anaerobic test) and statin intake. We found 50 carriers and 31 non-carriers of PYGM mutations. Although we found existence of heterozygotes manifesting some exercise-related muscle problems such as exacerbated myalgia or weakness, they only accounted for 14% of the carriers and muscle symptoms were milder than those commonly reported in patients. Further, no carrier (whether reporting symptoms or not) showed the second wind phenomenon or a flat blood lactate response to maximal-intensity exercise, both of which are hallmarks of McArdle disease. On the other hand, statin myotoxicity was not associated with muscle symptom onset.

Remote Intracerebral Hemorrhage After Intravenous Thrombolysis: Results From a Multicenter Study.

BACKGROUND AND PURPOSE: Remote parenchymal hemorrhage (rPH) after intravenous thrombolysis with recombinant tissue-type plasminogen activator may be associated with cerebral amyloid angiopathy, although supportive data are limited. We aimed to investigate risk factors of rPH after intravenous thrombolysis with recombinant tissue-type plasminogen activator. METHODS: This is an observational study of patients with ischemic stroke who were treated with intravenous thrombolysis with recombinant tissue-type plasminogen activator and were included in a multicenter prospective registry. rPH was defined as any extraischemic hemorrhage detected in the follow-up computed tomography. We collected demographic, clinical, laboratory, radiological, and outcome variables. In the subset of patients who underwent a magnetic resonance imaging examination, we evaluated the distribution and burden of cerebral microbleeds, cortical superficial siderosis, leukoaraiosis, and recent silent ischemia in regions anatomically unrelated to the ischemic lesion that caused the initial symptoms. We compared patients with rPH with those without rPH or parenchymal hemorrhage. Independent risk factors for rPH were obtained by multivariable logistic regression analyses. RESULTS: We evaluated 992 patients (mean age, 74.0±12.6 years; 52.9% were men), and 408 (41%) of them underwent a magnetic resonance imaging. Twenty-six patients (2.6%) had a rPH, 8 (0.8%) had both rPH and PH, 58 (5.8%) had PH, and 900 (90.7%) had no bleeding complication. Lobar cerebral microbleeds (odds ratio, 8.0; 95% confidence interval, 2.3-27.2) and recent silent ischemia (odds ratio, 4.8; 95% confidence interval, 1.6-14.1) increased the risk of rPH. CONCLUSIONS: The occurrence of rPH after intravenous thrombolysis with recombinant tissue-type plasminogen activator in patients with ischemic stroke is associated with lobar cerebral microbleeds and multiple ischemic lesions in different regions.

An Integrative Analysis of DNA Methylation Pattern in Myotonic Dystrophy Type 1 Samples Reveals a Distinct DNA Methylation Profile between Tissues and a Novel Muscle-Associated Epigenetic Dysregulation.

Myotonic dystrophy type 1 (DM1) is a progressive, non-treatable, multi-systemic disorder. To investigate the contribution of epigenetics to the complexity of DM1, we compared DNA methylation profiles of four annotated CpG islands (CpGis) in the DMPK locus and neighbouring genes, in distinct DM1 tissues and derived cells, representing six DM1 subtypes, by bisulphite sequencing. In blood, we found no differences in CpGi 74, 43 and 36 in DNA methylation profile. In contrast, a CTCF1 DNA methylation gradient was found with 100% methylation in congenital cases, 50% in childhood cases and 13% in juvenile cases. CTCF1 methylation correlated to disease severity and CTG expansion size. Notably, 50% of CTCF1 methylated cases showed methylation in the CTCF2 regions. Additionally, methylation was associated with maternal transmission. Interestingly, the evaluation of seven families showed that unmethylated mothers passed on an expansion of the CTG repeat, whereas the methylated mothers transmitted a contraction. The analysis of patient-derived cells showed that DNA methylation profiles were highly preserved, validating their use as faithful DM1 cellular models. Importantly, the comparison of DNA methylation levels of distinct DM1 tissues revealed a novel muscle-specific epigenetic signature with methylation of the CTCF1 region accompanied by demethylation of CpGi 43, a region containing an alternative DMPK promoter, which may decrease the canonical promoter activity. Altogether, our results showed a distinct DNA methylation profile across DM1 tissues and uncovered a novel and dual epigenetic signature in DM1 muscle samples, providing novel insights into the epigenetic changes associated with DM1.

Current Incidence and Risk Factors of Fecal Incontinence After Acute Stroke Affecting Functionally Independent People.

