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Rare neurological diseases include a vast group of heterogenous syndromes with primary impairment(s) in the peripheral and/or central nervous systems. Such rare disorders may have overlapping phenotypes, despite their distinct genetic etiology. One unique aspect of rare neurological diseases is their potential common association with altered epigenetic mechanisms. Epigenetic mechanisms include regulatory processes that control gene expression and cellular phenotype without changing the composition of the corresponding DNA sequences. Epigenetic factors include three types of proteins, the "readers, writers, and erasers" of DNA and DNA-bound proteins. Thus, epigenetic impairments of many neurological diseases may contribute to their pathology and manifested phenotypes. Here, we aim to provide a comprehensive review on the general etiology of selected rare neurological diseases, that include Rett Syndrome, Prader-Willi Syndrome, Rubinstein-Taybi Syndrome, Huntington's disease, and Angelman syndrome, with respect to their associated aberrant epigenetic mechanisms.
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OBJECTIVES: Clinical benefits of growth hormone (GH) in Prader-Willi syndrome (PWS) are proven and scoliosis is a known association of both PWS and GH therapy. The aims of this study were to assess GH prescribing practices and growth outcomes over time, the prevalence and predictors of scoliosis in GH-treated PWS children, and the near-final height of GH-treated PWS patients. DESIGN AND METHODS: This is a retrospective, descriptive study evaluating data from all clinic visits of patients aged 0-18 years with PWS, seen through the Children's Hospital at Westmead between March 1992 and May 2022 (n=75). RESULTS: A total of 64 patients were treated with GH (visits = 1,414). In the recent decade, the diagnosis of PWS and GH commencement were made significantly earlier in life. The prevalence of scoliosis was 41â¯%, in which age was the only significant predictor for scoliosis (odds ratio 1.19: 95â¯% CI [1.08-1.31; p=0.001]) adjusted for other predictors. In patients with data available at the age 16 years (23/28 treated with GH), those who were GH treated had significantly higher height SDS vs. nontreated group (SDS -0.67 vs. -2.58; p=0.0001) and lower BMI SDS (1.18 vs. 2.37; p<0.001). CONCLUSIONS: Significant improvements in growth and body composition were seen in the GH-treated group vs. non-treated group of children with PWS. There were no significant modifiable clinical predictors of scoliosis in children with PWS, but our findings confirm the high prevalence of scoliosis in GH-treated children with PWS reinforcing the need for close surveillance.
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Hormona de Crecimiento Humana , Síndrome de Prader-Willi , Escoliosis , Humanos , Síndrome de Prader-Willi/tratamiento farmacológico , Niño , Masculino , Femenino , Estudios Retrospectivos , Hormona de Crecimiento Humana/uso terapéutico , Hormona de Crecimiento Humana/administración & dosificación , Adolescente , Preescolar , Lactante , Escoliosis/epidemiología , Escoliosis/tratamiento farmacológico , Escoliosis/etiología , Recién Nacido , Estudios de Seguimiento , Pronóstico , Resultado del Tratamiento , Estatura/efectos de los fármacos , Centros de Atención Terciaria , PrevalenciaRESUMEN
Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of paternal genes on chromosome 15. The Aberrant Behavior Checklist (ABC) is a standardized rating scale for assessing problematic behaviors in persons with developmental disabilities. Our study aims to describe ABC scores in youth with PWS and track their change over time. The analysis included 69 patients. Mean ABC scores were compared in four age groups (5-8, 9-12, 13-16, and 17-22 years). A statistically significant difference was found only in the Irritability subscale, with lower scores in the 5-8 age group compared to the 9-12 age group. For change over time, scores for Irritability, Lethargy, Stereotypic Behavior, Hyperactivity subscales, and Total score were likely to decrease after age 12. Irritability subscale scores of males were predicted to increase more than those of females between ages of 5 and 12 . The Lethargy score in the nondeletion group had a greater reduction than the deletion group in the 12-20 year range. This study highlights the need for systematic collection and characterization of behavioral data given the burden of maladaptive behaviors that often persist for a lifetime.
