RESUMO
Since its first description in 1994, convection-enhanced delivery (CED) has become a reliable method of administering drugs directly into the brain parenchyma. More predictable and effective than simple diffusion, CED bypasses the challenging boundary of the blood brain barrier, which has frustrated many attempts at delivering large molecules or polymers into the brain parenchyma. Although most of the clinical work with CED has been carried out on adults with incurable neoplasms, principally glioblastoma multiforme, an increasing number of studies have recognized its potential for paediatric applications, which now include treatment of currently incurable brain tumours such as diffuse intrinsic pontine glioma (DIPG), as well as metabolic and neurotransmitter diseases. The roadmap for the development of hardware and use of pharmacological agents in CED has been well-established, and some neurosurgical centres throughout the world have successfully undertaken clinical trials, admittedly mostly early phase, on the basis of in vitro, small animal and large animal pre-clinical foundations. However, the clinical efficacy of CED, although theoretically logical, has yet to be unequivocally demonstrated in a clinical trial; this applies particularly to neuro-oncology.This review aims to provide a broad description of the current knowledge of CED as applied to children. It reviews published studies of paediatric CED in the context of its wider history and developments and underlines the challenges related to the development of hardware, the selection of pharmacological agents, and gene therapy. It also reviews the difficulties related to the development of clinical trials involving CED and looks towards its potential disease-modifying opportunities in the future.
Assuntos
Antineoplásicos , Neoplasias Encefálicas , Neoplasias do Tronco Encefálico , Glioma , Animais , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Convecção , Glioma/tratamento farmacológico , HumanosRESUMO
Autoimmune hemolytic anemia (AIHA) due to warm-reacting IgA autoantibodies is rare. Here, we explored the clinical and immunohematologic characteristics of patients suffering from IgA-associated warm AIHA (WAIHA) and their transfusion management. The 9-year study included 214 patients with WAIHA who were further classified into two groups: (1) IgA-associated WAIHA and (2) non-IgA-associated WAIHA. Clinical and laboratory details were obtained from patient files and the Hospital Information System. All immunohematologic investigations were performed following standard operating procedures and established protocols. Among the 214 patients with WAIHA, 17 (7.9%) belonged to the IgA-associated group; of these, two IgA-only WAIHA cases were found. The mean hemoglobin in this group was 5.58 g/dL, and 15 (88.2%) of these patients received a total of 32 units of packed red blood cell (RBC) transfusions. In vivo hemolytic markers were significantly abnormal in the IgA-associated WAIHA group when compared with the non-IgA group. Secondary WAIHA was found in 11 (64.7%) patients with IgA-associated WAIHA. Patients with IgA-associated WAIHA received more blood transfusions than individuals in the non-IgA group (p = 0.0004). A total of 17 (7.9%) patients with WAIHA experienced adverse events to blood transfusion. Detailed characterization of WAIHA with particular emphasis on IgA-associated and non-IgA-associated WAIHA is essential to evaluate the disease characteristics, access the degree of hemolysis, understand the immunohematologic behaviors of the antibodies, and manage blood transfusions.
