RESUMO
PURPOSE: The purpose of the study was to assess self-reported taste and smell perception after chemotherapy in breast cancer patients compared with women without cancer, and to assess whether taste and smell perception is associated with quality of life after the end of chemotherapy. METHODS: We included 135 newly diagnosed breast cancer patients who completed chemotherapy and 114 women without cancer. Questionnaires on taste, smell, and quality of life were completed shortly after and 6 months after chemotherapy (patients) or at two moments with 6 months' time window in between (comparisons). RESULTS: Self-reported taste and smell perception were significantly lower in patients shortly after chemotherapy compared to the comparison group. Most patients recovered 6 months after chemotherapy, although patients who were still receiving trastuzumab then reported a lower taste and smell perception compared to patients who were not. A lower self-reported taste and smell were statistically significantly associated with a worse quality of life, social, emotional, and role functioning shortly after chemotherapy. Six months after chemotherapy, taste and smell were statistically significantly associated with quality of life, social and role functioning, but only in patients receiving trastuzumab. CONCLUSIONS: Most taste and smell alterations recovered within 6 months after the end of chemotherapy for breast cancer, but not for patients receiving trastuzumab. These results highlight the importance of monitoring taste and smell alterations during and after treatment with chemotherapy and trastuzumab, as they may impact quality of life.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Transtornos do Olfato/epidemiologia , Olfato/efeitos dos fármacos , Paladar/efeitos dos fármacos , Adulto , Neoplasias da Mama/complicações , Neoplasias da Mama/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Transtornos do Olfato/induzido quimicamente , Transtornos do Olfato/patologia , Qualidade de Vida , Olfato/fisiologia , Inquéritos e Questionários , Paladar/fisiologia , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversosRESUMO
PURPOSE: Breast cancer patients receiving chemotherapy often experience symptoms such as nausea, vomiting and loss of appetite that potentially affect dietary habits. This study assessed the intake of energy, macronutrients and food groups before and during chemotherapy in breast cancer patients compared with women without cancer, and determined the association between symptoms and energy and macronutrient intake. METHODS: This study included 117 newly diagnosed breast cancer patients scheduled for chemotherapy and 88 women without cancer. Habitual intake before chemotherapy was assessed with a food frequency questionnaire. Two 24-h dietary recalls were completed on random days for each participant during the whole chemotherapy treatment for patients and within 6 months after recruitment for women without cancer. Shortly, after the dietary recall, participants filled out questionnaires on symptoms. RESULTS: Before chemotherapy, habitual energy and macronutrient intake was similar for breast cancer patients and women without cancer. During chemotherapy, breast cancer patients reported a significantly lower total energy, fat, protein and alcohol intake than women without cancer, as shown by a lower intake of pastry and biscuits, cheese, legumes and meat products. A decline in subjective taste perception, appetite and hunger and experiencing a dry mouth, difficulty chewing, lack of energy and nausea were associated with a lower energy intake. CONCLUSIONS: Symptoms induced by chemotherapy are associated with lower dietary intake and manifested by a lower intake of specific food groups. To ensure an optimal dietary intake during chemotherapy, it is important to monitor nutritional status and symptom burden during chemotherapy in breast cancer patients.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Dieta/métodos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Estado Nutricional , Inquéritos e QuestionáriosRESUMO
This paper reports the third proven human case of deficient S-adenosylhomocysteine (AdoHcy) hydrolase activity. The patient is similar to the only two previously reported cases with this disorder in having severe myopathy, developmental delay, elevated serum creatine kinase (CK) concentrations, and hypermethioninaemia. Although he has been followed from infancy, the basic enzyme deficiency was established only at age 26 years. The diagnosis was based on markedly elevated plasma concentrations of both AdoHcy and S-adenosylmethionine, some 20% of the mean control activity of AdoHcy hydrolase activity in haemolysates of his red-blood cells, and two missense mutations in his gene encoding AdoHcy hydrolase. He had low values of erythrocyte phosphatidylcholine and plasma free choline and marginally elevated excretion of guanidinoacetate, suggesting that the elevated AdoHcy may have been inhibiting methylation of phosphatidylethanolamine and guanidinoacetate. His leukocyte DNA was globally more methylated than the DNA's of his parents or the mean extent of methylation measured in age-matched control subjects.
