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1.
Genet Med ; 16(11): e1, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25356975

RESUMEN

PURPOSE: Glycogen storage disease type I (GSD I) is a rare disease of variable clinical severity that primarily affects the liver and kidney. It is caused by deficient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a deficiency in the microsomal transport proteins for glucose 6-phosphate (GSD Ib), resulting in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa. Patients with GSD I have a wide spectrum of clinical manifestations, including hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, and growth retardation. Individuals with GSD type Ia typically have symptoms related to hypoglycemia in infancy when the interval between feedings is extended to 3­4 hours. Other manifestations of the disease vary in age of onset, rate of disease progression, and severity. In addition, patients with type Ib have neutropenia, impaired neutrophil function, and inflammatory bowel disease. This guideline for the management of GSD I was developed as an educational resource for health-care providers to facilitate prompt, accurate diagnosis and appropriate management of patients. METHODS: A national group of experts in various aspects of GSD I met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. RESULTS: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (hepatic, kidney, gastrointestinal/nutrition, hematologic, cardiovascular, reproductive) involved in GSD I. Conditions to consider in the differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic and renal transplantation, and prenatal diagnosis, are also addressed. CONCLUSION: A guideline that facilitates accurate diagnosis and optimal management of patients with GSD I was developed. This guideline helps health-care providers recognize patients with all forms of GSD I, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It also helps to identify gaps in scientific knowledge that exist today and suggests future studies.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo I/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo I/terapia , Antiportadores/genética , Diagnóstico Diferencial , Glucosa-6-Fosfatasa/genética , Enfermedad del Almacenamiento de Glucógeno Tipo I/patología , Humanos , Proteínas de Transporte de Monosacáridos/genética
2.
Eur J Hum Genet ; 32(8): 928-937, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38678163

RESUMEN

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research.


Asunto(s)
Histonas , Fenotipo , Humanos , Masculino , Femenino , Histonas/genética , Niño , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Preescolar , Adolescente , Adulto , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología
3.
Genet Med ; 12(7): 385-95, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20445456

RESUMEN

Angelman syndrome is characterized by severe developmental delay, speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavioral phenotype that includes happy demeanor and excessive laughter. Microcephaly and seizures are common. Developmental delays are first noted at 3 to 6 months age, but the unique clinical features of the syndrome do not become manifest until after age 1 year. Management includes treatment of gastrointestinal symptoms, use of antiepileptic drugs for seizures, and provision of physical, occupational, and speech therapy with an emphasis on nonverbal methods of communication. The diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 78% of individuals with lack of maternal contribution. Less than 1% of individuals have a visible chromosome rearrangement. UBE3A sequence analysis detects mutations in an additional 11% of individuals. The remaining 10% of individuals with classic phenotypic features of Angelman syndrome have a presently unidentified genetic mechanism and thus are not amenable to diagnostic testing. The risk to sibs of a proband depends on the genetic mechanism of the loss of the maternally contributed Angelman syndrome/Prader-Willi syndrome region: typically <1% for probands with a deletion or uniparental disomy; as high as 50% for probands with an imprinting defect or a mutation of UBE3A. Members of the mother's extended family are also at increased risk when an imprinting defect or a UBE3A mutation is present. Chromosome rearrangements may be inherited or de novo. Prenatal testing is possible for certain genetic mechanisms.


Asunto(s)
Síndrome de Angelman/diagnóstico , Síndrome de Angelman/genética , Síndrome de Angelman/terapia , Humanos
4.
J Inherit Metab Dis ; 33 Suppl 3: S151-7, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20386986

