El difícil camino al diagnóstico del paciente con atrofia muscular espinal / The difficult path to diagnosis of the patient with spinal muscular atrophy

Introducción. Con las nuevas terapias, el diagnóstico temprano de la atrofia muscular espinal (AME) es esencial. El objetivo de este estudio es analizar los distintos componentes que influyen en el retraso diagnóstico. Población y métodos. Se incluyeron pacientes con un diagnóstico molecular de AME tipo I, II y III. Se estudiaron varios parámetros, como la edad al momento de la aparición del primer signo, qué signo fue y el intervalo entre este y el diagnóstico confirmado. Neurólogos especialistas realizaron entrevistas que se complementaron con la revisión de historias clínicas cuando fue necesario. Resultados. Se entrevistaron 112 pacientes. AME I n = 40, AME II n = 48, AME III n = 24. La mediana de edad en meses al momento del reporte del primer signo fue AME I: 1,5 (R 0-7), AME II: 9 (R 2-20), AME III: 18 (R 8-180). Los primeros signos fueron reconocidos por los padres en el 75 % al 85 % de las veces en todos los subtipos. La mediana del tiempo transcurrido entre el primer signo y la primera consulta médica fue menor a un mes en los tres tipos. La mediana de tiempo transcurrido en meses entre el primer signo y el diagnóstico molecular confirmado fue en AME I: 2 (R 0-11), en AME II: 10 (3-46) y en AME III: 31,5 (R 4-288). Conclusiones. Existe un significativo retraso en el diagnóstico de la AME relacionado fundamentalmente a la falta de sospecha clínica. La demora es menor en AME I y mayor en AME III. Otros factores incluyen deficiencias en el sistema de salud.

Introduction. News treatments, make early diagnosis of spinal muscular atrophy (SMA) critical. The objective of this study is to analyze the different factors that influence delay in diagnosis. Population and methods. Patients with a molecular diagnosis of types I, II, and III SMA were included. Several parameters were studied, such as age at onset of first sign, what sign it was, and the time from recognition of first sign to confirmed diagnosis. Neurologists specialized in SMA conducted interviews, supported by the review of medical records when deemed necessary. Results. A total of 112 patients were interviewed. SMA I n = 40, SMA II n = 48, SMA III n = 24. The median age in months at the time of reporting the first sign was SMA I: 1.5 (R: 0­7), SMA II: 9 (R: 2­20), SMA III: 18 (R: 8­180). In all subtypes, first signs were identified by parents from 75% to 85% of the times. The median time from first sign to first medical consultation was less than a month in all 3 types. The median time in months, from first sign to confirmed molecular diagnosis in SMA I was: 2 (R: 0­11), in SMA II: 10 (R: 3­46), in SMA III: 31.5 (R: 4­288). Conclusions. There is a significant delay in SMA diagnosis mainly related to the absence of clinical suspicion. The delay is shorter in SMA I and longer in SMA III. Other factors include deficiencies in the health care system.

A-case-report-of-zellweger-syndrome-with-global-deveopmental-delay

Peroxisome biogenesis disorder are related to spectrum of genetic diseases that range from severe Zellweger syndrome to milder infantile Refsum disease. Zellweger syndrome is characterized by dysmorphic features, severe hypotonia, seizures, failure to thrive, liver dysfunction and skeletal defects. We report a case of Zellweger syndrome, confirmed by clinical, biochemical and molecular findings, diagnosed in context of dysmorphism, and seizures.

Terapia miofuncional orofacial associada ao uso da placa palatina de memória em crianças com Trissomia do 21: estudo de casos / Orofacial myofunctional therapy associated with the use of the stimulating palatal plate in children with trisomy 21: case studies