Background: Previously published retrospective series show a high prevalence of fecal incontinence (FI) in stroke patients. We aimed to analyze in a prospective series the current incidence of FI in acute stroke in functionally independent patients and its evolution over time and the patient characteristics associated with the appearance of FI in acute stroke. Methods: We included consecutive patients with acute stroke admitted in our stroke unit who fulfilled the following inclusion criteria: a first episode of stroke, aged >18 years, with no previous functional dependency [modified Rankin Scale (mRS) ≤ 2] and without previous known FI. FI was assessed by a multidisciplinary trained team using dedicated questionnaires at 72 ± 24 h (acute phase) and at 90 ± 15 days (chronic phase). Demographic, medical history, clinical and stroke features, mortality, and mRS at 7 days were collected. Results: Three hundred fifty-nine (48.3%) of 749 patients (mean age 65.9 ± 10, 64% male, 84.1% ischemic) fulfilled the inclusion criteria and were prospectively included during a 20-month period. FI was identified in 23 patients (6.4%) at 72 ± 24 h and in 7 (1.9%) at 90 days ± 15 days after stroke onset. FI was more frequent in hemorrhagic strokes (18 vs. 5%, p 0.007) and in more severe strokes [median National Institute of Health Stroke Scale (NIHSS) 18 (14-22) vs. 5 (3-13), p < 0.0001]. No differences were found regarding age, sex, vascular risk factors, or other comorbidities, or affected hemisphere. Patients with NIHSS ≥12 (AUC 0.81, 95% CI 0.71 to 0.89) had a 17-fold increase for the risk of FI (OR 16.9, IC 95% 4.7-60.1) adjusted for covariates. Conclusions: At present, the incidence of FI in acute stroke patients without previous functional dependency is lower than expected, with an association of a more severe and hemorrhagic stroke. Due to its impact on the quality of life, it is necessary to deepen the knowledge of the underlying mechanisms to address therapeutic strategies.

Characterization of RAN Translation and Antisense Transcription in Primary Cell Cultures of Patients with Myotonic Dystrophy Type 1.

Myotonic Dystrophy type 1 (DM1) is a muscular dystrophy with a multi-systemic nature. It was one of the first diseases in which repeat associated non-ATG (RAN) translation was described in 2011, but has not been further explored since. In order to enhance our knowledge of RAN translation in DM1, we decided to study the presence of DM1 antisense (DM1-AS) transcripts (the origin of the polyglutamine (polyGln) RAN protein) using RT-PCR and FISH, and that of RAN translation via immunoblotting and immunofluorescence in distinct DM1 primary cell cultures, e.g., myoblasts, skin fibroblasts and lymphoblastoids, from ten patients. DM1-AS transcripts were found in all DM1 cells, with a lower expression in patients compared to controls. Antisense RNA foci were found in the nuclei and cytoplasm of a subset of DM1 cells. The polyGln RAN protein was undetectable in all three cell types with both approaches. Immunoblots revealed a 42 kD polyGln containing protein, which was most likely the TATA-box-binding protein. Immunofluorescence revealed a cytoplasmic aggregate, which co-localized with the Golgi apparatus. Taken together, DM1-AS transcript levels were lower in patients compared to controls and a small portion of the transcripts included the expanded repeat. However, RAN translation was not present in patient-derived DM1 cells, or was in undetectable quantities for the available methods.

Spanish Pompe registry: Baseline characteristics of first 49 patients with adult onset of Pompe disease. / Registro español de la enfermedad de Pompe: análisis de los primeros 49 pacientes con enfermedad de Pompe del adulto.

INTRODUCTION AND OBJECTIVES: Pompe disease is a rare autosomal recessive disorder produced by a deficiency of acid maltase. This deficit produces an accumulation of glycogen in tissues. Clinically it is mainly characterized by limb girdle and respiratory muscle weakness. In 2013, we developed the Spanish Pompe Registry. The objective of this article was to analyse the characteristics of the first 49 patients and disclose the existence of this registry within the medical community. MATERIAL AND METHODS: An observational retrospective study was undertaken. We analysed the 49 patients included in the Spanish Registry of Pompe Disease from May 2013 to October 2018. RESULTS: Patients were visited at 7 different Spanish hospitals. Twenty-six patients were women and 23 were men. The average age at the time of the analysis was 47.2 years. Ten patients were asymptomatic. The mean age of onset of symptoms was 29, and low limb girdle weakness was the most frequent initial symptom. Of the patients, 49% had respiratory involvement, and 70.8% of them required non-invasive mechanical ventilation. The most common mutation found was IVS1-13T>G in 85.3% of the patients. All symptomatic patients received treatment with ERT. CONCLUSIONS: This registry allows us to know the clinical and genetic characteristics of adult patients with Pompe disease in Spain. Moreover, it can be the basis for future studies of natural history to understand the impact of ERT in the course of the disease.

