Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
1.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
2.
Life (Basel) ; 10(9)2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32932790

RESUMO

There is limited data on pregnancy outcomes in Pompe Disease (PD) resulting from deficiency of the lysosomal enzyme acid alpha-glucosidase. Late-onset PD is characterized by progressive proximal muscle weakness and decline of respiratory function secondary to the involvement of the respiratory muscles. In a cohort of twenty-five females, the effects of both PD on the course of pregnancy and the effects of pregnancy on PD were investigated. Reproductive history, course of pregnancy, use of Enzyme replacement therapy (ERT), PD symptoms, and outcomes of each pregnancy were obtained through a questionnaire. Among 20 subjects that reported one or more pregnancies, one subject conceived while on ERT and continued therapy through two normal pregnancies with worsening of weakness during pregnancy and improvement postpartum. While fertility was not affected, pregnancy may worsen symptoms, or cause initial symptoms to arise. Complications with pregnancy or birth were not higher, except for an increase in the rate of stillbirths (3.8% compared to the national average of 0.2-0.7%). Given small sample size and possible bias of respondents being only women who have been pregnant, further data may be needed to better analyze the effects of pregnancy on PD, and the effects of ERT on pregnancy outcomes.

3.
Mol Genet Metab Rep ; 25: 100635, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32793419

RESUMO

Purpose: To improve our understanding of the behavioral, social, and emotional functioning of children and adolescents with Pompe disease. Method: Parents/guardians of 21 children (age 5-18y) with infantile (IPD) or late-onset (LOPD) Pompe disease on long-term enzyme replacement therapy completed three standardized checklists regarding their child's behavior: the Child Behavior Checklist (CBCL), Conners 3 Parent (Conners-3), Behavior Rating Inventory of Executive Function-2 (BRIEF2), and a survey of their child's educational services. Results: Descriptive statistics were used to summarize the findings for each behavior checklist. Age standard scores from each checklist were reported for the IPD (n = 17, 9 females, mean age = 9y, 4 mo; SD = 3y, 8mo) and LOPD (n = 4, 1 female; mean = 11y, 2mo; SD = 2y, 1mo) groups. The majority of children with Pompe exhibited age-appropriate behavior and emotional functioning on these standardized checklists. However, negative mood symptoms, learning problems, decreased participation in structured social activities, and attentional difficulties were more frequently reported in children with IPD in comparison to same-aged peers. Parents of children with LOPD reported fewer problematic behaviors but endorsed negative mood symptoms and difficulties with peer relations. Most children received accommodations in regular education classrooms at school. Conclusions: These standardized behavior checklists are useful screening tools for the early identification and treatment of behavior, emotional, and social concerns in children with Pompe disease.

5.
Neurology ; 95(6): e718-e732, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32518148

RESUMO

OBJECTIVE: To characterize the extent of CNS involvement in children with Pompe disease using brain MRI and developmental assessments. METHODS: The study included 14 children (ages 6-18 years) with infantile Pompe disease (IPD) (n = 12) or late-onset Pompe disease (LOPD) (n = 2) receiving enzyme replacement therapy. White matter (WM) hyperintense foci seen in the brain MRIs were systematically quantified using the Fazekas scale (FS) grading system with a novel approach: the individual FS scores from 10 anatomical areas were summed to yield a total FS score (range absent [0] to severe [30]) for each child. The FS scores were compared to developmental assessments of cognition and language obtained during the same time period. RESULTS: Mild to severe WM hyperintense foci were seen in 10/12 children with IPD (median age 10.6 years) with total FS scores ranging from 2 to 23. Periventricular, subcortical, and deep WM were involved. WM hyperintense foci were seen throughout the path of the corticospinal tracts in the brain in children with IPD. Two children with IPD had no WM hyperintense foci. Children with IPD had relative weaknesses in processing speed, fluid reasoning, visual perception, and receptive vocabulary. The 2 children with LOPD had no WM hyperintense foci, and high scores on most developmental assessments. CONCLUSION: This study systematically characterized WM hyperintense foci in children with IPD, which could serve as a benchmark for longitudinal follow-up of WM abnormalities in patients with Pompe disease and other known neurodegenerative disorders or leukodystrophies in children.


