Mental Retardation Syndrome Research Articles

Care of Children with DiGeorge Before and After Cultured Thymus Tissue Implantation

BackgroundChildren with complete DiGeorge anomaly (cDGA) have congenital athymia plus a myriad of other challenging clinical conditions. The term cDGA encompasses children with congenital athymia secondary to 22q11.2DS, CHARGE syndrome (coloboma, heart defects, choanal atresia, growth or mental retardation, genital abnormalities, and ear abnormalities and/or deafness), and other genetic abnormalities. Some children have no known genetic defects. Since 1993, more than 100 children with congenital athymia have been treated with cultured thymus tissue implantation (CTTI). Naïve T cells develop approximately 6 to 12 months after CTTI. Most of the children had significant comorbidities such as heart disease, hypoparathyroidism, and infections requiring complex clinical care post cultured thymus tissue implantation (CTTI).ObjectiveThe purpose of this guidance is to assist multidisciplinary teams in caring for children with cDGA both before and after CTTI.MethodsThirty-one specialists, in addition to the authors, were asked to share their experience in caring for children with cDGA at Duke University Health System, before and after CTTI. These specialists included physicians, nurses, dentists, therapists, and dieticians.ResultsThe goal of a multidisciplinary approach is to have children in the best possible condition for receiving CTTI and provide optimal care post CTTI through development of naïve T cells and beyond. The CTT (cultured thymus tissue) must be protected from high doses of steroids which can damage CTT. Organs must be protected from adverse effects of immunosuppression.ConclusionCreating a multidisciplinary team and a detailed plan of care for children with cDGA is important for optimal outcomes.

Risk factors for post-nephrectomy hypotension in pediatric patients.

Although hypotension is a life-threatening complication of nephrectomy in children, risk factors for its development remain unknown. We evaluated the incidence, clinical course, and associated risk factors of pediatric post-nephrectomy hypotension in an observational study. This retrospective observational study included the clinical data of children who underwent nephrectomy in our center between 2002 and 2020. Patients undergoing nephrectomy at kidney transplantation and those who developed hypotension before nephrectomy were excluded. The study included 55 nephrectomies in 51 patients, including 42 unilateral, 4 two-stage bilateral, and 5 simultaneous bilateral nephrectomies. The diagnoses were isolated Wilms tumor, neuroblastoma, congenital nephrotic syndrome, Denys-Drash syndrome, WAGR (Wilms tumor, aniridia, genitourinary malformations, and mental retardation) syndrome, and autosomal recessive polycystic kidney disease in 24, 10, 9, 6, 1, and 1 patient, respectively. Post-nephrectomy hypotension developed in 11 (20%) patients. Two patients (3.6%) had persistent hypotension; both had their kidneys resected, and one patient (1.8%) died. Male sex, kidney disease, resection of both kidneys, low estimated glomerular filtration rate, increased left ventricular posterior wall thickness in diastole, hypertension before nephrectomy, antihypertensive use, hyperreninemia, and hyperaldosteronism were significantly associated with post-nephrectomy hypotension. Multivariate logistic regression analysis revealed that hypertension before nephrectomy was the only significant risk factor for post-nephrectomy hypotension (P = 0.04). Hypertension before nephrectomy is a significant risk factor for pediatric post-nephrectomy hypotension. Life-threatening hypotension, which might occur after bilateral nephrectomy in infants, should be considered, especially in children with higher risks.

GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation

GDP-mannose-pyrophosphorylase-B (GMPPB) facilitates the generation of GDP-mannose, a sugar donor required for glycosylation. GMPPB defects cause muscle disease due to hypoglycosylation of α-dystroglycan (α-DG). Alpha-DG is part of a protein complex, which links the extracellular matrix with the cytoskeleton, thus stabilizing myofibers. Mutations of the catalytically inactive homolog GMPPA cause alacrima, achalasia, and mental retardation syndrome (AAMR syndrome), which also involves muscle weakness. Here, we showed that Gmppa-KO mice recapitulated cognitive and motor deficits. As structural correlates, we found cortical layering defects, progressive neuron loss, and myopathic alterations. Increased GDP-mannose levels in skeletal muscle and in vitro assays identified GMPPA as an allosteric feedback inhibitor of GMPPB. Thus, its disruption enhanced mannose incorporation into glycoproteins, including α-DG in mice and humans. This increased α-DG turnover and thereby lowered α-DG abundance. In mice, dietary mannose restriction beginning after weaning corrected α-DG hyperglycosylation and abundance, normalized skeletal muscle morphology, and prevented neuron degeneration and the development of motor deficits. Cortical layering and cognitive performance, however, were not improved. We thus identified GMPPA defects as the first congenital disorder of glycosylation characterized by α-DG hyperglycosylation, to our knowledge, and we have unraveled underlying disease mechanisms and identified potential dietary treatment options.

Clinical case of epilepsy, hearing loss and mental retardation syndrome associated with mutations in SPATA5 gene

We present the clinical case of patient with epilepsy, developmental retardation and hearing loss. The whole exome sequencing allowed to reveal compound heterozygous variants of the nucleotide sequence in SPATA5 gene (c.1714+1G>A, c.1678G>A). Mutations in the SPATA5 gene have been described in patients with epilepsy, hearing loss and mental retardation syndrome (MIM 616577). Paired parents were carriers of one heterozygous gene variant. Such mutations lead to the development of epileptic disorders in 3% of cases, and should be considered in patients not only as a possible cause of neurodegenerative diseases, but also leading to pathology with clinical manifestations mimicking mitochondrial disease.

Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study

PurposeEpilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency. MethodsWe thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms “MEF2C”, “seizures”, and “epilepsy”. ResultsEpilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms. ConclusionThe epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.

Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders.

Epigenetic processes are critical for governing the complex spatiotemporal patterns of gene expression in neurodevelopment. One such mechanism is the dynamic network of post-translational histone modifications that facilitate recruitment of transcription factors or even directly alter chromatin structure to modulate gene expression. This is a tightly regulated system, and mutations affecting the function of a single histone-modifying enzyme can shift the normal epigenetic balance and cause detrimental developmental consequences. In this review, we will examine select neurodevelopmental conditions that arise from mutations in genes encoding enzymes that regulate histone methylation and acetylation. The methylation-related conditions discussed include Wiedemann-Steiner, Kabuki, and Sotos syndromes, and the acetylation-related conditions include Rubinstein-Taybi, KAT6A, genitopatellar/Say-Barber-Biesecker-Young-Simpson, and brachydactyly mental retardation syndromes. In particular, we will discuss the clinical/phenotypic and genetic basis of these conditions and the model systems that have been developed to better elucidate cellular and systemic pathological mechanisms.

Early Management of Nephroblastoma: A Single-Center Study in a Sub-Saharan African Country

Introduction: Nephroblastoma is the most common renal cancer in pediatrics. The aim of this study was to describe the epidemiological, clinical, histological characteristics and the immediate outcome of patients with nephroblastoma. Methodology: This was a cross-sectional study of 18 cases of unilateral nephroblastoma, carried out in the pediatric oncology unit (UOP) of the CHU Gabriel Touré from January 2015 to December 2016. Results: The mean age of the patients was 33 months old. The sex ratio was 0.63. The average consultation time was 3 months. A case of malformation syndrome (aniridia and mental retardation) had been observed. The main reason for consultation was abdominal mass (100%) associated with deterioration of general condition (44%), pain (44%) and fever (17%). Stage I accounted for 61% and stage II 39%. The postoperative histological classification made it possible to find the high-risk blastematous type (33%), the regressive type of intermediate risk (11%) and the stromal type of intermediate risk (45%). Toxicities (haematological and digestive) were minimal. The 3-year overall survival was 90%. Conclusion: This study is characterized by the predominance of stages I and II and the fairly large percentage of histology at intermediate risk. These results are above all the result of multidisciplinary collaboration.

