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1.
Mol Genet Metab ; 132(1): 19-26, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33388234

RESUMO

BACKGROUND/AIMS: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age. METHODS: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter. RESULTS: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported. CONCLUSIONS: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.


Assuntos
Glicerol/análogos & derivados , Hiperamonemia/tratamento farmacológico , Fenilbutiratos/administração & dosagem , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Idade de Início , Amônia/sangue , Pré-Escolar , Feminino , Glicerol/administração & dosagem , Humanos , Hiperamonemia/sangue , Hiperamonemia/patologia , Lactente , Recém-Nascido , Masculino , Pediatria , Fenilacetatos/administração & dosagem , Diálise Renal , Distúrbios Congênitos do Ciclo da Ureia/sangue , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/patologia
2.
Am J Med Genet A ; 185(9): 2636-2645, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33913595

RESUMO

The increasing demand for advanced genomic services has finally come to the attention of healthcare systems and stakeholders who are now eager to find creative solutions to increase the pool of genomic literate providers. Training in genetics and dysmorphology has historically been conducted as a self-driven practice in pattern recognition, ideally within a formal or informal apprenticeship supervised by a master diagnostician. In recent times, case-based learning, framed by flipped classroom pedagogy have become the preferred teaching methods for complex medical topics such as genetics and genomics. To illuminate this perspective, our article was written in honor of the teaching style and pedagogy of Dr John M. Graham Jr and his lifelong commitment to medical education and mentoring.


Assuntos
Currículo/tendências , Educação Médica/tendências , Genética Médica/educação , Ensino/tendências , Humanos
3.
Am J Med Genet A ; 182(11): 2704-2708, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32820583

RESUMO

Classic homocystinuria is due to deficiency of cystathionine beta-synthase (CBS), a pyridoxine-dependent enzyme that, depending on the molecular variants, may be co-factor responsive. Elevated methionine is often used as the primary analyte to detect CBS deficiency (CBSD) on newborn screening (NBS), but is limited by increased detection of other biochemical disorders with less clear clinical significance such as methionine aminotransferase (MAT) I/III heterozygotes. Our state has implemented a two-tier NBS algorithm for CBSD that successfully reduced the number of MATI/III heterozygotes, yet effectively detected a mild, co-factor responsive form of CBSD. After initial diagnosis, newborns with CBSD often undergo a pyridoxine challenge with high-dose pyridoxine to determine responsiveness. Here we describe our NBS-identified patient with a mild form of pyridoxine responsive CBSD who developed respiratory failure and rhabdomyolysis consistent with pyridoxine toxicity during a pyridoxine challenge. This case highlights the need for weight-based dosing and duration recommendations for pyridoxine challenge in neonates.


Assuntos
Cistationina beta-Sintase/deficiência , Cistationina beta-Sintase/genética , Homocistinúria/tratamento farmacológico , Triagem Neonatal/métodos , Piridoxina/efeitos adversos , Insuficiência Respiratória/patologia , Rabdomiólise/patologia , Relação Dose-Resposta a Droga , Feminino , Homocistinúria/genética , Homocistinúria/patologia , Humanos , Recém-Nascido , Prognóstico , Piridoxina/administração & dosagem , Insuficiência Respiratória/induzido quimicamente , Rabdomiólise/induzido quimicamente , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/efeitos adversos
4.
J Inherit Metab Dis ; 42(1): 140-146, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30740726