RESUMO Indivíduos com Trissomia do 21 podem apresentar hipotonia muscular dos órgãos fonoarticulatórios, língua alargada, posicionada no assoalho oral e protrusa e ausência de selamento labial. A placa palatina de memória é um dispositivo intraoral que, associado à terapia miofuncional, visa à melhora da postura habitual dos lábios e da língua dessas crianças. O objetivo deste trabalho foi apresentar os casos de quatro crianças com Trissomia do 21, do sexo masculino, com média de idade de 6,7 e desvio-padrão de 7,8 meses, que fizeram uso da placa palatina de memória de forma associada à terapia miofuncional. As crianças utilizaram a placa por seis meses, realizaram exercícios baseados na terapia de regulação orofacial e receberam orientações quanto à alimentação e retirada de hábitos orais deletérios. Na primeira sessão e ao final do tratamento, foi realizada a gravação de 5 minutos da face de cada criança em repouso e a análise da postura habitual de língua e de lábios foi realizada por dois pesquisadores independentes. Observou-se maior melhora da postura de língua e de lábios dos participantes que iniciaram o tratamento mais precocemente e que apresentavam as alterações posturais mais severas.

ABSTRACT Individuals with trisomy 21 may have muscle hypotonia of the speech articulation organs, an enlarged protruding tongue positioned on the floor of the mouth, and a lack of lip closure. The stimulating palatal plate is an intraoral appliance that, associated with myofunctional therapy, aims to improve these children's habitual lip and tongue posture. This study aimed to present the cases of four male children with trisomy 21, with a mean age of 6.7 and a standard deviation of 7.8 months, who used the stimulating palatal plate in association with myofunctional therapy. The children used the plate for 6 months and did exercises based on the orofacial regulation therapy, and their parents received instructions on feeding them and removing deleterious oral habits. In the first session and at the end of the treatment, each child's face was video-recorded for 5 minutes at rest, and two researchers analyzed independently their habitual tongue and lip posture. Participants who began the treatment earlier and had the most severe postural changes had greater tongue and lip posture improvement.

Wrist-ankle acupuncture combined with rehabilitation for dysphagia caused by achalasia of cricopharyngeal muscle after stroke / 中国基层医药

Objective:To investigate the clinical efficacy of wrist-ankle acupuncture combined with rehabilitation for dysphagia caused by achalasia of the cricopharyngeal muscle after stroke.Methods:Sixty patients with dysphagia caused by achalasia of the cricopharyngeal muscle after stroke who received treatment in Wenzhou Hospital of Traditional Chinese Medicine from June 2019 to March 2020 were included in this study. They were randomly divided into a treatment group and a control group ( n = 30). All patients received routine drug treatment and swallowing rehabilitation training. The control group underwent routine acupuncture treatment. The treatment group received wrist-ankle acupuncture based on routine acupuncture treatment. Both groups were treated for 4 consecutive weeks. The clinical efficacy in the two groups was evaluated using the Video Fluoroscopic Swallowing Study (VFSS), Standardized Swallowing Assessment (SSA), and Swallow Quality-of-Life Questionnaire (SWAL-QOL). Results:Before treatment, there were no significant differences in VFSS, SSA, and SWAL-QOL scores between the two groups. After treatment, VFSS, SSA, and SWAL-QOL scores in the treatment group were (8.21 ± 0.77) points, (21.19 ± 1.42) points, (200.24 ± 11.12) points, and they were (6.01 ± 0.36) points, (23.31 ± 1.45) points, and (182.37 ± 12.06) points in the control group ( t = 3.26, 5.50, 6.31, all P < 0.05). Conclusion:Wrist-ankle acupuncture combined with rehabilitation is an effective treatment method for dysphagia caused by achalasia of the cricopharyngeal muscle after stroke. It can alleviate dysphagia and improve quality of life.

Lethargy and hypotonia in a preterm neonate: Usual symptom with unusual diagnosis of mitochondrial trifunctional protein deficiency

Methodical evaluation of a neonate with common clinical findings (hypotonia and lethargy) is important whenever it cannot be attributed to the frequent causes. This case report is on a preterm neonate with persistent hypotonia and metabolic acidosis who was evaluated and diagnosed with mitochondrial trifunctional protein deficiency. A preterm male baby, second born to second degree consanguineous parents, was found to have persistent lethargy and hypotonia with severe metabolic acidosis despite the shock being corrected. Strong clinical suspicion for inborn errors of metabolism (IEM) was considered despite negative reports of first tier investigations for IEM. He was started on carnitine and biotin. Whole exome sequencing of the baby and Sanger sequencing of mother revealed mutation in HADHA gene suggesting mitochondrial trifunctional protein (MTFP) deficiency. He was started on special infant formula containing medium chain triglycerides along with breastfeeding. When common causes cannot be attributed to the clinical picture, evaluation for uncommon aetiologies should be strongly considered. In case of IEMs, early diagnosis and appropriate therapeutic measures can have satisfactory growth and development in the child

