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1.
N Engl J Med ; 390(7): 623-629, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38354141

RESUMO

Wolman's disease, a severe form of lysosomal acid lipase deficiency, leads to pathologic lipid accumulation in the liver and gut that, without treatment, is fatal in infancy. Although continued enzyme-replacement therapy (ERT) in combination with dietary fat restriction prolongs life, its therapeutic effect may wane over time. Allogeneic hematopoietic stem-cell transplantation (HSCT) offers a more definitive solution but carries a high risk of death. Here we describe an infant with Wolman's disease who received high-dose ERT, together with dietary fat restriction and rituximab-based B-cell depletion, as a bridge to early HSCT. At 32 months, the infant was independent of ERT and disease-free, with 100% donor chimerism in the peripheral blood.


Assuntos
Gorduras na Dieta , Terapia de Reposição de Enzimas , Transplante de Células-Tronco Hematopoéticas , Fatores Imunológicos , Rituximab , Doença de Wolman , Humanos , Lactente , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Quimerismo , Gorduras na Dieta/efeitos adversos , Terapia de Reposição de Enzimas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Transplante Homólogo , Doença de Wolman/dietoterapia , Doença de Wolman/tratamento farmacológico , Doença de Wolman/imunologia , Doença de Wolman/terapia
2.
Int J Neonatal Screen ; 9(4)2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-38132825

RESUMO

Undiagnosed and untreated tyrosinemia type 1 (TT1) individuals carry a significant risk for developing liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Elevated succinylacetone (SA) is pathognomonic for TT1 and therefore often used as marker for TT1 newborn screening (NBS). While SA was long considered to be elevated in every TT1 patient, here we present a recent false-negative SA TT1 screen. A nine-year-old boy presented with HCC in a cirrhotic liver. Additional tests for the underlying cause unexpectedly revealed TT1. Nine years prior, the patient was screened for TT1 via SA NBS with a negative result: SA 1.08 µmol/L, NBS cut-off 1.20 µmol/L. To our knowledge, this report is the first to describe a false-negative result from the TT1 NBS using SA. False-negative TT1 NBS results may be caused by milder TT1 variants with lower SA excretion. Such patients are more likely to be missed in NBS programs and can be asymptomatic for years. Based on our case, we advise TT1 to be considered in patients with otherwise unexplained liver pathology, including fibrosis, cirrhosis and HCC, despite a previous negative TT1 NBS status. Moreover, because the NBS SA concentration of this patient fell below the Dutch cut-off value (1.20 µmol/L at that time), as well as below the range of cut-off values used in other countries (1.29-10 µmol/L), it is likely that false-negative screening results for TT1 may also be occurring internationally. This underscores the need to re-evaluate TT1 SA NBS programs.

3.
J Inherit Metab Dis ; 45(5): 952-962, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35722880

RESUMO

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.


Assuntos
Fenilcetonúrias , Tirosinemias , Criança , Humanos , Masculino , Saúde Mental , Redes e Vias Metabólicas , Testes Neuropsicológicos , Tirosinemias/genética
4.
Orphanet J Rare Dis ; 14(1): 285, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801588

RESUMO

BACKGROUND: Treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) and dietary phenylalanine and tyrosine restriction improves physical health and life expectancy in Tyrosinemia type 1 (TT1). However, neurocognitive outcome is suboptimal. This study aimed to investigate behavior problems and health-related quality of life (HR-QoL) in NTBC-dietary-treated TT1 and to relate this to phenylalanine and tyrosine concentrations. RESULTS: Thirty-one TT1 patients (19 males; mean age 13.9 ± 5.3 years) were included in this study. Emotional and behavioral problems, as measured by the Achenbach System of Empirically Based Assessment, were present in almost all domains. Attention and thought problems were particularly evident. HR-QoL was assessed by the TNO AZL Children's and Adults QoL questionnaires. Poorer HR-QoL as compared to reference populations was observed for the domains: independent daily functioning, cognitive functioning and school performance, social contacts, motor functioning, and vitality. Both internalizing and externalizing behavior problems were associated with low phenylalanine (and associated lower tyrosine) concentrations during the first year of life. In contrast, high tyrosine (and associated higher phenylalanine) concentrations during life and specifically the last year before testing were associated with more internalizing behavior and/or HR-QoL problems. CONCLUSIONS: TT1 patients showed several behavior problems and a lower HR-QoL. Associations with metabolic control differed for different age periods. This suggests the need for continuous fine-tuning and monitoring of dietary treatment to keep phenylalanine and tyrosine concentrations within target ranges in NTBC-treated TT1 patients.


