RESUMO
Methylmalonic acidemia cblB type (MMA cblB) is an autosomal recessive inborn error of amino acid metabolism that results in impaired synthesis of adenosylcobalamin, a cofactor of methylmalonyl-CoA mutase. It presents with episodes of coma, vomiting, hypotonia, metabolic acidosis, and hyperammonemia. End-stage kidney disease is a long-term complication. Treatments include vitamin B12 supplementation, L-carnitine, and a low-protein diet. Liver, kidney, or combined liver-kidney transplantations are promising options, but they are not without complications. We report a patient suffering from MMA cblB who developed end-stage kidney disease at 18 years of age. Kidney transplantation allowed him to recover normal kidney function and good metabolic control. Unfortunately, after two decades, he developed non-Hodgkin lymphoma and severe chemotherapy toxicity which led to his death. The risk of lymphoproliferative diseases is known to increase after solid organ transplantation. However, in MMA, factors including mitochondrial dysfunction and oncometabolites, may further increase the risk of malignancy and drug toxicity. Our report highlights the importance of considering the increased risk of cancer in long-term follow-up of MMA cblB patients, especially after solid organ transplantation. Moreover, when chemotherapy is needed, the increased risk of toxicity and metabolic decompensation should be considered and monitored.
RESUMO
Phenylketonuria (PKU) is a genetic disorder that follows an autosomal recessive inheritance pattern. Dietary treatment is the cornerstone of therapy and is based on natural protein restriction, Phe-free L-amino acid supplements (protein substitutes) and low protein foods. The aim of this project was to collect information about the clinical management of patients with PKU, focusing on understudied or unresolved issues such as blood phenylalanine (Phe) fluctuations and clinical symptoms, particularly gastro intestinal (GI) discomfort and sleep problems. The survey consisted of 10 open-ended and 12 multiple-choice questions that collected information about size of the PKU population in each center, the center's clinical practices and the outcomes observed by the center concerning adherence, clinical and biochemical abnormalities and clinical symptoms (GI and sleep). The questionnaire was sent to 72 experts from metabolic centers in 11 European countries. Thirty-three centers answered. The results of this survey provide information about the clinical practice in different age groups, concentrating on dietary tolerance, treatment adherence, and metabolic control. All the centers prescribed a Phe-restricted diet, with Phe-free/low Phe protein substitutes and low protein foods. Daily doses given of protein substitutes varied from 1 to 5, with adherence to the prescribed amounts decreasing with increasing age. Respondents identified that improvement in the flavor, taste, volume and smell of protein substitutes may improve adherence. Finally, the survey showed that clinical symptoms, such as GI discomfort and sleep problems occur in patients with PKU but are not systematically evaluated. Twenty-four-hour Phe fluctuations were not routinely assessed. The results highlight a strong heterogeneity of approach to management despite international PKU guidelines. More clinical attention should be given to gastrointestinal and sleep problems in PKU.
Assuntos
Fenilcetonúrias , Transtornos do Sono-Vigília , Humanos , Fenilcetonúrias/diagnóstico , Inquéritos e Questionários , Dieta com Restrição de Proteínas , Europa (Continente) , FenilalaninaRESUMO
BACKGROUND: Phenylketonuria (PKU) is a rare inborn error of metabolism affecting the catabolism of phenylalanine (Phe). To date, findings regarding health-related quality of life (HRQoL) in adults with early-treated classical PKU are discrepant. Moreover, little is known about metabolic, demographic, and cognitive factors associated with HRQoL. Hence, we aimed to investigate HRQoL and its association with demographic, metabolic, and cognitive characteristics in a large European sample of adults with early-treated classical PKU. RESULTS: This cross-sectional study included 124 adults with early-treated classical PKU from Hungary, Italy, Spain, Switzerland, and Turkey. All participants prospectively completed the PKU quality of life questionnaire (PKU-QoL), a questionnaire specifically designed to evaluate the impact of PKU and its treatment on HRQoL in individuals with PKU. In addition, information about Phe levels (concurrent and past year), demographic (age and sex), and cognitive variables (intelligence quotient, IQ) were collected. Most domains revealed little or no impact of PKU on HRQoL and more than three-quarters of the patients rated their health status as good, very good, or excellent. Nevertheless, some areas of concern for patients were identified. Patients were worried about the guilt that they experience if they do not adhere to the dietary protein restriction and they were most concerned about high Phe levels during pregnancy. Further, tiredness was the most affected symptom, and the supplements' taste was considered a main issue for individuals with PKU. The overall impact of PKU on HRQoL was higher in women (U = 1315.5, p = .012) and in adults with a lower IQ (rs = - 0.448, p = .005). The overall impact of dietary protein restriction was higher in adults with higher concurrent Phe levels (rs = 0.272, p = .007) and higher Phe levels during the past year (rs = 0.280, p = .009). CONCLUSION: The impact of PKU on most domains assessed in the PKU-QoL was considered to be low. These results likely reflect the successful implementation of the newborn screening resulting in the prevention of severe adverse long-term outcomes. However, a particular clinical focus should be given to patients with lower IQ, higher Phe levels, and women, as these variables were associated with a lower HRQoL.