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Prader-Willi syndrome (PWS) is a multisystemic disorder. Notably, many characteristic symptoms of PWS are correlated with locus coeruleus norepinephrine system (LC-NE) dysfunction, including impairment in arousal, learning, pain modulation, and stress-induced negative affective states. Although electrophysiological experiments in necdin-deficient mice, an established PWS animal model, have revealed decreased spontaneous neuronal firing activity in the LC and impaired excitability, the behavioral phenotypes related to LC-NE dysfunction remain unexplored. In this study, heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygous (+m/-p) animals. Compared to WT mice, Ndn + m/-p mice demonstrated impaired visual-spatial memory in the Y-maze test, reduced social interaction, impaired sexual recognition, and shorter falling latency on the Rotarod. Using the open field test (OFT) and elevated plus maze (EPM), we observed similar locomotion activity of Ndn + m/-p and WT mice, but Ndn + m/-p mice were less anxious. After acute restraint, Ndn + m/-p mice exhibited significant impairment in stress-induced anxiety. Additionally, the plasma norepinephrine surge following exposure to acute restraint stress was also impaired. Pretreatment with atomoxetine, a norepinephrine reuptake inhibitor aimed to enhance LC function, restored Ndn + m/-p mice to exhibit a normal response to acute restraint stress. Furthermore, by employing chemogenetic approaches to facilitate LC neuronal firing, post-stress anxious responses were also partially rescued in Ndn + m/-p mice. These data strongly suggest that LC dysfunction is implicated in the pathogenesis of stress-related neuropsychiatric symptoms in PWS. Manipulation of LC activity may hold therapeutic potential for patients with PWS.
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Obesity among adolescents poses a significant global health concern with profound short- and long-term impact on physical and mental well-being. The intricate relationship between obesity and the onset of diabetes remains ambiguous, particularly in cases where the manifestation may differ from that observed in individuals with uncomplicated obesity. Herein, we present the case of a 14-year-old male adolescent with Prader-Willi phenotype and subsequent obesity, exhibiting symptoms of polyuria and polydipsia over a 10-day period, indicative of potential diabetes mellitus (DM). Laboratory assessments revealed a hemoglobin A1c level of 10%, confirming the suspected diagnosis. Notably, despite the absence of ketosis, elevated C-peptide levels and the presence of slightly positive islet-cell antibodies warranted further investigation. While the presence of antibodies typically aligns with a diagnosis of type 1 DM, recent research has highlighted the occurrence of anti-insulin pancreatic cell antibodies in type 2 DM cases. This article aims to delve into the multifaceted issues surrounding adolescent obesity, atypical presentations of DM with positive antibodies, and the long-term management of patients with genetic syndromes.
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Prader-Willi syndrome (PWS) is a rare disorder characterised by varying nutritional phases that occur throughout the lifespan, ranging from failure to thrive to hyperphagia. If uncontrolled, the imbalance between energy intake and expenditure results in obesity development and increased morbidity and mortality risk. Although measures of energy requirements for accurate nutrition assessment are vital, the evidence appears sparse and heterogeneous; hence, the aim of this review was to examine the available literature on energy expenditure predicted or measured using various methods in individuals with PWS. Studies were sought that presented methods and results on resting energy expenditure or basal metabolic rate. A narrative synthesis was completed to present the study characteristics and results. Methods of determining energy requirements included predictive equations and indirect calorimetry. Differences amongst ages, growth hormone therapy, fasting status, and measures in which results were presented were limitations to appropriately summarising and identifying trends in energy expenditure. Indirect calorimetry was identified as the most accurate method; however, it is not widely available in all settings. Further research is encouraged to support the development of valid and reliable predictive equations that will better inform and improve the efficiency of clinical practice in supporting people with PWS.
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Calorimetría Indirecta , Metabolismo Energético , Síndrome de Prader-Willi , Humanos , Síndrome de Prader-Willi/metabolismo , Metabolismo Basal , Niño , Adulto , Femenino , Masculino , Adolescente , Evaluación Nutricional , Ingestión de Energía , Necesidades Nutricionales , Adulto Joven , PreescolarRESUMEN
Prader-Willi syndrome (PWS) is a complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region, known as the Prader Willi critical region. Nutritional clinical manifestations change with age and are described in four different phases. The phases span both extremes of the nutritional spectrum, beginning with an infant with poor sucking reflexes and failure to thrive then progressing to an adolescent who may have hyperphagia and be at risk for obesity. The phenotype is likely due to hypothalamic dysfunction due to genetic changes in the Prader Willi critical region. Researchers are examining the pathological mechanisms that determine the disease course.