Assuntos
Cicloexanonas/uso terapêutico , Nitrobenzoatos/uso terapêutico , Tirosinemias/sangue , Tirosinemias/tratamento farmacológico , Adolescente , Adulto , Criança , Humanos , Masculino , Fenilalanina/sangue , Qualidade de Vida , Tirosina/sangue , Adulto Jovem
5.
Nutrients ; 11(11)2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31752110

RESUMO

Tyrosinemia type 1 (TT1) treatment with 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) and a phenylalanine-tyrosine restricted diet is associated with low phenylalanine concentrations. Phenylalanine supplementation is prescribed without comprehensive consideration about its effect on metabolic control. We investigated the effect of phenylalanine supplementation on bloodspot phenylalanine, tyrosine, NTBC and succinylacetone. Eleven TT1 patients received 0, 20 and 40 mg/kg/day phenylalanine supplementation with the phenylalanine-tyrosine free L-amino acid supplements. Bloodspots were collected before breakfast, midday and evening meal. Differences between study periods, sample times and days within a study period were studied using (generalized) linear mixed model analyses. Twenty and 40 mg/kg/day phenylalanine supplementation prevented daytime phenylalanine decreases (p = 0.05) and most low phenylalanine concentrations, while tyrosine concentrations increased (p < 0.001). Furthermore, NTBC and succinylacetone concentrations did not differ between study periods. To conclude, 20 mg/kg/day phenylalanine supplementation can prevent most low phenylalanine concentrations without increasing tyrosine to concentrations above the target range or influencing NTBC and succinylacetone concentrations, while 40 mg/kg/day increased tyrosine concentrations to values above the targeted range. Additionally, this study showed that the effect of phenylalanine supplementation, and a possible phenylalanine deficiency, should be assessed using pre-midday meal blood samples that could be combined with an overnight fasted sample when in doubt.


Assuntos
Cicloexanonas/uso terapêutico , Heptanoatos/sangue , Nitrobenzoatos/uso terapêutico , Fenilalanina/administração & dosagem , Tirosina/sangue , Tirosinemias/tratamento farmacológico , Adolescente , Adulto , Criança , Suplementos Nutricionais , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Modelos Lineares , Masculino , Fenilalanina/sangue , Adulto Jovem
6.
Paediatr Drugs ; 21(6): 413-426, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31667718

RESUMO

Tyrosinemia type 1 (TT1) is a rare metabolic disease caused by a defect in tyrosine catabolism. TT1 is clinically characterized by acute liver failure, development of hepatocellular carcinoma, renal and neurological problems, and consequently an extremely poor outcome. This review showed that the introduction of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) in 1992 has revolutionized the outcome of TT1 patients, especially when started pre-clinically. If started early, NTBC can prevent liver failure, renal problems, and neurological attacks and decrease the risk for hepatocellular carcinoma. NTBC has been shown to be safe and well tolerated, although the long-term effectiveness of treatment with NTBC needs to be awaited. The high tyrosine concentrations caused by treatment with NTBC could result in ophthalmological and skin problems and requires life-long dietary restriction of tyrosine and its precursor phenylalanine, which could be strenuous to adhere to. In addition, neurocognitive problems have been reported since the introduction of NTBC, with hypothesized but as yet unproven pathophysiological mechanisms. Further research should be done to investigate the possible relationship between important clinical outcomes and blood concentrations of biochemical parameters such as phenylalanine, tyrosine, succinylacetone, and NTBC, and to develop clear guidelines for treatment and follow-up with reliable measurements. This all in order to ultimately improve the combined NTBC and dietary treatment and limit possible complications such as hepatocellular carcinoma development, neurocognitive problems, and impaired quality of life.


