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1.
Mol Genet Metab ; 141(3): 108144, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38277989

RESUMO

Glycogen storage disease type Ib (GSD Ib, biallelic variants in SLC37A4) is a rare disorder of glycogen metabolism complicated by neutropenia/neutrophil dysfunction. Since 2019, the SGLT2-inhibitor empagliflozin has provided a mechanism-based treatment option for the symptoms caused by neutropenia/neutrophil dysfunction (e.g. mucosal lesions, inflammatory bowel disease). Because of the rarity of GSD Ib, the published evidence on safety and efficacy of empagliflozin is still limited and does not allow to develop evidence-based guidelines. Here, an international group of experts provides 14 best practice consensus treatment recommendations based on expert practice and review of the published evidence. We recommend to start empagliflozin in all GSD Ib individuals with clinical or laboratory signs related to neutropenia/neutrophil dysfunction with a dose of 0.3-0.4 mg/kg/d given as a single dose in the morning. Treatment can be started in an outpatient setting. The dose should be adapted to the weight and in case of inadequate clinical treatment response or side effects. We strongly recommend to pause empagliflozin immediately in case of threatening dehydration and before planned longer surgeries. Discontinuation of G-CSF therapy should be attempted in all individuals. If available, 1,5-AG should be monitored. Individuals who have previously not tolerated starches should be encouraged to make a new attempt to introduce starch in their diet after initiation of empagliflozin treatment. We advise to monitor certain safety and efficacy parameters and recommend continuous, alternatively frequent glucose measurements during the introduction of empagliflozin. We provide specific recommendations for special circumstances like pregnancy and liver transplantation.


Assuntos
Compostos Benzidrílicos , Glucosídeos , Doença de Depósito de Glicogênio Tipo I , Neutropenia , Humanos , Neutrófilos/metabolismo , Consenso , Doença de Depósito de Glicogênio Tipo I/complicações , Doença de Depósito de Glicogênio Tipo I/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo I/genética , Neutropenia/tratamento farmacológico , Neutropenia/etiologia , Proteínas de Transporte de Monossacarídeos , Antiporters/metabolismo
2.
Cytokine ; 173: 156410, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37924740

RESUMO

Recently, it has been shown disturbances in oxidant/antioxidant system and increases in some inflammatory markers in animal studies and in some Mucopolysaccharidoses (MPSs) patients. In this study, we aimed to determine the oxidative stress/antioxidant parameters and pro-inflammatory cytokine levels in the serum of MPS patients, in order to evaluate the possible role of inflammation in these patient groups regarding to accumulated metabolites. MPS I (n = 3), MPS II (n = 8), MPS III (n = 4), MPS IVA (n = 3), MPS VI (n = 3), and VII (n = 1) patients and 20 age-matched healthy subjects were included into the study. There was no statistically significant change in activities of SOD, Catalase, GSH-Px and lipid peroxidation levels in erythrocytes between the MPS patients and healthy controls. While IL-1alpha (p = 0.054), IL-6 (p = 0.008) levels, and chitotriosidase activity (p = 0.003) elevated in MPS3 patients, IL1α (p = 0.006), IL-1ß (p = 0.006), IL-6 (p = 0.006), IFNγ (p = 0.006), and NFκB (p = 0.006) levels increased in MPS-6 patients. Elevated levels of IL-6, IL1α and chitotriosidase activity demonstrated macrophage activation in MPSIII untreated with enzyme replacement. Our study showed for the first time that high levels of IL1α, IL-6, IL1ß and NFκB were present in MPSVI patients, demonstrating the induction of inflammation by dermatan sulphate. The low level of paraoxonase in MPSVI patients may be a good marker for cardiac involvement. Overall, this study provides important insights into the relationship between lysosomal storage of glycosaminoglycan and inflammation in MPS patients. It highlights possible pathways for the increased release of inflammatory molecules and suggests new targets for the development of treatments.