Assuntos
Adenosil-Homocisteinase/deficiência , Erros Inatos do Metabolismo/diagnóstico , Adulto , Colina/metabolismo , Metilação de DNA , Eritrócitos/metabolismo , Saúde da Família , Humanos , Imageamento por Ressonância Magnética , Masculino , Erros Inatos do Metabolismo/patologia , Doenças Musculares/diagnóstico , Mutação de Sentido Incorreto , S-Adenosil-Homocisteína/sangue , S-Adenosilmetionina/sangueRESUMO
We report two unrelated cases of adult galactosaemia females with normal ovarian function and Q188R/R333G mutations. Clinical history has been followed for 40 years. Biochemical finding in one patient are consistent with the presence of small amounts of galactose-1-phosphate uridyltransferase (GALT) activity, which differs from classical galactosaemia.
Assuntos
Galactosemias/genética , Ovário/fisiologia , Adulto , DNA/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Uridina Difosfato Galactose/metabolismo , Uridina Difosfato Glucose/metabolismoRESUMO
BACKGROUND: Historically, warfarin has been discontinued or rapidly reversed with fresh frozen plasma in patients awaiting heart transplantation because of concerns regarding excessive bleeding. Because preoperative warfarin may have effects on bleeding after cardiac operations, we reviewed our experience to determine the risks in patients undergoing heart transplantation while maintained on warfarin. METHODS: The records of consecutive adult patients undergoing heart transplantation from January 1996 to December 1998 were reviewed. Preoperative and 24-hour postoperative data were obtained, including patient demographics; hematologic laboratory values; medication use; repeat or primary sternotomy data; allogeneic blood product administration; and chest tube drainage. Multivariate linear and logistic regression analyses were performed using these variables to determine risk factors for bleeding after heart transplantation. RESULTS: Ninety adult patients, mean age 50 years, underwent orthotopic heart transplantation during the 36-month period. No relationships existed between preoperative international normalized ratio (INR, mean = 1.83 +/- 0.1, p = 0.84) or postoperative INR (mean = 2.2 +/- 0.9, p = 0.63) and chest tube drainage (mean = 721 +/- 63 mL). Relationships were observed between total blood product administration and preoperative INR (partial r = 0.30, p = 0.01) and postoperative INR (partial r = -0.37, p = 0.002); however, preoperative INR did not correlate (p = 0.29) when perioperative use of fresh frozen plasma was factored as a covariate. Inverse relationships were evident between postoperative INR and total blood product exposures, as well as transfusions of platelets (partial r = -0.26, p = 0.03), fresh frozen plasma (partial r = -0.28, p = 0.02), and red cells (partial r = -0.25, p = 0.04). CONCLUSIONS: Although we noted no correlations between INR and chest tube output, inverse relationships were observed with transfusion requirements in the first 24 hours after transplantation. Preoperative warfarin may be safely continued in patients awaiting heart transplantation.
Assuntos
Transplante de Coração , Hemorragia Pós-Operatória/induzido quimicamente , Varfarina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Transfusão de Sangue , Tubos Torácicos , Humanos , Coeficiente Internacional Normatizado , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Contagem de Plaquetas , Cuidados Pós-Operatórios , Cuidados Pré-Operatórios , Curva ROC , Fatores de Risco , Varfarina/administração & dosagemRESUMO
We describe six patients with hepatic carnitine palmitoyl transferase (CPT1 A) deficiency who are members of a large extended Hutterite kindred living in widely scattered communities in the United States and Canadian Prairies. Two patients have significant neurological impairment due to severe recurrent hypoglycemic crises. The remaining four patients with earlier detection and treatment have near normal outcomes. The Canadian and American Hutterite families share two common ancestors who married in 1812, about 60 years before the Hutterites arrived in North America and prior to their subdivision into the three groups (Schmiedeleut, Dariusleut, and the Lehrerleut). These patients share a common haplotype on chromosome 11q13 and are all homozygous for a common CPT1 A G710E mutation, suggesting a founder effect. The clustering of such a rare disorder of fatty acid oxidation prompted us to initiate a pilot DNA-based neonatal screening program to determine the carrier frequency of this mutation in Hutterite newborns with the participation and support of the community. To date our carrier frequency is 1/16, close to the predicted frequency based on diagnosed patients and number of births. We believe our newborn screening program for CPT1 A deficiency in the Hutterite community will serve as a prototype model for delivery of targeted genetic services to other similar unique genetic isolates.