Acupuncture therapy combined with rhubarb applied to the umbilicus for constipation in patients with stage IV-V diabetic nephropathy / 中国基层医药

Objective:To investigate the efficacy of acupuncture therapy combined with rhubarb applied to the umbilicus in the treatment of constipation in patients with stage IV-V diabetic nephropathy.Methods:Ninety stage IV-V diabetic nephropathy patients with constipation, who received treatment in Wenzhou Hospital of Traditional Chinese Medicine from December 2019 to December 2020, were included in this study. They were randomly assigned to receive either routine treatment (control group, n = 45) or routine treatment plus acupuncture therapy combined with rhubarb applied to the umbilicus (study group, n = 45). Serum motilin, gastrin, and somatostatin levels and orocecal transit time pre- and post-treatment were compared between the two groups. The constipation severity was evaluated using the Constipation Severity Scale (CSS). Quality of life was evaluated using the Patient Assessment of Constipation Quality of Life Questionnaire. Clinical efficacy was compared between the two groups. Results:The somatostatin level and orocecal transit time post-treatment in the study group were (13.66 ± 4.24) ng/L and (80.58 ± 10.11) minutes, respectively, which were significantly lower than those in the control group [(19.31 ± 6.13) ng/L, (87.16 ± 12.04) minutes, t = 5.08, 2.80, both P < 0.05]. Serum motilin and gastrin levels post-treatment in the study group were (281.07 ± 41.16) ng/L and (181.07 ± 35.16) ng/L, respectively, which were significantly higher than those in the control group [(259.64 ± 39.83) ng/L, (162.65 ± 32.83) ng/L, t = 2.51, 2.56, both P < 0.05]. The scores of the Constipation Severity Scale and the Patient Assessment of Constipation Quality of Life Questionnaire post-treatment in the study group were (10.66 ± 3.14) points and (60.14 ± 13.64) points, respectively, which were significantly lower than those in the control group [ (15.31 ± 4.13) points, (71.61 ± 14.72) points, t = 6.01, 3.83, both P < 0.05). Total response rate was significantly higher in the study group than in the control group (97.78% vs. 80.00%, χ2 = 5.51, P < 0.05). Conclusion:Acupuncture therapy combined with rhubarb applied to the umbilicus can be used to treat constipation in patients with stage IV-V diabetic nephropathy. The combined therapy can adjust the secretion of gastrointestinal tract-related hormones, shorten orocecal transit time, improve clinical symptoms, and improve clinical efficacy and quality of life.

Clinical characteristics and genetic analysis of 23 newborns with hypotonia as the main manifestation / 中国新生儿科杂志

Objective:To study the role of neonatal panel detection based on next generation sequencing (NGS) combined with multiplex ligation-dependent probe amplification (MLPA) in the etiological differentiation of neonatal hypotonia.Methods:The clinical characteristics and gene test results of newborns with hypotonia as the main clinical manifestation treated at the Department of Neonatology of Jiangxi Provincial Children's Hospital from March 2017 to March 2021 were retrospectively analyzed.Results:A total of 23 children with hypotonia and feeding difficulties diagnosed by gene tests were included. 17 cases (73.9%) had obvious abnormal appearance, and 11 cases (47.8%) had congenital heart disease (atrial septal defect and/or patent ductus arteriosus). Among the 23 infants, 21 were detected by panel gene, 10 by methylation specific MLPA (MS-MLPA) and 4 by MLPA (SMN1 / SMN2). 14 cases of Prader-Willi syndrome, 4 cases of spinal muscular atrophy, 3 cases of congenital myopathy and 2 cases of Schaaf-Yang syndrome were diagnosed. 11 cases died (47.8%), 9 cases had growth retardation (39.1%), 2 cases had normal growth and development (8.7%), and 1 case survived without detailed information (4.3%). Newborns with unknown etiology and low muscle tone are often complicated with abnormal appearance and congenital heart disease. Neonatal panel combined with MLPA is helpful for accurate diagnosis.Conclusions:The detection of neonatal panel combined with MLPA is cheap, and can provide accurate diagnosis for most newborns with unexplained hypotonia in a short diagnosis cycle, which is conducive to the early formulation of clinical decision-making, and guide the treatment, follow-up and genetic consultation of children.