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CONTEXT: Several endocrine abnormalities were reported in children with Prader-Willi syndrome (PWS), including hypothyroidism. Growth hormone (GH) treatment may impact the thyroid hormone axis by direct inhibition of T4 or TSH secretion or by increased peripheral conversion of free T4 (FT4) to T3. OBJECTIVE: The objective of this study is to evaluate thyroid function during GH treatment in a large group of children with PWS. METHODS: Serum FT4, T3, and TSH are measured in a 2-year randomized controlled GH trial (RCT) and 10-year longitudinal GH study (GH treatment with 1.0 mg/m²/day [â¼0.035 mg/kg/day]). RESULTS: Forty-nine children with PWS were included in the 2-year RCT (median [interquartile range, IQR] age: GH group 7.44 [5.47-11.80] years, control group 6.04 [4.56-7.39] years). During the first 6 months, median (IQR) FT4 standard deviation score (SDS) decreased in the GH group from -0.84 (-1.07 to -0.62) to -1.32 (-1.57 to -1.08) (P < .001) and T3 SDS increased from 0.31 (-0.01-0.63) to 0.56 (0.32-0.79) (P = .08), while in the control group, FT4 and T3 SDS remained unchanged. In our 10-year GH study, 240 children with PWS (median [IQR] age: 1.27 (0.54-4.17) years] were included. Between 2 and 10 years, median (IQR) FT4 SDS remained unchanged, being -0.87 (-0.98 to -0.77) after 2 years and -0.88 (-1.03 to -0.74) after 10 years (P = .13). TSH SDS decreased from -0.35 (-0.50 to -0.21) after 2 years to -0.68 (-0.84 to -0.53) after 10 years (P < .001). CONCLUSIONS: Our findings suggest that GH treatment decreases FT4 levels, due to increased peripheral conversion of FT4 to T3 in the first months of treatment, but thereafter, FT4 and T3 normalize and remain stable during long-term GH treatment in almost all children and adolescents with PWS.
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Hormona de Crecimiento Humana , Síndrome de Prader-Willi , Humanos , Síndrome de Prader-Willi/tratamiento farmacológico , Síndrome de Prader-Willi/sangre , Niño , Masculino , Femenino , Preescolar , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/administración & dosificación , Estudios Longitudinales , Triyodotironina/sangre , Tiroxina/sangre , Tiroxina/uso terapéutico , Hormonas Tiroideas/sangre , Tirotropina/sangreRESUMEN
Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that terminates at PWAR1 in non-neurons. qRT-PCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing. Genome-wide transcriptome analyses revealed changes to 11 834 genes during neuronal differentiation, including the upregulation of most genes within the 15q11-q13 locus. To identify dynamic changes in chromatin loops linked to transcriptional activity, we performed a HiChIP validated by 4C, which identified two neuron-specific CTCF loops between MAGEL2-SNRPN and PWAR1-UBE3A. To determine if allele-specific differentially methylated regions (DMR) may be associated with CTCF loop anchors, whole genome long-read nanopore sequencing was performed. We identified a paternally hypomethylated DMR near the SNRPN upstream loop anchor exclusive to neurons and a paternally hypermethylated DMR near the PWAR1 CTCF anchor exclusive to undifferentiated cells, consistent with increases in neuronal transcription. Additionally, DMRs near CTCF loop anchors were observed in both cell types, indicative of allele-specific differences in chromatin loops regulating imprinted transcription. These results provide an integrated view of the 15q11-q13 epigenetic landscape during LUHMES neuronal differentiation, underscoring the complex interplay of transcription, chromatin looping, and DNA methylation. They also provide insights for future therapeutic approaches for AS and PWS.
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Congenital disorders of ventilatory control typically manifest as central apneas, periodic breathing, and hypoventilation in the neonatal period, but some may present at a later age. Obstructive apneas may be the initial presentation, and some may have associated autonomic nervous system dysfunction. Individuals with these disorders can have absent or impaired ventilatory and arousal responses to hypoxemia and hypercapnia. This article discusses the presentation, pathophysiology, evaluation, and management of congenital central hypoventilation syndrome, rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, Prader-Willi syndrome, and myelomeningocele.
