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1.
J Inherit Metab Dis ; 2021 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-33496032

RESUMEN

Isovaleric aciduria (IVA), a metabolic disease with severe (classic IVA) or attenuated phenotype (mild IVA), is included in newborn screening (NBS) programs worldwide. The long-term clinical benefit of screened individuals, however, is still rarely investigated. A national, prospective, observational, multi-center study of individuals with confirmed IVA identified by NBS between 1998 and 2018 was conducted. Long-term clinical outcomes of 94 individuals with IVA were evaluated, representing 73.4% (for classic IVA: 92.3%) of the German NBS cohort. In classic IVA (N = 24), NBS prevented untimely death except in one individual with lethal neonatal sepsis (3.8%) but did not completely prevent single (N = 10) or recurrent (N = 7) metabolic decompensations, 13 of them occurring already neonatally. IQ (mean ± SD, 90.7 ± 10.1) was mostly normal but below the reference population (P = .0022) and was even lower in individuals with severe neonatal decompensations (IQ 78.8 ± 7.1) compared to those without crises (IQ 94.7 ± 7.5; P = .01). Similar results were obtained for school placement. In contrast, individuals with mild IVA had excellent neurocognitive outcomes (IQ 105.5 ± 15.8; normal school placement) and a benign disease course (no metabolic decompensation, normal hospitalization rate), which did not appear to be impacted by metabolic maintenance therapy. In conclusion, NBS reduces mortality in classic IVA, but does not reliably protect against severe neonatal metabolic decompensations, crucial for favorable neurocognitive outcome. In contrast, individuals with mild IVA had excellent clinical outcomes regardless of metabolic maintenance therapy, questioning their benefit from NBS. Harmonized stratified therapeutic concepts are urgently needed.

2.
J Inherit Metab Dis ; 2021 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-33443316

RESUMEN

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.

3.
J Inherit Metab Dis ; 2020 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-33274439

RESUMEN

INTRODUCTION: Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder, caused by inherited deficiency of glutaryl-CoA dehydrogenase, mostly affecting the brain. Early identification by newborn screening (NBS) significantly improves neurologic outcome. It has remained unclear whether recommended therapy, particular low lysine diet, is safe or negatively affects anthropometric long-term outcome. METHODS: This national prospective, observational, multi-centre study included 79 patients identified by NBS and investigated effects of interventional and non-interventional parameters on body weight, body length, body mass index (BMI), and head circumference as well as neurological parameters. RESULTS: Adherence to recommended maintenance and emergency treatment (ET) had a positive impact on neurologic outcome and allowed normal anthropometric development until adulthood. In contrast, non-adherence to ET, resulting in increased risk of dystonia, had a negative impact on body weight (mean SDS -1.07; p=0.023) and body length (mean SDS -1.34; p=0.016). Consistently, longitudinal analysis showed a negative influence of severe dystonia on weight and length development over time (p<0.001). Macrocephaly was more often found in female (mean SDS 0.56) than in male patients (mean SDS -0.20; p=0.049), and also in individuals with high excreter phenotype (mean SDS 0.44) compared to low excreter patients (mean SDS -0.68; p=0.016). CONCLUSION: In GA1, recommended long-term treatment is effective and allows for normal anthropometric long-term development up to adolescence, with gender- and excreter type-specific variations. Delayed ET and severe movement disorder result in poor anthropometric outcome. TAKE-HOME MESSAGE: In one of the largest national cohorts of screened individuals with glutaric aciduria type 1, this study shows that dietary management according to the guideline is safe, ensuring normal growth up to adolescence and adulthood with gender- and excreter type-specific variations, whereas delayed emergency treatment and severe movement disorder result in poor anthropometric outcome. This article is protected by copyright. All rights reserved.