Schaaf-Yang syndrome in a neonate caused by MAGEL2 gene mutation: a case report / 中华围产医学杂志

In this study, we reported a patient with neonatal-onset Schaaf-Yang syndrome (SYS). The girl was the second singleton child of a healthy, nonconsanguineous couple. She suffered from hypoxic asphyxia at birth and soon developed persistent respiratory distress. She was also diagnosed with neonatal encephalopathy, congenital heart disease, pneumonia, sepsis, neonatal jaundice, congenital laryngeal achondroplasia, and paralysis of vocal cord were diagnosed after admission. She spent the first one month of life in the neonatal intensive care unit and was treated with mechanical ventilation, nutritional support and anti-infectives. Then the baby was discharged as her parents' request and died of respiratory failure at the age of 2 months. Whole exome sequencing detected, a heterozygous nonsense mutation of c.1912C>T(p.Q638X) in MAGEL2 in the fetus, which was inherited from her father but not found in her mother.

Genetic diagnosis and follow-up of 49 cases neonatal hypotonia / 中国小儿急救医学

Objective:To summarize the genetic etiology, clinical characteristics and outcomes of neonatal hypotonia in the early stage of NICU, to provide basis for clinicians to early identify diseases and choose reasonable treatments.Methods:The clinical data of neonates with hypotonia admitted to the Department of Neonatology of Children′s Hospital of Xinjiang Uygur Autonomous Region and People′s Hospital of Xinjiang Uygur Autonomous Region from July 2017 to July 2020 were analyzed.Results:A total of 49 children were enrolled in the study, all clinically manifested as unexplained hypotonia, accompanied by special appearance 29 cases(59.18%), metabolic abnormality 18 cases(36.73%), and cranial imagin abnormality 23 cases(46.93%). After gene sequencing a, total of 22(44.89%)patients were confirmed.Thirteen (26.53%) of them were copy number variation, and gene mutation in nine cases(18.36%). The oldest age of these patients was 3 years and 2 months now, while the youngest was 4 months.A total of 16 patients were dead(32.65%). Four (8.16%) patients were lost to follow-up.At present, eighteen (62.07%) patients had mental retardation, and eleven (37.93%) of whom still existed severe physical retardation.Conclusion:We could conduct genetic testing in NICU to improve the diagnosis rate of neonates with unexplained hypotonia, which have high rate of adverse events.Neonates with a clear diagnosis should be treated promptly and give the genetic counseling to reduce the risk for the next children.

Clinical phenotype and mutation characteristics of germline PIGA gene mutations / 中华实用儿科临床杂志

Objective:To analyze the clinical phenotype and genetic characteristics of children with germline PIGA gene mutations. Methods:The clinical presentations, blood biochemistry, electroencephalogram (EEG), brain magnetic resonance imaging (MRI) and genetic test results of 10 children diagnosed at the Department of Pediatrics of Peking University First Hospital between January 2014 and June 2020 were analyzed.Results:All these 10 children were male, with seizures and severe developmental delay.Five out of eight cases showed hypotonia.Four out of nine cases had facial deformity or multiple organ abnormalities.The onset age of seizures ranged from one month and 28 days to 10 months, with an average age of 4.8 months.There were various types of seizures, and all patients showed focal seizures.The seizures of 6 patients in these 10 cases could be induced by fever disease.Diffuse slow waves mixed focal or multifocal discharges of interictal EEG in 9 cases with PIGA-deficient.Brain MRI showed enlarged subarachnoid space in 44.4% (4/9 cases) of patients.Slight elevated serum alkaline phosphatase could be seen in 2 cases.Genetic analysis confirmed that a total of 8 different mutation sites were found, 7 of which were unreported.In this group, 4 cases were diagnosed with multiple congenital anomalies -hypotonia -seizures syndrome 2 (MCAHS2), 5 cases were diagnosed with developmental delay and epilepsy without deformity, and one case was not classified, respectively. Conclusions:Focal seizure was common in these patients with PIGA mutations, and often induced by fever disease.Interictal EEG was characterized by diffuse slow waves mixed focal or multifocal discharges.Enlarged subarachnoid space was the most common brain MRI abnormality in these patients.The phenotype of patients only partially conformed to typical MCAHS2 manifestations, and most of them had no deformity.