Assuntos
Anemia Hemolítica Autoimune , Anemia Hemolítica Autoimune/terapia , Autoanticorpos , Transfusão de Eritrócitos , Hemoglobinas , Hemólise , HumanosRESUMO
The outcome of 110 patients with paediatric onset mucopolysaccharidosis II (MPS II) since the commercial introduction of enzyme replacement therapy (ERT) in England in 2007 is reported. Median length of follow up was 10â¯years 3â¯months (rangeâ¯=â¯1â¯y 2â¯m to 18â¯years 6â¯month). 78 patients were treated with ERT, 18 had no ERT or disease modifying treatment 7 had haematopoietic stem cell transplant, 4 experimental intrathecal therapy and 3 were lost to follow up. There is clear evidence of improved survival (median age of death of ERT treated (nâ¯=â¯16)â¯=â¯15.13â¯years (rangeâ¯=â¯9.53 to 20.58â¯y), and untreated (nâ¯=â¯17)â¯=â¯11.43â¯y (0.5 to 19.13â¯y) pâ¯=â¯.0005). Early introduction of ERT improved respiratory outcome at 16â¯years, the median FVC (% predicted) of those in whom ERT initiated <8â¯yearsâ¯=â¯69% (rangeâ¯=â¯34-86%) and 48% (25-108) (pâ¯=â¯.045) in those started >8â¯years. However, ERT appears to have minimal impact on hearing, carpal tunnel syndrome or progression of cardiac valvular disease. Cardiac valvular disease occurred in 18/46 (40%), with progression occurring most frequently in the aortic valve 13/46 (28%). The lack of requirement for neurosurgical intervention in the first 8â¯years of life suggests that targeted imaging based on clinical symptomology would be safe in this age group after baseline assessments. There is also emerging evidence that the neurological phenotype is more nuanced than the previously recognized dichotomy of severe and attenuated phenotypes in patients presenting in early childhood.
Assuntos
Terapia de Reposição de Enzimas , Mucopolissacaridose II/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Coleta de Dados , Progressão da Doença , Inglaterra , Seguimentos , Humanos , Lactente , Mucopolissacaridose II/mortalidade , Fenótipo , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Enzyme replacement therapy (ERT) for infantile-onset Pompe disease has been commercially available for almost 10 years. We report the experience of its use in a cohort treated at three specialist lysosomal treatment centres in the UK. METHODS: A retrospective case-note review was performed, with additional data being gathered from two national audits on all such patients treated with ERT. The impact on the outcome of various characteristics, measured just prior to the initiation of ERT (baseline), was evaluated using logistic regression. RESULTS: Thirty-three patients were identified; 13/29 (45%) were cross-reactive immunological material (CRIM) negative, and nine were immunomodulated. At baseline assessment, 79% were in heart failure, 66% had failure to thrive and 70% had radiological signs of focal pulmonary collapse. The overall survival rate was 60%, ventilation-free survival was 40% and 30% of patients were ambulatory. Median follow-up of survivors was 4 years, 1.5 months (range 6 months to 13.5 years). As with previous studies, the CRIM status impacted on all outcome measures. However, in this cohort, baseline failure to thrive was related to death and lack of ambulation, and left ventricular dilatation was a risk factor for non-ventilator-free survival. CONCLUSION: The outcome of treated patients remains heterogeneous despite attempts at immunomodulation. Failure to thrive at baseline and left ventricular dilation appear to be associated with poorer outcomes.
Assuntos
Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/mortalidade , Cardiomiopatias/metabolismo , Cardiomiopatias/mortalidade , Reações Cruzadas , Terapia de Reposição de Enzimas/métodos , Feminino , Doença de Depósito de Glicogênio Tipo II/metabolismo , Humanos , Lactente , Lisossomos/metabolismo , Masculino , Estudos Retrospectivos , Taxa de Sobrevida , Reino Unido , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/mortalidadeRESUMO
Propionic acidemia (PA) is a severe metabolic disorder with cardiac and neurologic complications and a poor quality of life. Liver transplantation (LT) was thus proposed in PA to increase enzyme activity. We studied retrospectively LT in PA in two European centers. Twelve patients underwent 17 LTs between 1991 and 2013. They developed severe, unusual and unexpected complications, with high mortality (58%). When present, the cardiomyopathy resolved and no acute metabolic decompensation occurred allowing dietary relaxation. Renal failure was present in half of the patients before LT and worsened in all of them. We suggest that cardiac and renal functions should be assessed before LT and monitored closely afterward. A renal sparing immunosuppression should be used. We speculate that some complications may be related to accumulated toxicity of the disease and that earlier LT could prevent some of these consequences. As kidney transplantation has been performed successfully in methylmalonic acidemia, a metabolic disease in the same biochemical pathway, the choice of the organ to transplant could be further discussed.