Assuntos
Mucopolissacaridoses , Mucopolissacaridose VI , Animais , Humanos , Glicosaminoglicanos/metabolismo , Interleucina-6 , Antioxidantes , Mucopolissacaridoses/metabolismo , Inflamação
3.
Pediatr Blood Cancer ; 70(7): e30334, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37046411

RESUMO

BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder due to mutations in the TYMP gene. Clinical findings are characterized by neurologic manifestations and severe gastrointestinal dysfunction. The syndrome is usually fatal, the most effective treatment appears to be hematopoietic stem cell transplantation (HSCT). PROCEDURE: In this retrospective study, we evaluated HSCT that was performed using a reduced toxicity myeloablative conditioning regimen in patients with MNGIE at our center. RESULTS: A total of six allogeneic transplant procedures were performed in four patients. Three patients had fully matched donors, and one patient had a haploidentical donor. Treosulfan-based myeloablative conditioning regimen was applied in five of six transplants. Bone marrow was used as a stem cell source. One patient is being followed up in the 4th year of posttransplant with full chimeric and without graft versus host disease (GVHD). One patient died of acute stage IV gastrointestinal system GVHD. Two patients underwent second transplantation due to engraftment failure, one of which was the patient who had a haploidentical transplant. CONCLUSIONS: Treosulfan-based regimen is well tolerated, although engraftment failure with this conditioning regimen can be a significant problem. We share our haploidentical transplant experience, which will be the first reported case in the literature.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Estudos Retrospectivos , Transplante Homólogo/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Condicionamento Pré-Transplante/métodos
4.
BMC Med ; 20(1): 95, 2022 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-35341481

RESUMO

BACKGROUND: Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2'-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. METHODS: Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. RESULTS: All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients' phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. CONCLUSIONS: The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology.


Assuntos
Diabetes Mellitus Lipoatrófica , Insulinas , Adipócitos/metabolismo , Humanos , Insulinas/genética , Mutação , Timidina Fosforilase/genética , Timidina Fosforilase/metabolismo
5.
Genet Med ; 24(8): 1781-1788, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35503103

RESUMO

PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.


Assuntos
Doença de Depósito de Glicogênio Tipo I , Neutropenia , Adolescente , Adulto , Compostos Benzidrílicos , Criança , Pré-Escolar , Glucosídeos , Doença de Depósito de Glicogênio Tipo I/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo I/patologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Lactente , Recém-Nascido , Neutropenia/tratamento farmacológico , Estudos Retrospectivos , Inquéritos e Questionários , Adulto Jovem
6.
Blood Cells Mol Dis ; 76: 1-6, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30473482

RESUMO

Gaucher Disease (GD) is the most common lysosomal storage disorder has traditionally been classified into three clinical phenotypes. Type 3 GD is characterized by neurological involvement but neurological symptoms generally appear later in life than in type 2 disease. Neutropenia is much rarer than other hematological manifestations in GD and has not been scrutinized adequately. Severe congenital neutropenia (SCN) is a rare disease entity which is characterized by a paucity of peripherally circulating neutrophils with arrest of neutrophil maturation at the promyelocyte stage and consequent increased susceptibility to severe and recurrent infections. We report a patient who presented in the first year of life with visceral involvement and severe neutropenia in whom the propositus had a unique coexistence of Gaucher Disease and severe congenital neutropenia associated with a mutation in HAX1. In contrast to his expired siblings he had experienced no severe infections. These clinical observations suggest that enzyme replacement therapy may display a modulating factor with respect to the clinical course of SCN. SYNOPSIS: Our patient is the only report of the combination of Gaucher Disease and Kostmann Syndrome in the literature. The clinical course of our patient is not severe when comparing with exitus siblings and other Kostmann Syndrome patients. But when considering the patient's only clinical difference is ERT, this case is very important to emphasise the role of enzyme replacement therapy in bone marrow.