Assuntos
Carnitina O-Palmitoiltransferase/genética , Etnicidade/genética , Fígado/enzimologia , Adolescente , Adulto , Carnitina O-Palmitoiltransferase/deficiência , Criança , Pré-Escolar , Cromossomos Humanos Par 11/genética , DNA/química , DNA/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Efeito Fundador , Ligação Genética , Haplótipos , Humanos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/enzimologia , Doenças do Recém-Nascido/genética , Masculino , Manitoba , Repetições de Microssatélites , Mutação , Triagem Neonatal/métodos , América do Norte , Linhagem , Projetos PilotoRESUMO
To determine whether human X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome (IPEX; MIM 304930) is the genetic equivalent of the scurfy (sf) mouse, we sequenced the human ortholog (FOXP3) of the gene mutated in scurfy mice (Foxp3), in IPEX patients. We found four non-polymorphic mutations. Each mutation affects the forkhead/winged-helix domain of the scurfin protein, indicating that the mutations may disrupt critical DNA interactions.
Assuntos
Doenças dos Animais/genética , Proteínas de Ligação a DNA/genética , Diabetes Mellitus/congênito , Diabetes Mellitus/genética , Poliendocrinopatias Autoimunes/genética , Enteropatias Perdedoras de Proteínas/genética , Cromossomo X/genética , Sequência de Aminoácidos , Animais , Análise Mutacional de DNA , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição Forkhead , Ligação Genética/genética , Humanos , Recém-Nascido , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Mutação/genética , Alinhamento de Sequência , SíndromeRESUMO
We have reinvestigated a young woman, originally reported by us in 1983, who presented with exercise intolerance and lactic acidosis associated with severe deficiency of complex III and who responded to therapy with menadione and ascorbate. Gradually, she developed symptoms of a mitochondrial encephalomyopathy. Immunocytochemistry of serial sections of muscle showed a mosaic of fibers that reacted poorly with antibodies to subunits of complex III but reacted normally with antibodies to subunits of complexes I, II, or IV, suggesting a mutation of mtDNA. These findings demonstrate the diagnostic value of immunocytochemistry in identifying specific respiratory-chain deficiencies and, potentially, distinguishing between nuclear- or mtDNA-encoded defects. Sequence analysis revealed a stop-codon mutation (G15242A) in the mtDNA-encoded cytochrome b gene, resulting in loss of the last 215 amino acids of cytochrome b. PCR-RFLP analysis indicated that the G15242A mutation was heteroplasmic and was present in a high percentage (87%) of affected tissue (skeletal muscle) and a low percentage (0.7%) of unaffected tissue (blood) but was not detected in controls. Analysis of microdissected muscle fibers showed a significant correlation between the immunoreactivity toward the Rieske protein of complex III and the percentage of mutant mtDNA: immunopositive fibers had a median value of 33% of the G15242A mutation, whereas immunonegative, ragged-red fibers had a median value of 89%, indicating that the stop-codon mutation was pathogenic in this patient. The G15242A mutation was also present in several other tissues, including hair roots, indicating that it must have arisen either very early in embryogenesis, before separation of the primary germ layers, or in the maternal germ line. The findings in this patient are contrasted with other recently described patients who have mutations in the cytochrome b gene.
Assuntos
Códon de Terminação/genética , Grupo dos Citocromos b/genética , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Encefalomiopatias Mitocondriais/genética , Mutação/genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Clonagem Molecular , Grupo dos Citocromos b/química , Análise Mutacional de DNA , DNA Mitocondrial/genética , Complexo III da Cadeia de Transporte de Elétrons/genética , Feminino , Fibroblastos , Humanos , Imuno-Histoquímica , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Encefalomiopatias Mitocondriais/patologia , Dados de Sequência Molecular , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de RestriçãoRESUMO
Galactokinase is an essential enzyme in the metabolism of galactose. Patients with deficiencies in galactokinase exhibit early-onset cataracts. We examined the sequence of the human galactokinase gene (GK1) from 13 patients exhibiting galactokinase deficiency and identified 12 novel mutations. One of the mutations occurred in six of the 13 probands examined, and the remaining 11 were unique mutations. Expression of each of the mutant GK1 genes in Xenopus oocytes resulted in very low galactokinase activity levels. These results provide important information regarding the types of GK1 mutations that occur in the human population.