Expresión clínica de distrofia miotónica congénita / Clinical expression of congenital myotonic dystrophy

Introducción: La distrofia miotónica congénita es la forma clínica que produce la expresión fenotípica más grave, con alta morbilidad y mortalidad en los primeros meses de vida, dadas fundamentalmente por las complicaciones respiratorias. Objetivo: Describir una serie de casos con expresión clínica de distrofia miotónica congénita. Presentación de casos: La serie estaba conformada por cuatro pacientes con diagnóstico de la enfermedad en la provincia de Pinar del Río, Cuba. El estudio se realizó entre: enero de 2015-diciembre de 2019. Se revisaron las características clínicas, epidemiológicas y genéticas de la entidad. Se analizaron los antecedentes prenatales-perinatales de cada caso, las manifestaciones fenotípicas, los antecedentes familiares y el cálculo de la prevalencia. En el 100 por ciento de los casos se presentó parto pretérmino con depresión neonatal severa e hipotonía. Entre los antecedentes prenatales se describió la disminución de los movimientos fetales y el polihidramnios en el 75 y 50 por ciento de los casos, respectivamente. La totalidad de los pacientes eran descendientes de madres afectadas. Las principales complicaciones que condujeron a morbilidad y mortalidad en el 100 por ciento de los casos fueron las relacionadas con el sistema respiratorio, trastornos hidroelectrolíticos y las infecciones asociadas. Conclusiones: En el período neonatal son importantes los antecedentes prenatales-perinatales de los pacientes con distrofia miotónica. Estos antecedentes, constituyen acontecimientos que forman parte de la secuencia de hipoquinesia fetal dada por la afectación neuromuscular intraútero. Los antecedentes familiares y sobre todo cuando la madre está afectada conducen a expresiones severas en la descendencia(AU)

Introduction: Congenital myotonic dystrophy is a clinical form that produces the most severe phenotypic expression, with high morbility and mortality in the first months of life mainly due to respiratory complications. Objective: To describe a serie of cases with clinical expression of congenital myotonic dystrophy. Cases presentation: The serie was formed by 4 patients with diagnosis of the disease in Pinar del Río province, Cuba. The study was made from January, 2015 to December, 2019. There were reviewed the clinical, epidemiological and genetic characteristics of this entity. There were analyzed prenatal and perinatal backgrounds of each case, phenotypic manifestations, the family records and the prevalence calculations. In 100 percent of the cases it was presented preterm birth with severe neonatal depression and hypotonia. Among the prenatal backgrounds, it was described the decrease of the fetal movements and polyhydramnios in the 75 and 50 percent of the cases, respectively. All the patients were descendants of affected mothers. The main complications that led to morbility and mortality in 100 percent of the cases were the ones related with the respiratory system, hydrolectrolitic disorders and associated infections. Conclusions: In the neonatal period are important the prenatal-perinatal records of patients with myotonic dystrophy. This background shows events that are part of the fetal hypokinesia´s sequence caused by intrauterine neuromuscular affectation. Family background and especially when the mother is affected lead to severe expressions in the descendants(AU)

Hypotonic infant with Pallister–Killian syndrome diagnosed by cytogenetic microarray, without pigmentary skin changes and malformations

