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1.
Am J Med Genet A ; 182(4): 866-876, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31913576

RESUMEN

RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1-related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non-NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.


Asunto(s)
Síndrome de Costello/terapia , Displasia Ectodérmica/terapia , Insuficiencia de Crecimiento/terapia , Cardiopatías Congénitas/terapia , Terapia Molecular Dirigida , Mutación , Neurofibromatosis 1/terapia , Síndrome de Noonan/terapia , Proteínas ras/antagonistas & inhibidores , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Síndrome de Costello/genética , Síndrome de Costello/patología , Displasia Ectodérmica/genética , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/patología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Humanos , Colaboración Intersectorial , National Cancer Institute (U.S.) , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Síndrome de Noonan/genética , Síndrome de Noonan/patología , Informe de Investigación , Transducción de Señal , Estados Unidos , Proteínas ras/genética
2.
Am J Hum Genet ; 99(6): 1388-1394, 2016 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-27889061

RESUMEN

Human MITF is, by convention, called the "microphthalmia-associated transcription factor" because of previously published seminal mouse genetic studies; however, mutations in MITF have never been associated with microphthalmia in humans. Here, we describe a syndrome that we term COMMAD, characterized by coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness. COMMAD is associated with biallelic MITF mutant alleles and hence suggests a role for MITF in regulating processes such as optic-fissure closure and bone development or homeostasis, which go beyond what is usually seen in individuals carrying monoallelic MITF mutations.


Asunto(s)
Albinismo/genética , Alelos , Coloboma/genética , Sordera/genética , Megalencefalia/genética , Factor de Transcripción Asociado a Microftalmía/genética , Microftalmía/genética , Osteopetrosis/genética , Animales , Preescolar , Femenino , Homocigoto , Humanos , Lactante , Masculino , Linaje , Síndrome , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genética
3.
Am J Hum Genet ; 92(6): 1001-7, 2013 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-23731542

RESUMEN

Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal-recessive (AR) modes of inheritance have also been proposed. We performed whole-exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment.


Asunto(s)
Genes Dominantes , Mutación Missense , Miofibromatosis/congénito , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Secuencia de Aminoácidos , Secuencia de Bases , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Miofibromatosis/genética , Linaje , Receptor Notch3 , Receptores Notch/genética , Análisis de Secuencia de ADN
4.
Am J Med Genet A ; 170A(4): 967-77, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26692240

RESUMEN

We report 13 new individuals with duplications in Xp11.22-p11.23. The index family has one male and two female members in three generations with mild-severe intellectual disability (ID), speech delay, dysmorphic features, early puberty, constipation, and/or hand and foot abnormalities. Affected individuals were found to have two small duplications in Xp11.22 at nucleotide position (hg19) 50,112,063-50,456,458 bp (distal) and 53,160,114-53,713,154 bp (proximal). Collectively, these two regions include 14 RefSeq genes, prompting collection of a larger cohort of patients, in an attempt to delineate critical genes associated with the observed phenotype. In total, we have collected data on nine individuals with duplications overlapping the distal duplication region containing SHROOM4 and DGKK and eight individuals overlapping the proximal region including HUWE1. Duplications of HUWE1 have been previously associated with non-syndromic ID. Our data, with previously published reports, suggest that duplications involving SHROOM4 and DGKK may represent a new syndromic X-linked ID critical region associated with mild to severe ID, speech delay +/- dysarthria, attention deficit disorder, precocious puberty, constipation, and motor delay. We frequently observed foot abnormalities, 5th finger clinodactyly, tapering fingers, constipation, and exercise intolerance in patients with duplications of these two genes. Regarding duplications including the proximal region, our observations agree with previous studies, which have found associations with intellectual disability. In addition, expressive language delay, failure to thrive, motor delay, and 5th finger clinodactyly were also frequently observed in patients with the proximal duplication.