Assuntos
Cicloexanonas/efeitos adversos , Nitrobenzoatos/efeitos adversos , Tirosinemias/tratamento farmacológico , Cicloexanonas/uso terapêutico , Humanos , Nitrobenzoatos/uso terapêutico , Tirosina/sangue , Tirosinemias/complicações , Tirosinemias/dietoterapia
7.
Nutrients ; 11(10)2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31623189

RESUMO

Tyrosinemia type 1 (TT1) is a rare metabolic disease caused by a defect in the tyrosine degradation pathway. Neurocognitive deficiencies have been described in TT1 patients, that have, among others, been related to changes in plasma large neutral amino acids (LNAA) that could result in changes in brain LNAA and neurotransmitter concentrations. Therefore, this project aimed to investigate plasma and brain LNAA, brain neurotransmitter concentrations and behavior in C57 Bl/6 fumarylacetoacetate hydrolase deficient (FAH-/-) mice treated with 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and/or diet and wild-type mice. Plasma and brain tyrosine concentrations were clearly increased in all NTBC treated animals, even with diet (p < 0.001). Plasma and brain phenylalanine concentrations tended to be lower in all FAH-/- mice. Other brain LNAA, were often slightly lower in NTBC treated FAH-/- mice. Brain neurotransmitter concentrations were usually within a normal range, although serotonin was negatively correlated with brain tyrosine concentrations (p < 0.001). No clear behavioral differences between the different groups of mice could be found. To conclude, this is the first study measuring plasma and brain biochemistry in FAH-/- mice. Clear changes in plasma and brain LNAA have been shown. Further research should be done to relate the biochemical changes to neurocognitive impairments in TT1 patients.


Assuntos
Aminoácidos Neutros/sangue , Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Cicloexanonas/farmacologia , Dieta com Restrição de Proteínas , Inibidores Enzimáticos/farmacologia , Ácido Hidroxi-Indolacético/metabolismo , Nitrobenzoatos/farmacologia , Tirosinemias/terapia , Ração Animal , Animais , Biomarcadores/sangue , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Feminino , Hidrolases/deficiência , Hidrolases/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tirosinemias/sangue , Tirosinemias/fisiopatologia , Tirosinemias/psicologia
8.
Nutrients ; 11(9)2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461828

RESUMO

Phenylketonuria (PKU) is treated with dietary restrictions and sometimes tetrahydrobiopterin (BH4). PKU patients are at risk for developing micronutrient deficiencies, such as vitamin B12 and folic acid, likely due to their diet. Tyrosinemia type 1 (TT1) is similar to PKU in both pathogenesis and treatment. TT1 patients follow a similar diet, but nutritional deficiencies have not been investigated yet. In this retrospective study, biomarkers of micronutrients in TT1 and PKU patients were investigated and outcomes were correlated to dietary intake and anthropometric measurements from regular follow-up measurements from patients attending the outpatient clinic. Data was analyzed using Kruskal-Wallis, Fisher's exact and Spearman correlation tests. Furthermore, descriptive data were used. Overall, similar results for TT1 and PKU patients (with and without BH4) were observed. In all groups high vitamin B12 concentrations were seen rather than B12 deficiencies. Furthermore, all groups showed biochemical evidence of vitamin D deficiency. This study shows that micronutrients in TT1 and PKU patients are similar and often within the normal ranges and that vitamin D concentrations could be optimized.


Assuntos
Aminoácidos/administração & dosagem , Dieta com Restrição de Proteínas , Suplementos Nutricionais , Micronutrientes/sangue , Estado Nutricional , Fenilcetonúrias/dietoterapia , Tirosinemias/dietoterapia , Adolescente , Adulto , Idoso , Aminoácidos/efeitos adversos , Biomarcadores/sangue , Biopterinas/análogos & derivados , Biopterinas/uso terapêutico , Criança , Pré-Escolar , Cicloexanonas/uso terapêutico , Dieta com Restrição de Proteínas/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Nitrobenzoatos/uso terapêutico , Fenilcetonúrias/sangue , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/fisiopatologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Tirosinemias/sangue , Tirosinemias/fisiopatologia , Deficiência de Vitamina B 12/sangue , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/etiologia , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/etiologia , Adulto Jovem
9.
Hum Mol Genet ; 27(17): 3029-3045, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29878199

