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Journal of Pediatric Endocrinology &... Sep 2023Glycogen storage disease (GSD) type 1a is an inherited autosomal recessive metabolic disease caused by a deficiency in glucose-6-phosphatase activity. The objectives of... (Review)
Review
Glycogen storage disease (GSD) type 1a is an inherited autosomal recessive metabolic disease caused by a deficiency in glucose-6-phosphatase activity. The objectives of this research were to systematically review the published literature on the epidemiology of GSD 1a and to assess the performance of reported epidemiology measures in a simulation model. In this systematic literature review 2,539 record titles and abstracts were screened. Of these, only 11 studies contained relevant data on GSD 1a disease epidemiology. Reported disease frequency ranged from 0.085/100,000 to 10.3/100,000 newborns when considering all the GSD literature. When this was narrowed to GSD 1 and GSD 1a, the range was tightened to 0.25-3.02/100,000 and 0.085-4.9/100,000 newborns, respectively. Most of the identified studies counted the number of diagnoses in a defined period and related to the number of births in the same (Dx method) or different time period (DoB method). The simulation model results indicate that in most of the situations, the Dx method provides a closer estimate to the true disease incidence than the DoB method. Despite the scarcity of epidemiology data, the results of this systematic review strongly support that GSD 1a and its parent disease groups (GSD and GSD 1) are rare diseases.
Topics: Infant, Newborn; Humans; Pregnancy; Female; Glycogen Storage Disease Type I; Glucose-6-Phosphatase; Parents; Parturition
PubMed: 37615591
DOI: 10.1515/jpem-2023-0127 -
Current Pediatric Reviews 2023Silver-Russell syndrome (SRS) is a developmental disorder involving extreme growth failure, characteristic facial features and underlying genetic heterogeneity. As the...
BACKGROUND
Silver-Russell syndrome (SRS) is a developmental disorder involving extreme growth failure, characteristic facial features and underlying genetic heterogeneity. As the clinical heterogeneity of SRS makes diagnosis a challenging task, the worldwide incidence of SRS could vary from 1:30,000 to 1:100,000. Although various chromosomal, genetic, and epigenetic mutations have been linked with SRS, the cause had only been identified in half of the cases.
MATERIAL AND METHODS
To have a better understanding of the SRS clinical presentation and mutation/ epimutation responsible for SRS, a systematic review of the literature was carried out using appropriate keywords in various scientific databases (PROSPERO protocol registration CRD42021273211). Clinical features of SRS have been compiled and presented corresponding to the specific genetic subtype. An attempt has been made to understand the recurrence risk and the role of model organisms in understanding the molecular mechanisms of SRS pathology, treatment, and management strategies of the affected patients through the analysis of selected literature.
RESULTS
156 articles were selected to understand the clinical and molecular heterogeneity of SRS. Information about detailed clinical features was available for 228 patients only, and it was observed that body asymmetry and relative macrocephaly were most prevalent in cases with methylation defects of the 11p15 region. In about 38% of cases, methylation defects in ICRs or genomic mutations at the 11p15 region have been implicated. Maternal uniparental disomy of chromosome 7 (mUPD7) accounts for about 7% of SRS cases, and rarely, uniparental disomy of other autosomes (11, 14, 16, and 20 chromosomes) has been documented. Mutation in half of the cases is yet to be identified. Studies involving mice as experimental animals have been helpful in understanding the underlying molecular mechanism. As the clinical presentation of the syndrome varies a lot, treatment needs to be individualized with multidisciplinary effort.
CONCLUSION
SRS is a clinically and genetically heterogeneous disorder, with most of the cases being implicated with a mutation in the 11p15 region and maternal disomy of chromosome 7. Recurrence risk varies according to the molecular subtype. Studies with mice as a model organism have been useful in understanding the underlying molecular mechanism leading to the characteristic clinical presentation of the syndrome. Management strategies often need to be individualized due to varied clinical presentations.