Медико-генетическое изучение населения Республики Северная Осетия Алания. II. Нозологический спектр наследственной патологии в трех районах

Представлен нозологический спектр моногенных наследственных болезней (МНБ) в трех районах Республики Северная Осетия Алания (РСОА) - Правобережном, Ардонском и Кировском, общей численностью 119 590 человек. Обследовано все население районов по протоколу генетико-эпидемиологических исследований (разработка ФГБНУ «МГНЦ»), выявлено и диагностировано 600 пациентов (из 418 семей) с различными МНБ. Всего выявлено 135 нозологических форм - 65 с аутосомно-доминантным типом наследования (АД), 57 с аутосомно-рецессивным (АР) и 14 с Х-сцепленным (Х-сц.). Определены распространенность заболеваний, частые и редкие нозологические формы. Проведено сравнение нозологического спектра и распространенности отдельных МНБ с таковыми в ранее обследованных популяциях европейской части России. Выявлены особенности разнообразия МНБ. Более высокие значения распространенности, чем в других популяциях РФ выявлены синдром Элерса-Данло, миотоническая дистрофия, несиндромальная умственная отсталость с различными типами наследования, различные формы пигментного ретинита и др. Ряд заболеваний, частых в обследованных регионах РФ, наоборот, встречались реже - вульгарный ихтиоз, нейрофиброматоз, наследственная моторно-сенсорная нейропатия и ихтиозиформная эритродеремия. In this article we present the nosological spectrum of monogenic hereditary diseases (MHD) in three districts of the Republic of North Ossetia - Alania (RNOA) - Pravoberezhny, Ardonsky and Kirovsky, with a total population of 119,590 people. The entire population of the districts was examined according to the Protocol of genetic and epidemiological studies (developed by the Federal state budgetary Research Centre for Medical Genetics), 600 patients (from 418 families) with various NBS were identified and diagnosed. We identified 136 nosological forms of MHD - 65 with autosomal dominant type of inheritance (AD), 57 with autosomal recessive (AR) and 14 with X-linked (X-lin.). We determine the prevalence of diseases, frequent and rare nosological forms. The nosological spectrum and prevalence of individual MHD were compared with previously surveyed populations in the European part of Russia: Kirov, Kostroma, Arkhangelsk, Tver, Bryansk, Rostov regions, Krasnodar territory and the Republics of Karachay-Cherkessia, Adygea, Tatarstan, Bashkortostan, Mari El, Udmurtia and Chuvashia. Features of the MHD diversity are revealed. With higher prevalence values than in other populations of the Russian Federation, Ehlers-Danlo syndrome, myotonic dystrophy, non - syndromic mental retardation with various types of inheritance and various forms of retinitis pigmentosa, etc. A number of diseases that are frequent in the Russian Federation have shown on the contrary lower prevalence values - vulgar ichthyosis, neurofibromatosis, hereditary motor-sensory neuropathy and ichthyosiform erythroderemia.

&lt;p&gt;A de novo &lt;em&gt;CTNNB1&lt;/em&gt; Novel Splice Variant in an Adult Female with Severe Intellectual Disability&lt;/p&gt;