RESUMO

Genomics methodologies have significantly improved elucidation of Mendelian disorders. The combination with high-throughput functional-omics technologies potentiates the identification and confirmation of causative genetic variants, especially in singleton families of recessive inheritance. In a cohort of 99 individuals with abnormal Golgi glycosylation, 47 of which being unsolved, glycomics profiling was performed of total plasma glycoproteins. Combination with whole-exome sequencing in 31 cases revealed a known genetic defect in 15 individuals. To identify additional genetic factors, hierarchical clustering of the plasma glycomics data was done, which indicated a subgroup of four patients that shared a unique glycomics signature of hybrid type N-glycans. In two siblings, compound heterozygous mutations were found in SLC10A7, a gene of unknown function in human. These included a missense mutation that disrupted transmembrane domain 4 and a mutation in a splice acceptor site resulting in skipping of exon 9. The two other individuals showed a complete loss of SLC10A7 mRNA. The patients' phenotype consisted of amelogenesis imperfecta, skeletal dysplasia, and decreased bone mineral density compatible with osteoporosis. The patients' phenotype was mirrored in SLC10A7 deficient zebrafish. Furthermore, alizarin red staining of calcium deposits in zebrafish morphants showed a strong reduction in bone mineralization. Cell biology studies in fibroblasts of affected individuals showed intracellular mislocalization of glycoproteins and a defect in post-Golgi transport of glycoproteins to the cell membrane. In contrast to yeast, human SLC10A7 localized to the Golgi. Our combined data indicate an important role for SLC10A7 in bone mineralization and transport of glycoproteins to the extracellular matrix.


Assuntos
Doenças do Desenvolvimento Ósseo/etiologia , Calcificação Fisiológica , Defeitos Congênitos da Glicosilação/complicações , Genômica , Glicômica , Mutação , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/deficiência , Simportadores/genética , Adulto , Animais , Doenças do Desenvolvimento Ósseo/metabolismo , Doenças do Desenvolvimento Ósseo/patologia , Células Cultivadas , Estudos de Coortes , Exoma , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Glicosilação , Complexo de Golgi/metabolismo , Complexo de Golgi/patologia , Humanos , Lactente , Masculino , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Linhagem , Fenótipo , Transporte Proteico , Simportadores/metabolismo , Adulto Jovem , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo
10.
J Inherit Metab Dis ; 41(4): 641-646, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28894950

RESUMO

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism (IEM) due to mutations in the CYP27A1 gene. The clinical picture ranges from being nearly asymptomatic in early childhood, up to severe disability at adult age. Infantile-onset diarrhea and juvenile-onset cataract are the earliest symptoms in childhood. In the current study, we evaluated the presence of autism spectrum disorder (ASD) in a large cohort of CTX patients. METHODS: We performed a retrospective patient file study in 77 genetically confirmed Dutch CTX patients to determine the frequency of ASD. In addition, we compared plasma cholestanol levels in CTX patients with and without a diagnosis of ASD and tried to establish a relation between CYP27A1 genotype and ASD. RESULTS: In our CTX cohort, 10 patients (13%; nine pediatric and one adult) with ASD were identified. At the time of diagnosis of ASD, most patients only exhibited symptoms of diarrhea and/or intellectual disability without signs of cataract or neurological symptoms. No correlation was found between the presence of ASD and the level of cholestanol or CYP27A1 genotype. The behavioral problems stabilized or improved after treatment initiation with chenodeoxycholic acid (CDCA) in all pediatric patients. CONCLUSIONS: We conclude that ASD is an early and probably underestimated frequent feature in CTX. Metabolic screening for CTX should be performed in patients with ASD when accompanied by diarrhea, intellectual disability, juvenile cataract, and/or neurological involvement. Early recognition allows for earlier initiation of specific treatment and will improve clinical outcome. Our results add CTX to the list of treatable IEMs associated with ASD.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Xantomatose Cerebrotendinosa/diagnóstico , Adolescente , Adulto , Transtorno do Espectro Autista/sangue , Catarata/etiologia , Ácido Quenodesoxicólico/uso terapêutico , Criança , Pré-Escolar , Colestanol/sangue , Diarreia/etiologia , Feminino , Humanos , Deficiência Intelectual/etiologia , Masculino , Estudos Retrospectivos , Xantomatose Cerebrotendinosa/sangue , Xantomatose Cerebrotendinosa/tratamento farmacológico , Adulto Jovem
11.
J Inherit Metab Dis ; 41(2): 181-186, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29170874