Assuntos
Transplante de Fígado/efeitos adversos , Acidemia Propiônica/cirurgia , Criança , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Acidemia Propiônica/fisiopatologiaRESUMO
Pyruvate carboxylase is a mitochondrial enzyme essential for the tricarboxylic acid cycle (TCA), gluconeogenesis and fatty-acid synthesis. Pyruvate carboxylase deficiency (PCD) mostly presents with life-limiting encephalopathy (types A/B). A milder type C presentation is rare, with a comparatively favourable prognosis. Therapies remain essentially supportive. Triheptanoin is an odd-chain triglyceride, with the potential to replenish TCA intermediates (anaplerosis), and its metabolites cross the blood-brain-barrier. Outcomes of triheptanoin treatment in PCD types A/B have been disappointing, but have not been reported in type C. Here, we present two new patients with PCD type C, and report the response to treatment with triheptanoin in one. Patient 1 (P1) presented with neonatal-onset lactic acidosis and recurrent symptomatic lactic acidosis following exercise and during illnesses, with frequent hospitalisations. Speech development was delayed. MRI-brain showed delayed cerebral myelination. Patient 2 (P2) presented with episodic ketoacidosis, hyperlactataemia and hypoglycaemia at 2 years of age, with gross motor delay and mild global volume loss on MRI brain. Treatment with triheptanoin was commenced in P1 at 3 years of age with up-titration to 35 mL/day (25% of daily energy intake) over 6 months, due to transient diarrhoea. Dietary long-chain triglycerides were restricted, with fat-soluble vitamin supplementation. Subsequently, hospitalisations during intercurrent illnesses decreased, post-exertional hyperlactataemia resolved and exercise tolerance improved. Continued developmental progress was observed, and repeat MRI 18 months after initiation showed improved myelination. Triheptanoin was well-tolerated and appeared efficacious during 2 years' follow-up, and has potential to restore energy homeostasis and myelin synthesis in PCD type C.
RESUMO
BACKGROUND: Tyrosinaemia type 1 (HT1) is treated with a tyrosine and phenylalanine-restricted diet, amino acids free of phenylalanine and tyrosine, and nitisinone (NTBC). Treatment guidelines recommend plasma tyrosine between 200-400 µm and phenylalanine at least >30 µm. There is little information on the diurnal variation of plasma tyrosine or phenylalanine in HT1. Low plasma phenylalanine <30 µm may be associated with poor growth and cognitive delay. The present study aimed to document diurnal variation of tyrosine and phenylalanine plasma concentrations and growth in children with HT1. METHODS: Median tyrosine and phenylalanine plasma concentrations were reviewed retrospectively over 3 years in 11 subjects (median age 4 years) with HT1. Subjects routinely collected morning fasting blood samples but afternoon nonfasted samples were taken in the clinic (<10% of samples). Growth Z-scores were calculated. RESULTS: The percentage of all plasma phenylalanine concentrations <30 µm was 8.6% and <40 µm was 13.6%. Only 2% of fasting morning phenylalanine concentrations were <30 µm, compared to 83% of nonfasting afternoon samples. All but one child had a height Z-score <0. CONCLUSIONS: Blood phenylalanine concentrations were consistently lower in the afternoon. Taking blood samples at variable time points in the day may lead to variation in interpreting dietary control. A detailed study is necessary to examine the 24-h diurnal variation of plasma phenylalanine and tyrosine in HT1. It is possible that phenylalanine concentrations may be very low for a substantive time over 24 h and the potential impact that this may have on cognitive development and growth in children is unknown.