4.
Mol Genet Metab Rep ; 25: 100681, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33294374

RESUMEN

AARS1 deficiency belongs to the group of disorders affecting aminoacyl-tRNA synthetases. To date, AARS1 deficiency has only been linked to neurologic disorders. We report a 6-year-old girl with microcephaly and developmental delay who presented with repeated episodes of acute liver failure. Whole-exome sequencing revealed compound heterozygosity for two missense variants within the AARS1 gene, p.[Leu298Gln];[Arg751Gly]), whose functional relevance was demonstrated by decreased enzymatic activity in fibroblasts. This is the first report that shows that AARS1 variants may be associated with recurrent acute liver failure.

5.
Ophthalmic Genet ; : 1-5, 2020 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-33107778

RESUMEN

Introduction: LCHADD causes retinopathy associated with low vision, visual field defects, nyctalopia and myopia. We report a retrospective long-term single-center study of 6 LCHADD patients trying to clarify if early diagnosis has an impact on the course and outcome of chorioretinal degeneration. Methods: Long-term follow-up of visual acuity and staging of chorioretinal degeneration by fundus photography, optical coherence tomography (OCT) and autofluorescence (AF) in all six patients. Three patients (2 m/1 f; age 8-14.8 years) were diagnosed by newborn screening, a single patient early within the first year of life and treated promptly while the other two (1 m/1 f; age 23-24 years) were diagnosed later after developing symptoms. All carried HADHA variants; five were homozygous for the common p.E510Q variant, in one from the symptomatically diagnosed group p.[E510Q]; [R291*] was detected. Results: All patients showed retinal alterations, but early diagnosis was associated with a milder phenotype and a longer preservation of visual function. Among symptomatic patients, only one showed mild retinal involvement at the time of diagnosis. Conclusion: Despite the small number our study suggests that early diagnosis does not prevent retinopathy but might contribute to a milder phenotype with retained good visual acuity over time. OCT and AF are reliable non-invasive diagnostic tools to estimate the progression of early-stage retinal changes in LCHADD patients.

6.
Artículo en Inglés | MEDLINE | ID: mdl-33007476

RESUMEN

OBJECTIVES: Investigation whether in depth characterization of virus variant patterns can be used for epidemiological analysis of the first SARS-CoV-2 infection clusters in Hamburg, Germany. METHODS: Metagenomic RNA- and amplicon-sequencing and subsequent variant calling in 25 respiratory samples from SARS-CoV-2 infected patients involved in the earliest infection clusters in Hamburg. RESULTS: Amplikon sequencing and cluster analyses of these SARS-CoV-2 sequences allowed the identification of the first infection cluster and five non-related infection clusters occurring at the beginning of the viral entry of SARS-CoV-2 in the Hamburg metropolitan region. Viral genomics together with epidemiological analyses revealed that the index patient acquired the infection in Northern Italy and transmitted it to two out of 134 contacts. Single nucleotide polymorphisms clearly distinguished the virus variants of the index and other clusters and allowed to track in which sequences worldwide these mutations were first described. Minor variant analyses identified the transmission of intra-host variants in the index cluster and household clusters. CONCLUSIONS: SARS-CoV-2 variant tracing allows the identification of infection clusters and the follow up of infection chains occurring in the population. Furthermore, the follow up of minor viral variants in infection cluster can provide further resolution on transmission events indistinguishable on consensus sequence level.

7.
Brain ; 143(8): 2437-2453, 2020 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-32761064

RESUMEN

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

8.
J Clin Med ; 9(3)2020 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-32182687

RESUMEN

Mucolipidosis type II (MLII) is a rare lysosomal storage disorder caused by defective trafficking of lysosomal enzymes. Severe skeletal manifestations are a hallmark of the disease including hip dysplasia. This study aims to describe hip morphology and the natural course of hip pathologies in MLII by systematic evaluation of plain radiographs, ultrasounds and magnetic resonance imaging (MRI). An international two-centered study was performed by retrospective chart review. All MLII patients with at least one pelvic radiograph were included. A total of 16 patients were followed over a mean of 3.5 years (range 0.2-10.7 years). Typical age-dependent radiographic signs identified were femoral cloaking (7/16), rickets/hyperparathyroidism-like changes (6/16) and constrictions of the supra-acetabular part of the os ilium (16/16) and the femoral neck (7/16). The course of acetabular and migration indexes (AI, MI) significantly increased in female patients. However, in the overall group, there was no relevant progression of acetabular dysplasia with a mean AI of 23.0 (range 5°-41°) and 23.7° (range 5°-40°) at the first and last assessments, respectively. Better knowledge on hip morphology in MLII could lead to earlier diagnosis, improved clinical management and enables assessment of effects of upcoming therapies on the skeletal system.