RESUMO

BACKGROUND: Glutamate formiminotransferase deficiency (FTCD deficiency) or formiminoglutamic aciduria is the second most common of the known inherited disorders of folate metabolism. Initial case reports suggested that patients may have severe intellectual disability and megaloblastic anemia. However, these cases were obtained from screening cohorts of patients with developmental delay. Subsequently, patients with milder clinical phenotypes have been reported. The full phenotypic spectrum of this disorder remains unknown. METHODS: In many states, FTCD deficiency can be incidentally detected on tandem mass spectrometry-based newborn screening of dried blood spots. In this work, we report the outcomes of infants identified to have FTCD deficiency through newborn screening. RESULTS: During the study period, 18 patients were identified to have FTCD deficiency and were referred and evaluated at one of the two participating metabolic centers. The overall rate of FTCD deficiency detected through the New Jersey screening program over the study time period was 1:58,982. At a mean age of 56 months at last follow-up: 3/18 (16%) had developmental delays requiring individualized education plans, no patients had profound intellectual disability; 4/16 (25%) had mild self-limited anemia, no patients had profound anemia. CONCLUSIONS: These data suggest that the majority of individuals with FTCD deficiency detected by newborn screening are asymptomatic.

5.
Am J Med Genet A ; 170(12): 3343-3346, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27612211

RESUMO

Wiedemann-Rautenstrauch syndrome, also known as neonatal progeroid syndrome, is a rare condition with fewer than 40 patients reported in the literature. Characteristic physical findings include neonatal progeroid appearance, sparse scalp hair, prominent scalp veins, and lipoatrophy; in addition, neonatal teeth are often a distinctive finding. The inheritance pattern of this disorder has been postulated to be autosomal recessive, although a specific gene has not been identified. Here we report an infant with the characteristic phenotypic features of Wiedemann-Rautenstrauch syndrome in whom exome sequencing identified two pathogenic variants in POLR3A: c.1909+18G>A; p.(Y637Cfs*23) and c.2617C>T; p.(R873*). Mutations in POLR3A (OMIM #614258) are associated with 4H leukodystrophy syndrome characterized by the triad of hypomyelination, hypodontia, and hypogonadotrophic hypogonadism. The present patient's genotype implies a broader phenotypic range for POLR3A mutations and might expand the clinical spectrum. This proband is notable because she had two null pathogenic variants. Replication in other patients clinically diagnosed with Wiedemann-Rautenstrauch syndrome is needed to further demonstrate this gene-disease association. © 2016 Wiley Periodicals, Inc.


Assuntos
Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/genética , Estudos de Associação Genética , Fenótipo , Progéria/diagnóstico , Progéria/genética , RNA Polimerase III/genética , Deleção de Sequência , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Alelos , Substituição de Aminoácidos , Feminino , Genótipo , Humanos , Lactente , Diagnóstico Pré-Natal
6.
Nat Genet ; 39(9): 1071-3, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17704777

RESUMO

We have identified a recurrent de novo pericentromeric deletion in 16p11.2-p12.2 in four individuals with developmental disabilities by microarray-based comparative genomic hybridization analysis. The identification of common clinical features in these four individuals along with the characterization of complex segmental duplications flanking the deletion regions suggests that nonallelic homologous recombination mediated these rearrangements and that deletions in 16p11.2-p12.2 constitute a previously undescribed syndrome.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 16/genética , Adolescente , Criança , Pré-Escolar , Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Feminino , Genoma Humano , Humanos , Hibridização in Situ Fluorescente , Hibridização de Ácido Nucleico/métodos , Síndrome
7.
Genet Med ; 17(3): 205-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25144890

RESUMO

PURPOSE: Biotinidase deficiency, if untreated, usually results in neurological and cutaneous symptoms. Biotin supplementation markedly improves and likely prevents symptoms in those treated early. All states in the United States and many countries perform newborn screening for biotinidase deficiency. However, there are few studies about the outcomes of the individuals identified by newborn screening. METHODS: We report the outcomes of 142 children with biotinidase deficiency identified by newborn screening in Michigan over a 25-year period and followed in our clinic; 22 had profound deficiency and 120 had partial deficiency. RESULTS: Individuals with profound biotinidase and partial deficiency identified by newborn screening were started on biotin therapy soon after birth. With good compliance, these children appeared to have normal physical and cognitive development. Although some children exhibited mild clinical problems, these are unlikely attributable to the disorder. Biotin therapy appears to prevent the development of neurological and cutaneous problems in our population. CONCLUSION: Individuals with biotinidase deficiency ascertained by newborn screening and treated since birth appeared to exhibit normal physical and cognitive development. If an individual does develop symptoms, after compliance and dosage issues are excluded, then other causes must be considered.Genet Med 17 3, 205-209.