Assuntos
Fenilalanina/sangue , Tirosina/sangue , Tirosinemias/sangue , Criança , Pré-Escolar , Ritmo Circadiano , Proteínas Alimentares/administração & dosagem , Proteínas Alimentares/sangue , Feminino , Humanos , Masculino , Fenilalanina/administração & dosagem , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Tirosina/administração & dosagem , Tirosinemias/dietoterapiaRESUMO
BACKGROUND: In glutaric aciduria type 1 (GA1), dietary treatment with emergency management (EM) is essential to prevent encephalopathic crisis (EC). In the present study, dietary practices were examined in a single UK centre without access to newborn screening. METHODS: Twenty GA1 patients (11 males, median age: 10.2 years, range 2.2-24.1 years) were evaluated. Nine presented without EC (median diagnosis age: 1.1 years, range 4 days to 8 years) and 11 with EC (median diagnosis age 10 months, range 6 months to 1.7 years). Dietary treatment, neurological outcome, anthropometry and biochemical/haematological markers were assessed. RESULTS: Diet treatment varied according to age of diagnosis and symptom severity. Four of six pre-encephalopathic children diagnosed before 2 years of age were treated with carnitine, protein restriction (medium l.2 g kg day(-1)) and lysine-free/low tryptophan protein substitute (PS) (medium dose: 1.6 g kg day(-1)). EM consisted of natural protein cessation and glucose polymer with PS delivered via an enteral feeding tube. Older children (>3 years) without EC were given carnitine and protein restriction, and seven of nine EC patients had PS via an enteral feeding tube. Clinical deterioration occurred in two patients without EC; one taking PS and protein restriction (with a second untreatable pathology) and one after protein restriction only. In patients presenting with EC, four died and one had some improvement in movement, with the rest remaining stable but with severe disability. Patients taking PS had better nutritional markers [serum vitamin B(12) (P < 0.001), albumin (P < 0.001), haemoglobin (P < 0.001) and essential plasma amino acids]. CONCLUSIONS: Early diagnosis of GA1 before EC is essential because PS and protein restriction with meticulous EM prevents EC. PS also improves nutritional status irrespective of clinical condition.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Encefalopatias Metabólicas/dietoterapia , Dieta com Restrição de Proteínas , Proteínas Alimentares , Lisina/administração & dosagem , Padrões de Prática Médica , Triptofano/administração & dosagem , Adolescente , Adulto , Fatores Etários , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/mortalidade , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Biomarcadores/sangue , Encefalopatias/etiologia , Encefalopatias/prevenção & controle , Encefalopatias Metabólicas/complicações , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas/mortalidade , Encefalopatias Metabólicas/terapia , Carnitina/uso terapêutico , Criança , Pré-Escolar , Proteínas Alimentares/efeitos adversos , Proteínas Alimentares/uso terapêutico , Dietética/métodos , Pessoas com Deficiência , Diagnóstico Precoce , Nutrição Enteral , Feminino , Glucose/uso terapêutico , Glutaril-CoA Desidrogenase/deficiência , Humanos , Lisina/efeitos adversos , Masculino , Índice de Gravidade de Doença , Triptofano/efeitos adversos , Reino Unido/epidemiologia , Adulto JovemRESUMO
This article documents both the neurological and physical outcomes of the first published set of siblings undergoing transplantation at differing ages for α-mannosidosis. The older brother, the index case, was diagnosed at the age of 3 years and underwent transplantation at 13 years for the treatment of increasing somatic problems and recurrent infections. The younger brother had undergone transplantation pre-symptomatically at 6 months of age. Their clinical, radiological and developmental outcomes are documented and compared with the previous published cases, with the case for early transplantation being weighted against other potential therapies.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Tempo para o Tratamento , alfa-Manosidose/cirurgia , Adolescente , Desenvolvimento do Adolescente , Desenvolvimento Infantil , Predisposição Genética para Doença , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hereditariedade , Humanos , Lactente , Masculino , Seleção de Pacientes , Linhagem , Fenótipo , Fatores de Risco , Irmãos , Fatores de Tempo , Resultado do Tratamento , alfa-Manosidose/complicações , alfa-Manosidose/diagnóstico , alfa-Manosidose/enzimologia , alfa-Manosidose/genética , alfa-Manosidose/fisiopatologia , alfa-Manosidose/psicologiaAssuntos