Preliminary Findings on CTG Expansion Determination in Different Tissues from Patients with Myotonic Dystrophy Type 1.

Myotonic Dystrophy type 1 (DM1) is characterized by a high genetic and clinical variability. Determination of the genetic variability in DM1 might help to determine whether there is an association between CTG (Cytosine-Thymine-Guanine) expansion and the clinical manifestations of this condition. We studied the variability of the CTG expansion (progenitor, mode, and longest allele, respectively, and genetic instability) in three tissues (blood, muscle, and tissue) from eight patients with DM1. We also studied the association of genetic data with the patients' clinical characteristics. Although genetic instability was confirmed in all the tissues that we studied, our results suggest that CTG expansion is larger in muscle and skin cells compared with peripheral blood leukocytes. While keeping in mind that more research is needed in larger cohorts, we have provided preliminary evidence suggesting that the estimated progenitor CTG size in muscle could be potentially used as an indicator of age of disease onset and muscle function impairment.

The Need for Establishing a Universal CTG Sizing Method in Myotonic Dystrophy Type 1.

The number of cytosine-thymine-guanine (CTG) repeats ('CTG expansion size') in the 3'untranslated region (UTR) region of the dystrophia myotonica-protein kinase (DMPK) gene is a hallmark of myotonic dystrophy type 1 (DM1), which has been related to age of disease onset and clinical severity. However, accurate determination of CTG expansion size is challenging due to its characteristic instability. We compared five different approaches (heat pulse extension polymerase chain reaction [PCR], long PCR-Southern blot [with three different primers sets-1, 2 and 3] and small pool [SP]-PCR) to estimate CTG expansion size in the progenitor allele as well as the most abundant CTG expansion size, in 15 patients with DM1. Our results indicated variability between the methods (although we found no overall differences between long PCR 1 and 2 and SP-PCR, respectively). While keeping in mind the limited sample size of our patient cohort, SP-PCR appeared as the most suitable technique, with an inverse significant correlation found between CTG expansion size of the progenitor allele, as determined by this method, and age of disease onset (r = -0.734, p = 0.016). Yet, in light of the variability of the results obtained with the different methods, we propose that an international agreement is needed to determine which is the most suitable method for assessing CTG expansion size in DM1.

Three-dimensional imaging in myotonic dystrophy type 1: Linking molecular alterations with disease phenotype.

OBJECTIVE: We aimed to determine whether 3D imaging reconstruction allows identifying molecular:clinical associations in myotonic dystrophy type 1 (DM1). METHODS: We obtained myoblasts from 6 patients with DM1 and 6 controls. We measured cytosine-thymine-guanine (CTG) expansion and detected RNA foci and muscleblind like 1 (MBNL1) through 3D reconstruction. We studied dystrophia myotonica protein kinase (DMPK) expression and splicing alterations of MBNL1, insulin receptor, and sarcoplasmic reticulum Ca(2+)-ATPase 1. RESULTS: Three-dimensional analysis showed that RNA foci (nuclear and/or cytoplasmic) were present in 45%-100% of DM1-derived myoblasts we studied (range: 0-6 foci per cell). RNA foci represented <0.6% of the total myoblast nuclear volume. CTG expansion size was associated with the number of RNA foci per myoblast (r = 0.876 [95% confidence interval 0.222-0.986]) as well as with the number of cytoplasmic RNA foci (r = 0.943 [0.559-0.994]). Although MBNL1 colocalized with RNA foci in all DM1 myoblast cell lines, colocalization only accounted for 1% of total MBNL1 expression, with the absence of DM1 alternative splicing patterns. The number of RNA foci was associated with DMPK expression (r = 0.967 [0.079-0.999]). On the other hand, the number of cytoplasmic RNA foci was correlated with the age at disease onset (r = -0.818 [-0.979 to 0.019]). CONCLUSIONS: CTG expansion size modulates RNA foci number in myoblasts derived from patients with DM1. MBNL1 sequestration plays only a minor role in the pathobiology of the disease in these cells. Higher number of cytoplasmic RNA foci is related to an early onset of the disease, a finding that should be corroborated in future studies.

Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease. / Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert.

BACKGROUND AND OBJECTIVES: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. MATERIAL AND METHODS: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. RECOMMENDATIONS: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. CONCLUSION: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.