Assuntos
Biotina/uso terapêutico , Deficiência de Biotinidase/dietoterapia , Deficiência de Biotinidase/diagnóstico , Triagem Neonatal/métodos , Complexo Vitamínico B/uso terapêutico , Biotinidase/genética , Deficiência de Biotinidase/patologia , Análise Mutacional de DNA/métodos , Humanos , Recém-Nascido , Michigan , Estudos Retrospectivos , Resultado do Tratamento
8.
J Inherit Metab Dis ; 38(5): 839-46, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25567501

RESUMO

INTRODUCTION: Women with inherited metabolic disorders, including those with previously life-limiting conditions such as MMA, are reaching child-bearing age more often due to advances in early diagnosis and improved pediatric care. Information surrounding maternal and fetal complications associated with the underlying disorders remains largely unexplored. METHODS: Pregnancies affected by maternal MMA were ascertained through study 04-HG-0127 "Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders" (clinicaltrials.gov identifier: NCT00078078) and via literature review. Prenatal and delivery records in study participants were reviewed. RESULTS: Seventeen pregnancies were identified in women with isolated MMA, including three abortions, one termination, and 13 completed pregnancies [three cases with cblA (four pregnancies), four cases of mut- (one cobalamin responsive, three non-responsive), five cases with unknown type of MMA]. Seventeen percent (3/17) of the pregnancies resulted in a first trimester abortion, while 38.5% (5/13) of the completed pregnancies resulted in preterm deliveries. A cesarean delivery rate of 53.8% (7/13) was noted among the cohort. Fetal distress or nonreassuring fetal status was the indication for 57% (4/7) cesarean deliveries. One patient was reported to have metabolic crisis as well as episodes of mild hyperammonemia. Malformations or adverse outcomes in the progeny were not observed. CONCLUSION: Although there have been a small number of pregnancies identified in women with MMA, the cumulative results suggest that the majority of pregnancies can be complicated by cesarean delivery and increased risk of prematurity. A pregnancy registry could clarify perinatal complications and define management approaches needed to ensure optimal maternal and fetal outcomes in this growing patient population.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Complicações na Gravidez , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/embriologia , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Cesárea/estatística & dados numéricos , Feminino , Desenvolvimento Fetal/fisiologia , Humanos , Recém-Nascido , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/metabolismo , Complicações na Gravidez/patologia , Resultado da Gravidez/epidemiologia , Estudos Retrospectivos , Adulto Jovem
9.
Genet Med ; 15(2): 123-31, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23060045

RESUMO

PURPOSE: High sustained antibody titers complicate many disorders treated with a therapeutic protein, including those treated with enzyme replacement therapy, such as Pompe disease. Although enzyme replacement therapy with alglucosidase alfa (Myozyme) in Pompe disease has improved the prognosis of this otherwise lethal disorder, patients who develop high sustained antibody titers to alglucosidase alfa enter a prolonged phase of clinical decline resulting in death despite continued enzyme replacement therapy. Clinically effective immune-tolerance induction strategies have yet to be described in the setting of an entrenched immune response characterized by high sustained antibody titers, wherein antibody-producing plasma cells play an especially prominent role. METHODS: We treated three patients with infantile Pompe disease experiencing marked clinical decline due to high sustained antibody titers. To target the plasma cell source of high sustained antibody titers, a regimen based on bortezomib (Velcade) was used in combination with rituximab, methotrexate, and intravenous immunoglobulin. RESULTS: The treatment regimen was well tolerated, with no obvious side effects. Patient 1 had a 2,048-fold, and patients 2 and 3 each had a 64-fold, reduction in anti-alglucosidase alfa antibody titer, with concomitant sustained clinical improvement. CONCLUSION: The addition of bortezomib to immunomodulatory regimens is an effective and safe treatment strategy in infantile Pompe disease, with potentially broader clinical implications.