The catenin beta-1 (CTNNB1) gene, encoding a sub-unit of the cadherin/catenin protein complex that is involved in the Wnt signalling pathway important for proper interneuron development, is considered to be causative for the rare autosomal dominant mental retardation syndrome, formerly called MRD19 but later renamed neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV). Its main characteristics are moderate to severe intellectual disability (ID), disruptive autistic behaviours, microcephaly, absent or limited speech, facial dysmorphisms, peripheral hypertonia/spasticity, motor delay and visual defects. So far, 35 patients have been reported with a de novo loss-of-function variant in CTNNB1. In two other patients, a deletion comprising the full gene was found. Four out of the 37 patients were of adult age (range: 27–51 years), while the majority was infant or adolescent (range: 0–20 years). Here, a 32-year-old severely intellectually disabled female patient is described in whom exome sequencing disclosed a de novo heterozygous splice site variant in the CTNNB1 gene [Chr3(GRCh37): g.41267064G>T; NM_001904.3: 23. c.734+1G>T; r. spl?]. Somatic investigation disclosed significant microcephaly and minor facial dysmorphisms. Neurological examination demonstrated severe kyphoscoliosis, distal spastic tetraparesis, especially of the legs with increased tendon reflexes and bilateral Babinski sign, resulting in severely impaired walking capability with a broad-based gait. Apart from strabismus, no ophthalmological abnormalities were found. Here, the reported variant in the CTNNB1 gene was not published earlier nor is included in the international databases. This specific variant is considered to be causative for the severe ID, autism and the somato-neurological phenotype of the patient and corresponds with a diagnosis of NEDSDV.

The clinical-phenotype continuum in DYNC1H1-related disorders\u2014genomic profiling and proposal for a novel classification

Mutations in the cytoplasmic dynein 1 heavy chain gene (DYNC1H1) have been identified in rare neuromuscular (NMD) and neurodevelopmental (NDD) disorders such as spinal muscular atrophy with lower extremity dominance (SMALED) and autosomal dominant mental retardation syndrome 13 (MRD13). Phenotypes and genotypes of ten pediatric patients with pathogenic DYNC1H1 variants were analyzed in a multi-center study. Data mining of large-scale genomic variant databases was used to investigate domain-specific vulnerability and conservation of DYNC1H1. We identified ten patients with nine novel mutations in the DYNC1H1 gene. These patients exhibit a broad spectrum of clinical findings, suggesting an overlapping disease manifestation with intermixed phenotypes ranging from neuropathy (peripheral nervous system, PNS) to severe intellectual disability (central nervous system, CNS). Genomic profiling of healthy and patient variant datasets underlines the domain-specific effects of genetic variation in DYNC1H1, specifically on toleration towards missense variants in the linker domain. A retrospective analysis of all published mutations revealed domain-specific genotype–phenotype correlations, i.e., mutations in the dimerization domain with reductions in lower limb strength in DYNC1H1–NMD and motor domain with cerebral malformations in DYNC1H1–NDD. We highlight that the current classification into distinct disease entities does not sufficiently reflect the clinical disease manifestation that clinicians face in the diagnostic work-up of DYNC1H1-related disorders. We propose a novel clinical classification for DYNC1H1-related disorders encompassing a spectrum from DYNC1H1–NMD with an exclusive PNS phenotype to DYNC1H1–NDD with concomitant CNS involvement.

Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome: a new case report from Indonesia and review of the literature

DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures; MIM 220500) is a rare multisystem genetic disorder, mainly characterized by sensorineural deafness, shortened terminal phalanges with small nails of hands and feet, intellectual deficit, and seizures. The disease is caused by homozygous or compound heterozygous mutation in the TBC1 domain family member 24 (TBC1D24) gene (gene locus/MIM 613577) on chromosome 16p13. We report the first case of DOORS syndrome from Indonesia. A review of the literature was conducted and cases compared. A 27-day-old baby girl was brought to us with a history of recurrent seizures and absence of all finger- and toenails since birth. In addition, physical examination revealed left eye strabismus and a single transverse palmar crease on both hands. X-rays of the hands and feet showed absence of the distal phalanx of her right and left fingers II-V and the distal phalanx of her right and left toes I-V, respectively. Brainstem-evoked response audiometry test revealed profound bilateral sensorineural deafness. Pentalogy of Fallot was diagnosed by echocardiography, while an abnormal diffuse epileptiform pattern was found on electroencephalography. This is the first report of an association between pentalogy of Fallot and single transverse palmar crease in DOORS syndrome.

PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development.