Assuntos
Terapia de Reposição de Enzimas , Doença de Gaucher/complicações , Neutropenia/congênito , Proteínas Adaptadoras de Transdução de Sinal/genética , Medula Óssea/efeitos dos fármacos , Síndrome Congênita de Insuficiência da Medula Óssea , Doença de Gaucher/tratamento farmacológico , Humanos , Lactente , Masculino , Mutação , Neutropenia/complicações
7.
Mol Genet Metab ; 122(1-2): 67-75, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28689740

RESUMO

2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency, also known as beta-ketothiolase deficiency, is an inborn error of ketone body utilization and isoleucine catabolism. It is caused by mutations in the ACAT1 gene and may present with metabolic ketoacidosis. In order to obtain a more comprehensive view on this disease, we have collected clinical and biochemical data as well as information on ACAT1 mutations of 32 patients from 12 metabolic centers in five countries. Patients were between 23months and 27years old, more than half of them were offspring of a consanguineous union. 63% of the study participants presented with a metabolic decompensation while most others were identified via newborn screening or family studies. In symptomatic patients, age at manifestation ranged between 5months and 6.8years. Only 7% developed a major mental disability while the vast majority was cognitively normal. More than one third of the identified mutations in ACAT1 are intronic mutations which are expected to disturb splicing. We identified several novel mutations but, in agreement with previous reports, no clear genotype-phenotype correlation could be found. Our study underlines that the prognosis in MAT deficiency is good and MAT deficient individuals may remain asymptomatic, if diagnosed early and preventive measures are applied.


Assuntos
Acetil-CoA C-Aciltransferase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/genética , Ácidos Graxos/metabolismo , Isoleucina/metabolismo , Corpos Cetônicos/metabolismo , Acetil-CoA C-Acetiltransferase/genética , Acetil-CoA C-Aciltransferase/genética , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Criança , Pré-Escolar , Consanguinidade , Feminino , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Triagem Neonatal , Prognóstico , Estudos Retrospectivos , Adulto Jovem
8.
Mol Genet Metab ; 121(3): 206-215, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28583327

RESUMO

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis and leucine degradation, caused by mutations in the HMGCL gene. In order to obtain a comprehensive view on this disease, we have collected clinical and biochemical data as well as information on HMGCL mutations of 37 patients (35 families) from metabolic centers in Belgium, Germany, The Netherlands, Switzerland, and Turkey. All patients were symptomatic at some stage with 94% presenting with an acute metabolic decompensation. In 50% of the patients, the disorder manifested neonatally, mostly within the first days of life. Only 8% of patients presented after one year of age. Six patients died prior to data collection. Long-term neurological complications were common. Half of the patients had a normal cognitive development while the remainder showed psychomotor deficits. We identified seven novel HMGCL mutations. In agreement with previous reports, no clear genotype-phenotype correlation could be found. This is the largest cohort of HMGCLD patients reported so far, demonstrating that HMGCLD is a potentially life-threatening disease with variable clinical outcome. Our findings suggest that the clinical course of HMGCLD cannot be predicted accurately from HMGCL genotype. The overall outcome in HMGCLD appears limited, thus rendering early diagnosis and strict avoidance of metabolic crises important.


Assuntos
Acetil-CoA C-Acetiltransferase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Bélgica , Criança , Pré-Escolar , Ácidos Graxos/metabolismo , Feminino , Estudos de Associação Genética , Alemanha , Humanos , Lactente , Corpos Cetônicos/metabolismo , Leucina/metabolismo , Masculino , Mutação , Países Baixos , Oxo-Ácido-Liases/genética , Avaliação de Resultados da Assistência ao Paciente , Suíça , Turquia , Adulto Jovem
9.
Metab Brain Dis ; 32(3): 675-678, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28281033