RESUMO

INTRODUCTION: In hereditary tyrosinemia type 1 (HT1) patients, the dose of NTBC that leads to the absence of toxic metabolites such as succinylacetone (SA) is still unknown. Therefore, the aims of this study were to investigate the variation and concentrations of 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) during the day in relation to the detection of SA, while comparing different dosing regimens. METHODS: All patients were treated with NTBC (mean 1.08 ± 0.34 mg/kg/day) and a low phenylalanine-tyrosine diet. Thirteen patients received a single dose of NTBC and five patients twice daily. Home bloodspots were collected four times daily for three consecutive days measuring NTBC and SA concentrations. Statistical analyses were performed by using mixed model analyses and generalized linear mixed model analyses to study variation and differences in NTBC concentrations and the correlation with SA, respectively. RESULTS: NTBC concentrations varied significantly during the day especially if NTBC was taken at breakfast only (p = 0.026), although no significant difference in NTBC concentrations between different dosing regimens could be found (p = 0.289). Momentary NTBC concentrations were negatively correlated with SA (p < 0.001). Quantitatively detectable SA was only found in subjects with once daily administration of NTBC and associated with momentary NTBC concentrations <44.3 µmol/l. DISCUSSION: NTBC could be less stable than previously considered, thus dosing NTBC once daily and lower concentrations may be less adequate. Further research including more data is necessary to establish the optimal dosing of NTBC.


Assuntos
Cicloexanonas/administração & dosagem , Nitrobenzoatos/administração & dosagem , Tirosinemias/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Cicloexanonas/sangue , Cicloexanonas/farmacocinética , Dieta com Restrição de Proteínas , Teste em Amostras de Sangue Seco , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Lactente , Masculino , Nitrobenzoatos/sangue , Nitrobenzoatos/farmacocinética , Estudos Prospectivos , Espectrometria de Massas em Tandem , Fatores de Tempo , Resultado do Tratamento , Tirosinemias/sangue , Tirosinemias/diagnóstico , Adulto Jovem
12.
PLoS One ; 12(9): e0185342, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28949985

RESUMO

INTRODUCTION: Hereditary Tyrosinemia type 1 (HT1) is a rare metabolic disease caused by a defect in the tyrosine degradation pathway. Current treatment consists of 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and a tyrosine and phenylalanine restricted diet. Recently, neuropsychological deficits have been seen in HT1 patients. These deficits are possibly associated with low blood phenylalanine concentrations and/or high blood tyrosine concentrations. Therefore, the aim of the present study was threefold. Firstly, we aimed to calculate how the plasma amino acid profile in HT1 patients may influence the presumptive brain influx of all large neutral amino acids (LNAA). Secondly, we aimed to investigate the effect of phenylalanine supplementation on presumptive brain phenylalanine and tyrosine influx. Thirdly, we aimed to theoretically determine minimal target plasma phenylalanine concentrations in HT1 patient to ensure adequate presumptive brain phenylalanine influx. METHODS: Data of plasma LNAA concentrations were obtained. In total, 239 samples of 9 HT1 children, treated with NTBC, diet, and partly with phenylalanine supplementation were collected together with 596 samples of independent control children. Presumptive brain influx of all LNAA was calculated, using Michaelis-Menten parameters (Km) and Vmax-values obtained from earlier articles. RESULTS: In HT1 patients, plasma concentrations and presumptive brain influx of tyrosine were higher. However, plasma and especially brain influx of phenylalanine were lower in HT1 patients. Phenylalanine supplementation did not only tend to increase plasma phenylalanine concentrations, but also presumptive brain phenylalanine influx, despite increased plasma tyrosine concentrations. However, to ensure sufficient brain phenylalanine influx in HT1 patients, minimal plasma phenylalanine concentrations may need to be higher than considered thus far. CONCLUSION: This study clearly suggests a role for disturbed brain LNAA biochemistry, which is not well reflected by plasma LNAA concentrations. This could play a role in the pathophysiology of the neuropsychological impairments in HT1 patients and may have therapeutic implications.