Recessive mutations in Post-GPI attachment to proteins 3 (PGAP3) cause the rare neurological disorder hyperphosphatasia with mental retardation syndrome 4 type (HPMRS4). Here, we report a novel homozygous nonsense mutation in PGAP3 (c.265C>T-p.Gln89*), in a 3-year-old boy with unique novel clinical features. These include decreased intrauterine fetal movements, dysgenesis of the corpus callosum, olfactory bulb agenesis, dysmorphic features, cleft palate, left ear constriction, global developmental delay, and hypotonia. The zebrafish functional modeling of PGAP3 loss resulted in HPMRS4-like features, including structural brain abnormalities, dysmorphic cranial and facial features, hypotonia, and seizure-like behavior. Remarkably, morphants displayed defective neural tube formation during the early stages of nervous system development, affecting brain morphogenesis. The significant aberrant midbrain and hindbrain formation demonstrated by separation of the left and right tectal ventricles, defects in the cerebellar corpus, and caudal hindbrain formation disrupted oligodendrocytes expression leading to shorter motor neurons axons. Assessment of zebrafish neuromuscular responses revealed epileptic-like movements at early development, followed by seizure-like behavior, loss of touch response, and hypotonia, mimicking the clinical phenotype human patients. Altogether, we report a novel pathogenic PGAP3 variant associated with unique phenotypic hallmarks, which may be related to the gene’s novel role in brain morphogenesis and neuronal wiring.

A novel homozygous variant in an Iranian pedigree with cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4.

BackgroundCerebellar ataxia, mental retardation, and dysequilibrium (CAMRQ) syndrome is a rare and early‐onset neurodevelopmental disorder. Four subtypes of this syndrome have been identified, which are clinically and genetically different. To date, altogether 32 patients have been described with ATP8A2 mutations and phenotypic features assigned to CAMRQ type 4. Herein, three additional patients in an Iranian consanguineous family with non‐progressive cerebellar ataxia, severe hypotonia, intellectual disability, dysarthria, and cerebellar atrophy have been identified.MethodsFollowing the thorough clinical examination, consecutive detections including chromosome karyotyping, chromosomal microarray analysis, and whole exome sequencing (WES) were performed on the proband. The sequence variants derived from WES interpreted by a standard bioinformatics pipeline. Pathogenicity assessment of candidate variant was done by in silico analysis. The familial cosegregation of the WES finding was carried out by PCR‐based Sanger sequencing.ResultsA novel homozygous missense variant (c.1339G > A, p.Gly447Arg) in the ATP8A2 gene was identified and completely segregated with the phenotype in the family. In silico analysis and structural modeling revealed that the p.G477R substitution is deleterious and induced undesired effects on the protein stability and residue distribution in the ligand‐binding pocket. The novel sequence variant occurred within an extremely conserved subregion of the ATP‐binding domain.ConclusionOur findings expand the spectrum of ATP8A2 mutations and confirm the reported genotype‐phenotype correlation. These results could improve genetic counseling and prenatal diagnosis in families with clinical presentations related to CAMRQ4 syndrome.

Clinical phenotype and genetic analysis of a Chinese patient featuring X-linked Claes-Jensen type syndromic mental retardation

To explore the genetic basis of a Chinese patient featuring global developmental delay. Peripheral venous blood samples from the proband and his parents and sister were taken for the extraction of DNA. Target capture and next generation sequencing was carried out to detect genetic variants associated with the disease. Suspected variant was validated by Sanger sequencing. Genetic testing discovered that the proband has carried hemizygous c.150G>T and c.150+1G>T variants of the KDM5C gene which are inherited from his mother. His younger sister also carried the variants. The c.150+1G>A variant was unreported previously, which has altered a splice site and was predicted to be pathogenic by bioinformatics analysis. The hemizygous c.150+1G>T variant of the KDM5C gene, known to underlie X-linked Claes-Jensen type syndromic mental retardation, probably accounts for the disorder in the patient. Identification of this variant has enriched the variant spectrum of the KDM5C gene.