RESUMO

Biotinidase deficiency is characterized by severe neurological manifestations as hypotonia, lethargy, ataxia, hearing loss, seizures and developmental retardation in its classical form. Late-onset biotinidase deficiency presents distinctly from the classical form such as limb weakness and vision problems. A 14-year-old boy presented with progressive vision loss and upper limb weakness. The patient was initiated steroid therapy with a preliminary diagnosis of neuromyelitis optica spectrum disorder due to the craniospinal imaging findings demonstrating optic nerve, brainstem and longitudinally extensive spinal cord involvement. Although the patient exhibited partial clinical improvement after pulse steroid therapy, craniocervical imaging performed one month after the initiation of steroid therapy did not show any regression. The CSF IgG index was <0.8 (normal: <0.8), oligoclonal band and aquaporin-4 antibodies were negative. Metabolic investigations revealed a low biotinidase enzyme activity 8% (0.58 nmoL/min/mL; normal range: 4.4 to 12). Genetic testing showed c.98-104delinsTCC and p.V457 M mutations in biotinidase (BTD) gene. At the third month of biotin replacement therapy, control craniospinal MRI demonstrated a complete regression of the lesions. The muscle strength of the case returned to normal. His visual acuity was 7/10 in the left eye and 9/10 in the right. The late-onset form of the biotinidase deficiency should be kept in mind in all patients with myelopathy with or without vision loss, particularly in those with inadequate response to steroid therapy. The family screening is important to identify asymptomatic individuals and timely treatment.


Assuntos
Biotina/uso terapêutico , Deficiência de Biotinidase/diagnóstico por imagem , Neuromielite Óptica/diagnóstico por imagem , Doenças da Medula Espinal/diagnóstico por imagem , Transtornos da Visão/diagnóstico por imagem , Adolescente , Deficiência de Biotinidase/complicações , Deficiência de Biotinidase/tratamento farmacológico , Diagnóstico Diferencial , Humanos , Masculino , Neuromielite Óptica/complicações , Neuromielite Óptica/tratamento farmacológico , Doenças da Medula Espinal/complicações , Doenças da Medula Espinal/tratamento farmacológico , Resultado do Tratamento , Transtornos da Visão/complicações , Transtornos da Visão/tratamento farmacológico
10.
Neuropediatrics ; 46(2): 98-103, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25642805

RESUMO

Pediatric movement disorders are still a diagnostic challenge, as many patients remain without a (genetic) diagnosis. Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis. MEGDEL syndrome (3-MethylGlutaconic aciduria, Deafness, Encephalopathy, Leigh-like syndrome MIM #614739) is a clinically and biochemically highly distinctive dystonia deafness syndrome accompanied by 3-methylglutaconic aciduria, severe developmental delay, and progressive spasticity. Mutations are found in SERAC1, encoding a phosphatidylglycerol remodeling enzyme essential for both mitochondrial function and intracellular cholesterol trafficking. Based on the homogenous phenotype, we hypothesized an accordingly characteristic MRI pattern. A total of 43 complete MRI studies of 30 patients were systematically reevaluated. All patients presented a distinctive brain MRI pattern with five characteristic disease stages affecting the basal ganglia, especially the putamen. In stage 1, T2 signal changes of the pallidum are present. In stage 2, swelling of the putamen and caudate nucleus is seen. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease. It later increases, reflecting progressive putaminal involvement. This "eye" was found in all patients with MEGDEL syndrome during a specific age range, and has not been reported in other disorders, making it pathognomonic for MEDGEL and allowing diagnosis based on MRI findings.


Assuntos
Gânglios da Base/patologia , Surdez/patologia , Distúrbios Distônicos/patologia , Doenças Mitocondriais/patologia , Pré-Escolar , Surdez/complicações , Surdez/genética , Progressão da Doença , Distúrbios Distônicos/complicações , Distúrbios Distônicos/genética , Humanos , Lactente , Imageamento por Ressonância Magnética , Doenças Mitocondriais/complicações , Putamen/patologia , Síndrome
11.
Hum Genet ; 133(1): 29-39, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23982343