Assuntos
Encefalopatias Metabólicas Congênitas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Deficiências do Desenvolvimento/diagnóstico por imagem , Doença de Depósito de Glicogênio Tipo II/diagnóstico por imagem , Imageamento por Ressonância Magnética , Neuroimagem , Adolescente , Idade de Início , Encéfalo/patologia , Encefalopatias Metabólicas Congênitas/etiologia , Criança , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Estudos Transversais , Deficiências do Desenvolvimento/etiologia , Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/complicações , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/psicologia , Humanos , Transtornos da Linguagem/diagnóstico por imagem , Transtornos da Linguagem/etiologia , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Substância Branca/diagnóstico por imagem
6.
Mol Genet Metab ; 126(2): 106-116, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30655185

RESUMO

BACKGROUND: Individuals with late-onset Pompe disease (LOPD) and the common c.-32-13 T > G variant are widely thought to have milder, adult-onset disease. This belief, and the consequent low suspicion of clinical involvement in children, has led to delays in diagnosis and treatment initiation in patients with early onset of symptoms. Previous reports of LOPD in children do not include description of the early-onset phenotype. This description of signs and symptoms, some of which are subtle and less known, is important to facilitate prompt identification and appropriate treatment in symptomatic children. METHODS: Retrospective chart review of a cohort of 84 LOPD patients with the c.-32-13 T > G variant was conducted to identify patients diagnosed clinically (as opposed to through newborn screening) who had clinically documented symptom-onset within the first two years of life. RESULTS: Four patients had early onset of symptoms, with age at onset ranging from 10 days to 20 months. Initial symptoms included delay in achievement of gross motor milestones, signs of proximal muscle weakness, swallow and feeding difficulties, and sleep apnea. Early and characteristic alterations in posture and movement were identified in all patients. Age at diagnosis ranged from 10 months to 26 months. Median age at enzyme replacement therapy (ERT) initiation was 23.5 months. Despite ERT, progression of musculoskeletal involvement and residual muscle weakness was evident in all patients, as evidenced by ptosis, myopathic facies, scoliosis, lumbar lordosis, scapular winging, and trunk and lower extremity weakness. Standardized functional assessments showed gross motor function below age level as measured by the Alberta Infant Motor Scales, the Peabody Developmental Motor Scales-2, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, and the six-minute walk test. CONCLUSIONS: Onset of symptoms including delay in achievement of gross motor milestones, signs of proximal muscle weakness, swallow and feeding difficulties, and sleep apnea in the first two years of life is not uncommon in individuals with LOPD and the c.-32-13 T > G variant. Patients with early-onset disease appear to have a more, rapid and severe progression of disease with persistent residual muscle deficits which partially improve with higher doses of ERT. Careful evaluation for specific and characteristic patterns of posture and movement in patients with this variant is necessary to identify those who have early onset of disease. Increased awareness of the early-onset signs and symptoms may also enable early identification of disease onset in children who are diagnosed through newborn screening.


Assuntos
Variação Genética , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/genética , alfa-Glucosidases/genética , Terapia de Reposição de Enzimas , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Estudos Retrospectivos , Fatores de Tempo
7.
Genet Med ; 21(4): 772-789, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30659246

RESUMO

PURPOSE: Glycogen storage disease (GSD) types VI and IX are rare diseases of variable clinical severity affecting primarily the liver. GSD VI is caused by deficient activity of hepatic glycogen phosphorylase, an enzyme encoded by the PYGL gene. GSD IX is caused by deficient activity of phosphorylase kinase (PhK), the enzyme subunits of which are encoded by various genes: ɑ (PHKA1, PHKA2), ß (PHKB), É£ (PHKG1, PHKG2), and δ (CALM1, CALM2, CALM3). Glycogen storage disease types VI and IX have a wide spectrum of clinical manifestations and often cannot be distinguished from each other, or from other liver GSDs, on clinical presentation alone. Individuals with GSDs VI and IX can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth. This guideline for the management of GSDs VI and IX was developed as an educational resource for health-care providers to facilitate prompt and accurate diagnosis and appropriate management of patients. METHODS: A national group of experts in various aspects of GSDs VI and IX met to review the limited evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. Evidence bases for these rare disorders are largely based on expert opinion, particularly when targeted therapeutics that have to clear the US Food and Drug Administration (FDA) remain unavailable. RESULTS: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems involved in GSDs VI and IX. Conditions to consider in a 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, and prenatal diagnosis are addressed. CONCLUSION: A guideline that will facilitate the accurate diagnosis and optimal management of patients with GSDs VI and IX was developed. This guideline will help health-care providers recognize patients with GSDs VI and IX, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.