Asunto(s)
Duplicación Cromosómica , Cromosomas Humanos X , Estudios de Asociación Genética , Trastornos de los Cromosomas Sexuales/diagnóstico , Trastornos de los Cromosomas Sexuales/genética , Adolescente , Adulto , Anciano , Niño , Mapeo Cromosómico , Hibridación Genómica Comparativa , Facies , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Adulto Joven
6.
Am J Med Genet A ; 161A(10): 2420-30, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23918763

RESUMEN

Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis.


Asunto(s)
Cabello/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenotipo , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Adulto , Encéfalo/anomalías , Encéfalo/patología , Preescolar , Resultado Fatal , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Síndrome de Noonan/complicaciones , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/patología , Adulto Joven
7.
Am J Med Genet A ; 161A(8): 1833-52, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23813913

RESUMEN

Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , Proteínas 14-3-3/genética , Encéfalo/anomalías , Trastornos de la Conducta Infantil/patología , Trastornos Generalizados del Desarrollo Infantil/patología , Cromosomas Humanos Par 17/genética , Duplicación de Gen , Proteínas Asociadas a Microtúbulos/genética , Adolescente , Adulto , Encéfalo/patología , Niño , Trastornos de la Conducta Infantil/genética , Trastornos Generalizados del Desarrollo Infantil/genética , Preescolar , Femenino , Humanos , Lactante , Masculino , Fenotipo
8.
Hum Mutat ; 33(3): 457-66, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22213154

RESUMEN

Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed.


Asunto(s)
Coloboma/genética , Bases de Datos Genéticas , Factor de Transcripción PAX2/genética , Insuficiencia Renal/genética , Reflujo Vesicoureteral/genética , Animales , Humanos
10.
Mol Genet Metab ; 94(4): 498-502, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18524659

RESUMEN

A male infant was diagnosed prenatally with a partial ornithine transcarbamylase (OTC) gene deletion and managed from birth. However, he displayed neurological abnormalities and developed pleural effusions, ascites and anasarca not solely explained by OTC deficiency (OTCD). Further evaluation of the gene locus using exon-specific PCR and high-density SNP array copy number analysis revealed a 3.9-Mb deletion from Xp11.4 to Xp21.1 including five additional gene deletions, three causing the known genetic diseases: Retinitis pigmentosa (RP3), X-linked chronic granulomatous disease (CGD) and McLeod syndrome. The case illustrates (1) the complexities of managing a patient with neonatal onset OTCD, CGD, RP3 and McLeod syndrome, (2) the need for detailed evaluation in seemingly "isolated" gene deletions and (3) the clinical utility of high-density copy number analysis for rapidly characterizing chromosomal lesions.


Asunto(s)
Cromosomas Humanos X/genética , Eliminación de Gen , Enfermedad Granulomatosa Crónica/metabolismo , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/genética , Ornitina Carbamoiltransferasa/metabolismo , Retinitis Pigmentosa/metabolismo , Mapeo Cromosómico , Resultado Fatal , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Enfermedad Granulomatosa Crónica/genética , Humanos , Lactante , Masculino , Ornitina Carbamoiltransferasa/genética , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/metabolismo , Retinitis Pigmentosa/genética
11.
Am J Med Genet A ; 146A(23): 3038-53, 2008 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-19006208