RESUMO

Proteoglycan (PG) synthesis begins with the sequential addition of a "linker chain", made up of four sugar residues, to a specific region of a core protein. Defects in the enzymes catalyzing steps two to four of the linker chain synthesis have been shown to cause autosomal recessive human phenotypes while no mutation has yet been reported in humans for the xylosyltransferases 1 and 2 (XT1 and XT2), the initiating enzymes in the linker chain formation. Here, we present a consanguineous Turkish family with two affected individuals presenting with short stature, distinct facial features, alterations of fat distribution, and moderate intellectual disability. X-rays showed only mild skeletal changes in the form of a short femoral neck, stocky and plump long bones and thickened ribs. Using a combination of whole-exome sequencing (WES), determination of homozygous stretches by WES variants, and classical linkage analysis, we identified the homozygous missense mutation c.C1441T in XYLT1, encoding XT1, within a large homozygous stretch on chromosome 16p13.12-p12.1. The mutation co-segregated with the phenotype in the family, is not found in over 13,000 alleles in the exome variant server and is predicted to change a highly conserved arginine at position 481 (p.R481W) located in the putative catalytical domain. Immunostaining of primary patient fibroblasts showed a loss of predominance of Golgi localization in mutant cells. Moreover, western blot analysis of decorin in cell culture supernatant demonstrated glycosylation differences between patient and control cells. Our data provide evidence that functional alterations of XT1 cause an autosomal recessive short stature syndrome associated with intellectual disability.


Assuntos
Nanismo/genética , Deficiência Intelectual/genética , Pentosiltransferases/genética , Consanguinidade , Exoma , Feminino , Genes Recessivos , Ligação Genética , Homozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Pentosiltransferases/metabolismo , Fenótipo , Proteoglicanas/metabolismo , Análise de Sequência de DNA , Síndrome , Turquia , Raios X , UDP Xilose-Proteína Xilosiltransferase
12.
Metab Brain Dis ; 29(3): 809-12, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24788897

RESUMO

X linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease characterized by progressive demyelination of the central nervous system, adrenocortical insufficiency and elevated levels of very long chain fatty acids (VLCFAs). It is caused by mutations in ABCD1 gene located at Xq28. More than 1,300 mutations have been identified to date which is unique to each patient. In this study we report the mutational analysis of 2 X-ALD patients (1 male and 1 female) showing variable clinical spectrum. The mutation analysis of the female patient revealed IVS5-6delC (c.1489-6delC) and p. P543L variations in compound heterozygous state. The male patient was found to be hemizygous for a novel mutation, p. R104P. In conclusion, while defining a novel mutation, the cases presented herein may contribute to the mutation and clinical spectrum of X-ALD.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/genética , Mutação , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP , Criança , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
J Pediatr Endocrinol Metab ; 37(1): 33-41, 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-37925743

RESUMO

OBJECTIVES: Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder of long-chain fatty acid oxidation. Three clinical phenotypes, lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form, have been described in CPT II deficiency. The myopathic form is usually mild and can manifest from infancy to adulthood, characterised by recurrent rhabdomyolysis episodes. The study aimed to investigate the clinical features, biochemical, histopathological, and genetic findings of 13 patients diagnosed with the myopathic form of CPT II deficiency at Ege University Hospital. METHODS: A retrospective study was conducted with 13 patients with the myopathic form of CPT II deficiency. Our study considered demographic data, triggers of recurrent rhabdomyolysis attacks, biochemical metabolic screening, and molecular analysis. RESULTS: Ten patients were examined for rhabdomyolysis of unknown causes. Two patients were diagnosed during family screening, and one was diagnosed during investigations due to increased liver function tests. Acylcarnitine profiles were normal in five patients during rhabdomyolysis. Genetic studies have identified a c.338C>T (p.Ser113Leu) variant homozygous in 10 patients. One patient showed a novel frameshift variant compound heterozygous with c.338C>T (p.Ser113Leu). CONCLUSIONS: Plasma acylcarnitine analysis should be preferred as it is superior to DBS acylcarnitine analysis in diagnosing CPT II deficiency. Even if plasma acylcarnitine analysis is impossible, CPT2 gene analysis should be performed. Our study emphasizes that CPT II deficiency should be considered in the differential diagnosis of recurrent rhabdomyolysis, even if typical acylcarnitine elevation does not accompany it.