Assuntos
Aminoácidos Neutros/metabolismo , Encéfalo/metabolismo , Fenilalanina/administração & dosagem , Tirosinemias/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido
13.
Adv Exp Med Biol ; 959: 101-109, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28755188

RESUMO

Hereditary Tyrosinemia type I (HT1) is clinically mainly characterised by severe liver disease. Most patients present in their first months of life with liver failure, but others can present later with issues of compensated cirrhosis, renal tubulopathy or acute intermittent porphyria. If patients survive the acute phase with liver failure or if they present later with compensated cirrhosis, they often develop hepatocellular carcinoma early but also later in life. The course of the disease changed after the introduction of 2-(2 nitro-4-3 trifluoro-methylbenzoyl)-1, 3-cyclohexanedione (NTBC), which blocks the tyrosine degradation pathway at an earlier step. Therefore, the toxic products did not accumulate anymore and all clinical problems resolved. However, the risk (although clearly decreased) for developing liver cancer remained, especially if NTBC treatment is initiated late, a slow decrease of the tumor marker α-fetoprotein is seen or if the α-fetoprotein concentrations remain just above the normal range. A rise of α-fetoprotein in these HT1 patients is more or less pathognomonic for liver cancer. Although hepatoblastoma development occurs in HT1 patients, most HT1 patients develop hepatocellular carcinoma (HCC) or a mixed type of carcinoma consisting of HCC and hepatoblastoma. Due to the small risk of liver cancer development, screening for liver cancer (especially HCC) is still recommended in HT1 patients using regular measures of α-fetoprotein and imaging. Ultrasound is mostly the modality of choice for surveillance, because it is widely available, it does not use radiation and is noninvasive. When a suspicious lesion is present, the higher sensitivity of MRI could be used for characterization and staging of lesions. At this moment, no HCC development in pre-symptomatically treated patients is reported. These different situations could possibly indicate that NTBC can prevent the start of the development of HCC when initiated early, but can't stop the development of HCC if it is prescribed at a later stage, stressing the importance of early diagnosis.


Assuntos
Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Tirosinemias/complicações , Tirosinemias/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Cicloexanonas/uso terapêutico , Detecção Precoce de Câncer/métodos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Nitrobenzoatos/uso terapêutico , Tirosinemias/metabolismo
14.
Adv Exp Med Biol ; 959: 111-122, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28755189

RESUMO

Clinically, Hereditary Tyrosinemia type I (HTI) is especially characterized by severe liver dysfunction in early life. However, recurrent neurological crises are another main finding in these patients when they are treated with a tyrosine and phenylalanine restricted diet only. This is caused by the accumulation of δ-aminolevulinic acid due to the inhibitory effect of succinylacetone on the enzyme that metabolizes δ-aminolevulinic acid. Due to the biochemical and clinical resemblance of these neurological crises and acute intermittent porphyria, this group of symptoms in HTI patients is mostly called porphyria-like-syndrome. The neurological crises in HTI patients disappeared after the introduction of treatment with 2-(2 nitro-4-3 trifluoro-methylbenzoyl)-1, 3-cyclohexanedione (NTBC). However, if NTBC treatment is stopped for a while, severe neurological dysfunction will reappear.If NTBC treatment is started early and given continuously, all clinical problems seem to be solved. However, recent research findings indicate that HTI patients have a non-optimal neurocognitive outcome, showing (among others) a lower IQ and impaired executive functioning and social cognition. Unfortunately the exact neuropsychological profile of these HTI patients is not known yet, neither are the exact pathophysiological mechanisms underlying these impairments. It may be hypothesized that the biochemical changes such as high blood tyrosine or low blood phenylalanine concentrations are important in this respect, but an direct toxic effect of NTBC or production of toxic metabolites (that previously characterized the disease before introduction of NTBC) cannot be excluded either. This chapter discusses the neurological and neuropsychological symptoms associated with HTI in detail. An extended section on possible underlying pathophysiological mechanisms of such symptoms is also included.