RESUMEN

Chondrodysplasia punctata (CDP) is etiologically a heterogeneous condition and has been associated with single gene disorders, chromosome abnormalities and teratogenic exposures. The first publication of the association between CDP and maternal autoimmune connective tissue disorder was by Curry et al. 1993]. Chondrodysplasia punctata associated with maternal collagen vascular disease. A new etiology? Presented at the David W. Smith Workshop on Morphogenesis and Malformations, Mont Tremblant, Quebec, August 1993] and subsequently, other cases have been reported. We report on eight cases of maternal collagen vascular disease associated with fetal CDP and included the cases reported by Curry et al. 1993. Chondrodysplasia punctata associated with maternal collagen vascular disease. A new etiology? Presented at the David W. Smith Workshop on Morphogenesis and Malformations, Mont Tremblant, Quebec, August 1993] and Costa et al. [1993]. Maternal systemic lupus erythematosis (SLE) and chondrodysplasia punctata in two infants. Coincidence or association? 1st Meeting of Bone Dysplasia Society, Chicago, June 1993] which were reported in an abstract form. We suggest that maternal autoimmune diseases should be part of the differential diagnosis and investigation in newborns/fetuses with CDP. Thus, in addition to cardiac evaluation, fetuses/newborn to mothers with autoimmune diseases should have fetal ultrasound/newborn examination and if indicated, X-rays, looking for absent/hypoplastic nasal bone, brachydactyly, shortened long bones and epiphyseal stippling.


Asunto(s)
Condrodisplasia Punctata/diagnóstico por imagen , Condrodisplasia Punctata/inmunología , Lupus Eritematoso Sistémico/complicaciones , Enfermedad Mixta del Tejido Conjuntivo/complicaciones , Complicaciones del Embarazo , Esclerodermia Sistémica/complicaciones , Adulto , Autoinmunidad , Peso al Nacer , Condrodisplasia Punctata/etiología , Femenino , Humanos , Lactante , Embarazo , Radiografía , Adulto Joven
12.
Am J Med Genet A ; 146A(13): 1637-54, 2008 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-18536050

RESUMEN

Polymicrogyria is a malformation of cortical development characterized by loss of the normal gyral pattern, which is replaced by many small and infolded gyri separated by shallow, partly fused sulci, and loss of middle cortical layers. The pathogenesis is unknown, yet emerging data supports the existence of several loci in the human genome. We report on the clinical and brain imaging features, and results of cytogenetic and molecular genetic studies in 29 patients with polymicrogyria associated with structural chromosome rearrangements. Our data map new polymicrogyria loci in chromosomes 1p36.3, 2p16.1-p23, 4q21.21-q22.1, 6q26-q27, and 21q21.3-q22.1, and possible loci in 1q44 and 18p as well. Most and possibly all of these loci demonstrate incomplete penetrance and variable expressivity. We anticipate that these data will serve as the basis for ongoing efforts to identify the causal genes located in these regions.


Asunto(s)
Aberraciones Cromosómicas , Malformaciones del Desarrollo Cortical/genética , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Adolescente , Adulto , Aneuploidia , Encéfalo/patología , Niño , Preescolar , Rotura Cromosómica , Deleción Cromosómica , Cromosomas Artificiales Bacterianos/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 4/genética , Cromosomas Humanos Par 6/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Cariotipificación , Masculino , Malformaciones del Desarrollo Cortical/patología , Fenotipo , Translocación Genética
13.
J Am Diet Assoc ; 107(3): 466-78, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17324666

RESUMEN

This review is an update for food and nutrition professionals about single-gene autosomal recessive disorders and Prader-Willi syndrome. These disorders highlight the application of new genetic tools for screening newborns for conditions managed by medical nutrition therapy. Early detection and dietary treatment have been crucial since the 1960s for patients diagnosed with phenylketonuria. The same concept of reducing the dietary substrate that accumulates in disease is applied today for some conditions difficult to diagnose a decade ago. More than 6,000 human single-gene disorders have been identified to date, including more than 100 protein-based metabolic disorders. Tandem mass spectrometry has facilitated newborn screening for more disorders at low cost and high speed. Presently, screening newborns for 29 disorders is recommended in the United States and many states are doubling or tripling the number of tests offered in their screening programs. Complex dietary therapies have evolved for rare disorders, such as fatty acid oxidation, urea cycle, organic acid metabolism, glycogen storage, and energy production. Diagnosis-specific therapy may challenge routine dietary recommendations, such as encouraging fatty and sugary foods or avoiding fruits and milk, and treatment options have spawned a market in special formulas and substitute foods; recommended references and Web sites are provided to assist food and nutrition professionals in navigating this territory. Single-gene autosomal recessive disorders have increased the need for, and created opportunities for, food and nutrition professionals, especially those who enjoy biochemistry.