Assuntos
Fenilcetonúrias , Qualidade de Vida , Recém-Nascido , Gravidez , Humanos , Adulto , Feminino , Estudos Transversais , Nível de Saúde , Triagem Neonatal , FenilalaninaRESUMO
OBJECTIVES: Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a severe urea cycle disorder. Patients can present with hyperammonemic coma in the first days of life. Treatment includes nitrogen scavengers, reduced protein intake and supplementation with L-arginine and/or L-citrulline. N-carbamoyl glutamate (NCG) has been hypothesized to stimulate the residual CPS1 function, although only few patients are reported. CASE PRESENTATION: We report a patient with neonatal-onset CPS1 deficiency who received NCG in association with nitrogen scavenger and L-citrulline. The patient carried the novel variants CPS1-c.2447A>G p.(Gln816Arg) and CPS1-c.4489T>C p.(Tyr1497His). The latter is localized in the C-terminal allosteric domain of the protein, and is implicated in the binding of the natural activator N-acetyl-L-glutamate. NCG therapy was effective in controlling ammonia levels, allowing to increase the protein intake. CONCLUSIONS: Our data show that the response to NCG can be indicated based on the protein structure. We hypothesize that variants in the C-terminal domain may be responsive to NCG therapy.
Assuntos
Doença da Deficiência da Carbamoil-Fosfato Sintase I , Distúrbios Congênitos do Ciclo da Ureia , Humanos , Recém-Nascido , Carbamoil-Fosfato Sintase (Amônia)/química , Carbamoil-Fosfato Sintase (Amônia)/metabolismo , Doença da Deficiência da Carbamoil-Fosfato Sintase I/metabolismo , Doença da Deficiência da Carbamoil-Fosfato Sintase I/terapia , Citrulina/uso terapêutico , Ácido GlutâmicoRESUMO
The gold standard treatment for phenylketonuria (PKU) is a lifelong low-phenylalanine (Phe) diet supplemented with Phe-free protein substitutes. Adherence to therapy becomes difficult after childhood. Supplementing with large neutral amino acids (LNAAs) has been proposed as an alternative medication to Phe-free protein substitutes (i.e., amino acid mixtures). The aim of this study was to evaluate adherence to therapy and quality of life (QoL) in a cohort of sub-optimally controlled adult PKU patients treated with a new LNAA formulation. Twelve patients were enrolled in a 12-month-trial of slow-release LNAAs (1g/kg/day) plus a Phe-restricted diet. Medication adherence was measured with the Morisky Green Levine Medication Adherence Scale; the QoL was measured using the phenylketonuria-quality of life (PKU-QoL) questionnaire. Phe, tyrosine (Tyr) levels, and Phe/Tyr ratios were measured fortnightly. Before treatment, 3/12 patients self-reported a 'medium' adherence to medication and 9/12 reported a low adherence; 60% of patients reported a full adherence over the past four weeks. After 12 months of LNAA treatment, all patients self-reported a high adherence to medication, with 96% reporting a full adherence. Phe levels remained unchanged, while Tyr levels increased in most patients. The Phy/Tyr ratio decreased. All patients had a significant improvement in the QoL. LNAAs may give patients a further opportunity to improve medication adherence and, consequently, their QoL.