Topics: Humans; Animals; Mice; Mice, Inbred ICR; Silver-Russell Syndrome; Uniparental Disomy; Genomic Imprinting
PubMed: 35293298
DOI: 10.2174/1573396318666220315142542 -
Phytotherapy Research : PTR Apr 2022This systematic review was designed to determine the clinical efficacy and safety of curcumin supplementation for pediatric patients based on clinical trials in... (Review)
Review
This systematic review was designed to determine the clinical efficacy and safety of curcumin supplementation for pediatric patients based on clinical trials in children. We systematically searched electronic databases including PubMed, EMBASE, Web of Science, and Scopus for all studies that investigated curcumin administration in the pediatric population without any time frame limitation. Finally, we identified 16 studies for this review. Clinical efficacy and safety of curcumin were assessed in children with inflammatory and immune disorders (including asthma, inflammatory bowel disease (IBD), and juvenile idiopathic arthritis (JIA)), metabolic disorders, autosomal dominant polycystic kidney disease (ADPKD), cystic fibrosis (CF), tetralogy of Fallot (TOF), and infectious diseases. Curcumin was administered in a wide range of doses (45 mg-4,000 mg daily) and durations (2-48 weeks). Overall, curcumin was well tolerated in all studies and improved the severity of inflammatory and immune disorders and metabolic diseases. However, more studies are needed to clarify the role of curcumin supplementation among children with ADPKD, CF, TOF, and infectious diseases. Because of substantial heterogeneity in methodological quality, design, outcomes, dose, duration of intake, formulations, and study populations across studies, no quantitative analysis was performed. Additional large-scale, randomized, placebo-controlled clinical trials are needed to confirm the results of the conducted studies.
Topics: Child; Curcumin; Dietary Supplements; Female; Humans; Inflammatory Bowel Diseases; Male; Polycystic Kidney, Autosomal Dominant; Treatment Outcome
PubMed: 34904764
DOI: 10.1002/ptr.7350 -
Journal of Lipid Research Mar 2022Syndromes associated with LCAT deficiency, a rare autosomal recessive condition, include fish-eye disease (FED) and familial LCAT deficiency (FLD). FLD is more severe... (Review)
Review
Syndromes associated with LCAT deficiency, a rare autosomal recessive condition, include fish-eye disease (FED) and familial LCAT deficiency (FLD). FLD is more severe and characterized by early and progressive chronic kidney disease (CKD). No treatment is currently available for FLD, but novel therapeutics are under development. Furthermore, although biomarkers of LCAT deficiency have been identified, their suitability to monitor disease progression and therapeutic efficacy is unclear, as little data exist on the rate of progression of renal disease. Here, we systematically review observational studies of FLD, FED, and heterozygous subjects, which summarize available evidence on the natural history and biomarkers of LCAT deficiency, in order to guide the development of novel therapeutics. We identified 146 FLD and 53 FED patients from 219 publications, showing that both syndromes are characterized by early corneal opacity and markedly reduced HDL-C levels. Proteinuria/hematuria were the first signs of renal impairment in FLD, followed by rapid decline of renal function. Furthermore, LCAT activity toward endogenous substrates and the percentage of circulating esterified cholesterol (EC%) were the best discriminators between these two syndromes. In FLD, higher levels of total, non-HDL, and unesterified cholesterol were associated with severe CKD. We reveal a nonlinear association between LCAT activity and EC% levels, in which subnormal levels of LCAT activity were associated with normal EC%. This review provides the first step toward the identification of disease biomarkers to be used in clinical trials and suggests that restoring LCAT activity to subnormal levels may be sufficient to prevent renal disease progression.
Topics: Humans; Biomarkers; Heterozygote; Lecithin Cholesterol Acyltransferase Deficiency; Mutation; Phosphatidylcholine-Sterol O-Acyltransferase
PubMed: 35065092
DOI: 10.1016/j.jlr.2022.100169 -
International Journal of Molecular... Oct 2022The CTNNB1 Syndrome is a rare neurodevelopmental disorder associated with developmental delay, intellectual disability, and delayed or absent speech. The aim of the... (Review)
Review
The CTNNB1 Syndrome is a rare neurodevelopmental disorder associated with developmental delay, intellectual disability, and delayed or absent speech. The aim of the present study is to systematically review the available data on the prevalence of clinical manifestations and to evaluate the correlation between phenotype and genotype in published cases of patients with CTNNB1 Syndrome. Studies were identified by systematic searches of four major databases. Information was collected on patients' genetic mutations, prenatal and neonatal problems, head circumference, muscle tone, EEG and MRI results, dysmorphic features, eye abnormalities, early development, language and comprehension, behavioral characteristics, and additional clinical problems. In addition, the mutations were classified into five groups according to the severity of symptoms. The study showed wide genotypic and phenotypic variability in patients with CTNNB1 Syndrome. The most common moderate-severe phenotype manifested in facial dysmorphisms, microcephaly, various motor disabilities, language and cognitive impairments, and behavioral abnormalities (e.g., autistic-like or aggressive behavior). Nonsense and missense mutations occurring in exons 14 and 15 were classified in the normal clinical outcome category/group because they had presented an otherwise normal phenotype, except for eye abnormalities. A milder phenotype was also observed with missense and nonsense mutations in exon 13. The autosomal dominant CTNNB1 Syndrome encompasses a wide spectrum of clinical features, ranging from normal to severe. While mutations cannot be more generally categorized by location, it is generally observed that the C-terminal protein region (exons 13, 14, 15) correlates with a milder phenotype.