Registro español de la enfermedad de Pompe: análisis de los primeros 49 pacientes con enfermedad de Pompe del adulto / Spanish Pompe registry: Baseline characteristics of first 49 patients with adult onset of Pompe disease

INTRODUCCIÓN Y OBJETIVOS: La enfermedad de Pompe es una enfermedad rara con herencia autosómica recesiva por un déficit de maltasa ácida. Este déficit produce un acúmulo de glucógeno en los tejidos. Desde una perspectiva clínica, se caracteriza principalmente por una debilidad de cinturas y una afectación de la musculatura respiratoria. En 2013 se creó el registro español de enfermedad de Pompe. El objetivo de este artículo es analizar las características de los primeros 49 pacientes y divulgar la existencia de este registro dentro de la comunidad médica. MATERIAL Y MÉTODOS: Se realizó un estudio observacional en el que se analizaron las variables de los pacientes incluidos en el registro español de enfermedad de Pompe desde mayo de 2013 hasta octubre de 2018. RESULTADOS: Los 49 pacientes proceden de 7 hospitales españoles. Veintiséis pacientes son mujeres y 23, hombres. La edad media en el momento del análisis fue de 47,2 años. Diez pacientes estaban asintomáticos. La edad media de inicio de los síntomas fue 29 años; la debilidad de cintura pélvica fue el síntoma inicial más frecuente. El 49% de los pacientes tenían afectación respiratoria, el 70,8% necesitaba ventilación mecánica no invasiva. El análisis genético encontró la mutación IVS1−13T>G en el 85,3% de los pacientes. Todos los pacientes sintomáticos recibían tratamiento con ERT. CONCLUSIONES: Este registro permite conocer las características clínico-genéticas de pacientes adultos con enfermedad de Pompe en España, además de ser la base de futuros estudios de historia natural y del impacto de la ERT en el curso de la enfermedad

INTRODUCTION AND OBJECTIVES: Pompe disease is a rare autosomal recessive disorder produced by a deficiency of acid maltase. This deficit produces an accumulation of glycogen in tissues. Clinically it is mainly characterized by limb girdle and respiratory muscle weakness. In 2013, we developed the Spanish Pompe Registry. The objective of this article was to analyse the characteristics of the first 49 patients and disclose the existence of this registry within the medical community. MATERIAL AND METHODS: An observational retrospective study was undertaken. We analysed the 49 patients included in the Spanish Registry of Pompe Disease from May 2013 to October 2018. RESULTS: Patients were visited at 7 different Spanish hospitals. Twenty-six patients were women and 23 were men. The average age at the time of the analysis was 47.2 years. Ten patients were asymptomatic. The mean age of onset of symptoms was 29, and low limb girdle weakness was the most frequent initial symptom. Of the patients, 49% had respiratory involvement, and 70.8% of them required non-invasive mechanical ventilation. The most common mutation found was IVS1−13T>G in 85.3% of the patients. All symptomatic patients received treatment with ERT. CONCLUSIONS: This registry allows us to know the clinical and genetic characteristics of adult patients with Pompe disease in Spain. Moreover, it can be the basis for future studies of natural history to understand the impact of ERT in the course of the disease

Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert / Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease

Antecedentes y objetivos: La enfermedad de Steinert o distrofia miotónica tipo 1 (DM1), (OMIM 160900) es la miopatía más prevalente en el adulto. Es una enfermedad multisistémica con alteración de prácticamente todos los órganos y tejidos y una variabilidad fenotípica muy amplia, lo que implica que deba ser atendida por diferentes especialistas que dominen las alteraciones más importantes. En los últimos años se ha avanzado de manera exponencial en el conocimiento de la enfermedad y en su manejo. El objetivo de la guía es establecer recomendaciones para el diagnóstico, el pronóstico, el seguimiento y el tratamiento de las diferentes alteraciones de la DM1. Material y métodos: Esta guía de consenso se ha realizado de manera multidisciplinar. Se ha contado con neurólogos, neumólogos, cardiólogos, endocrinólogos, neuropediatras y genetistas que han realizado una revisión sistemática de la literatura. Recomendaciones: Se recomienda realizar un diagnóstico genético con cuantificación precisa de tripletes CTG. Los pacientes con DM1 deben seguir control cardiológico y neumológico de por vida. Antes de cualquier cirugía con anestesia general debe realizarse una evaluación respiratoria. Debe monitorizarse la presencia de síntomas de disfagia periódicamente. Debe ofrecerse consejo genético a los pacientes con DM1 y a sus familiares. Conclusión: La DM1 es una enfermedad multisistémica que requiere un seguimiento en unidades especializadas multidisciplinares

Background and objectives: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. Material and methods: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. Recommendations: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. Conclusion: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up