Proteínas de Fusão bcr-abl/genética , Deleção de Genes , Genes p53 , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Mieloide de Fase Crônica/genética , Cromossomos Humanos Par 9 , Análise Citogenética , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Mieloide de Fase Crônica/diagnóstico , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: The objective was the identification and functional characterization of mutations in the ABCA1 gene in four patients with severe HDL deficiency. SUBJECTS: Patients were referred to the clinic because of almost complete HDL deficiency. METHODS: The ABCA1 gene was sequenced directly. The analysis of the ABCA1 protein, ABCA1 mRNA and ABCA1-mediated cholesterol efflux was performed in cultured fibroblasts. Intracellular localization of ABCA1 mutants was investigated in transfected HEK293 cells. RESULTS: Two patients were homozygous for mutations in the coding region of the ABCA1 gene, resulting in an amino acid substitution (p.A1046D) and a truncated protein (p.I74YFsX76). The third patient was homozygous for a splice site mutation in intron 35 (c.4773 + 1g>a), resulting in an in-frame deletion of 25 amino acids (del p.D1567_K1591) in ABCA1. These patients had clinical manifestations of accumulation of cholesterol in the reticulo-endothelial system. The fourth patient, with preclinical atherosclerosis, was a compound heterozygote for two missense mutations (p.R587W/p.W1699C). ABCA1-mediated cholesterol efflux was abolished in fibroblasts from patients with p.A1046D and del p.D1567_K1591 mutants and in fibroblasts homozygous for p.R587W. A reduced ABCA1 protein content was observed in these cells, suggesting an increased intracellular degradation. The mutant p.W1699C was largely retained in the endoplasmic reticulum, when expressed in HEK293 cells. CONCLUSIONS: The homozygotes for mutations which abolish ABCA1 function showed overt signs of involvement of the reticulo-endothelial system. This was not the case in the compound heterozygote for missense mutations, suggesting that this patient retains some residual ABCA1 function that reduces cholesterol accumulation in the reticulo-endothelial system.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Colesterol/metabolismo , Lipoproteínas HDL/deficiência , Mutação de Sentido Incorreto/genética , Transportador 1 de Cassete de Ligação de ATP , Adulto , Idoso , Substituição de Aminoácidos , Apolipoproteína A-I/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons/genética , Feminino , Fibroblastos/metabolismo , Mutação da Fase de Leitura , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Citrin deficiency is a disorder with two phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and adult-onset type II citrullinaemia (CTLN2). NICCD presents in the first few weeks of life with prolonged cholestasis and metabolic abnormalities including aminoacidaemia (notably citrulline, tyrosine, threonine, arginine and methionine) and galactosuria. Symptoms resolve within the first year of life, thus making a diagnosis difficult after this time. Although patients subsequently remain generally healthy, some may develop more severe symptoms of CTLN2, characterized by neurological changes, one or more decades later. To date more than 400 cases have been reported, almost all from East Asia (mainly Japan). Here we describe the first two cases of NICCD in infants from the UK, one of caucasian origin and one of Pakistani origin. Both showed typical clinical and biochemical changes with a diagnosis confirmed by the presence of previously unreported mutations in the SLC25A13 gene. The presence of citrin deficiency in other ethnic groups means that NICCD needs to be considered in the diagnosis of any neonate with an unexplained cholestasis. We discuss both the difficulties in diagnosing these patients in populations where very few DNA mutations have been identified and the problems faced in the management of these patients. These findings also raise the possibility of adults with CTLN2 in whom a diagnosis has yet to be made.