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Hipoventilación , Apnea Central del Sueño , Humanos , Apnea Central del Sueño/terapia , Apnea Central del Sueño/fisiopatología , Apnea Central del Sueño/diagnóstico , Hipoventilación/congénito , Hipoventilación/terapia , Hipoventilación/fisiopatología , Hipoventilación/diagnóstico , Síndrome de Prader-Willi/fisiopatología , Síndrome de Prader-Willi/terapia , Síndrome de Prader-Willi/complicaciones , Síndrome de Prader-Willi/diagnóstico , Recién NacidoRESUMEN
PURPOSE: An investigation for the co-occurrence of two unrelated genetic disorders of muscular dystrophy and Prader-Willi syndrome (PWS) (OMIM#176270) using joint whole genome sequencing (WGS). METHODS: Trio WGS joint analysis was performed to investigate the genetic etiology in a proband with PWS, prolonged muscular hypotonia associated hyperCKemia, and early-onset obesity. The parents were unaffected. RESULTS: Results showed maternal isodisomy uniparental disomy (UPD) in chromosome 15, expanding from 15q11.2 to 15q22.2, including PWS regions at 15q11.2-15q13. Maternal heterodisomy was detected from 15q22.2 to 15q26.3. A pathogenic variant, NM_000070.3(CAPN3):c.550del (p.Thr184fs), was identified at 15q15.1 in a heterozygous state in the mother that was homozygous in the proband due to maternal isodisomy. CONCLUSION: This is the first study of the concurrent molecular etiology of PWS and calpainopathy (OMIM#253600) in the same patient. This report highlights the utility of joint analysis and the need for the assessment of autosomal recessive disease in regions of isodisomy in patients with complex and unexplained phenotypes.
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Calpaína , Cromosomas Humanos Par 15 , Síndrome de Prader-Willi , Disomía Uniparental , Humanos , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/patología , Calpaína/genética , Femenino , Cromosomas Humanos Par 15/genética , Disomía Uniparental/genética , Secuenciación Completa del Genoma , Masculino , Proteínas MuscularesRESUMEN
Introduction: Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypothalamic-pituitary deficiencies including hypogonadism. In girls with PWS, hypogonadism can present early in childhood, leading to genital hypoplasia, delayed puberty, incomplete pubertal development, and infertility. In contrast, girls can present with premature activation of the adrenal axis leading to early pubarche and advanced bone age. We aim to evaluate the progression of puberty and adrenarche signals in girls with PWS. Methodology: A longitudinal retrospective cohort study included girls with PWS followed at a Pediatric Endocrinology Outpatient Clinic in a Tertiary University Hospital in Sao Paulo, Brazil from 2002 to 2022. Data collected via chart review included clinical information on birth history, breast and pubic hair Tanner stages, presence of genital hypoplasia, age at menarche, regularity of menstrual cycles, body mass index (BMI) z-score, final height, age of initiation of estrogen replacement and growth hormone replacement, as well as results for PWS genetic subtype; biochemical investigation (LH, FSH, estradiol, DHEA-S); radiographic bone age and pelvic ultrasound. Results: A total of 69 girls were included in the study and the mean age of puberty onset was 10.2 years in those who started puberty after the age of 8 years. Breast Tanner stage IV was reached by 29.1% girls at a mean age of 14.9 years. Spontaneous menarche was present in 13.8% and only one patient had regular menstrual cycles. Early adrenarche was seen in 40.4% of cases. Conclusion: Our study demonstrated in a large sample that girls with PWS often present with delayed onset of puberty despite frequent premature adrenarche. Based on our results, we suggest an estrogen replacement protocol for girls with PWS to be started at the chronological age or bone age of 12-13 years, taking into consideration the uterus size. Further prospective studies are needed.