Assuntos
Aminoácidos Neutros/administração & dosagem , Proteínas Alimentares/administração & dosagem , Suplementos Nutricionais , Fenilalanina/efeitos adversos , Fenilcetonúrias/dietoterapia , Cooperação e Adesão ao Tratamento , Adulto , Resina de Colestiramina , Estudos de Coortes , Feminino , Humanos , Masculino , Qualidade de Vida , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
The standard treatment for phenylketonuria (PKU) is a lifelong low-phenylalanine (Phe) diet, supplemented with Phe-free protein substitutes; however, adult patients often show poor adherence to therapy. Alternative treatment options include the use of large neutral amino acids (LNAA). The aim of this study was to determine the Phe, tyrosine (Tyr), and Phe/Tyr ratio in a cohort of sub-optimally controlled adult patients with classical PKU treated with a new LNAA formulation. Twelve patients received a Phe-restricted diet plus a slow-release LNAA product taken three times per day, at a dose of 1 g/kg body weight (mean 0.8 ± 0.24 g/kg/day), over a 12-month period. The product is in a microgranulated formulation, which incorporates all amino acids and uses sodium alginate as a hydrophilic carrier to prolong its release. This LNAA formulation provides up to 80% of the total protein requirement, with the rest of the protein supplied by natural food. Patients had fortnightly measurements of Phe and Tyr levels over a 12-month period after the introduction of LNAA. All patients completed the 12-month treatment period. Overall, adherence to the new LNAA tablets was very good compared with a previous amino acid mixture, for which taste was a major complaint by patients. Phe levels remained unchanged (p = 0.0522), and Tyr levels increased (p = 0.0195). Consequently, the Phe/Tyr ratio decreased significantly (p < 0.05) in the majority of patients treated. In conclusion, LNAA treatment increases Tyr levels in sub-optimally controlled adult PKU patients, while offering the potential to improve their adherence to treatment.
Assuntos
Aminoácidos Neutros/uso terapêutico , Fenilalanina/sangue , Fenilcetonúrias/sangue , Fenilcetonúrias/tratamento farmacológico , Tirosina/sangue , Adulto , Barreira Hematoencefálica , Dieta , Suplementos Nutricionais , Feminino , Humanos , Itália , Masculino , Cooperação do Paciente , Satisfação do Paciente , Fenilalanina/administração & dosagem , Fenilcetonúrias/dietoterapia , Paladar , Adulto JovemRESUMO
Newborn screening for phenylketonuria (PKU) and early introduction of dietary therapy has been remarkably successful in preventing the severe neurological features of PKU, including mental retardation and epilepsy. However, concerns remain that long-term outcome is still suboptimal, particularly in adult patients who are no longer on strict phenylalanine-restricted diets. With our systematic literature review we aimed to describe the neurological phenotype of adults with early-treated phenylketonuria (ETPKU). The literature search covered the period from 1 January 1990 up to 16 April 2018, using the NLM MEDLINE controlled vocabulary. Of the 643 records initially identified, 83 were included in the analysis. The most commonly reported neurological signs were tremor and hyperreflexia. The overall quality of life (QoL) of ETPKU adults was good or comparable to control populations, and there was no evidence for a significant incidence of psychiatric disease or social difficulties. Neuroimaging revealed that brain abnormalities are present in ETPKU adults, but their clinical significance remains unclear. Generally, intelligence quotient (IQ) appears normal but specific deficits in neuropsychological and social functioning were reported in early-treated adults compared with healthy individuals. However, accurately defining the prevalence of these deficits is complicated by the lack of standardized neuropsychological tests. Future research should employ standardized neurological, neuropsychological, and neuroimaging protocols, and consider other techniques such as advanced imaging analyses and the recently validated PKU-specific QoL questionnaire, to precisely define the nature of the impairments within the adult ETPKU population and how these relate to metabolic control throughout life.