Assuntos
Colestase Intra-Hepática/genética , Citrulinemia/genética , Pré-Escolar , Colestase Intra-Hepática/epidemiologia , Colestase Intra-Hepática/etiologia , Citrulinemia/complicações , Citrulinemia/epidemiologia , Consanguinidade , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Transporte da Membrana Mitocondrial/genética , Mutação , Paquistão/epidemiologia , Paquistão/etnologia , Reino Unido/epidemiologia , População Branca/genéticaRESUMO
BACKGROUND: In phenylketonuria (PKU), protein substitute is an essential part of dietary treatment. Short-term studies have demonstrated that liquid protein substitutes (LPS) are efficacious, and improve compliance in teenagers and adults with PKU, although there are no data available to demonstrate that their effectiveness is sustained over time. The present retrospective study aimed to evaluate the long-term efficacy of ready-to-drink protein substitute in a group of people with PKU. METHODS: Thirty-four patients (17 females and 17 males, median age 14.9 years, range 7.2-53.8 years) with PKU on dietary management were recruited from Birmingham Children's Hospital. All patients who were taking a LPS for a median of 2.4 years (range 6 months to 4.1 years), had their plasma phenylalanine concentrations, anthropometric and nutritional biochemical markers reviewed, both before and when taking the LPS. RESULTS: There was a significant improvement in median plasma phenylalanine (P < 0.05), vitamin B(12) (P < 0.01), calcium (P < 0.05) and albumin (P < 0.05) concentrations in subjects (n = 13) aged >18 years when taking the LPS. In the children aged 7-18 years (n = 21), median plasma phenylalanine concentrations were maintained on LPS. Their plasma selenium concentrations (P < 0.05) deteriorated, but calcium (P < 0.05), albumin (P < 0.01), haemoglobin (P < 0.01) and haematocrit (P < 0.01) significantly improved. CONCLUSIONS: This retrospective review suggested that, in adult patients, the long-term use of LPS is associated with better compliance by lowering blood phenylalanine and improving nutritional biochemical markers.
Assuntos
Proteínas Alimentares/administração & dosagem , Alimentos Formulados , Fenilalanina/sangue , Fenilcetonúrias/dietoterapia , Adolescente , Adulto , Biomarcadores/sangue , Cálcio/sangue , Criança , Feminino , Alimentos Formulados/normas , Hematócrito , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fenilcetonúrias/sangue , Estudos Retrospectivos , Selênio/sangue , Albumina Sérica , Resultado do Tratamento , Vitamina B 12/sangue , Adulto JovemRESUMO
BACKGROUND: The long-term efficacy of vitamin and mineral preparations in dietary-treated adult patients with phenylketonuria (PKU) is unreported. AIM: In an open, intervention trial, the acceptability, safety and impact on biochemical and haematological micronutrient status of a new vitamin and mineral tablet (Phlexy Vits, SHS International) was investigated. METHODS: Fifteen subjects with PKU (median age 21 years, range 8-33 years) on low-phenylalanine diet from two PKU centres were recruited. No vitamins or minerals were added to their protein substitute and for 12 months they took their full daily requirements of vitamin and minerals from Phlexy Vits (5 tablets/daily). All but two subjects had taken alternative vitamin and mineral supplements before the trial. Fasting bloods were taken at baseline (week -2 and at week 0), 4 and 12 months for a range of biochemical and nutritional measurements. RESULTS: By 4 months, serum vitamin B(12) (p = 0.003), serum manganese (p=0.03) and plasma (p=0.03) and red blood cell (p=0.004) glutathionine peroxidase (GSHPx) all significantly increased but remained within normal reference ranges. By 12 months, serum vitamin B(12) (p<0.05) and plasma GSHPx (p<0.05) remained increased. The Phlexy Vits tablets scored better than conventional vitamin and mineral supplements for overall acceptability (p<0.05), and ease of swallowing (p=0.1) at 4 months, although swallowing score deteriorated by 12 months (p<0.05). There was a small but significant deterioration in compliance with taking the vitamin and mineral supplements between 4 and 12 months (p<0.05). CONCLUSION: In the long term, these comprehensive vitamin and mineral tablets appeared acceptable and improved biochemical nutritional status, although there were long-term compliance and swallowing issues.