Assuntos
Galactoquinase/deficiência , Galactoquinase/genética , Galactosemias/genética , Mutação , Sequência de Bases , Pré-Escolar , Clonagem Molecular , Elementos de DNA Transponíveis , Éxons , Feminino , Galactosemias/enzimologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase , Proteínas Recombinantes/biossíntese , Deleção de SequênciaRESUMO
Cardiomyopathy in childhood is associated with high morbidity and mortality rates. Many metabolic causes have been identified, including genetic or acquired defects in mitochondrial energy production affecting beta-oxidation, carnitine transport, and the electron transport chain. Combining conventional inotropic and antiarrhythmic therapy with metabolic interventions has improved overall outcome. L-carnitine, a natural substance involved in mitochondrial transport of fatty acids, is one such therapy and plays a central role in the regulation of the inner mitochondrial supply of free coenzyme A. Carnitine deficiency can be caused by both genetic and environmental causes with resultant signs and symptoms of metabolic disease, including cardiomyopathy. Administration of L-carnitine can result in improvement or resolution of the cardiomyopathy.
Assuntos
Cardiomiopatias/etiologia , Carnitina/fisiologia , Metabolismo Energético , Mitocôndrias Cardíacas/metabolismo , Miopatias Mitocondriais/complicações , Cardiomiopatias/diagnóstico , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Carnitina/deficiência , Carnitina/uso terapêutico , Criança , Diagnóstico Diferencial , Humanos , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/metabolismo , Contração Miocárdica , Miocárdio/metabolismoRESUMO
We report three cases of folinic acid-responsive intractable neonatal seizures. All patients were born at term following normal gestation and delivery. In the first infant, seizures began on the 5th day of life and were unresponsive to phenobarbital, pyridoxine, and valproate, but stopped within 24 hours of initiation of folinic acid treatment at the age of 6 months. Her sibling had died at age 6 months with intractable seizures. In the second infant, seizures began in the 2nd hour of life. These were initially controlled with phenobarbital; however, at 3 months of age she developed status epilepticus refractory to anticonvulsants, steroids, and pyridoxine and she required repeated induction of pentobarbital coma. Seizures stopped within 24 hours of starting folinic acid. Seizures and encephalopathy were noted in the third infant on the 2nd day of life. These were controlled with phenobarbital, but at 8 weeks of age seizures recurred and were difficult to control despite the addition of phenytoin. Immediately after folinic acid was initiated the seizures stopped. Breakthrough seizures in all patients have responded to increases in folinic acid; two of the three remain on standard anticonvulsants. All patients have global developmental delay. Cranial magnetic resonance imaging in the second patient shows diffuse atrophy, and in the third patient shows increased signal on T2 images in the white matter of the frontal and parietal lobes. Analysis of cerebrospinal fluid from these patients using high-performance liquid chromatography with electrochemical detection has consistently revealed an as-yet unidentified compound, which can be used as a marker for this condition. We suggest that cerebrospinal fluid be analyzed for the presence of this compound and a trial of folinic acid be considered in neonates with unexplained early onset intractable seizures.