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Síndrome de Prader-Willi , Pubertad , Humanos , Femenino , Síndrome de Prader-Willi/fisiopatología , Niño , Estudios Retrospectivos , Adolescente , Pubertad/fisiología , Estudios Longitudinales , Centros de Atención Terciaria , Menarquia/fisiología , Brasil/epidemiología , Estudios de Cohortes , Adrenarquia , Pubertad Precoz/epidemiologíaAsunto(s)
Piperidinas , Síndrome de Prader-Willi , Humanos , Síndrome de Prader-Willi/tratamiento farmacológico , Piperidinas/farmacología , Piperidinas/administración & dosificación , Antagonistas de los Receptores Histamínicos H3/farmacología , Antagonistas de los Receptores Histamínicos H3/administración & dosificación , Agonismo Inverso de Drogas , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos H3/efectos de los fármacosRESUMEN
Background: It has been reported that central adrenal insufficiency (CAI) in pediatric patients (pts) with Prader-Willi syndrome (PWS) may be a potential cause of their sudden death. In addition, the risk of CAI may increase during treatment with recombinant human growth hormone (rhGH). Objective: To prevent both over- and undertreatment with hydrocortisone, we evaluated the prevalence of CAI in a large multicenter cohort of pediatric pts with PWS analyzing adrenal response in the low-dose ACTH test (LDAT) and/or the glucagon stimulation test (GST) and reviewing the literature. Methods: A total of 46 pts with PWS were enrolled to the study, including 34 treated with rhGH with a median dose of 0.21 mg/kg/week. LDAT was performed in 46 pts, and GST was carried out in 13 pts. Both tests were conducted in 11 pts. The tests began at 8:00 a.m. Hormones were measured by radioimmunoassays. Serum cortisol response >181.2 ng/mL (500 nmol/L) in LDAT and >199.3 ng/mL (550 nmol/L) in GST was considered a normal response. Additionally, cortisol response delta (the difference between baseline and baseline) >90 ng/mL and doubling/tripling of baseline cortisol were considered indicators of normal adrenal reserve. Results: Three GSTs were not diagnostic (no hypoglycemia obtained). LDAT results suggested CAI in four pts, but in two out of four pts, and CAI was excluded in GST. GST results suggested CAI in only one patient, but it was excluded in LDAT. Therefore, CAI was diagnosed in 2/46 pts (4.3%), 1 treated and 1 untreated with rhGH, with the highest cortisol values of 162 and 175 ng/dL, but only in one test. However, in one of them, the cortisol delta response was >90 ng/mL and peak cortisol was more than tripled from baseline. Finally, CAI was diagnosed in one patient treated with rhGH (2.2%). Conclusion: We present low prevalence of CAI in pediatric pts with PWS according to the latest literature. Therefore, we do not recommend to routinely screen the function of the hypothalamic-pituitary-adrenal axis (HPAA) in all pts with PWS, both treated and untreated with rhGH. According to a review of the literature, signs and symptoms or low morning ACTH levels suggestive of CAI require urgent and appropriate diagnosis of HPAA by stimulation test. Our data indicate that the diagnosis of CAI should be confirmed by at least two tests to prevent overtreatment with hydrocortisone.
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Hidrocortisona , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Síndrome de Prader-Willi , Humanos , Síndrome de Prader-Willi/tratamiento farmacológico , Síndrome de Prader-Willi/sangre , Síndrome de Prader-Willi/complicaciones , Femenino , Masculino , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Niño , Preescolar , Hidrocortisona/sangre , Adolescente , Insuficiencia Suprarrenal/diagnóstico , Insuficiencia Suprarrenal/sangre , Insuficiencia Suprarrenal/tratamiento farmacológico , Insuficiencia Suprarrenal/epidemiología , Lactante , Hormona de Crecimiento Humana/sangre , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/administración & dosificación , Glucagón/sangreRESUMEN
Prader-Willi syndrome (PWS) is the most common genetic syndrome with obesity and results from loss of expression of paternally inherited genes on chromosome 15q11-q13 by a variety of mechanisms which include large deletions (70%-75%), maternal uniparental disomy (UPD) (20%-30%), and imprinting defects (2%-5%) or balanced translocations. Individuals often have a characteristic behavior disorder with mild intellectual disability, infantile hypotonia associated with poor sucking, short stature, and obesity. PWS is characterized by hypothalamic-pituitary axis dysfunction with growth hormone (GH) deficiency, hypogonadism, and several other hormonal deficiencies resulting in short stature, centrally driven excessive appetite (hyperphagia), central obesity, cryptorchidism, and decreased lean body mass. In this study, we determined and sought differences in the incidence of thyroid abnormalities among the common genetic subtypes in a cohort of 52 subjects with PWS because there was limited literature available. We also sought the effects of growth hormone (GH) treatment on the thyroid profile. Fifty-two subjects with a genetically confirmed diagnosis of PWS were included in this study at the University of California, Irvine. Blood samples for baseline thyroxine stimulating hormone (TSH) and free thyroxine (fT4) levels were obtained in the