9.
Genet Med ; 22(3): 610-621, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31761904

RESUMEN

PURPOSE: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. METHODS: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. RESULTS: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the ß-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: ß-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). CONCLUSION: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

10.
J Inherit Metab Dis ; 43(3): 540-548, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31816104

RESUMEN

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterised by impaired glucose liver homeostasis and proximal renal tubular dysfunction. It is caused by pathogenic variants in SLC2A2 coding for the glucose transporter GLUT2. Main clinical features include hepatomegaly, fasting hypoglycaemia, postprandial hyperglycaemia, Fanconi-type tubulopathy occasionally with rickets, and a severe growth disorder. While treatment for renal tubular dysfunction is well established, data regarding optimal nutritional therapy are scarce. Similarly, detailed clinical evaluation of treated FBS patients is lacking. These unmet needs were an incentive to conduct the present pilot study. We present clinical findings, laboratory parameters and molecular genetic data on 11 FBS patients with emphasis on clinical outcome under various nutritional interventions. At diagnosis, the patients' phenotypic severity could be classified into two categories: a first group with severe growth failure and rickets, and a second group with milder signs and symptoms. Three patients were diagnosed early and treated because of family history. All patients exhibited massive glucosuria at diagnosis and some in both groups had fasting hypoglycaemic episodes. Growth retardation improved drastically in all five patients treated by intensive nutritional intervention (nocturnal enteral nutrition) and uncooked cornstarch with final growth parameters in the normal range. The four severely affected patients who were treated with uncooked cornstarch alone did not catch up growth. All patients received electrolytes and l-carnitine supplementation to compensate for the tubulopathy. This is one of the largest series of FBS on therapeutic management with evidence that nocturnal enteral nutrition rescues growth failure.

11.
Am J Hum Genet ; 105(2): 302-316, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31256877

RESUMEN

Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.


Asunto(s)
ARN Helicasas DEAD-box/genética , Mutación Missense , Proteínas de Neoplasias/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , ARN Helicasas/genética , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Secuenciación del Exoma Completo
13.
Dtsch Arztebl Int ; 116(12): 197-204, 2019 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-31056085

RESUMEN

BACKGROUND: In developed countries, global developmental disorders are encounter- ed in approximately 1% of all children. The causes are manifold, and no exogenous cause can be identified in about half of the affected children. The parallel investi- gation of the coding sequences of all genes of the affected individual (whole exome sequencing, WES) has developed into a successful diagnostic method for identify- ing the cause of the problem. It is not yet clear, however, when WES should best be used in routine clinical practice in order to exploit the potential of this method to the fullest. METHODS: In an interdisciplinary study, we carried out standardized clinical pheno- typing and a systematic genetic analysis (WES of the index patient and his or her parents, so-called trio WES) in 50 children with developmental disturbances of unclear etiology and with nonspecific neurological manifestations. RESULTS: In 21 children (42% of the collective), we were able to identify the cause of the disorder by demonstrating a mutation in a gene known to be associated with disease. Three of these children subsequently underwent specific treatment. In 22 other children (44%), we detected possibly etiological changes in candidate genes not currently known to be associated with human disease. CONCLUSION: Our detection rate of at least 42% is high in comparison with the results obtained in other studies from Germany and other countries to date and implies that WES can be used to good effect as a differential diagnostic tool in pediatric neurol- ogy. WES should be carried out in both the index patient and his or her parents (trio- WES) and accompanied by close interdisciplinary collaboration of human geneti- cists and pediatricians, by comprehensive and targeted phenotyping (also after the diagnosis is established), and by the meticulous evaluation of all gene variants.