Assuntos
Carnitina O-Palmitoiltransferase , Rabdomiólise , Humanos , Carnitina , Carnitina O-Palmitoiltransferase/genética , Estudos Retrospectivos , Rabdomiólise/etiologia , Rabdomiólise/genética
15.
Pediatr Int ; 54(5): 717-20, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23005907

RESUMO

Non-ketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder of glycine metabolism. We report a newborn case of NKH and discuss the effects of this rare disease on brain metabolism and structure together with amplitude-integrated electroencephalography, cranial magnetic resonance and magnetic resonance spectroscopy findings which are very rarely reported together so far.


Assuntos
Encéfalo/metabolismo , Hiperglicinemia não Cetótica/diagnóstico , Encéfalo/patologia , Eletroencefalografia , Feminino , Humanos , Hiperglicinemia não Cetótica/patologia , Recém-Nascido , Espectroscopia de Ressonância Magnética
16.
JIMD Rep ; 63(1): 25-28, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35028268

RESUMO

Galactose mutarotase (GALM) deficiency is an inherited metabolic disease caused by the deficiency of the first enzyme in the Leloir pathway. GALM deficiency was first reported in 2018. To date, eight cases have been reported. We are presenting two siblings with GALM deficiency; one patient presented with cataracts and her brother was asymptomatic. We evaluated the first case due to a cataract at 3 months old. She had elevated galactose and galactose-1-phosphate and normal galactose-1-phosphate uridylyltransferase (GALT) activity. Genetic analysis and other laboratory and clinical findings excluded galactokinase-1 (GALK1) and UDP-galactose 4'-epimerase (GALE) deficiencies. She had a homozygous mutation p. Gly277Arg (c.829G>A) in the GALM (NM_138801) gene. She was 3 years old at the last visit, and her physical examination was normal, except for cataracts. The same mutation was found to be homozygous in the patient's asymptomatic sibling during family screening. He had normal blood galactose and galactose-1-phosphate. This study highlights the importance of evaluating the whole galactose metabolism in terms of GALM deficiency in patients with cataracts.

17.
Turk J Pediatr ; 64(5): 946-950, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36305448

RESUMO

BACKGROUND: Methylmalonyl CoA epimerase (MCE) deficiency was first reported in 2006 and only a few cases have been reported so far. The clinical spectrum of MCE deficiency ranges from asymptomatic to lifethreatening metabolic decompensation attacks. CASE: Herein we report a patient diagnosed with MCE deficiency with recurrent acute metabolic ketoacidosis attacks and moderate MMA-uria that persisted in periods without decompensation. At presentation, organic acid profiles were dominated by increased 3 hydroxybutyrate. CONCLUSIONS: 3-Oxothiolase deficiency as a main ketolysis defects disorder was initially suspected. However, the subsequently repeated organic acid analyses demonstrated mild and persistent elevation of methylmalonic acid. This report provides a new phenotype of the clinical and biochemical characterization of MCE deficiency.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Humanos , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Racemases e Epimerases/genética
18.
J Pediatr Endocrinol Metab ; 35(7): 913-923, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35671204