Assuntos
Genômica , Doença de Depósito de Glicogênio/genética , Hipoglicemia/genética , Fosforilase Quinase/genética , Gerenciamento Clínico , Genética Médica/tendências , Glicogênio/genética , Glicogênio/metabolismo , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/epidemiologia , Doença de Depósito de Glicogênio/terapia , Guias como Assunto , Humanos , Hipoglicemia/metabolismo , Hipoglicemia/terapia , Fígado/metabolismo , Fígado/patologia , Mutação , Fosforilase Quinase/química , Estados Unidos/epidemiologia
8.
J Inherit Metab Dis ; 40(6): 823-830, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801758

RESUMO

PRKAG2 encodes the γ2 subunit of AMP-activated protein kinase (AMPK), which is an important regulator of cardiac metabolism. Mutations in PRKAG2 cause a cardiac syndrome comprising ventricular hypertrophy, pre-excitation, and progressive conduction-system disease, which is typically not diagnosed until adolescence or young adulthood. However, significant variability exists in the presentation and outcomes of patients with PRKAG2 mutations, with presentation in infancy being underrecognized. The diagnosis of PRKAG2 can be challenging in infants, and we describe our experience with three patients who were initially suspected to have Pompe disease yet ultimately diagnosed with mutations in PRKAG2. A disease-causing PRKAG2 mutation was identified in each case, with a novel missense mutation described in one patient. We highlight the potential for patients with PRKAG2 mutations to mimic Pompe disease in infancy and the need for confirmatory testing when diagnosing Pompe disease.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Mutação/genética , Pré-Escolar , Feminino , Doença de Depósito de Glicogênio Tipo II/genética , Humanos , Lactente , Recém-Nascido , Masculino
9.
Mol Genet Metab ; 120(1-2): 96-100, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27692944

RESUMO

OBJECTIVE: PRKAG2 syndrome, an autosomal dominant disorder, is characterized by severe infantile hypertrophic cardiomyopathy and heart rhythm disturbances to cases with a later presentation and a spectrum of manifestations including cardiac manifestations, myopathy and seizures. The cardiac features of PRKAG2 resemble the cardiac manifestations of Pompe disease. We present a patient who was initially diagnosed with Pompe disease and treated with alglucosidase-alfa enzyme replacement therapy (ERT); however, he was eventually diagnosed to carrying a PRKAG2 pathogenic gene mutation; he did not have Pompe disease instead he was a carrier for the common adult leaky splice site mutation in the GAA gene. CASE REPORT: At 2.5months, the patient had hypotonia/generalized muscle weakness, a diagnosis of non-classic infantile Pompe disease was made based on low acid alpha-glucosidase activity and the patient started on ERT at 11months. However, 1month later, the patient began to have seizures. As the patient's medical history was somewhat unusual for infantile Pompe disease, further evaluation was initiated and included a glycogen storage disease sequencing panel which showed that the patient had a pathogenic mutation in PRKAG2 which had been reported previously. ERT was discontinued and patient had a progression of motor deficits. ERT was reinitiated by the treating physician, and a clinical benefit was noted. CONCLUSION: This report outlines the benefits of ERT with alglucosidase alfa in a patient with PRKAG2 syndrome, the decline in his condition when the ERT infusions were discontinued, and the significant positive response when ERT was reinitiated.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Doença de Depósito de Glicogênio/tratamento farmacológico , Mutação , alfa-Glucosidases/uso terapêutico , Pré-Escolar , Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio/genética , Humanos , Masculino , Resultado do Tratamento
10.
J. inborn errors metab. screen ; 5: e160060, 2017. tab
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1090922

