RESUMO
Cornstarch has been the primary treatment for glycogen storage disease type Ia (GSD Ia) for over 35 years. When cornstarch was first described as a treatment, few people survived beyond early childhood. As the prognosis for this population has improved, the need to ensure appropriate cornstarch dosing for different age groups has become imperative. Records from 115 patients (10-62 years of age) with GSD Ia evaluated at our center between 2015 and 2017 were reviewed. Data collected included weight, age, genetic mutation, amount and frequency of cornstarch doses, body mass index, gender, 24-hour glucose and lactate concentrations, and biochemical markers of metabolic control. The data demonstrate that adult treatment needs vary greatly from younger age groups, and the required cornstarch support decreases with age (P < .001). The required number of doses, however, did not change with a mean of six doses (range 4-8) daily in all age groups. General laboratory findings across time demonstrate that significantly reducing the amount of starch required to maintain euglycemia with aging can be done without sacrificing metabolic control. Carbohydrate requirements decrease with aging, and older patients were found to require less cornstarch. Failure to lower the cornstarch doses contributes to over-treatment in adults with GSD Ia. Not only does this lead to worsening hepatomegaly and excessive weight gain, but over-treatment contributes to relative hyperinsulinism and rebound hypoglycemia. This knowledge is essential in designing nutritional therapies for the aging GSD population.
Assuntos
Glicemia/metabolismo , Doença de Depósito de Glicogênio Tipo I/dietoterapia , Amido/metabolismo , Amido/farmacologia , Adolescente , Adulto , Biomarcadores , Criança , Feminino , Doença de Depósito de Glicogênio Tipo I/sangue , Doença de Depósito de Glicogênio Tipo I/metabolismo , Humanos , Hipoglicemia/prevenção & controle , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Viral mediated gene therapy has progressed after overcoming early failures, and gene therapy has now been approved for several conditions in Europe and the USA. Glycogen storage disease (GSD) type Ia, caused by a deficiency of glucose-6-phosphatase-α, has been viewed as an outstanding candidate for gene therapy. This follow-up report describes the long-term outcome for the naturally occurring GSD-Ia dogs treated with rAAV-GPE-hG6PC-mediated gene therapy. METHODS: A total of seven dogs were treated with rAAV-GPE-hG6PC-mediated gene therapy. The first four dogs were treated at birth, and three dogs were treated between 2 and 6 months of age to assess the efficacy and safety in animals with mature livers. Blood and urine samples, radiographic studies, histological evaluation, and biodistribution were assessed. RESULTS: Gene therapy improved survival in the GSD-Ia dogs. With treatment, the biochemical studies normalized for the duration of the study (up to 7 years). None of the rAAV-GPE-hG6PC-treated dogs had focal hepatic lesions or renal abnormalities. Dogs treated at birth required a second dose of rAAV after 2-4 months; gene therapy after hepatic maturation resulted in improved efficacy after a single dose. CONCLUSION: rAAV-GPE-hG6PC treatment in GSD-Ia dogs was found to be safe and efficacious. GSD-Ia is an attractive target for human gene therapy since it is a monogenic disorder with limited tissue involvement. Blood glucose and lactate monitoring can be used to assess effectiveness and as a biomarker of success. GSD-Ia can also serve as a model for other hepatic monogenic disorders.
Assuntos
Terapia Genética/métodos , Doença de Depósito de Glicogênio Tipo I/terapia , Animais , Glicemia/metabolismo , Dependovirus/genética , Modelos Animais de Doenças , Cães , Europa (Continente) , Vetores Genéticos , Glucose-6-Fosfatase/genética , Hipoglicemia/genética , Hipoglicemia/metabolismo , Rim/metabolismo , Fígado/metabolismoRESUMO
The hepatic glycogen storage diseases (GSDs) are a group of disorders where abnormal storage or release of glycogen leads to potentially life-threatening hypoglycemia and metabolic disturbances. Dietary interventions have markedly improved the outcome for these disorders, from a previously fatal condition to one where people can do well with proper care. This article chronicles the evolution of dietary management and treatment of the hepatic GSDs (types 0, I, III, VI, IX, and XI). We examine historic and current approaches for preventing hypoglycemia associated with GSDs. There is a lack of consensus on the optimal dietary management of GSDs despite decades of research, and the ongoing controversies are discussed.