Asunto(s)
Secuenciación del Exoma Completo , Niño , Alemania , Humanos
14.
J Inherit Metab Dis ; 42(6): 1192-1230, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-30982989

RESUMEN

In 2012, we published guidelines summarizing and evaluating late 2011 evidence for diagnosis and therapy of urea cycle disorders (UCDs). With 1:35 000 estimated incidence, UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death, even while effective therapies do exist. In the 7 years that have elapsed since the first guideline was published, abundant novel information has accumulated, experience on newborn screening for some UCDs has widened, a novel hyperammonemia-causing genetic disorder has been reported, glycerol phenylbutyrate has been introduced as a treatment, and novel promising therapeutic avenues (including gene therapy) have been opened. Several factors including the impact of the first edition of these guidelines (frequently read and quoted) may have increased awareness among health professionals and patient families. However, under-recognition and delayed diagnosis of UCDs still appear widespread. It was therefore necessary to revise the original guidelines to ensure an up-to-date frame of reference for professionals and patients as well as for awareness campaigns. This was accomplished by keeping the original spirit of providing a trans-European consensus based on robust evidence (scored with GRADE methodology), involving professionals on UCDs from nine countries in preparing this consensus. We believe this revised guideline, which has been reviewed by several societies that are involved in the management of UCDs, will have a positive impact on the outcomes of patients by establishing common standards, and spreading and harmonizing good practices. It may also promote the identification of knowledge voids to be filled by future research.


Asunto(s)
Guías de Práctica Clínica como Asunto , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/terapia , Adulto , Edad de Inicio , Niño , Consenso , Endocrinología/organización & administración , Endocrinología/normas , Europa (Continente)/epidemiología , Humanos , Hiperamonemia/diagnóstico , Hiperamonemia/epidemiología , Hiperamonemia/terapia , Recién Nacido , Tamizaje Neonatal/métodos , Tamizaje Neonatal/normas , Pediatría/organización & administración , Pediatría/normas , Guías de Práctica Clínica como Asunto/normas , Trastornos Innatos del Ciclo de la Urea/epidemiología
15.
Clin Chim Acta ; 492: 69-71, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30771299

RESUMEN

PURPOSE: CLN2 disease is a genetic disorder caused by dysfunction of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) that belongs to the neuronal ceroid lipofuscinoses (NCL) and leads to epilepsy, dementia, and death in young persons. CLN2 disease has recently become treatable by enzyme replacement, which can only be effective when the disease is diagnosed early. We have investigated the reliability of a test for TPP1 deficiency in dried blood specimens (DBS) to detect CLN2 disease. RESULTS: During a 12-year period we have received 3882 samples for testing TPP1. Quality of samples was checked by measuring two additional lysosomal enzyme activities. For 50 samples with subnormal TPP1 activity and good sample quality, we obtained adequate clinical and molecular genetic data. All 50 patients had doubtless evidence of CLN2 disease (including seven atypical patients) as shown by clinical findings and the presence of known pathogenic CLN2 variants. Our institution is a major reference center for NCL, and we have never received information that a patient with a normal DBS test was later diagnosed with CLN2 disease. CONCLUSIONS: We consider our TPP1 test on DBS to be a reliable, convenient and inexpensive tool for a first diagnostic step in suspected CLN2 disease.


Asunto(s)
Aminopeptidasas/sangre , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/sangre , Pruebas con Sangre Seca/métodos , Fluorometría/métodos , Lipofuscinosis Ceroideas Neuronales/sangre , Lipofuscinosis Ceroideas Neuronales/enzimología , Serina Proteasas/sangre , Femenino , Humanos , Masculino , Lipofuscinosis Ceroideas Neuronales/genética , Fenotipo , Factores de Tiempo
16.
Liver Transpl ; 25(6): 889-900, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30712285