RESUMO

Abstract Pulmonary arterial hypertension (PAH) is a rare and highly fatal disease that has been reported in 8 patients with glycogen storage disease type I (GSDI). We describe an additional case of an acute presentation of PAH in a 14-year-old patient with GSDI, which was successfully treated with inhaled nitric oxide and sildenafil. We investigated the incidence of PAH in 28 patients with GSDI on routine echocardiography and found no evidence of PAH and no significant cardiac abnormalities. This study highlights that PAH is a rare disease overall, but our case report and those previously described suggest an increased incidence in patients with GSDI. Should cardiopulmonary symptoms develop, clinicians caring for patients with GSDI should have a high degree of suspicion for acute PAH and recognize that prompt intervention can lead to survival in this otherwise highly fatal disease.

11.
Comp Med ; 66(1): 41-51, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26884409

RESUMO

Glycogen storage disease type IIIa (GSD IIIa) is caused by a deficiency of glycogen debranching enzyme activity. Hepatomegaly, muscle degeneration, and hypoglycemia occur in human patients at an early age. Long-term complications include liver cirrhosis, hepatic adenomas, and generalized myopathy. A naturally occurring canine model of GSD IIIa that mimics the human disease has been described, with progressive liver disease and skeletal muscle damage likely due to excess glycogen deposition. In the current study, long-term follow-up of previously described GSD IIIa dogs until 32 mo of age (n = 4) and of family-owned GSD IIIa dogs until 11 to 12 y of age (n = 2) revealed that elevated concentrations of liver and muscle enzyme (AST, ALT, ALP, and creatine phosphokinase) decreased over time, consistent with hepatic cirrhosis and muscle fibrosis. Glycogen deposition in many skeletal muscles; the tongue, diaphragm, and heart; and the phrenic and sciatic nerves occurred also. Furthermore, the urinary biomarker Glc4, which has been described in many types of GSD, was first elevated and then decreased later in life. This urinary biomarker demonstrated a similar trend as AST and ALT in GSD IIIa dogs, indicating that Glc4 might be a less invasive biomarker of hepatocellular disease. Finally, the current study further demonstrates that the canine GSD IIIa model adheres to the clinical course in human patients with this disorder and is an appropriate model for developing novel therapies.


Assuntos
Doenças do Cão/metabolismo , Doença de Depósito de Glicogênio Tipo III/veterinária , Fatores Etários , Animais , Biomarcadores/sangue , Biomarcadores/urina , Modelos Animais de Doenças , Progressão da Doença , Doenças do Cão/patologia , Cães , Feminino , Glicogênio/metabolismo , Doença de Depósito de Glicogênio Tipo III/metabolismo , Doença de Depósito de Glicogênio Tipo III/patologia , Hepatomegalia/metabolismo , Hepatomegalia/patologia , Hepatomegalia/veterinária , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/veterinária , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Doenças Musculares/veterinária , Especificidade da Espécie , Urolitíase/metabolismo , Urolitíase/patologia , Urolitíase/veterinária
12.
Mol Genet Metab ; 116(3): 152-6, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26372341

RESUMO

The skeletal muscle manifestations of late-onset Pompe disease (LOPD) cause significant gait impairment. However, the specific temporal and spatial characteristics of abnormal gait in LOPD have not been objectively analyzed or described in the literature. This pilot study evaluated the gait of 22 individuals with LOPD using the GAITRite® temporospatial gait analysis system. The gait parameters were compared to normal reference values, and correlations were made with standard measures of disease progression. The LOPD population demonstrated significant abnormalities in temporospatial parameters of gait including a trend towards decreased velocity and cadence, a prolonged stance phase, prolonged time in double limb support, shorter step and stride length, and a wider base of support. Precise descriptions and analyses of gait abnormalities have much potential in increasing our understanding of LOPD, especially in regards to how its natural history may be modified by the use of enzyme replacement therapy (ERT) and other interventions. Gait analysis may provide a sensitive early marker of the onset of clinical symptoms and signs, offer an additional objective measure of disease progression and the impact of intervention, and serve as a potentially important clinical endpoint. The additional data from comprehensive gait analysis may personalize and optimize physical therapy management, and the clarification of specific gait patterns in neuromuscular diseases could be of clinical benefit in the ranking of a differential diagnosis.