Assuntos
Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/patologia , Tirosinemias/complicações , Tirosinemias/patologia , Cicloexanonas/uso terapêutico , Humanos , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Nitrobenzoatos/uso terapêutico , Fenilalanina/metabolismo , Tirosina/metabolismo , Tirosinemias/tratamento farmacológico , Tirosinemias/metabolismo
15.
Adv Exp Med Biol ; 959: 197-204, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28755197

RESUMO

Since the introduction of 2-(2 nitro-4-3 trifluoro-methylbenzoyl)-1, 3-cyclohexanedione (NTBC), life expectancy of HT1 patients greatly improved. However, due to treatment with NTBC, tyrosine concentrations greatly increase. As a consequence to possible neurocognitive problems, the main objective of dietary therapy in HT1 is to provide adequate nutrition allowing normal growth and development while strictly controlling tyrosine levels in blood (and tissues). Although no well-defined target levels exist, tyrosine concentrations below 400 µmol/L are considered to be safe. To achieve this aim a diet restricted in natural protein and supplemented with a special tyrosine and phenylalanine-free amino acid mixture is necessary.Dietary management could be strenuous at diagnosis due to several different problems. If vomiting and diarrhea are a major issue at diagnosis, frequent feeding with additional energy from low protein food is needed for catch-up growth. Initiation of dietary treatment is usually easier if diagnosis is directly after birth. Based on newborn screening when infants are still reasonable healthy. If presenting clinically infants may experience serious difficulties in taking the amino acid mixtures probably due to feeding problems while when presenting after some 2-3 months taste development and the difference in the taste of amino acid mixtures compared to regular formula and breast milk increase difficulties with the treatment.Following a dietary treatment is even harder than taking some medicine. Older children and adolescents often relax the diet and at some age become reluctant to stick to a strict regimen. Therefore, adequate training and information should be given to the patients and the family at regular intervals. To achieve this, a multidisciplinary approach involving pediatricians/physicians, dieticians, psychologists and social workers is an asset for the care of patients with HT1.


Assuntos
Cicloexanonas/uso terapêutico , Nitrobenzoatos/uso terapêutico , Tirosinemias/dietoterapia , Tirosinemias/tratamento farmacológico , Dieta/métodos , Humanos , Fenilalanina/metabolismo , Tirosina/metabolismo , Tirosinemias/metabolismo
16.
Pediatr Nephrol ; 32(5): 733-741, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27289364

RESUMO

Methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type, is the most common genetic type of functional cobalamin (vitamin B12) deficiency. This metabolic disease is characterized by marked heterogeneity of neurocognitive disease (microcephaly, seizures, developmental delay, ataxia, hypotonia) and variable extracentral nervous system involvement (failure to thrive, cardiovascular, renal, ocular) manifesting predominantly early in life, sometimes during gestation. To enhance awareness and understanding of renal disease associated with cblC defect, we studied biochemical, genetic, clinical, and histopathological data from 36 patients. Consistent clinical chemistry features of renal disease were intravascular hemolysis, hematuria, and proteinuria in all patients, with nephrotic-range proteinuria observed in three. Renal function ranged from normal to renal failure, with eight patients requiring (intermittent) dialysis. Two thirds were diagnosed with atypical (diarrhea-negative) hemolytic uremic syndrome (HUS). Renal histopathology analyses of biopsy samples from 16 patients revealed glomerular lesions typical of thrombotic microangiopathy (TMA). Treatment with hydroxycobalamin improved renal function in the majority, including three in whom dialysis could be withdrawn. Neurological sequelae were observed in 44 % and cardiopulmonary involvement in 39 % of patients, with half of the latter group demonstrating pulmonary hypertension. Mortality reached 100 % in untreated patients and 79 and 56 % in those with cardiopulmonary or neurological involvement, respectively. In all patients presenting with unclear intravascular hemolysis, hematuria, and proteinuria, cblC defect should be ruled out by determination of blood/plasma homocysteine levels and/or genetic testing, irrespective of actual renal function and neurological status, to ensure timely diagnosis and treatment.


Assuntos
Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/genética , Idade de Início , Criança , Hematínicos/uso terapêutico , Síndrome Hemolítico-Urêmica/etiologia , Síndrome Hemolítico-Urêmica/genética , Síndrome Hemolítico-Urêmica/fisiopatologia , Humanos , Hidroxocobalamina/uso terapêutico , Testes de Função Renal , Transplante de Rim , Microangiopatias Trombóticas/fisiopatologia , Microangiopatias Trombóticas/terapia
17.
Orphanet J Rare Dis ; 11(1): 87, 2016 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-27356512