RESUMEN

Liver transplantation (LT) has been shown to be a feasible treatment in patients with severe forms of maple syrup urine disease (MSUD). Because of a sufficient extrahepatic enzyme activity in non-MSUD individuals, the organ of MSUD patients can be used as a domino graft. We performed a retrospective data collection of all LTs for MSUD carried out at the University Medical Center Hamburg-Eppendorf (2016-2018). Moreover, data from all consecutive domino LTs of the MSUD grafts either transplanted at our institution or allocated to other transplant centers were analyzed. During the study period, 15 LTs in MSUD patients were performed (12 children, 3 adults; median age, 10.9 years; range, 0.3-26.1 years). Biliary complications occurred in 20%, and 13.3% suffered from bleeding complications. No further surgical problems occurred. At present, all MSUD patients are alive with a well-functioning liver graft and on an unrestricted diet. In total, 14 consecutive domino LTs were performed. No surgical complications requiring intervention occurred. One patient died because of HCC relapse, and all other patients are alive with good liver graft function. In conclusion, the use of MSUD livers as domino grafts is safe and allows application of LT in MSUD patients without net extraction of a liver graft from the limited donor pool.


Asunto(s)
Selección de Donante/estadística & datos numéricos , Enfermedad Hepática en Estado Terminal/cirugía , Trasplante de Hígado/métodos , Enfermedad de la Orina de Jarabe de Arce/cirugía , Complicaciones Posoperatorias/epidemiología , Adolescente , Adulto , Aloinjertos/provisión & distribución , Niño , Preescolar , Protocolos Clínicos , Selección de Donante/normas , Femenino , Estudios de Seguimiento , Hepatectomía/métodos , Humanos , Lactante , Hígado , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/normas , Trasplante de Hígado/estadística & datos numéricos , Donadores Vivos/estadística & datos numéricos , Masculino , Enfermedad de la Orina de Jarabe de Arce/diagnóstico , Enfermedad de la Orina de Jarabe de Arce/genética , Complicaciones Posoperatorias/etiología , Asignación de Recursos/estadística & datos numéricos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Receptores de Trasplantes/estadística & datos numéricos , Adulto Joven
18.
Genet Med ; 21(3): 601-607, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30245509

RESUMEN

PURPOSE: TANGO2-related disorders were first described in 2016 and prior to this publication, only 15 individuals with TANGO2-related disorder were described in the literature. Primary features include metabolic crisis with rhabdomyolysis, encephalopathy, intellectual disability, seizures, and cardiac arrhythmias. We assess whether genotype and phenotype of TANGO2-related disorder has expanded since the initial discovery and determine the efficacy of exome sequencing (ES) as a diagnostic tool for detecting variants. METHODS: We present a series of 14 individuals from 11 unrelated families with complex medical and developmental histories, in whom ES or microarray identified compound heterozygous or homozygous variants in TANGO2. RESULTS: The initial presentation of patients with TANGO2-related disorders can be variable, including primarily neurological presentations. We expand the phenotype and genotype for TANGO2, highlighting the variability of the disorder. CONCLUSION: TANGO2-related disorders can have a more diverse clinical presentation than previously anticipated. We illustrate the utility of routine ES data reanalysis whereby discovery of novel disease genes can lead to a diagnosis in previously unsolved cases and the need for additional copy-number variation analysis when ES is performed.


Asunto(s)
Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Adolescente , Translocador Nuclear del Receptor de Aril Hidrocarburo/fisiología , Encefalopatías/genética , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Discapacidades del Desarrollo/genética , Exoma , Familia , Femenino , Genotipo , Humanos , Discapacidad Intelectual/genética , Masculino , Linaje , Fenotipo , Convulsiones/genética , Secuenciación del Exoma Completo/métodos
19.
Am J Hum Genet ; 103(4): 579-591, 2018 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-30290153