ATP8A2 and AKAP10 Gene Mutations in a Patient with Prader-Willi Syndrome: A Case Report and Literature Review

Introduction: Prader-Willi syndrome (PWS) is an epigenetic disease. Cerebellar ataxia, mental retardation, and disequilibrium syndrome type 4 (CAMRQ4) is a genetic disorder caused by ATP8A2 gene mutation. AKAP10 gene is related to autosomal dominant cardiac conduction defect and cardiac susceptibility. Here, we report a PWS infant with ATP8A2 and AKAP10 mutations, who presented multiple dysmorphic features and review correlative literature. Case Presentation: A 3-month-old boy presented to our unit because of developmental delay after birth. He had a poor response, feeble cry, hypotonia of extremities, empty scrotum, and characteristic facial features. The whole-exome sequencing showed c.187C&gt;G (p.P63A) in exon 2 originated from his father and c.2138T&gt;C (p.I713T) in exon 23 originated from his mother, which were compound heterozygous variants of the ATP8A2 gene. A c.43delC heterozygous variant in exon 1 of the AKAP10 gene was also detected. Genetic analysis revealed normal copy numbers but abnormal methylation in the 15q11-13 region, which implied nondeletion type PWS. Conclusions: In patients with dysmorphic facial features, hypotonia and developmental delay, PWS should be considered in the differential diagnosis. Moreover, other complicated hereditary diseases should be considered in patients with PWS.

Integration of Bioinformatics in the Clinical and Genomic Characterization of Retinitis Pigmentosa, Noonan Syndrome and Martin-Probs Mental Retardation Syndrome, in the Same Individual. Case report

Introducción: El avance en las técnicas bioinformáticas ha permitido realizar acercamientos y mejoras en los diagnósticos clínicos, correlacionando genotipo – fenotipo y permitiendo el acercamiento a una terapia personalizada. Objetivo: Realizar mediante técnicas bioinformáticas, la caracterización molecular y de expresión génica de una paciente con manifestaciones clínicas (dismorfias, retraso en el desarrollo) de una enfermedad compleja (poligénica). Materiales y métodos: Se realizó la secuenciación de exoma completo a partir de una muestra de sangre periférica. Se analizaron los datos obtenidos mediante análisis in-sílico, utilizando programas como SIFT, Mutation Tester, UMD y Provean, para determinar la significancia clínica de variantes encontradas; además se usó programa GeneMania para determinar las interacciones génicas. Resultados:Se encontraron 3 variantes en los genes SEMA4A, PTPN11 y RAB40A, asociados a Retinitis pigmentosa 35, Síndrome de Noonan y Sindrome de retraso mental Martin-Probs, respectivamente; encontrando según los softwares predictores, en el primer caso un significado clínico aparentemente benigno, y en los dos últimos genes un significado clínico patogénico. El análisis de redes génicas reveló alteraciones en funciones biológicas como la señalización mediada por fosfatidilinositol, respuesta al factor del crecimiento fibroblástico, vía de señalización de neutrofina y la morfogénesis de vasos sanguíneo que permitieron explicar gran parte de la sintomatología observada. Conclusión: El análisis personalizado de las patologías complejas mediante el uso de la clínica, herramientas genómicas y bioinformaticas han permitido un avance significativo en las técnicas para el procesamiento y análisis de datos, beneficiando los estudios científicos que permiten el acercamiento a un correcto diagnóstico y adecuada consejería genética.

50 Years Ago in TheJournal ofPediatrics: Familial Hyperphosphatasia with Mental Retardation, Seizures, and Neurologic Deficits