morning after an overnight fast for 8-12 h. Statistical analyses were performed with SPSS (SPSS Inc., 21.0). Mean values were analyzed by one-way ANOVA, and student's t-test and statistical significance were set at p < 0.05. The subjects included 26 males and 26 females with an age range of 3-38 years. There were 29 subjects with chromosome 15q11-q13 deletions and 23 with UPD; 28 were GH treated currently or in the past, and 24 never received GH. There was no significant difference in age or body mass index (BMI) (kg/m2) between GH-treated versus non-GH-treated groups. BMI was higher in the deletion group compared to the UPD group (p = 0.05). We identified two individuals who were clinically diagnosed and treated for hypothyroidism, one of whom was on GH supplements. We identified two additional individuals with subclinical hypothyroidism who were not on GH treatment, giving a frequency of 7.6% (4/52) in this cohort of patients. We did not find significant differences in thyroid function (TSH) in the deletion versus UPD groups. We found significant differences in thyroid function, however, between GH-treated and non-GH-treated groups. The mean TSH was lower (2.25 ± 1.17 uIU/M, range 0.03-4.92 uIU/M versus 2.80 ± 1.44 uIU/M, range 0.55-5.33 uIU/M respectively, p = 0.046), and the free T4 levels were significantly higher (1.13 ± 0.70 and 1.03 ± 0.11 ng/dL, respectively, p = 0.05) in the GH-treated individuals compared to non-GH-treated individuals. In this cohort of subjects with PWS, we identified two previously diagnosed individuals with hypothyroidism and two individuals with subclinical hypothyroidism (4/52, 7.6%), three of whom were not receiving GH treatment. We did not find any significant differences in thyroid function between molecular subtypes; however, we found that euthyroid status (lower TSH levels and higher free T4 levels) was significantly higher in individuals who were treated with GH compared to the untreated group. We recommend that individuals with PWS should be screened regularly for thyroid deficiency and start treatment early with GH in view of the potentially lower incidence of thyroid deficiency.
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Background: Prader-Willi syndrome (PWS) is a multisystem genetic disorder caused by chromosomal imprinting gene defects, with approximately 70% of cases resulting from paternal deletion of the chromosomal region 15. The main clinical features include severe infantile hypotonia, early-onset childhood obesity, hyperphagia, and underdeveloped external genitalia. As individuals with PWS age, they may exhibit irritability, social dysfunction, impaired gonadal development, and metabolic syndrome. Previous literature places the prevalence of type 2 diabetes mellitus (T2DM) in PWS at approximately 7-24%. Oxytocin is a neuropeptide secreted by the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus and regulates energy metabolism, which is involved in PWS. Due to age limitations, very few patients progress to diabetic nephropathy during childhood, and reports of typical diabetic nephropathy in PWS during childhood are extremely rare. Dulaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist which can be used in the treatment of T2DM. Case Description: This article reports a case of a child with PWS complicated by stage III diabetic nephropathy, providing a retrospective analysis of the diagnosis and treatment process, as well as a review of domestic and international literature, to enhance understanding of this condition. And this article provides a treatment idea for PWS patients with diabetic nephropathy. Conclusions: It is very important to enhance understanding of PWS. And we offer new diagnostic and possible therapeutic approaches for pediatric patients with diabetic nephropathy.
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The neurodevelopmental disorders Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) both arise from genomic alterations within human chromosome 15q11-q13. A deletion of the SNORD116 cluster, encoding small nucleolar RNAs, or frameshift mutations within MAGEL2 result in closely related phenotypes in individuals with PWS or SYS, respectively. By investigation of their subcellular localization, we observed that in contrast to a predominant cytoplasmic localization of wild-type (WT) MAGEL2, a truncated MAGEL2 mutant was evenly distributed between the cytoplasm and the nucleus. To elucidate regulatory pathways that may underlie both diseases, we identified protein interaction partners for WT or mutant MAGEL2, in particular the survival motor neuron protein (SMN), involved in spinal muscular atrophy, and the fragile-X-messenger ribonucleoprotein (FMRP), involved in autism spectrum disorders. The interactome of the non-coding RNA SNORD116 was also investigated by RNA-CoIP. We show that WT and truncated MAGEL2 were both involved in RNA metabolism, while regulation of transcription was mainly observed for WT MAGEL2. Hence, we investigated the influence of MAGEL2 mutations on the expression of genes from the PWS locus, including the SNORD116 cluster. Thereby, we provide evidence for MAGEL2 mutants decreasing the expression of SNORD116, SNORD115, and SNORD109A, as well as protein-coding genes MKRN3 and SNRPN, thus bridging the gap between PWS and SYS.