RESUMEN

p21-activated kinases (PAKs) are serine/threonine protein kinases acting as effectors of CDC42 and RAC, which are members of the RHO family of small GTPases. PAK1's kinase activity is autoinhibited by homodimerization, whereas CDC42 or RAC1 binding causes PAK1 activation by dimer dissociation. Major functions of the PAKs include actin cytoskeleton reorganization, for example regulation of the cellular protruding activity during cell spreading. We report the de novo PAK1 mutations c.392A>G (p.Tyr131Cys) and c.1286A>G (p.Tyr429Cys) in two unrelated subjects with developmental delay, secondary macrocephaly, seizures, and ataxic gait. We identified enhanced phosphorylation of the PAK1 targets JNK and AKT in fibroblasts of one subject and of c-JUN in those of both subjects compared with control subjects. In fibroblasts of the two affected individuals, we observed a trend toward enhanced PAK1 kinase activity. By using co-immunoprecipitation and size-exclusion chromatography, we observed a significantly reduced dimerization for both PAK1 mutants compared with wild-type PAK1. These data demonstrate that the two PAK1 variants function as activating alleles. In a cell spreading assay, subject-derived fibroblasts showed significant enrichment in cells occupied by filopodia. Interestingly, application of the PAK1 inhibitor FRAX486 completely reversed this cellular phenotype. Together, our data reveal that dominantly acting, gain-of-function PAK1 mutations cause a neurodevelopmental phenotype with increased head circumference, possibly by a combined effect of defective homodimerization and enhanced kinase activity of PAK1. This condition, along with the developmental disorders associated with RAC1 and CDC42 missense mutations, highlight the importance of RHO GTPase members and effectors in neuronal development.


Asunto(s)
Mutación con Ganancia de Función/genética , Trastornos del Neurodesarrollo/genética , Quinasas p21 Activadas/genética , Actinas/genética , Estudios de Casos y Controles , Línea Celular , Niño , Preescolar , Citoesqueleto/genética , Femenino , Células HEK293 , Humanos , Masculino , Proteína Quinasa de Distrofia Miotónica/genética , Fosforilación/genética , Transducción de Señal/genética , Proteína de Unión al GTP rac1/genética
20.
Neurogenetics ; 19(3): 151-156, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29808465

RESUMEN

The human WWOX (WW domain-containing oxidoreductase) gene, originally known as a tumor suppressor gene, has been shown to be important for brain function and development. In recent years, mutations in WWOX have been associated with a wide phenotypic spectrum of autosomal recessively inherited neurodevelopmental disorders. Whole exome sequencing was completed followed by Sanger sequencing to verify segregation of the identified variants. Functional WWOX analysis was performed in fibroblasts of one patient. Transcription and translation were assessed by quantitative real-time PCR and Western blotting. We report two related patients who presented with early epilepsy refractory to treatment, progressive microcephaly, profound developmental delay, and brain MRI abnormalities. Additionally, one of the patients showed bilateral optic atrophy. Whole exome sequencing revealed homozygosity for a novel missense variant affecting the evolutionary conserved amino acid Gln230 in the catalytic short-chain dehydrogenase/reductase (SDR) domain of WWOX in both girls. Functional studies showed normal levels of WWOX transcripts but absence of WWOX protein. To our knowledge, our patients are the first individuals presenting the more severe end of the phenotypic spectrum of WWOX deficiency, although they were only affected by a single missense variant of WWOX. This could be explained by the functional data indicating an impaired translation or premature degradation of the WWOX protein.


Asunto(s)
Discapacidades del Desarrollo/genética , Mutación Missense , Espasmos Infantiles/genética , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/genética , Oxidorreductasa que Contiene Dominios WW/deficiencia , Oxidorreductasa que Contiene Dominios WW/genética , Afganistán , Edad de Inicio , Células Cultivadas , Niño , Consanguinidad , Discapacidades del Desarrollo/complicaciones , Epilepsia/complicaciones , Epilepsia/genética , Familia , Femenino , Células HEK293 , Humanos , Recién Nacido , Linaje , Dominios Proteicos/genética , Estabilidad del ARN/genética , Índice de Severidad de la Enfermedad , Espasmos Infantiles/complicaciones , Proteínas Supresoras de Tumor/química , Proteínas Supresoras de Tumor/metabolismo , Oxidorreductasa que Contiene Dominios WW/química , Oxidorreductasa que Contiene Dominios WW/metabolismo
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