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Suplementos Nutricionais , Fenilcetonúrias/terapia , Adolescente , Adulto , Criança , Dieta , Feminino , Humanos , Masculino , Necessidades Nutricionais , Cooperação do Paciente , Fenilalanina/sangue , Fenilalanina/metabolismo , Fenilcetonúrias/sangue , Fenilcetonúrias/dietoterapia , Comprimidos , Vitaminas/metabolismoRESUMO
BACKGROUND: Metabolic control in phenylketonuria (PKU) may be influenced by parental ability because dietary treatment involves complex food choices. This is an observational study to compare maternal carer (MC) knowledge and parental education with phenylalanine concentrations in children with PKU. METHODS: Children (n = 46; 26 boys) aged 1-10 years (median age 6 years) on dietary treatment were recruited. Their median lifetime and median phenylalanine concentrations in the year prior to study were estimated. MC completed a questionnaire to assess dietary knowledge. RESULTS: Overall maternal knowledge on most aspects of diet was good and there was a correlation between annual median blood phenylalanine concentrations, but at the age of 5-6 years of age only, and higher maternal carer scores on PKU knowledge (r = -0.646; P < 0.0001). Three of only four children (12%) with median phenylalanine concentrations above 500 micromol L(-1) in the year prior to study had both parents leave school without educational qualifications. Children who had median phenylalanine concentrations (n = 3; 7%) over the recommended ranges at 3 years of age or earlier continued to have poor control. CONCLUSIONS: Blood phenylalanine control within the first 3 years of age, poor parental educational achievement at school level, and unsatisfactory maternal dietary knowledge may all influence longer-term blood phenylalanine control in children.
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Conhecimentos, Atitudes e Prática em Saúde , Mães/educação , Mães/psicologia , Fenilalanina/sangue , Fenilcetonúrias/sangue , Criança , Pré-Escolar , Escolaridade , Feminino , Humanos , Lactente , Masculino , Relações Mãe-Filho , Relações Pais-Filho , Educação de Pacientes como AssuntoRESUMO
Carnitine-acylcarnitine translocase (CACT) deficiency is a rare disorder that results in long-chain fatty acids being unavailable for mitochondrial beta-oxidation and ketogenesis. It can present in the neonatal period or infancy with a severe clinical form, typically with convulsions, hypothermia, encephalopathy, cardiomyopathy and liver dysfunction, or with a milder phenotype with episodes of hypoglycaemia and hyperammonaemia during intercurrent illness. Investigations show hypoketonaemia, intermittent dicarboxyluria and hypocarnitinaemia with grossly elevated acylcarnitines. Enzyme assay or DNA analysis confirms the diagnosis. The severe phenotype results in severe disability or death. The less severe phenotype can also cause significant disability secondary to hypoglycaemia and/or hyperammonaemia at presentation. We report the outcome of two siblings with CACT deficiency. The index patient presented at the age of 2 months during a respiratory illness with hypoglycaemia, hyperammonaemia and cardiorespiratory collapse. Acylcarnitine profiles showed decreased free carnitine but striking elevations of long-chain acylcarnitines. Urine organic acids showed dicarboxylic aciduria. Fatty acid oxidation studies showed reduced oleate and myristate oxidation. His acylcarnitine profile normalized after he was started on a medium-chain triglyceride (MCT) low-fat diet and carnitine supplementation. Low CACT activity on enzyme assay confirmed the diagnosis. He has resulting profound developmental delay and epilepsy. The sibling was prospectively treated with a low-fat MCT diet and carnitine supplementation. Acylcarnitine profile at birth also showed elevated long-chain acylcarnitines. Fatty acid oxidation studies confirmed the diagnosis. To date he has normal development and has not had any significant periods of hypoglycaemia or hyperammonaemia.