Mabry C, Bautista A, Kirk RFH, Dublilier LD, Braunstein H, Koepke JA. J Pediatr 1970;77:74-85. Mabry et al reported the first 4 patients with hyperphosphatasia with mental retardation syndrome (HPMRS) to present with generalized seizures and facial dysmorphism. The syndrome can be distinguished from other developmental disabilities by the stable elevation of alkaline phosphatase without bone disease.1Thompson M.D. Nezarati M.M. Gillessen-Kaesbach G. Meinecke P. Mendoza-Londono R. Mornet E. et al.Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: five new patients with Mabry syndrome.Am J Med Genet A. 2010; 152A: 1661-1669Crossref PubMed Scopus (36) Google Scholar Few published reports of the syndrome appeared before we identified a patient whose seizures responded to pyridoxine.2Cole D.E. Thompson M.D. Neurogenic aspects of Mabry syndrome.Subcell Biochem. 2015; 76: 343-361Crossref PubMed Scopus (12) Google Scholar Improved syndromology1Thompson M.D. Nezarati M.M. Gillessen-Kaesbach G. Meinecke P. Mendoza-Londono R. Mornet E. et al.Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: five new patients with Mabry syndrome.Am J Med Genet A. 2010; 152A: 1661-1669Crossref PubMed Scopus (36) Google Scholar made it possible to use next-generation sequencing to identify the recessive mutations that cause what became known as Mabry syndrome (OMIM 239300).2Cole D.E. Thompson M.D. Neurogenic aspects of Mabry syndrome.Subcell Biochem. 2015; 76: 343-361Crossref PubMed Scopus (12) Google Scholar There are at least 6 phenotypes. HPMRS 1, 2, 5, and 6 result from disruption of 4 genes encoding phosphatidylinositol glycan (PIG) anchor biosynthesis enzymes that act in the endoplasmic reticulum: type V (PIGV) type O (PIGO), type W (PIGW), and type Y (PIGY). HPMRS 4 and 3 result from disruption of 2 genes encoding postattachment to proteins (PGAP) enzymes that stabilize glycosylphosphatidylinositol attachment to proteins in the golgi: PGAP3 and PGAP2.3Carmody L. Blau H. Danis D. Gourdine J.-P. Vasilevsky N. Krawitz P. et al.Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes.Orphanet J Rare Dis. 2020; 15: 40Crossref PubMed Scopus (13) Google Scholar The report by Mabry et al describes the first of at least 21 inherited glycosylphosphatidylinositol biosynthesis defects (GPIBDs) that together compose approximately 0.15% of all developmental disabilities.4Pagnamenta A.T. Murakami Y. Taylor J.M. Anzilotti C. Howard M.F. Miller V. et al.Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders.Eur J Hum Genet. 2017; 25: 669-679Crossref PubMed Scopus (48) Google Scholar The HPMRS3 (GPIBD8 [MIM: 614207]) phenotype presented by Mabry et al, resulting from biallelic inheritance of PGAP2 mutations, is the prototypical HPMRS phenotype among GPIBDs.5Thompson M.D. Knaus A.A. Barshop B.A. Caliebe A. Muhle H. Nguyen T.T.M. et al.A post glycosylphosphatidylinositol (GPI) attachment to proteins, type 2 (PGAP2) variant identified in Mabry syndrome index cases: Molecular genetics of the prototypical inherited GPI disorder.Eur J Med Genet. 2019; (https://www.ncbi.nlm.nih.gov/pubmed/31805394. Accessed May 15, 2020)PubMed Google Scholar This work demonstrates the value of case studies to basic science, clinical innovation, and patient follow-up.

Children and Adolescents with Pulmonary Arterial Hypertension: Baseline and Follow-Up Data from the Polish Registry of Pulmonary Hypertension (BNP-PL).

We present the results from the pediatric arm of the Polish Registry of Pulmonary Hypertension. We prospectively enrolled all pulmonary arterial hypertension (PAH) patients, between the ages of 3 months and 18 years, who had been under the care of each PAH center in Poland between 1 March 2018 and 30 September 2018. The mean prevalence of PAH was 11.6 per million, and the estimated incidence rate was 2.4 per million/year, but it was geographically heterogeneous. Among 80 enrolled children (females, n = 40; 50%), 54 (67.5%) had PAH associated with congenital heart disease (CHD-PAH), 25 (31.25%) had idiopathic PAH (IPAH), and 1 (1.25%) had portopulmonary PAH. At the time of enrolment, 31% of the patients had significant impairment of physical capacity (WHO-FC III). The most frequent comorbidities included shortage of growth (n = 20; 25%), mental retardation (n = 32; 40%), hypothyroidism (n = 19; 23.8%) and Down syndrome (n = 24; 30%). The majority of children were treated with PAH-specific medications, but only half of them with double combination therapy, which improved after changing the reimbursement policy. The underrepresentation of PAH classes other than IPAH and CHD-PAH, and the geographically heterogeneous distribution of PAH prevalence, indicate the need for building awareness of PAH among pediatricians, while a frequent coexistence of PAH with other comorbidities calls for a multidisciplinary approach to the management of PAH children.