Assuntos
Anticorpos/análise , Ácidos Borônicos/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/prevenção & controle , Imunoglobulinas Intravenosas/uso terapêutico , Metotrexato/uso terapêutico , Pirazinas/uso terapêutico , Anticorpos/imunologia , Antineoplásicos/uso terapêutico , Bortezomib , Criança , Pré-Escolar , Quimioterapia Combinada , Doença de Depósito de Glicogênio Tipo II/imunologia , Humanos , Masculino , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Plasmócitos/metabolismo , Resultado do Tratamento
10.
Hum Mutat ; 33(3): 485-7, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22213132

RESUMO

Congenital disorders of glycosylation (CDG) comprise a clinically and biochemically heterogeneous group of monogenetic-inherited, multisystemic diseases that affect the biosynthesis of N- and/or O-glycans linked to glycoconjugates. Recently, we identified the first patient with a defect in the cytosolic-orientated GDP-mannose:Man(3-4) GlcNAc(2)-PP-dolichol alpha-1,2-mannosyltransferase (ALG11), who presented an accumulation of shortened dolichol-linked oligosaccharides leading to CDG-Ip (ALG11-CDG). Here we describe an improved metabolic labeling method that allowed the identification of three new CDG-Ip cases that were missed so far in routine diagnostics. Although all CDG-Ip patients carry different mutations in the ALG11 gene, they share a variety of clinical syndromes like an unremarkable prenatal period followed by developmental delay, psychomotor, and mental retardation, strabismus convergens and seizures occurring in the first year of life.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/enzimologia , Dolicóis/química , Feminino , Glicosilação , Humanos , Masculino , Manosiltransferases/genética , Oligossacarídeos/química , Oligossacarídeos/metabolismo
11.
Am J Med Genet A ; 158A(2): 269-91, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22228622

RESUMO

The macrocephaly-capillary malformation syndrome (M-CM), which we here propose to rename the megalencephaly-capillary malformation syndrome (MCAP; alternatively the megalencephaly-capillary malformation-polymicrogyria syndrome), and the more recently described megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) are two megalencephaly (MEG) disorders that involve a unique constellation of physical and neuroimaging anomalies. We compare the features in 42 patients evaluated for physical and neuroimaging characteristics of MCAP and MPPH and propose a more global view of these syndromes based on classes of developmental abnormalities that include primary MEG and growth dysregulation, developmental vascular anomalies (primarily capillary malformations), distal limb anomalies (such as syndactyly and polydactyly), cortical brain malformations (most distinctively polymicrogyria, PMG), and variable connective tissue dysplasia. Based on these classes of developmental abnormalities, we propose that MCAP diagnostic criteria include progressive MEG with either vascular anomalies or syndactyly. In parallel, we propose that MPPH diagnostic criteria include progressive MEG and PMG, absence of the vascular anomalies and syndactyly characteristic of MCAP, and absence of brain heterotopia.


Assuntos
Encéfalo/patologia , Capilares/patologia , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/patologia , Diagnóstico Diferencial , Hidrocefalia/patologia , Megalencefalia/diagnóstico , Megalencefalia/patologia , Encéfalo/crescimento & desenvolvimento , Criança , Pré-Escolar , Feminino , Humanos , Hidrocefalia/diagnóstico , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico , Malformações do Desenvolvimento Cortical/patologia , Megalencefalia/classificação , Morfogênese , Neuroimagem/métodos , Polidactilia/diagnóstico , Polidactilia/patologia , Sindactilia/diagnóstico , Sindactilia/patologia
12.
Eur J Med Genet ; 63(12): 104076, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32980525