RESUMO

OBJECTIVES: Alkaptonuria is a rare autosomal recessive genetic disorder resulting from the deficiency of homogentisate 1,2 dioxygenase (HGD), the third enzyme in the tyrosine degradation pathway. Homogentisic acid produced in excess oxidizes into ochronotic pigment polymer. Accumulation of this pigment in various tissues leads to systemic disease. METHODS: Clinical, laboratory, molecular findings and treatment characteristics of 35 patients followed up in Ege University Pediatric Nutrition, and Metabolism Department with the diagnosis of alkaptonuria were evaluated retrospectively. RESULTS: Twenty-four males (68.57%) and 11 females (31.42%) with a confirmed diagnosis of alkaptonuria from 32 different families were included in the study. We identified 11 different genetic variants; six of these were novel. c.1033C>T, c.676G>A, c.664G>A, c.731_734del, c.1009G>T, c.859_862delins ATAC were not previously reported in the literature. 24 (68.57%) patients only adhered to a low-protein diet in our study group. Seven (20%) patients initiated a low protein diet and NTBC therapy. Mean urinary HGA decreased by 88.7% with nitisinone. No statistical changes were detected in urinary HGA excretion with the low protein diet group. CONCLUSIONS: In our study, alkaptonuria patients were diagnosed at different ages, from infancy to adulthood, and progressed with other systemic involvement in the follow-up. Since the initial period is asymptomatic, giving potentially effective treatment from an early age is under discussion. Raising disease awareness is very important in reducing disease mortality and morbidity rates.


Assuntos
Alcaptonúria , Adulto , Alcaptonúria/diagnóstico , Alcaptonúria/epidemiologia , Alcaptonúria/genética , Criança , Feminino , Seguimentos , Homogentisato 1,2-Dioxigenase/genética , Homogentisato 1,2-Dioxigenase/metabolismo , Ácido Homogentísico/metabolismo , Humanos , Masculino , Estudos Retrospectivos , Tirosina
19.
Eur J Pediatr ; 169(2): 241-3, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19434424

RESUMO

Betaine therapy was given for 2 years to a 2-year-old boy with 5,10-methylenetetrahydrofolate reductase deficiency. Used as a methyl donor to lower homocysteine levels through methylation of methionine, betaine has been reported to be effective in treating homocystinuria. Satisfactory biochemical and clinical responses were obtained with the following regimen: betaine started in the newborn period at increasing doses to reach 1 g given six times a day. It is suggested that frequent administration of a moderate dose may provide clinical and biochemical benefit.


Assuntos
5,10-Metilenotetra-Hidrofolato Redutase (FADH2)/deficiência , Betaína/administração & dosagem , Deficiência de Ácido Fólico/tratamento farmacológico , 5,10-Metilenotetra-Hidrofolato Redutase (FADH2)/sangue , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Deficiência de Ácido Fólico/enzimologia , Seguimentos , Homocisteína/sangue , Homocisteína/efeitos dos fármacos , Humanos , Lipotrópicos/administração & dosagem , Masculino , Fatores de Tempo
20.
Talanta ; 209: 120558, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31892015

RESUMO

Cystinosis is an autosomal recessive disorder characterized by the accumulation of cystine in lysosomes, causing irreversible damage to organs, especially the kidneys. Intracellular leukocyte cystine concentrations are used to diagnose cystinosis and to monitor cysteamine treatment. The aim of this study was to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method without derivatization capable of measuring leukocyte intracellular cystine concentrations. During development, the effects of using three different protein precipitation agents were evaluated in terms of sensitivity and the matrix effect, with 12% trichloroacetic acid providing the highest sensitivity. The effects of different blood collection tubes were also assessed in terms of recovery, matrix effect, and protein content. Compared to other methods, our method was quicker (run time of 3 min), was linear over the range 0.078-100 µM, and had lower limits of detection (0.0192 µM) and quantification (0.0582 µM). The intra-day and inter-day reproducibility %CVs were ≤10%. and the method had excellent recovery rates (94%-106%). Other parameters including matrix selectivity, injection carryover, leukocyte lysate stability were also validated and met the acceptance criterias of European Medicines Agency (EMA) Guideline. The assay was successfully applied to quantify cystine leukocyte concentration in healthy and cystinosis patients.


Assuntos
Cistina/análise , Cistinose/diagnóstico , Leucócitos/química , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodos , Cistinose/sangue , Humanos , Limite de Detecção
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