Assuntos
Anticonvulsivantes/administração & dosagem , Leucovorina/administração & dosagem , Espasmos Infantis/tratamento farmacológico , Dano Encefálico Crônico/diagnóstico , Dano Encefálico Crônico/etiologia , Proteínas do Líquido Cefalorraquidiano/líquido cefalorraquidiano , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fatores de Risco , Espasmos Infantis/diagnóstico , Espasmos Infantis/etiologia , Estado Epiléptico/diagnóstico , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/etiologia , Resultado do TratamentoRESUMO
OBJECTIVES: The aims of this article are to report on a review of cases of maternal phenylketonuria in the International Maternal Phenylketonuria Collaborative Study that were initially diagnosed during or after a pregnancy, to alert health care practitioners to the possible existence of women with undiagnosed phenylketonuria whose fetuses are at risk, and to emphasize that not all adults with untreated phenylketonuria are mentally retarded. STUDY DESIGN: The study was conducted through retrospective database review. RESULTS: Of 414 women with live-born infants, 17 fulfilled our criteria. Six had phenylketonuria diagnosed after they had produced >/=1 affected offspring, 2 had phenylketonuria diagnosed as a result of transient postnatal hyperphenylalaninemia in an offspring, and 9 had phenylketonuria diagnosed by prenatal screening. Undiagnosed maternal phenylketonuria in North America and Europe is currently estimated at 1 case/100,000 births; this rate could be higher elsewhere. CONCLUSIONS: Physicians and midwives should consider a protocol of selective prenatal screening or case finding to detect undiagnosed phenylketonuria among their patients.
Assuntos
Doenças Fetais/diagnóstico , Fenilcetonúria Materna/diagnóstico , Diagnóstico Pré-Natal , Adolescente , Adulto , Feminino , Humanos , Fenilalanina/sangue , Gravidez , Resultado da Gravidez , Estudos RetrospectivosRESUMO
D-2-Hydroxyglutaric aciduria has been observed in patients with extremely variable clinical symptoms, creating doubt about the existence of a disease entity related to the biochemical finding. An international survey of patients with D-2-hydroxyglutaric aciduria was initiated to solve this issue. The clinical history, neuroimaging, and biochemical findings of 17 patients were studied. Ten of the patients had a severe early-infantile-onset encephalopathy characterized by epilepsy, hypotonia, cerebral visual failure, and little development. Five of these patients had a cardiomyopathy. In neuroimaging, all patients had a mild ventriculomegaly, often enlarged frontal subarachnoid spaces and subdural effusions, and always signs of delayed cerebral maturation. In all patients who underwent neuroimaging before 6 months, subependymal cysts over the head or corpus of the caudate nucleus were noted. Seven patients had a much milder and variable clinical picture, most often characterized by mental retardation, hypotonia, and macrocephaly, but sometimes no related clinical problems. Neuroimaging findings in 3 patients variably showed delayed cerebral maturation, ventriculomegaly, or subependymal cysts. Biochemical findings included elevations of D-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid in both groups. Cerebrospinal fluid gamma-aminobutyric acid was elevated in almost all patients investigated. Urinary citric acid cycle intermediates were variably elevated. The conclusion of the study is that D-2-hydroxyglutaric aciduria is a distinct neurometabolic disorder with at least two phenotypes.
Assuntos
Coreia/urina , Epilepsia/urina , Glutaratos/urina , Biomarcadores , Ventrículos Cerebrais/patologia , Pré-Escolar , Coreia/diagnóstico por imagem , Coreia/patologia , Cistos , Epêndima/patologia , Epilepsia/diagnóstico por imagem , Epilepsia/patologia , Saúde da Família , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Hipotonia Muscular/diagnóstico por imagem , Hipotonia Muscular/patologia , Hipotonia Muscular/urina , Fenótipo , Tomografia Computadorizada por Raios X , Baixa Visão/diagnóstico por imagem , Baixa Visão/patologia , Baixa Visão/urina , Ácido gama-Aminobutírico/líquido cefalorraquidianoRESUMO
Glycogen storage disease type 0 (GSD-0) is a rare form of fasting hypoglycemia presenting in infancy or early childhood and accompanied by high blood ketones and low alanine and lactate concentrations. Although feeding relieves symptoms, it often results in postprandial hyperglycemia and hyperlactatemia. The glycogen synthase (GS) activity has been low or immeasurable in liver biopsies, whereas the liver glycogen content has been only moderately decreased. To investigate whether mutations in the liver GS gene (GYS2) on chromosome 12p12.2 were involved in GSD-0, we determined the exon-intron structure of the GYS2 gene and examined nine affected children from five families for linkage of GSD-0 to the GYS2 gene. Mutation screening of the 16 GYS2 exons was done by single-strand conformational polymorphism (SSCP) and direct sequencing. Liver GS deficiency was diagnosed from liver biopsies (GS activity and glycogen content). GS activity in the liver of the affected children was extremely low or nil, resulting in subnormal glycogen content. After suggestive linkage to the GYS2 gene had been established (LOD score = 2.9; P < 0.01), mutation screening revealed several different mutations in these families, including a premature stop codon in exon 5 (Arg246X), a 5'-donor splice site mutation in intron 6 (G+1T--> CT), and missense mutations Asn39Ser, Ala339Pro, His446Asp, Pro479Gln, Ser483Pro, and Met491Arg. Seven of the affected children carried mutations on both alleles. The mutations could not be found in 200 healthy persons. Expression of the mutated enzymes in COS7 cells indicated severely impaired GS activity. In conclusion, the results demonstrate that GSD-0 is caused by different mutations in the GYS2 gene.