Topics: Pregnancy; Female; Humans; Codon, Nonsense; Phenotype; Intellectual Disability; Syndrome; Genotype; Mutation; Eye Abnormalities; beta Catenin
PubMed: 36293418
DOI: 10.3390/ijms232012564 -
Pediatric Neurology Jul 2022Hereditary hyperekplexia (HPX) is a genetic neurodevelopmental disorder recently defined by the triad of (1) neonatal hypertonia, (2) excessive startle reflexes, and (3)... (Review)
Review
Hereditary hyperekplexia (HPX) is a genetic neurodevelopmental disorder recently defined by the triad of (1) neonatal hypertonia, (2) excessive startle reflexes, and (3) generalized stiffness following the startle. Defects in GLRA1 are the most common cause of HPX, inherited both in an autosomal dominant and autosomal recessive manner. GLRA1 mutations can also cause milder phenotypes in the startle syndromes spectrum, but the prevalence is uncertain and no clear genotype-phenotype correlation has emerged yet. Moreover, the prevalence of neurodevelopmental outcomes has not been clearly defined. Here we report a new family of patients with a typical HPX phenotype, linked to a novel GLRA1 mutation, inherited with a recessive pattern. We then perform a systematic review of the literature of GLRA1-related HPX, describing the main epidemiological features of 210 patients. We found that GLRA1-related phenotypes do not necessarily fulfill the current criteria for HPX, including also milder and later-onset phenotypes. Among clinical features of the disease, neurodevelopmental issues were reported in a third of the sample; interestingly, we found that these problems, particularly when severe, were more common in homozygous than in heterozygous patients. Additional clinical and preclinical studies are needed to define predictors of adverse neurodevelopmental outcomes and underlying mechanisms.
Topics: Humans; Muscle Rigidity; Phenotype; Receptors, Glycine; Reflex, Startle; Stiff-Person Syndrome
PubMed: 35636282
DOI: 10.1016/j.pediatrneurol.2022.05.002 -
The Cochrane Database of Systematic... Dec 2021Cystic fibrosis is the most common life-limiting autosomal recessive genetic disorder in white populations. Distal intestinal obstruction syndrome (DIOS) is an important... (Review)
Review
BACKGROUND
Cystic fibrosis is the most common life-limiting autosomal recessive genetic disorder in white populations. Distal intestinal obstruction syndrome (DIOS) is an important morbidity in cystic fibrosis. It is the result of the accumulation of viscid faecal material within the bowel which combines with thick, sticky mucus produced in the intestines of people with cystic fibrosis. The intestine may be completely blocked (complete DIOS) or only partially blocked (incomplete DIOS). Once a diagnosis of DIOS has been made, the goal of therapy is to relieve the acute complete or incomplete faecal obstruction and ultimately prevent the need for surgical intervention.
OBJECTIVES
This review aimed to evaluate the effectiveness and safety of different treatment regimens for the treatment of DIOS (complete and incomplete) in children and adults with cystic fibrosis.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of search: 09 September 2021. We also searched online trial registries. Date of last search: 12 October 2021.
SELECTION CRITERIA
Randomised controlled trials, quasi-randomised controlled trials (including cross-over trials (to be judged on an individual basis)) comparing the use of laxative agents or surgery for treating DIOS in children, young people and adults with cystic fibrosis to each other, placebo or no intervention.
DATA COLLECTION AND ANALYSIS
Two authors independently screened papers, extracted trial details and assessed for risk of bias. The authors assessed the quality of evidence using GRADE.
MAIN RESULTS
There was one trial with 20 participants (16 females) included in the review. The mean age of participants was 13.1 years. The trial was a double-blinded, randomised cross-over trial which had a duration of 12 months in total and compared high-dose and low-dose pancreatic enzyme therapy. As only the abstract of the trial was available, the overall risk of bias was judged to be unclear. The trial did not address either of our primary outcomes (time until resolution of DIOS and treatment failure rate), but reported episodes of acute DIOS, presence of abdominal mass and abdominal pain. There were no numerical data available for these outcomes, but the authors stated that there was no difference between treatment with high-dose or low-dose pancreatic enzymes. The overall certainty of the evidence was found to be very low.