Asunto(s)
Errores Innatos del Metabolismo/diagnóstico , Tamizaje Neonatal , Trastornos Nutricionales/diagnóstico , Síndrome de Prader-Willi/genética , Pruebas Genéticas , Humanos , Recién Nacido , Espectrometría de Masas/métodos , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/terapia , Trastornos Nutricionales/genética , Trastornos Nutricionales/terapia , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/terapia
14.
JIMD Rep ; 20: 1-4, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25690727

RESUMEN

In multiple carboxylase deficiency (MCD), the biotin-dependent carboxylases have decreased activity due to either biotinidase deficiency or holocarboxylase synthetase (HS) deficiency. We report the case of two siblings from Ghana, the first of which presented shortly after birth with profound lactic acidosis and a urine organic acid profile consistent with MCD. In the first sibling, treatment with pulverized biotin tablets (20 mg) was begun immediately, but the patient died at 10 days of age from cardiac arrest secondary to refractory metabolic acidosis. Autopsy revealed a biotin bezoar. Sequencing of HCLS showed homozygosity for a novel missense variant (p.G241W). The second sibling had a similar presentation at birth: severe metabolic acidosis and respiratory distress. A urine organic acid profile was consistent with HS deficiency; he was treated with biotin powder (20 mg), and after 24 h, the lactate decreased significantly; by day 5 of life, the patient was tolerating 40 mg of biotin, feeding by mouth and off all other medications and support. This is the first report of the p.G241W mutation. To our knowledge, this is also the first mutation described in West African patients with HS deficiency and the cases demonstrate that it is biotin responsive. Additionally, our experience suggests that the powdered form of biotin supplementation may be more digestible than tablets for the treatment of severe neonatal HS deficiency.

15.
Mol Genet Metab Rep ; 3: 47-54, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26937396

RESUMEN

We describe a young girl with dilated cardiomyopathy, long QT syndrome, and possible energy deficiency. Two major sequence changes were identified by whole exome sequencing (WES) and mitochondrial DNA analysis that were interpreted as potentially causative. Changes were identified in the KCNH2 gene and mitochondrial tRNA for cysteine. A variation was also seen in MYPBC3. Since the launch of WES as a clinically available technology in 2010, there has been concern regarding the identification of variants unrelated to the patient's phenotype. However, in cases where targeted sequencing fails to explain the clinical presentation, the underlying etiology could be more complex than anticipated. In this situation, the extensive reach of this tool helped explain both her phenotype and family history.

16.
Cold Spring Harb Mol Case Stud ; 1(1): a000455, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27148570

RESUMEN

Seven patients with similar phenotypes of developmental delay and microcephaly were found by whole-exome sequencing to have de novo loss-of-function mutations in POGZ. POGZ is a pogo transposable element-derived protein with a zinc finger cluster. The protein is involved in normal kinetochore assembly and mitotic sister chromatid cohesion and mitotic chromosome segregation. POGZ deficiency may affect mitosis, disrupting brain development and function.

17.
AJNR Am J Neuroradiol ; 24(7): 1471-4, 2003 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12917150

RESUMEN

We present a unique finding of an elevated level of pyruvate at 2.37 ppm revealed by in vivo MR spectroscopy of a female neonate. Low fibroblast pyruvate dehydrogenase (PDH) complex activity subsequently confirmed a diagnosis of PDH deficiency. Abnormalities of brain development consistent with PDH deficiency were also evident on fetal and postnatal MR images. To our knowledge, this is the first report of pyruvate being shown in vivo in a child and the first report of MR spectroscopy aiding in the diagnosis of inborn error in pyruvate metabolism before confirmation by conventional enzymatic testing. This finding has potential implications for earlier diagnosis in patients with defects in mitochondrial metabolism.