RESUMO

Methionine adenosyltransferase I/III deficiency, also known as Mudd's disease, is a rare inborn error of methionine metabolism. Because pathophysiological mechanisms of the disease remain poorly understood, the consequences of this disorder and the need for medical management remain uncertain; likewise, the effect of medical interventions on clinical outcomes in Mudd's disease is largely unknown due to a relative lack of published longitudinal clinical data. There are few reports of adults in the medical literature affected with this disease. Clinical symptoms of reported adults range from asymptomatic to individuals with neurological, developmental, or behavioral symptoms. Here we report three siblings affected with Mudd's disease that were ascertained following an abnormal newborn screen for hypermethioninemia in the case of our index patient. All three had a variable degree of longstanding neurologic or psychiatric symptoms which had not prompted a clinical investigation for a genetic or metabolic disorder prior to identification through our clinic. While the causal association of these symptoms to the metabolic disorder remains unclear in these cases, all three patients demonstrated a degree of amelioration of symptoms and/or improvement in measurements on standardized psychiatric ratings scales when specific therapy for the metabolic disorder was instituted. The symptoms, treatment, and outcomes over the course of six years of follow-up are presented here, expanding the possible natural history of Mudd's disease.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Glicina N-Metiltransferase/deficiência , Metionina Adenosiltransferase/deficiência , Fenótipo , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Dietoterapia , Feminino , Glicina N-Metiltransferase/genética , Humanos , Recém-Nascido , Masculino , Metionina Adenosiltransferase/genética , Linhagem
13.
J Pediatr Genet ; 8(2): 54-57, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31061746

RESUMO

Methionine S-adenosyltransferase deficiency, due to mutations in MAT1A , is the most common cause of persistent isolated hypermethioninemia (PIH). While the recessive form may cause neurological consequences, the dominant form is typically benign. This condition may be found in asymptomatic infants through newborn screening programs. We describe 16 asymptomatic individuals with PIH. Our data reiterates the benign nature of PIH and reports two novel mutations in the gene. There were a disproportionate number of individuals with African descent in this cohort.

14.
Am J Med Genet A ; 143A(24): 2981-3008, 2007 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-18000912

RESUMO

Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly-Capillary Malformation (M-CM). This syndrome has been traditionally known as Macrocephaly-Cutis Marmorata Telangiectatica Congenita (M-CMTC), but we explain why M-CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases. White matter irregularities with increased signal on T2-weighted images were commonly observed findings. A distinctive feature in more than half the patients was cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. In four such cases, we confirmed that the tonsillar herniation was an acquired event. Concurrently, with the development of these findings, ventriculomegaly (frequently obstructive) and dilated dural venous sinuses were observed in conjunction with prominent Virchow-Robin spaces in many of those in whom cerebellar tonsil herniation had developed. We postulate that this constellation of unusual features suggests a dynamic process of mechanical compromise in the posterior fossa, perhaps initiated by a rapidly growing cerebellum, which leads to congestion of the venous drainage with subsequently compromised cerebrospinal fluid reabsorption, all of which increases the posterior fossa pressure and leads to acquired tonsillar herniation. We make a distinction between congenital Chiari I malformation and acquired cerebellar tonsil herniation in this syndrome. We also observed numerous examples of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria which primarily involved the perisylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth. Other findings included a high frequency of cavum septum pellucidum or vergae, thickened corpus callosum, prominent optic nerve sheaths and a single case of venous sinus thrombosis. One patient was found to have a frontal perifalcine mass resembling a meningioma at age 5 years. This is the second apparent occurrence of this specific tumor in M-CM.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Craniofaciais/diagnóstico , Imageamento por Ressonância Magnética/métodos , Anormalidades Múltiplas/patologia , Adolescente , Peso ao Nascer , Encéfalo/anormalidades , Capilares/patologia , Criança , Pré-Escolar , Corpo Caloso/patologia , Anormalidades Craniofaciais/patologia , Feminino , Humanos , Lactente , Masculino , Síndrome , Telangiectasia/diagnóstico , Telangiectasia/patologia
15.
J Neurosurg ; 106(4 Suppl): 296-301, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17465364