AUTHORS' CONCLUSIONS
There is a clear lack of evidence for the treatment of DIOS in people with cystic fibrosis. The included abstract did not address our primary outcome measures and did not provide numerical data for the two secondary outcomes it did address. Therefore, we cannot justify the use of high-dose pancreatic enzymes for treating DIOS, nor can we comment on the efficacy and safety of other laxative agents. From our findings, it is clear that more randomised controlled trials need to be conducted in this area.
Topics: Abdominal Pain; Adolescent; Adult; Child; Cystic Fibrosis; Female; Humans; Intestinal Obstruction; Pancreas; Randomized Controlled Trials as Topic
PubMed: 34936086
DOI: 10.1002/14651858.CD012798.pub3 -
Neuropediatrics Oct 2023Autosomal dominant mutations of the gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE)....
BACKGROUND
Autosomal dominant mutations of the gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE). This systematic review aims to identify the best reported therapy for these patients, relating to phenotype, neurodevelopmental outcome, and an eventual correlation between phenotype and genotype.
METHODS
We searched on PubMed using the search terms "" AND "therapy" and "" AND "treatment"; we found 304 articles. Of these, 29 met our criteria. We collected the data from 194 patients. All 29 articles were retrospective studies.
RESULTS
In all, 104 patients were classified as DEE and 90 as BFNS. After treatment began, 95% of BFNS patients became seizure free, whereas the seizures stopped only in 73% of those with DEE. Phenobarbital and sodium channel blockers were the most used treatment in BFNS. Most of the DEE patients (95%) needed polytherapy for seizure control and even that did not prevent subsequent developmental impairment (77%).Missense mutations were discovered in 96% of DEE patients; these were less common in BFNS (50%), followed by large deletion (16%), truncation (16%), splice donor site (10%), and frameshift (7%).
CONCLUSION
Phenobarbital or carbamazepine appears to be the most effective antiseizure medication for children with a "benign" variant. On the contrary, polytherapy is often needed for DEE patients, even if it does not seem to improve neurological outcomes. In DEE patients, most mutations were located in S4 and S6 helix, which could serve as a potential target for the development of more specific treatment in the future.
Topics: Child; Infant, Newborn; Humans; Retrospective Studies; KCNQ2 Potassium Channel; Epilepsy, Benign Neonatal; Mutation; Seizures; Phenotype; Genotype; Phenobarbital
PubMed: 36948217
DOI: 10.1055/a-2060-4576 -
Genetics in Medicine : Official Journal... Feb 2024Persistent human papillomavirus infection (PHPVI) causes cutaneous, anogenital, and mucosal warts. Cutaneous warts include common warts, Treeman syndrome, and... (Review)
Review
PURPOSE
Persistent human papillomavirus infection (PHPVI) causes cutaneous, anogenital, and mucosal warts. Cutaneous warts include common warts, Treeman syndrome, and epidermodysplasia verruciformis, among others. Although more reports of monogenic predisposition to PHPVI have been published with the development of genomic technologies, genetic testing is rarely incorporated into clinical assessments. To encourage broader molecular testing, we compiled a list of the various monogenic etiologies of PHPVI.
METHODS
We conducted a systematic literature review to determine the genetic, immunological, and clinical characteristics of patients with PHPVI.
RESULTS
The inclusion criteria were met by 261 of 40,687 articles. In 842 patients, 83 PHPVI-associated genes were identified, including 42, 6, and 35 genes with strong, moderate, and weak evidence for causality, respectively. Autosomal recessive inheritance predominated (69%). PHPVI onset age was 10.8 ± 8.6 years, with an interquartile range of 5 to 14 years. GATA2,IL2RG,DOCK8, CXCR4, TMC6, TMC8, and CIB1 are the most frequently reported PHPVI-associated genes with strong causality. Most genes (74 out of 83) belong to a catalog of 485 inborn errors of immunity-related genes, and 40 genes (54%) are represented in the nonsyndromic and syndromic combined immunodeficiency categories.
CONCLUSION
PHPVI has at least 83 monogenic etiologies and a genetic diagnosis is essential for effective management.
Topics: Humans; Child, Preschool; Child; Adolescent; Papillomavirus Infections; Warts; Epidermodysplasia Verruciformis; Skin; Syndrome; Membrane Proteins; Guanine Nucleotide Exchange Factors
PubMed: 37978863
DOI: 10.1016/j.gim.2023.101028 -
Orphanet Journal of Rare Diseases Sep 2020Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13....
Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life.These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations.These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.
Topics: Alstrom Syndrome; Child; Consensus; Humans; Practice Guidelines as Topic; Quality of Life
PubMed: 32958032
DOI: 10.1186/s13023-020-01468-8