Assuntos
Encéfalo/patologia , Transtornos do Neurodesenvolvimento/diagnóstico , Fenilcetonúrias/complicações , Adulto , Suplementos Nutricionais , Humanos , Recém-Nascido , Testes de Inteligência , Triagem Neonatal , Transtornos do Neurodesenvolvimento/etiologia , Neuroimagem , Testes Neuropsicológicos , Fenótipo , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/dietoterapia , Qualidade de VidaRESUMO
BACKGROUND: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. CONCLUSIONS: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.
Assuntos
Acidose/genética , Acidose/metabolismo , Acil-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Debilidade Muscular/genética , Debilidade Muscular/metabolismo , Riboflavina/uso terapêutico , Acidose/patologia , Atividades Cotidianas , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Cardiomiopatia Hipertrófica/patologia , Complexo I de Transporte de Elétrons/metabolismo , Feminino , Humanos , Masculino , Doenças Mitocondriais/patologia , Debilidade Muscular/tratamento farmacológico , Debilidade Muscular/patologia , PrognósticoRESUMO
Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 µM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis.
Assuntos
Alquil e Aril Transferases/genética , Ataxia/diagnóstico , Ataxia/genética , Mitocôndrias Musculares/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Debilidade Muscular/diagnóstico , Debilidade Muscular/genética , Mutação Puntual , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Acidose Láctica/sangue , Acidose Láctica/genética , Acidose Láctica/patologia , Alquil e Aril Transferases/deficiência , Ataxia/sangue , Ataxia/patologia , Consanguinidade , Evolução Fatal , Feminino , Expressão Gênica , Insuficiência Hepática/sangue , Insuficiência Hepática/genética , Insuficiência Hepática/patologia , Humanos , Recém-Nascido , Deficiência Intelectual/sangue , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mitocôndrias Musculares/enzimologia , Mitocôndrias Musculares/patologia , Doenças Mitocondriais/sangue , Doenças Mitocondriais/patologia , Debilidade Muscular/sangue , Debilidade Muscular/patologia , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Proteinúria/sangue , Proteinúria/genética , Proteinúria/patologia , Aminoacidúrias Renais/sangue , Aminoacidúrias Renais/genética , Aminoacidúrias Renais/patologia , Análise de Sequência de DNA , Ubiquinona/sangue , Ubiquinona/genéticaRESUMO
Dietary management for phenylketonuria was established over half a century ago, and has rendered an immense success in the prevention of the severe mental retardation associated with the accumulation of phenylalanine. However, the strict low-phenylalanine diet has several shortcomings, not the least of which is the burden it imposes on the patients and their families consequently frequent dietary non-compliance. Imperfect neurological outcome of patients in comparison to non-PKU individuals and nutritional deficiencies associated to the PKU diet are other important reasons to seek alternative therapies. In the last decade there has been an impressive effort in the investigation of other ways to treat PKU that might improve the outcome and quality of life of these patients. These studies have lead to the commercialization of sapropterin dihydrochloride, but there are still many questions regarding which patients to challenge with sapropterin what is the best challenge protocol and what could be the implications of this treatment in the long-term. Current human trials of PEGylated phenylalanine ammonia lyase are underway, which might render an alternative to diet for those patients non-responsive to sapropterin dihydrochloride. Preclinical investigation of gene and cell therapies for PKU is ongoing. In this manuscript, we will review the current knowledge on novel pharmacologic approaches to the treatment of phenylketonuria.
Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Fenilcetonúrias/terapia , Biopterinas/análogos & derivados , Biopterinas/uso terapêutico , Terapia Genética , Humanos , Fenilalanina Amônia-Liase/uso terapêutico , Fenilcetonúrias/tratamento farmacológico , Fenilcetonúrias/genéticaRESUMO
Ethylmalonic encephalopathy is caused by mutations in ETHE1, a mitochondrial matrix sulfur dioxygenase, leading to failure to detoxify sulfide, a product of intestinal anaerobes and, in trace amounts, tissues. Metronidazole, a bactericide, or N-acetylcysteine, a precursor of sulfide-buffering glutathione, substantially prolonged the lifespan of Ethe1-deficient mice, with the combined treatment being additive. The same dual treatment caused marked clinical improvement in five affected children, with hardly any adverse or side effects.