Assuntos
Cromossomos Humanos Par 12/genética , Doença de Depósito de Glicogênio/genética , Glicogênio Sintase/genética , Hipoglicemia/etiologia , Fígado/enzimologia , Mutação Puntual , Animais , Western Blotting , Células COS , Pré-Escolar , Análise Mutacional de DNA , DNA Complementar/genética , Ingestão de Alimentos , Éxons/genética , Feminino , Ligação Genética , Doença de Depósito de Glicogênio/classificação , Doença de Depósito de Glicogênio/enzimologia , Glicogênio Sintase/deficiência , Humanos , Íntrons/genética , Masculino , Mutagênese Sítio-Dirigida , Linhagem , Fenótipo , Polimorfismo de Fragmento de Restrição , Polimorfismo Conformacional de Fita Simples , Splicing de RNARESUMO
CONTEXT: Inborn errors of metabolism are genetic conditions that affect the normal biochemical functions of the body in any organ and at any age. More than 500 metabolic diseases are known; almost all are classified as orphan diseases under the US Food and Drug Administration guidelines (incidence < 200,000 persons) and each has its own requirements for diagnosis and treatment. Management of these complex, lifelong, multisystem disorders often requires a coordinated, multidisciplinary approach involving several subspecialists and which may include complex laboratory evaluations, genetic counseling, nutritional therapy, and unusual therapeutic approaches that have been used in only a small number of cases. RESULTS: Not infrequently, inborn errors of metabolism fall outside current standard diagnostic and treatment guidelines of managed care plans. This results in delays in diagnosis and appropriate management, with increased costs to patients and to society. CONCLUSIONS: Patients with inborn errors of metabolism should not be discriminated against and all health plans should specify that access to specialists and metabolic centers are a covered benefit of the plan. The acceptance of treatment guidelines, the development of international disease classification codes for the disorders, and the performance of cost-benefit analyses would all greatly facilitate this process. However, without recognition that these disorders require such services, and steps to provide them by the insurance industry, the care of children with metabolic disorders and other chronic diseases will continue to be a source of frustration and anger among the caregivers and the families they serve.
Assuntos
Programas de Assistência Gerenciada/normas , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/terapia , Análise Custo-Benefício , Dietoterapia/economia , Acessibilidade aos Serviços de Saúde/normas , Humanos , Programas de Assistência Gerenciada/economia , Erros Inatos do Metabolismo/economia , Erros Inatos do Metabolismo/epidemiologia , Guias de Prática Clínica como Assunto , Preconceito , Mecanismo de Reembolso , Estados Unidos/epidemiologia , United States Food and Drug Administration , Cobertura Universal do Seguro de SaúdeRESUMO
Thiamine-responsive megaloblastic anemia, also known as "TRMA" or "Rogers syndrome," is an early-onset autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and sensorineural deafness, responding in varying degrees to thiamine treatment. On the basis of a linkage analysis of affected families of Alaskan and of Italian origin, we found, using homozygosity mapping, that the TRMA-syndrome gene maps to a region on chromosome 1q23.2-23.3 (maximum LOD score of 3.7 for D1S1679). By use of additional consanguineous kindreds of Israeli-Arab origin, the putative disease-gene interval also has been confirmed and narrowed, suggesting genetic homogeneity. Linkage analysis generated the highest combined LOD-score value, 8.1 at a recombination fraction of 0, with marker D1S2799. Haplotype analysis and recombination events narrowed the TRMA locus to a 16-cM region between markers D1S194 and D1S2786. Several heterozygote parents had diabetes mellitus, deafness, or megaloblastic anemia, which raised the possibility that mutations at this locus predispose carriers in general to these manifestations. Characterization of the metabolic defect of TRMA may shed light on the role of thiamine deficiency in such common diseases.