Assuntos
Transtornos Neurológicos da Marcha/fisiopatologia , Marcha , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Diagnóstico Diferencial , Progressão da Doença , Terapia de Reposição de Enzimas , Humanos , Lactente , Pessoa de Meia-Idade , Projetos Piloto , Adulto Jovem
13.
Am J Case Rep ; 16: 196-201, 2015 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-25835646

RESUMO

BACKGROUND: Prior autopsy reports demonstrate glycogen deposition in Schwann cells of the peripheral nerves in patients with infantile and late-onset Pompe disease (LOPD), but little is known about associated clinical features. CASE REPORT: Here, we report the first confirmed cases of small-fiber neuropathy (SFN) in LOPD and present the results of a first attempt at screening for SFN in this patient population. After confirming small-fiber neuropathy in 2 LOPD patients, 44 consecutive Pompe patients (iOPD=7, LOPD n=37) presenting to the Duke University Glycogen Storage Disease Program between September 2013 and November 2014 were asked to complete the 21-item Small-Fiber Neuropathy Screening List (SFNSL), where a score of ≥11 is considered to be a positive screen. Fifty percent of patients had a positive SFN screen (mean score 11.6, 95% CI 9.0-14.2). A modest correlation between the SFNSL score and current age was seen (r=0.38, p=0.01), along with a correlation with duration of ERT (r=0.31, p=0.0495). Trends toward correlation with forced vital capacity and age at diagnosis were also present. Women had a higher mean SFNSL score (14.2) than men (8.2, p=0.017). CONCLUSIONS: SFN may occur in association with Pompe disease and precede the diagnosis. Further studies are needed to determine its true prevalence and impact.


Assuntos
Eritromelalgia/diagnóstico , Eritromelalgia/etiologia , Doença de Depósito de Glicogênio Tipo II/complicações , Fatores Etários , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Inquéritos e Questionários , Capacidade Vital
14.
Muscle Nerve ; 51(5): 722-30, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25155446

RESUMO

INTRODUCTION: Previous examination of whole-body muscle involvement in Pompe disease has been limited to physical examination and/or qualitative magnetic resonance imaging (MRI). In this study we assess the feasibility of quantitative proton-density fat-fraction (PDFF) whole-body MRI in late-onset Pompe disease (LOPD) and compare the results with manual muscle testing. METHODS: Seven LOPD patients and 11 disease-free controls underwent whole-body PDFF MRI. Quantitative MR muscle group assessments were compared with physical testing of muscle groups. RESULTS: The 95% upper limits of confidence intervals for muscle groups were 4.9-12.6% in controls and 6.8-76.4% in LOPD patients. LOPD patients showed severe and consistent tongue and axial muscle group involvement, with less marked involvement of peripheral musculature. MRI was more sensitive than physical examination for detection of abnormality in multiple muscle groups. CONCLUSION: This integrated, quantitative approach to muscle assessment provides more detailed data than physical examination and may have clinical utility for monitoring disease progression and treatment response.


Assuntos
Doença de Depósito de Glicogênio Tipo II/patologia , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Debilidade Muscular/fisiopatologia , Músculo Esquelético/patologia , Imagem Corporal Total/métodos , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Exame Físico , Projetos Piloto , Sensibilidade e Especificidade , Índice de Gravidade de Doença
15.
Genet Med ; 16(11): e1, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25356975

RESUMO

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.


Assuntos
Doença de Depósito de Glicogênio Tipo I/diagnóstico , Doença de Depósito de Glicogênio Tipo I/terapia , Antiporters/genética , Diagnóstico Diferencial , Glucose-6-Fosfatase/genética , Doença de Depósito de Glicogênio Tipo I/patologia , Humanos , Proteínas de Transporte de Monossacarídeos/genética
16.
Obstet Gynecol ; 122(6): 1246-54, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24201678