Pallister–Killian syndrome (PKS) is a rare genetic developmental disorder characterized, by intellectual disability, seizures, streaks of hypo- or hyperpigmentation and characteristic dysmorphic features. PKS is characterized by the presence of cytogenetic abnormality in form of a supernumerary isochromosome 12p, in a tissue limited mosaicism. The isochromosome 12p is usually not detected in karyotype done from peripheral blood. Presence of patchy pigmentary skin lesions suggest the possibility of mosaicism and karyotype from skin is done which clinches the diagnosis. We describe an infant with severe hypotonia in whom trisomy 12p was detected by chromosomal microarray performed on peripheral blood. The karyotype from blood was normal and combining this information with three copies of 12p in microarray suggests the possibility of tetrasomy12p in mosaic form. The infant did not have any skin patchy pigmentary changes and malformations and hence, the diagnosis of PKS was not clinically suspected. Cytogenetic microarray is the first test for evaluation of cases with developmental delay and intellectual disability, PKS diagnosis may come as a surprise in unsuspected cases without characteristic skin pigmentary abnormality and malformations.

A novel de novo mutation in the PURA gene associated with a new clinical finding: large brainstem

We report the case of a Caucasian Spanish boy, who showed profound neonatal hypotonia, feeding difficulties, apnea, severe developmental delay, epilepsy, bilateral convergent strabismus, poor verbal language development and a large brainstem. Whole-exome sequence uncovered a novel de novo mutation in the purine-rich element binding protein A gene (PURA; NM_005859.4:c.72del:p.(- Gly25AlafsTer53)) that encodes the transcriptional activator protein Pur-alpha (PURA). Mutations in this gene have been identified in patients with PURA syndrome, a rare disorder characterized by an early hypotonia, developmental delay, severe intellectual disability with or without epilepsy, and disability in expressive language development. Although, up to 75 cases have been identified worldwide, to the best of our knowledge, this is the first patient described with a brainstem larger than normal. In conclusion, our data expand both genetic and phenotypic spectrum associated with PURA gene mutations.

Rare Cases of PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome in a Korean Family Identified by Next Generation Sequencing

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive connective tissue disorder characterized by muscular hypotonia, hyperextensible skin, skin fragility, joint hypermobility, and progressive kyphoscoliosis. The disorder results from a deficiency of the enzyme collagen lysyl hydroxylase 1 due to mutations in the gene PLOD1. We describe the rare cases of kEDS in Korean siblings with two novel compound heterozygous variants, c.926_934del (p.Leu309_Leu311del) and c.2170_2172del (p.Phe724del) in the PLOD1 gene. They had congenital hypotonia, joint laxity, skin hyperextensibility, Marfanoid habitus, high myopia and atrophic scarring. The younger sibling had an early-onset progressive kyphoscoliosis, while the older sibling showed mild scoliosis during childhood. Intrafamilial variability of the clinical severity and age of kyphoscoliosis onset observed in our cases.

Childhood Neuromuscular Disorders

@#Infantile and childhood neuromuscular disorders are a significant cause of motor delays in childhood. Neuromuscular disorders may present either with hypotonia and weakness in early infancy or falls and difficulties in walking later in childhood. The first goal in approaching a patient with suspected muscle disease is to ascertain the correct site of the lesion, followed by the cause of the lesion. Extraordinary breakthroughs in the area of genetic testing have resulted in a decrease in reliance on muscle biopsies and neurophysiological testing. The importance of recognising such disorders is because viable treatment options are now available for the treatment of affected children. Early recognition allows patients to receive therapy at a stage of the disease that will give the best long-term outcomes. Even in the absence of definitive treatment, supportive management and preventive care have revolutionized the care of neuromuscular disorders with longer quality life spans in a good majority of patients.

Diagnóstico y tratamiento de las miopatías congénitas / Diagnosis and treatment of congenital myopaties

Existen importantes avances en el campo de las miopatías congénitas en los últimos años que obligan a la revisión y actualización constante de este grupo de enfermedades. La identificación creciente de nuevos genes y fenotipos asociados a genes ya conocidos, fue posible en gran medida gracias al avance de las técnicas de secuenciación de nueva generación, cada vez más accesibles. El conocer mejor el espectro fenotípico de estas entidades, permite establecer una correlación fenotipo/genotipo en algunos subgrupos. La mejor compresión de la fisiopatología e historia natural de estas enfermedades, son fundamentales para el desarrollo de nuevas terapias. Los primeros ensayos clínicos en el campo de la terapia génica ya son una realidad y están mostrando resultados positivos, creando una nueva expectativa en paciente, familiares y especialistas, lo que se verá reflejado en la necesidad de adaptar los protocolos de atención, diagnóstico y tratamiento de algunas de estas entidades. Es fundamental que los neuropediatras, pediatras, fisioterapeutas y otros profesionales involucrados en el cuidado de estos pacientes, estén informados y actualizados de los avances en este grupo de enfermedades.