Assuntos
Anemia Megaloblástica/genética , Cromossomos Humanos Par 1/genética , Diabetes Mellitus Tipo 1/genética , Genes Recessivos , Perda Auditiva Neurossensorial/genética , Tiamina/uso terapêutico , Alaska , Anemia Megaloblástica/tratamento farmacológico , Anemia Megaloblástica/etnologia , Árabes , Mapeamento Cromossômico , Consanguinidade , Diabetes Mellitus Tipo 1/etnologia , Feminino , Haplótipos/genética , Perda Auditiva Neurossensorial/etnologia , Homozigoto , Humanos , Israel/etnologia , Itália/etnologia , Escore Lod , Masculino , Repetições de Microssatélites , Linhagem , Federação Russa/etnologia , SíndromeRESUMO
Inborn errors of the pyruvate dehydrogenase complex (PDC) are associated with lactic acidosis, neuroanatomic defects, developmental delay, and early death. PDC deficiency is a clinically heterogeneous disorder, with most mutations located in the coding region of the X-linked alpha subunit of the first catalytic component, pyruvate dehydrogenase (E1). Treatment of E1 deficiency hs included cofactor replacement, activation of PDC with dichloroacetate, and ketogenic diets. In this report, we describe the outcome of ketogenic diet treatment in seven boys with E1 deficiency. These patients were divided into two groups based on their mutations (R349H, three patients; and R234G, four patients, two sibling pairs). All seven patients received ketogenic diets with varying degrees of carbohydrate restriction. Clinical outcome was compared within each group and between siblings as related to the intensity and duration of dietary intervention. Subjects who either had the diet initiated earlier in life or who were placed on greater carbohydrate restriction had increased longevity and improved mental development. Based on the improved outcomes of patients with identical mutations, it appears that a nearly carbohydrate-free diet initiated shortly after birth may be useful in the treatment of E1 deficiency.
Assuntos
Corpos Cetônicos/biossíntese , Doença da Deficiência do Complexo de Piruvato Desidrogenase/dietoterapia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/metabolismo , Desenvolvimento Infantil , Carboidratos da Dieta/administração & dosagem , Humanos , Recém-Nascido , Longevidade , Masculino , Mutação , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Resultado do TratamentoRESUMO
A new amino acid formulation and a variety of treatment products incorporating it were evaluated for long-term safety, efficacy, and acceptance in 25 subjects with phenylketonuria over a period of 5 years. Palatability of the treatment was improved by reducing the required intake of amino acids, reformulating the mixture to have better taste, and providing vitamins and minerals as tablets. The hypotheses were that these strategies would improve compliance and metabolic control and maintain nutritional status in subjects. Compliance with treatment was determined from mean reported intakes (4-day diet records) and from mean 'received' intakes using receipts of treatment products actually shipped to individuals upon request. Mean amino acid intakes prescribed were significantly reduced from study entry to end, from 1.2 g/kg to 0.7 g/kg (p < 0.001). Reported intakes were similarly reduced from 1.3 g/kg to 0.7 g/kg (p < 0.001). While actually 'received' intakes of amino acid formula were also significantly reduced (p < 0.001), intakes by this measure were much lower than either prescribed or reported, 0.9 g/kg at entry and 0.4 g/kg at the end of the study, suggesting that acceptance of the treatment (usage of products), even when made more palatable, is below clinical expectations. In spite of these findings, mean serum proteins and minerals, height and weight were not significantly reduced during the study, supporting the safety of lowered intakes of amino acids and of nutritionally incomplete products. While the increase in mean serum phenylalanine concentration from 0.38 to 0.48 mmol/L was significant (p < 0.03), this mean rise of 0.1 mmol/L during a corresponding mean age increase of 4.2 years (from 6.9 to 11.1 years) is lower than in other recent reports from longitudinal studies of outcomes during this age range in subjects treated with traditional products. These data support the safety and efficacy of a more palatable and flexible approach to treatment.