RESUMO

The authors report on three patients with a congenital brain overgrowth syndrome, macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC), who experienced neurological sequelae associated with herniation of the cerebellar tonsils through the foramen magnum. In two of these patients, the authors document postnatal brain overgrowth that contributed to recurrent descent of the cerebellar tonsils and complicated the surgical treatment in one of the patients. The authors address the neurosurgical concerns related to this syndrome with special attention to acquired tonsillar ectopia and postulate that some patients may be at risk for progressive tonsillar herniation and consequent neurological symptoms due to cerebellar overgrowth. Ectopic cerebellar tonsils have been reported previously in cases of M-CMTC, and this phenomenon may be a secondary event associated with brain overgrowth rather than due to a congenitally small posterior fossa.


Assuntos
Encéfalo/anormalidades , Doenças Cerebelares/cirurgia , Encefalocele/cirurgia , Telangiectasia/congênito , Doenças Cerebelares/complicações , Encefalocele/complicações , Humanos , Lactente , Masculino , Telangiectasia/complicações
16.
JCI Insight ; 1(9)2016 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-27631024

RESUMO

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Malformações do Desenvolvimento Cortical/genética , Mosaicismo , Malformações Vasculares/genética , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Mutação , Fenótipo , Distribuição Tecidual
17.
Clin Chim Acta ; 446: 171-4, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25920691

RESUMO

BACKGROUND: Classic galactosemia (CG) is a potentially lethal genetic disorder that results from profound loss of galactose-1-phosphate uridylyltransferase (GALT). CG is detected by newborn screening (NBS) in many countries; however, conclusive diagnosis can be complex due to broad and overlapping ranges of GALT activity. Molecular studies can also be complex due to allelic heterogeneity at the GALT locus. METHODS: We conducted both biochemical and molecular follow-up studies for an infant flagged by NBS for possible galactosemia. To clarify the diagnosis we also conducted biochemical and RNA studies of lymphoblasts prepared from the child and one parent. RESULTS: We identified a novel noncoding GALT variant, c.377+17C>T, that was homozygous in the child and heterozygous in both parents. The child and both parents also showed diminished GALT activity in red blood cells, and transformed lymphoblasts from the child and one parent further showed diminished GALT activity. However, qRT-PCR studies demonstrated apparently normal GALT mRNA levels in lymphoblasts, and Gal-1P values measured in the child following galactose exposure in infancy and at 1 year were normal. CONCLUSIONS: These results highlight the existence of rare but apparently benign variants in GALT and underscore the need for functional studies to distinguish pathogenic from benign variants.


Assuntos
Galactosemias/diagnóstico , Homozigoto , Mutação , UTP-Hexose-1-Fosfato Uridililtransferase/genética , Adulto , Doenças Assintomáticas , Células Cultivadas , Consanguinidade , Feminino , Galactosemias/sangue , Galactosemias/genética , Galactosefosfatos/metabolismo , Expressão Gênica , Loci Gênicos , Testes Genéticos , Herpesvirus Humano 4/crescimento & desenvolvimento , Heterozigoto , Humanos , Recém-Nascido , Linfócitos/metabolismo , Linfócitos/virologia , Masculino , Triagem Neonatal , Transformação Genética , UTP-Hexose-1-Fosfato Uridililtransferase/deficiência
19.
Nat Genet ; 44(8): 934-40, 2012 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-22729224

RESUMO

Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism.


Assuntos
Malformações do Desenvolvimento Cortical/genética , Megalencefalia/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Classe I de Fosfatidilinositol 3-Quinases , Exoma , Mutação em Linhagem Germinativa , Humanos , Hidrocefalia/enzimologia , Hidrocefalia/genética , Hidrocefalia/patologia , Malformações do Desenvolvimento Cortical/enzimologia , Malformações do Desenvolvimento Cortical/patologia , Megalencefalia/enzimologia , Megalencefalia/patologia , Mutação de Sentido Incorreto , Síndrome
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