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Péptidos y Proteínas de Señalización Intracelular , Proteínas Intrínsecamente Desordenadas , Síndrome de Prader-Willi , Humanos , Cromosomas Humanos Par 15/genética , Citoplasma/metabolismo , Células HEK293 , Mutación , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Síndrome de Prader-Willi/genética , Proteínas/genética , Proteínas/metabolismo , ARN Nucleolar Pequeño/genéticaRESUMEN
BACKGROUND: Prader-Willi syndrome (PWS) is commonly associated with intellectual disability, but also with a specific behavioural phenotype and a high predisposition to psychiatric comorbidity. This study examines the psychiatric care situation of people with PWS. METHOD: A structured online questionnaire was administered to carers of people with PWS living in Germany, asking about demographic, diagnostic and treatment parameters as well as personal experiences. RESULTS: Of 77 people with PWS, 44.2% had at least one psychiatric comorbid diagnosis. The main reasons for seeking psychiatric care were emotional outbursts and aggressive behaviour. 34.9% reported that they were currently seeking psychiatric care without success. However, 32.5% of PWS had been treated with psychotropic medication, mainly antipsychotics. CONCLUSIONS: Psychiatric comorbidity appears to be undertreated in PWS, especially in the ambulatory setting. Uncertainty among mental health care providers may also lead to frequent off-label use of psychotropic medications.
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Comorbilidad , Trastornos Mentales , Síndrome de Prader-Willi , Humanos , Síndrome de Prader-Willi/tratamiento farmacológico , Masculino , Femenino , Adulto , Trastornos Mentales/epidemiología , Persona de Mediana Edad , Adulto Joven , Alemania/epidemiología , Adolescente , Psicotrópicos/uso terapéutico , Servicios de Salud Mental/estadística & datos numéricos , Aceptación de la Atención de SaludRESUMEN
OBJECTIVES: Children with Prader-Willi Syndrome (PWS) may develop premature pubarche (PP). We investigated the frequency of PP, and its potential precursors and sequelae, in PWS. DESIGN, PATIENTS AND MEASUREMENTS: A chart review of children with PWS treated at our institution between 1990 and 2021 was performed. PP was defined as Tanner stage 2 (TS2) pubic hair in girls <8 and boys <9 years old. Demographic, anthropometric, and laboratory data were collected to assess predisposing factors and consequences of PP in comparison to patients with PWS who had normal pubarche (NP). RESULTS: Analysis included 43 children with PWS, 23 (53.5%) with PP and 20 (46.5%) with NP. Median age at pubarche was 7.0 years in PP group and 10.0 years in NP group. Age at pubarche was not correlated with age of recombinant human growth hormone (rhGH) initiation, body mass index (BMI) z-score, or homeostasis model assessment of insulin resistance (HOMA-IR) at pubarche. BMI z-score at pubarche was modestly correlated with degree of pubarchal BA advancement (p = 0.033). Those with PP were more likely to have a lower high-density lipoprotein (HDL) (1.05 mmol/L vs. 1.41 mmol/L in the NP group, p = 0.041). The difference between target and final height did not differ between groups (p = 0.507). CONCLUSION: PP is common in PWS but does not compromise final height in comparison to the NP group. Obesity and insulin resistance were not associated with PP in children with PWS, contrary to what has been seen in obese children without PWS.
Asunto(s)
Síndrome de Prader-Willi , Pubertad Precoz , Humanos , Síndrome de Prader-Willi/complicaciones , Femenino , Niño , Masculino , Pubertad Precoz/etiología , Pubertad Precoz/epidemiología , Factores de Riesgo , Preescolar , Índice de Masa Corporal , Estudios RetrospectivosRESUMEN
The current study examines the efficacy of an 8-week pretend play intervention targeting social-cognitive abilities in children with Prader-Willi syndrome (PWS), ages 6-9. PWS is a rare disorder associated with various social, emotional, and cognitive challenges linked to pretend play impairments, and for which interventions are sparse. Nineteen children were quasi-randomized to receive the intervention or be part of a waitlist control group. Participants who received the intervention (n = 10) demonstrated significant improvements in various components of pretend play, most notably in organization of play, which may generalize to broader social-cognitive gains. These findings provide evidence of the intervention's efficacy in enhancing pretend play skills and related social-cognitive abilities during this critical period of development for children with PWS.