Assuntos
Acetilcisteína/administração & dosagem , Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Metronidazol/administração & dosagem , Acetilcisteína/efeitos adversos , Administração Oral , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/efeitos adversos , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/metabolismo , Encefalopatias Metabólicas Congênitas/mortalidade , Pré-Escolar , Dioxigenases/genética , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Lactente , Masculino , Malonatos/metabolismo , Metronidazol/efeitos adversos , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , Resultado do TratamentoRESUMO
OBJECTIVE: The impact of homocysteine on cardiovascular disease can be more detrimental in women than in men, but it is unknown whether this applies to high-risk women. We therefore investigated the association of hyperhomocysteinemia with coronary artery disease (CAD) and cardiovascular mortality in high-risk women referred for CAD, both in the total population and in the hypertensive and normotensive cohorts. DESIGN: A prospective study cohort. SETTING: A tertiary centre. INCLUSION CRITERIA: 262 consecutive Caucasian postmenopausal women referred for coronary angiography. EXCLUSION CRITERIA: acute myocardial infarction and vitamin supplementation. MAIN OUTCOME MEASURE(S): We assessed total plasma homocysteine (tHcy), folate levels, and the MTHFR677C-->T polymorphism. CAD was defined as a modified Duke Index score greater than 0; hyperhomocysteinemia as tHcy levels of 15 micromol/l or greater. The primary study outcome was cardiovascular mortality at follow-up. RESULTS: Mild/moderate and severe hyperhomocysteinemia was found in 15.1 and 1.6% of women, respectively, without differences between CAD and non-CAD women. By the ATPIII criteria, 92.2% of the women were in the highest risk class and 55% had CAD; however, no association of tHcy with the CAD score was found. After a median follow-up of 3.6 years, 23 women (9.1%) had died, 15 (6%) of cardiovascular causes. Women with high tHcy levels showed the worst all-cause and cardiovascular death-free survival at Kaplan-Meier and Cox regression analysis. Moreover, in the hypertensive cohort only women with hyperhomocysteinemia showed increased cardiovascular mortality. CONCLUSION: Hyperhomocysteinemia is common in high-risk women and adversely affects their prognosis, although it is unrelated to the CAD atherosclerotic burden.
Assuntos
Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Doença da Artéria Coronariana/mortalidade , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Idoso , Estudos de Coortes , Angiografia Coronária , Doença da Artéria Coronariana/patologia , Feminino , Ácido Fólico/sangue , Seguimentos , Homocisteína/sangue , Humanos , Estudos Longitudinais , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Polimorfismo Genético , Pós-Menopausa , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , População BrancaRESUMO
Intracellular cobalamin is converted to adenosylcobalamin, coenzyme for methylmalonyl-CoA mutase and to methylcobalamin, coenzyme for methionine synthase, in an incompletely understood sequence of reactions. Genetic defects of these steps are defined as cbl complementation groups of which cblC, cblD (described in only two siblings), and cblF are associated with combined homocystinuria and methylmalonic aciduria. Here we describe three unrelated patients belonging to the cblD complementation group but with distinct biochemical phenotypes different from that described in the original cblD siblings. Two patients presented with isolated homocystinuria and reduced formation of methionine and methylcobalamin in cultured fibroblasts, defined as cblD-variant 1, and one patient with isolated methylmalonic aciduria and deficient adenosylcobalamin synthesis in fibroblasts, defined as cblD-variant 2. Cell lines from the cblD-variant 1 patients clearly complemented reference lines with the same biochemical phenotype, i.e. cblE and cblG, and the cblD-variant 2 cell line complemented cells from the mutant classes with isolated deficiency of adenosylcobalamin synthesis, i.e. cblA and cblB. Also, no pathogenic sequence changes in the coding regions of genes associated with the respective biochemical phenotypes were found. These findings indicate heterogeneity within the previously defined cblD mutant class and point to further complexity of intracellular cobalamin metabolism.