Asunto(s)
Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnóstico , Ácido Pirúvico/metabolismo , Anomalías Múltiples , Ventrículos Cerebrales/anomalías , Ventrículos Cerebrales/metabolismo , Femenino , Humanos , Recién Nacido , Espectroscopía de Resonancia Magnética , Mitocondrias/metabolismo , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/metabolismo , Ultrasonografía Prenatal
18.
Med Image Anal ; 18(5): 699-710, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24835178

RESUMEN

Down syndrome, the most common single cause of human birth defects, produces alterations in physical growth and mental retardation. If missed before birth, the early detection of Down syndrome is crucial for the management of patients and disease. However, the diagnostic accuracy for pediatricians prior to cytogenetic results is moderate and the access to specialists is limited in many social and low-economic areas. In this study, we propose a simple, non-invasive and automated framework for Down syndrome detection based on disease-specific facial patterns. Geometric and local texture features are extracted based on automatically detected anatomical landmarks to describe facial morphology and structure. To accurately locate the anatomical facial landmarks, a hierarchical constrained local model using independent component analysis (ICA) is proposed. We also introduce a data-driven ordering method for selecting dominant independent components in ICA. The hierarchical structure of the model increases the accuracy of landmark detection by fitting separate models to different groups. Then the most representative features are selected and we also demonstrate that they match clinical observations. Finally, a variety of classifiers are evaluated to discriminate between Down syndrome and healthy populations. The best performance achieved 0.967 accuracy and 0.956 F1 score using combined features and linear discriminant analysis. The method was also validated on a dataset with mixed genetic syndromes and high performance (0.970 accuracy and 0.930 F1 score) was also obtained. The promising results indicate that our method could assist in Down syndrome screening effectively in a simple, non-invasive way, and extensible to detection of other genetic syndromes.


Asunto(s)
Síndrome de Down/genética , Síndrome de Down/patología , Cara/anomalías , Cara/patología , Pruebas Genéticas/métodos , Modelos Anatómicos , Reconocimiento de Normas Patrones Automatizadas/métodos , Puntos Anatómicos de Referencia/patología , Preescolar , Simulación por Computador , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Modelos Estadísticos , Fotograbar/métodos , Análisis de Componente Principal , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Procesamiento de Señales Asistido por Computador
19.
Mol Genet Metab Rep ; 1: 237-240, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-27896094

RESUMEN

This is the first reported case of a patient with both non-ketotic hyperglycinemia and propionic acidemia. At 2 years of age, the patient was diagnosed with non-ketotic hyperglycinemia by elevated glycine levels and mutations in the GLDC gene (paternal allele: c.1576_1577insC delT and c.1580delGinsCAA; p.S527Tfs*13, and maternal allele: c.1819G>A; p.G607S). At 8 years of age after having been placed on ketogenic diet, he became lethargic and had severe metabolic acidosis with ketonuria. Urine organic acid analysis and plasma acylcarnitine profile were consistent with propionic acidemia. He was found to have an apparently homozygous mutation in the PCCB gene: c.49C>A; p.Leu17Met. The patient was also treated with natural protein restriction, carnitine, biotin, and thiamine and had subjective and biochemical improvement.

20.
Mol Genet Metab Rep ; 1: 66-70, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-27896076

RESUMEN

We present a sibling pair with Leigh-like disease, progressive hypotonia, regression, and chronic encephalopathy. Whole exome sequencing in the younger sibling demonstrated a homozygous thiamine pyrophosphokinase (TPK) mutation. Initiation of high dose thiamine, niacin, biotin, α-lipoic acid and ketogenic diet in this child demonstrated improvement in neurologic function and re-attainment of previously lost milestones. The diagnosis of TPK deficiency was difficult due to inconsistent biochemical and diagnostic parameters, rapidity of clinical demise and would not have been made in a timely manner without the use of whole exome sequencing. Molecular diagnosis allowed for attempt at dietary modification with cofactor supplementation which resulted in an improved clinical course.

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