Assuntos
Carnitina Aciltransferases/deficiência , Carnitina/uso terapêutico , Dieta com Restrição de Gorduras , Suplementos Nutricionais , Proteínas de Membrana Transportadoras/deficiência , Erros Inatos do Metabolismo/dietoterapia , Erros Inatos do Metabolismo/tratamento farmacológico , Carnitina/análogos & derivados , Carnitina/sangue , Ácidos Dicarboxílicos/urina , Ácidos Graxos/metabolismo , Humanos , Hiperamonemia/etiologia , Hiperamonemia/prevenção & controle , Hipoglicemia/etiologia , Hipoglicemia/prevenção & controle , Lactente , Masculino , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/metabolismo , Oxirredução , Linhagem , Fenótipo , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the commonest disorder of fatty acid metabolism, with a high incidence of morbidity and mortality at presentation. We report a 16 year old girl with first presentation of MCAD deficiency following an alcoholic binge and subsequent period of starvation. Presentation was as acute encephalopathy progressing to coma. Renal, cardiac and hepatic failures were managed with intensive supportive care including mechanical ventilation, inotropic support, blood products and renal replacement therapy. Diagnosis of MCAD deficiency was confirmed on day 6. The patient was discharged from hospital on day 20 with a mild proximal myopathy, which subsequently resolved. The diagnosis of MCAD deficiency requires a high index of suspicion at all ages. Precipitating factors in later life may include alcohol.
Assuntos
Acil-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Adolescente , Idade de Início , Consumo de Bebidas Alcoólicas , Encefalopatias/diagnóstico , Coma , Feminino , HumanosRESUMO
UNLABELLED: In phenylketonuria (PKU), compliance with taking protein substitute is an issue in teenage and older patients. A 'ready to drink' protein substitute may overcome many of the practical issues associated with its administration. OBJECTIVE: To investigate the efficacy of a liquid protein substitute in a 6-week, three-part, randomized, crossover, controlled study. METHODS: 27 subjects (15 female; 12 male) with PKU with a median age of 30 years (range 8-49 years) were recruited. One subject withdrew from the study. Their median daily dose of protein equivalent was 60 g (range 45-75 g). In parts 1 and 2, subjects were randomized to either a liquid or a powder protein substitute with the same nutritional composition per unit (each 130 ml liquid pouch or 25 g powder sachet contained 15 g protein equivalent). In part 3, subjects chose liquid, powder or a combination of both. Weekly blood phenylalanine (Phe) concentrations were estimated, and during weeks 2, 4 and 6 subjects completed a daily questionnaire on administration issues. RESULTS: All but one of 26 subjects chose the liquid in part 3 as either their sole (69%, n = 18) or partial source (28%, n = 7) of protein substitute. Blood Phe concentrations were significantly better on the liquid (p = 0.03). With the liquid protein substitute, subjects were less self-consciousness (p = 0.003) and found it easier to take away from home (p = 0.001). Overall, the liquid was easier (p < 0.0001), more convenient (p = 0.002) and resulted in less wastage of protein substitute (p = 0.001). CONCLUSION: Liquid protein substitute was popular and efficacious, reduced self-consciousness and overall improved compliance of teenagers and adults with PKU.
Assuntos
Dieta , Suplementos Nutricionais , Fenilalanina/sangue , Fenilcetonúrias/terapia , Tirosina/sangue , Adolescente , Adulto , Bebidas , Criança , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenilalanina/química , Proteínas/química , Tirosina/químicaRESUMO
Breast feeding has proven benefits for many infants with inherited metabolic disorders (IMDs) but, with the exception of phenylketonuria, there are few reports in other conditions. A questionnaire, completed by dietitians and clinicians from 27 IMD centres from 15 countries (caring for a total of over 8000 patients with IMDs on diet) identified breast feeding experience in IMD. Successful, demand breast feeding (in combination with an infant amino acid formula free of precursor amino acids) was reported in 17 infants with MSUD, 14 with tyrosinaemia type I, and 5 with homocystinuria. Eighty-nine per cent were still breast fed at 16 weeks. Fewer infants with organic acidaemias were demand breast fed (7 with propionic acidaemia; 6 with methylmalonic acidaemia and 13 with isovaleric acidaemia) (usually preceded by complementary feeds of a protein-free infant formula or infant amino acid formula free of precursor amino acids). Only 12 infants with urea cycle disorders were given demand breast feeds, but this was unsuccessful beyond 8 days in CPS deficiency. Further work is needed in developing guidelines for feeding and for clinical and biochemical monitoring for breast-fed infants with IMDs.