Important advances have been made in the field of congenital myopathies in recent years, forcing clinicians to constantly review and update this group of diseases. The increasing identification of new genes and phenotypes associated with already known genes has been possible to a great extent thanks to the development accomplished in next generation sequencing techniques, which are increasingly accessible. Knowing better the phenotypic spectrum of these entities allows to establish a phenotype/genotype correlation in some subgroups. The best understanding of the pathophysiology and natural history of these diseases are fundamental to design new therapies. The first clinical trials in the field of gene therapy are already a reality and are showing positive results, creating a new expectation for patients, families and specialists, which will be reflected in the need to adapt the protocols of care, diagnosis and treatment of some of these entities. It is essential that pediatric neurologists, pediatricians, physiotherapists and other professionals involved in the care of these patients are informed and updated on the advances in this group of diseases.

Enfermedad de Pompe infantil: Diagnóstico y tratamiento / Infantile-onset Pompe disease: Diagnosis and management

La enfermedad de Pompe, o deficiencia de maltasa ácida o glucogenosis tipo II, es una grave enfermedad genética, autosómica recesiva, progresiva, poco frecuente, causada por la deficiencia en la enzima alfa glucosidasa. En la edad pediátrica, puede presentarse con la "forma clásica", la más conocida, con grave compromiso cardíaco y franca hipotonía, o con la "forma no clásica", con comienzo temprano del compromiso motor. La "forma de comienzo tardío" del adulto también puede ocurrir en la infancia o en la adolescencia. Se actualizan los hallazgos clínicos y de diagnóstico disponibles, ya que un tratamiento temprano con reemplazo de la enzima faltante puede mejorar la supervivencia y la calidad de vida del paciente. Se revisan los beneficios y los efectos adversos del tratamiento disponible y nuevas líneas de investigación terapéutica.

Pompe disease, also known as acid maltase deficiency or glycogenosis type II, is a rare severe, autosomal, recessive, and progressive genetic disorder caused by deficiency in alpha-glucosidase. The classic infantile-onset is the most broadly known form of Pompe disease, which presents with severe heart involvement and clear hypotonia, while the non-classic presentation occurs with early motor involvement. Late-onset Pompe disease develops in adults, but it may also occur during childhood or adolescence. Here we update the available clinical and diagnostic findings because an early management with enzyme replacement therapy may improve patients' survival and quality of life. We also review the benefits and adverse effects of available treatments and new lines of therapeutic research.

Manifestaciones clínicas asociadas al síndrome de Prader-Willi / Clinical Manifestations Associated with Prader-Willi Syndrome

RESUMEN El síndrome de Prader-Willi (SPW) es un trastorno genético, que afecta el neurodesarrollo que, a pesar de su baja frecuencia, merece ser considerado como un trastorno de relevancia clínica al ser la causa más frecuente de obesidad de origen genético. Las manifestaciones clínicas que derivan de SPW tienen origen en la desregulación hipotalámica, por lo que al comprender la trascendencia e implicación de ésta se entenderá la amplia gama de manifestaciones que pueden presentarse con severidad variable y cuyas complicaciones a su vez afectan la salud y socialización a largo plazo lo que influye sobre la calidad de vida de los pacientes con SPW. El diagnóstico preciso permite distinguir este síndrome de otros trastornos genéticos y de otras patologías que afectan la función hipotalámica a la vez que posibilita estimar la gravedad de las manifestaciones y el riesgo de repetición en una misma familia. Por ello, esta revisión se presenta con el objetivo de describir las manifestaciones clínicas del síndrome de Prader-Willi que orienten la sospecha clínica, las similitudes que comparte éste con otros trastornos, así como dar a conocer las técnicas de diagnóstico disponibles que favorecen el abordaje de los pacientes y facilitar su manejo integral oportunamente.