RESUMO

BACKGROUND: Hereditary Tyrosinemia type 1 (HT1) is a rare metabolic disorder caused by a defect in the enzyme Fumarylacetoacetate Hydrolase. Due to this defect, toxic products accumulate which, in turn, cause liver and kidney dysfunction. Treatment with 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and diet has diminished these problems, but recent data indicate that HT1 patients have neurocognitive problems. However, the neuropsychological profile of these patients is unknown. Therefore, this study aimed to investigate this neuropsychological profile by comparing HT1 patients with healthy controls. METHODS: Neurocognitive testing was performed in a heterogeneous group of 19 NTBC and dietary treated HT1 patients (five female, fourteen male; mean age 12.9 ± 4.8 years; range 7.9-23.6 years) and 19 age and gender matched controls (five female, fourteen male; mean age 13.2 ± 4.6 years; range 8.1-24.8 years). IQ scores were estimated and all participants performed the Amsterdam Neuropsychological Tasks, measuring executive functions (inhibition, cognitive flexibility and working memory) and social cognition (face recognition and identification of facial emotions). RESULTS: HT1 patients showed poorer estimated IQ, executive functioning (working memory and cognitive flexibility), and social cognition compared to healthy controls. Lower IQ scores in HT1 patients were mostly unrelated to scores on executive function- and social cognition tasks and therefore did not account for group differences in these domains. Further analyses within the HT1 patient group (comparing different groups of patients based on the age at diagnosis and the clinical symptoms at diagnosis) did not reveal any significant results. The duration of NTBC treatment was negatively correlated with IQ. CONCLUSIONS: Despite the heterogeneity of the patient group, these data clearly show that IQ, executive functioning and social cognition are affected in HT1 patients, and that IQ screening is not sufficient for cognitive monitoring of these patients. Further research should focus on the underlying pathophysiological mechanisms of these impairments to consequently try to improve treatment strategies.


Assuntos
Tirosinemias/fisiopatologia , Adolescente , Adulto , Criança , Cognição/fisiologia , Feminino , Humanos , Masculino , Memória de Curto Prazo/fisiologia , Testes Neuropsicológicos , Adulto Jovem
18.
Pediatrics ; 135(3): e749-52, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25667247

RESUMO

Patients with hereditary tyrosinemia type 1 have an elevated risk of developing hepatocellular carcinoma, especially if initiation of treatment with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione is delayed. Hepatocellular carcinoma can usually be suspected when there are increased α1-fetoprotein levels and characteristic imaging features. The present case shows that a lack of a clear increase in α1-fetoprotein should still lead to consideration of liver transplantation when imaging features change.


Assuntos
Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/etiologia , Tirosinemias/complicações , alfa-Fetoproteínas/metabolismo , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/diagnóstico , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Lactente , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , Imageamento por Ressonância Magnética , Tirosinemias/sangue , Tirosinemias/diagnóstico
19.
Orphanet J Rare Dis ; 9: 107, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25081276

RESUMO

BACKGROUND: Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data. METHODS: Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications. RESULTS: Early treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 µM) and NTBC-levels in the therapeutic range (20-40 µM). Side effects of NTBC are mild and often transient. Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood). CONCLUSION: Based on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.


Assuntos
Cicloexanonas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Triagem Neonatal/métodos , Nitrobenzoatos/uso terapêutico , Tirosinemias/diagnóstico , Tirosinemias/terapia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Cicloexanonas/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Falência Hepática/diagnóstico , Falência Hepática/cirurgia , Transplante de Fígado , Masculino , Nitrobenzoatos/efeitos adversos , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológico , Insuficiência Renal/diagnóstico , Insuficiência Renal/cirurgia , Estudos Retrospectivos , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
20.
N Engl J Med ; 370(6): 533-42, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24499211

RESUMO

BACKGROUND: Congenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest. METHODS: Homozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation. RESULTS: Phosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls. CONCLUSIONS: Phosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. (Funded by the Netherlands Organization for Scientific Research and others.).


Assuntos
Glucofosfatos/genética , Doença de Depósito de Glicogênio/genética , Fenótipo , Fosfoglucomutase/genética , Galactose/uso terapêutico , Genes Recessivos , Glucose/metabolismo , Glucofosfatos/metabolismo , Doença de Depósito de Glicogênio/dietoterapia , Doença de Depósito de Glicogênio/metabolismo , Glicoproteínas/biossíntese , Glicosilação , Humanos , Masculino , Mutação , Fosfoglucomutase/metabolismo , RNA Mensageiro/análise
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