RESUMO

OBJECTIVE: To evaluate menorrhagia in a cohort of women with glycogen storage disease type I because it appears to be an under-recognized problem in females of reproductive age. METHODS: A retrospective chart review was performed on 13 menstruating patients with glycogen storage disease type I (age 23-48 years) for a diagnosis of menorrhagia. RESULTS: Nine (69%) (confidence interval 0.39-0.91) women had development of menorrhagia. Median hemoglobin values in these patients were generally low (range 9.5-12.85 g/dL) but not different from those of the nonmenorrhagia group (hemoglobin range 9.55-11.0 g/dL) with glycogen storage disease type I. Four patients with menorrhagia required hospitalization or emergency department visits for treatment of menorrhagia. Two of the four patients hospitalized required blood transfusion, with an additional patient requiring a transfusion during pregnancy. Eight patients (89%) either were recommended to have or required medical or surgical treatment of their menorrhagia. CONCLUSION: Glycogen storage disease type I is associated with menorrhagia. The evaluation should include assessment of coagulation functions and referral to a gynecologist, hematologist, or both, because bleeding diathesis and polycystic ovary syndrome are common in patients with glycogen storage disease type I.


Assuntos
Adenoma/complicações , Doença de Depósito de Glicogênio Tipo I/sangue , Doença de Depósito de Glicogênio Tipo I/complicações , Neoplasias Hepáticas/complicações , Menorragia/sangue , Menorragia/complicações , Adulto , Anemia/sangue , Anemia/etiologia , Glicemia/metabolismo , Feminino , Hemoglobinas/metabolismo , Hormônios/uso terapêutico , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/complicações , Ácido Láctico/sangue , Menorragia/terapia , Pessoa de Meia-Idade , Agregação Plaquetária , Estudos Retrospectivos , Adulto Jovem , Fator de von Willebrand/metabolismo
17.
Mol Genet Metab ; 107(3): 496-500, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23062577

RESUMO

Glycogen storage disorder type III (GSD III) is a rare autosomal recessive disorder resulting from a deficiency of glycogen debranching enzyme, critical in cytosolic glycogen degradation. GSD IIIa, the most common form of GSD III, primarily affects the liver, cardiac muscle, and skeletal muscle. Although skeletal muscle weakness occurs commonly in GSD IIIa, bulbar muscle involvement has not been previously reported. Here we present three GSD IIIa patients with clinical evidence of bulbar weakness based on instrumental assessment of lingual strength. Dysarthria and/or dysphagia, generally mild in severity, were evident in all three individuals. One patient also underwent correlative magnetic resonance imaging (MRI) which was remarkable for fatty infiltration at the base of the intrinsic tongue musculature, as well as abnormal expansion of the fibro-fatty lingual septum. Additionally, we provide supportive evidence of diffuse glycogen infiltration of the tongue at necropsy in a naturally occurring canine model of GSD IIIa. While further investigation in a larger group of patients with GSD III is needed to determine the incidence of bulbar muscle involvement in this condition and whether it occurs in GSD IIIb, clinical surveillance of lingual strength is recommended.


Assuntos
Tecido Adiposo/patologia , Doença de Depósito de Glicogênio Tipo III/patologia , Glicogênio/metabolismo , Debilidade Muscular/patologia , Língua/patologia , Tecido Adiposo/metabolismo , Adulto , Animais , Criança , Transtornos de Deglutição/metabolismo , Transtornos de Deglutição/patologia , Cães , Disartria/metabolismo , Disartria/patologia , Feminino , Sistema da Enzima Desramificadora do Glicogênio/deficiência , Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio Tipo III/metabolismo , Humanos , Pessoa de Meia-Idade , Debilidade Muscular/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação , Língua/metabolismo
18.
Genet Med ; 12(7): 446-63, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20631546

RESUMO

PURPOSE: Glycogen storage disease type III is a rare disease of variable clinical severity affecting primarily the liver, heart, and skeletal muscle. It is caused by deficient activity of glycogen debranching enzyme, which is a key enzyme in glycogen degradation. Glycogen storage disease type III manifests a wide clinical spectrum. Individuals with glycogen storage disease type III present with hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation. Those with type IIIa have symptoms related to liver disease and progressive muscle (cardiac and skeletal) involvement that varies in age of onset, rate of disease progression, and severity. Those with type IIIb primarily have symptoms related to liver disease. This guideline for the management of glycogen storage disease type III was developed as an educational resource for health care providers to facilitate prompt and accurate diagnosis and appropriate management of patients. METHODS: An international group of experts in various aspects of glycogen storage disease type III 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 (cardiovascular, gastrointestinal/nutrition, hepatic, musculoskeletal, and neuromuscular) involved in glycogen storage disease type III. Conditions to consider in a 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 transplantation, and prenatal diagnosis, are addressed. CONCLUSIONS: A guideline that will facilitate the accurate diagnosis and appropriate management of individuals with glycogen storage disease type III was developed. This guideline will help health care providers recognize patients with all forms of glycogen storage disease type III, expedite diagnosis, and minimize stress and negative sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.