TASK channels: channelopathies, trafficking, and receptor-mediated inhibition

TWIK-related acid-sensitive K+ (TASK) channels contribute to the resting membrane potential in various kinds of cells, such as brain neurons, smooth muscle cells, and endocrine cells. Loss-of-function mutations at multiple sites in the KCNK3 gene encoding for TASK1 channels are one of the causes of pulmonary arterial hypertension in humans, whereas a mutation at only one site is reported for TASK3 channels, resulting in a syndrome of mental retardation, hypotonia, and facial dysmorphism. TASK channels are subject to regulation by G protein-coupled receptors (GPCRs). Two mechanisms have been proposed for the GPCR-mediated inhibition of TASK channels: a change in gating and channel endocytosis. The most feasible mechanism for altered gating is diacylglycerol binding to a site in the C-terminus, which is shared by TASK1 and TASK3. The inhibition of channel function by endocytosis requires the presence of a tyrosine residue subjected to phosphorylation by the non-receptor tyrosine kinase Src and a dileucine motif in the C-terminus of TASK1. Therefore, homomeric TASK1 and heteromeric TASK1-TASK3 channels, but not homomeric TASK3, are internalized by GPCR stimulation. Tyrosine phosphorylation by Src is expected to result in a conformational change in the C-terminus, allowing for AP-2, an adaptor protein for clathrin, to bind to the dileucine motif. It is likely that a raft membrane domain is a platform where TASK1 is located and the signaling molecules protein kinase C, Pyk2, and Src are recruited in sequence in response to GPCR stimulation.

Brain-specific Wt1 deletion leads to depressive-like behaviors in mice via the recruitment of Tet2 to modulate Epo expression.

Major depressive disorder (MDD) is the most common psychiatric disease worldwide. The precise molecular and cellular mechanisms underlying this disorder remain largely unknown. Wilms' tumor 1 (Wt1), a transcription factor, plays critical roles in cancer and organ development. Importantly, deletion of the 11p13 region that contains the WT1 gene is a major cause of WARG syndrome (Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation), which is characterized by psychiatric disease, including depression. However, the roles and mechanisms of WT1 in embryonic neurogenesis and psychiatric disease remain unclear. Here, we demonstrate that the brain-specific deletion of Wt1 results in abnormal cell distribution during embryonic neurogenesis, which is accompanied by enhanced proliferation of neural progenitors and reduced neuronal differentiation. Moreover, neurons exhibit abnormal morphology during cortical development following Wt1 ablation. Furthermore, Wt1cKO mice exhibit depressive-like behaviors, including immobility, despair, and anhedonia. Mechanistically, Wt1 recruits Tet2 to the promoter of erythropoietin (Epo), which results in enhanced 5-hydroxymethylcytosine (5hmC) levels and the promotion of Epo expression. Either Epo plasmid electroporation or Epo protein injection can partially restore the deficiency caused by Wt1 deletion. Importantly, administration of Epo to both embryos and adults can ameliorate the depressive-like behavior of Wt1cKO mice. In addition, WT1 plays a similar role in human neural progenitor cells (hNPCs) proliferation and differentiation. Taken together, our findings reveal the critical role and regulatory mechanism of Wt1 in embryonic neurogenesis and behavioral modulation, which could contribute to the understanding of MDD etiology and therapy.