ABSTRACT Prader-Willi syndrome (PWS) is a genetic disorder that affects neurodevelopment, which, despite its low frequency, deserves to be consideredaclinically relevant disorder since it is themost frequent cause of genetically derived obesity. The clinical manifestations that derive from SPW correlate to those from a hypothalamic dysregulation, so that, understanding the importance and implication of the hypothalamic involvement, the wide range of manifestations that can present with variable severity and whose complications in turn affect the health can be understood. and long-term socialization affecting the quality of life of patients with PWS. An accurate diagnosis can discriminate this syndrome from other genetic disorders and from non-genetic pathologies that affect hypothalamic function, while also allowing to estimate the severity in a specific patient and the risk of repetition in other family members. Therefore, the present descriptive review is aimed to describe the clinical manifestations of Prader-Willi syndrome to guide the clinical diagnosis; the signs and symptoms that can differentiate this syndrome from other disorders, as well as presenting a description of the actual diagnostic techniques that can allow a prompt and precise diagnosis, and thus, translate in a comprehensive and timely approach of the patients with PWS.

Effects of Copy Number Variations on Developmental Aspects of Children With Delayed Development

OBJECTIVE: To determine effects of copy number variations (CNV) on developmental aspects of children suspected of having delayed development. METHODS: A retrospective chart review was done for 65 children who underwent array-comparative genomic hybridization after visiting physical medicine & rehabilitation department of outpatient clinic with delayed development as chief complaints. Children were evaluated with Denver Developmental Screening Test II (DDST-II), Sequenced Language Scale for Infants (SELSI), or Preschool Receptive-Expressive Language Scale (PRES). A Mann-Whitney U test was conducted to determine statistical differences of developmental quotient (DQ), receptive language quotient (RLQ), and expressive language quotient (ELQ) between children with CNV (CNV(+) group, n=16) and children without CNV (CNV(–) group, n=37). RESULTS: Of these subjects, the average age was 35.1 months (mean age, 35.1±24.2 months). Sixteen (30.2%) patients had copy number variations. In the CNV(+) group, 14 children underwent DDST-II. In the CNV(–) group, 29 children underwent DDST-II. Among variables, gross motor scale was significantly (p=0.038) lower in the CNV(+) group compared with the CNV(–) group. In the CNV(+) group, 5 children underwent either SELSI or PRES. In the CNV(–) group, 27 children underwent above language assessment examination. Both RLQ and ELQ were similar between the two groups. CONCLUSION: The gross motor domain in DQ was significantly lower in children with CNV compared to that in children without CNV. This result suggests that additional genetic factors contribute to this variability. Active detection of genomic imbalance could play a vital role when prominent gross motor delay is presented in children with delayed development.

Clinical and molecular characterization of Korean children with infantile and late-onset Pompe disease: 10 years of experience with enzyme replacement therapy at a single center / 소아과

PURPOSE: Pompe disease (PD) is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase resulting from pathogenic GAA variants. This study describes the clinical features, genotypes, changes before and after enzyme replacement therapy (ERT), and long-term outcomes in patients with infantile-onset PD (IOPD) and late-onset PD (LOPD) at a tertiary medical center. METHODS: The medical records of 5 Korean patients (2 male, 3 female patients) diagnosed with PD between 2002 and 2013 at Samsung Medical Center in Seoul, Republic of Korea were retrospectively reviewed for data, including clinical and genetic characteristics at diagnosis and clinical course after ERT. RESULTS: Common initial symptoms included hypotonia, cyanosis, and tachycardia in patients with IOPD and limb girdle weakness in patients with LOPD. Electrocardiography at diagnosis revealed hypertrophic cardiomyopathy in all patients with IOPD who showed a stable disease course during a median follow-up period of 10 years. Patients with LOPD showed improved hepatomegaly and liver transaminase level after ERT. CONCLUSION: As ERT is effective for treatment of PD, early identification of this disease is very important. Thus, patients with IOPD should be considered candidates for clinical trials of new drugs in the future.