Assuntos
Doença de Depósito de Glicogênio Tipo III/diagnóstico , Doença de Depósito de Glicogênio Tipo III/terapia , Fígado/patologia , Músculo Esquelético/patologia , Humanos , Fígado/metabolismo , Músculo Esquelético/metabolismo , Prognóstico
19.
Genet Med ; 12(7): 424-30, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20648714

RESUMO

PURPOSE: Glycogen Storage Disease Type III (limit dextrinosis; Cori or Forbes disease) is an autosomal recessive disorder of glycogen metabolism caused by deficient activity of glycogen debranching enzyme in liver and muscle (Glycogen Storage Disease Type IIIa) or liver only (Glycogen Storage Disease Type IIIb). These two clinically distinct phenotypes are caused by mutations in the same gene (amylo-1,6-glucosidase or AGL). Although most patients with Glycogen Storage Disease Type III have private mutations, common mutations have been identified in some populations, and two specific mutations in exon 3, c.18_19delGA (p.Gln6HisfsX20) and c.16C>T (p.Gln6X), are associated with the Glycogen Storage Disease Type IIIb phenotype. METHODS: To further examine the heterogeneity found in Glycogen Storage Disease Type III patients, we have sequenced the AGL gene in 34 patients with a clinically and/or biochemically confirmed diagnosis of Glycogen Storage Disease Type III. RESULTS: We have identified 38 different mutations (25 novel and 13 previously reported) and have compiled a list of all mutations previously reported in the literature. DISCUSSION: We conclude that Glycogen Storage Disease Type III is a highly heterogeneous disorder usually requiring full gene sequencing to identify both pathogenic mutations. The finding of at least one of the two exon 3 mutations in all of the Glycogen Storage Disease Type IIIb patients tested allows for diagnosis of this subtype without the need for a muscle biopsy.


Assuntos
Heterogeneidade Genética , Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio Tipo III/genética , Mutação/genética , Miocárdio/enzimologia , Sequência de Aminoácidos , Éxons/genética , Humanos , Íntrons/genética , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos
20.
Genet Med ; 12(7): 413-23, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20526204

RESUMO

PURPOSE: Glycogen Storage Disease Type III, glycogen debranching enzyme deficiency, causes accumulation of glycogen in liver, skeletal, and cardiac muscle. Some patients develop increased left ventricular thickness by echocardiography, but the rate of increase and its significance remain unclear. METHODS: We evaluated 33 patients with Glycogen Storage Disease Type III, 23 with IIIa and 10 with IIIb, ages 1 month to 55.5 years, by echocardiography for wall thickness, left ventricular mass, shortening and ejection fractions, at 1 time point (n = 33) and at 2 time points in patients with more than 1 echocardiogram (13 of the 33). RESULTS: Of 23 cross-sectional patients with type IIIa, 12 had elevated left ventricular mass, 11 had elevated wall thickness. One type IIIb patient had elevated left ventricular mass but four had elevated wall thickness. For those with multiple observations, 9 of 10 with type IIIa developed increased left ventricular mass over time, with three already increased at first measurement. Shortening and ejection fractions were generally normal. CONCLUSION: Elevated left ventricular mass and wall thickness is more common in patients with type IIIa but develops rarely in type IIIb, although ventricular systolic function is preserved. This suggests serial echocardiograms with attention to left ventricular thickness and mass are important for care of these patients.


Assuntos
Ecocardiografia , Doença de Depósito de Glicogênio Tipo III/diagnóstico por imagem , Miocárdio/patologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio Tipo III/genética , Ventrículos do Coração/diagnóstico por imagem , Humanos , Lactente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação/genética , Disfunção Ventricular Esquerda/genética , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...