RESUMEN

Patients with type Ia glycogen storage disease (GSD) have been surviving well into adulthood since continuous glucose therapy was introduced in the 1970s, and there have been many documented successful pregnancies in women with this condition. Historically, few individuals with type Ib GSD, however, survived into adulthood prior to the introduction of granulocyte colony stimulating factor (G-CSF) in the late 1980s. There are no previously published reports of pregnancies in GSD type Ib. In this case report we describe the course and management of five successful pregnancies in three patients with GSD type Ib. Patient 1 experienced an increase in glucose requirement in all three of her pregnancies, starting from the second trimester onwards. There were no major complications related to neutropenia except for oral ulcers. The infants did well, except for respiratory distress in two of them at birth. Patient 2 used cornstarch to maintain euglycemia, but precise dosing was not part of her regimen, and, hence, an increase in metabolic demands was difficult to demonstrate. She developed a renal calculus and urinary tract infection during her pregnancy and had chronic iron deficiency anemia but no neutropenia. The neonate did well after delivery. Patient 3 had poor follow-up during pregnancy. Increasing glucose requirements, worsening lipid profile, neutropenia associated with multiple infections, and anemia were noted. The newborn infant did well after delivery. In addition to the case reports, the challenges of the usage of G-CSF, the treatment of enterocolitis, and comparisons with the management of GSD Ia are discussed.


Asunto(s)
Glucosa/administración & dosificación , Enfermedad del Almacenamiento de Glucógeno Tipo I/terapia , Nacimiento Vivo , Atención Perinatal , Complicaciones del Embarazo/terapia , Almidón/administración & dosificación , Adulto , Biomarcadores/sangre , Glucemia/metabolismo , Vías de Administración de Medicamentos , Esquema de Medicación , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo I/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo I/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Humanos , Lípidos/sangre , Embarazo , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/diagnóstico , Complicaciones del Embarazo/genética , Sobrevivientes , Factores de Tiempo , Resultado del Tratamiento
6.
Am J Med Genet A ; 146A(2): 204-7, 2008 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-18076119

RESUMEN

The syndrome of megalencephaly, mega corpus callosum and complete lack of motor development (MCC; OMIM 603387) is an apparently rare condition since only three sporadic cases have been reported [Gohlich-Ratmann et al. (1998); Am J Med Genet 79:161-167]. We describe an additional case that was not diagnosed until age 15 months. The MRI showed generalized, severe enlargement of the corpus callosum and thickening of the cortex. The cause for the MCC syndrome is unknown and both autosomal recessive and spontaneous dominant genetic mechanisms are possibilities.


Asunto(s)
Agenesia del Cuerpo Calloso , Discapacidades del Desarrollo/diagnóstico , Cabeza/anomalías , Trastornos de la Destreza Motora/diagnóstico , Discapacidades del Desarrollo/genética , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Trastornos de la Destreza Motora/genética , Síndrome
7.
Eur J Hum Genet ; 18(4): 436-41, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19904302

RESUMEN

Microdeletion of chromosome 2q23.1 results in a novel syndrome previously reported in five individuals. Many of the del(2)(q23.1) cases were thought to have other syndromes such as Angelman, Prader-Willi, or Smith-Magenis because of certain overlapping clinical features. We report two new cases of the 2q23.1 microdeletion syndrome, describe the syndrome phenotype, define the minimal critical region, and analyze the expression of critical region genes toward identification of the causative gene(s) for the disorder. Individuals with del(2)(q23.1) have severe developmental and cognitive delays, minimal speech, seizures, microcephaly, mild craniofacial dysmorphism, behavioral disorders, and short stature. The deletions encompassing 2q23.1 range from >4 Mb to <200 kb, as identified by oligonucleotide and BAC whole-genome array comparative hybridization. The minimal critical region includes a single gene, MBD5, deleted in all cases, whereas all but one case also include deletion of EPC2. Quantitative real-time PCR of patient lymphoblasts/lymphocytes showed an approximately 50% reduced expression of MBD5 and EPC2 compared with controls. With similar phenotypes among the 2q23.1 deletion patients, the idea of one or more common genes causing the pathological defect seen in these patients becomes evident. As all five previous cases and the two cases in this report share one common gene, MBD5, we strongly suspect that haploinsufficiency of MBD5 causes most of the features observed in this syndrome.


Asunto(s)
Proteínas de Unión al ADN/genética , Haplotipos , Discapacidad Intelectual/genética , Microcefalia/genética , Convulsiones/genética , Trastornos del Habla/genética , Adolescente , Adulto , Niño , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 2/genética , Hibridación Genómica Comparativa , Femenino , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/patología , Masculino , Microcefalia/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Convulsiones/patología , Trastornos del Habla/patología , Síndrome , Adulto Joven
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