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1.
Mol Genet Metab Rep ; 37: 101020, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38053940

RESUMO

Ornithine transcarbamylase deficiency (OTCD) is an X-linked defect of ureagenesis and the most common urea cycle disorder. Patients present with hyperammonemia causing neurological symptoms, which can lead to coma and death. Liver transplantation (LT) is the only curative therapy, but has several limitations including organ shortage, significant morbidity and requirement of lifelong immunosuppression. This study aims to identify the characteristics and outcomes of patients who underwent LT for OTCD. We conducted a retrospective study for OTCD patients from 5 UK centres receiving LT in 3 transplantation centres between 2010 and 2022. Patients' demographics, family history, initial presentation, age at LT, graft type and pre- and post-LT clinical, metabolic, and neurocognitive profile were collected from medical records. A total of 20 OTCD patients (11 males, 9 females) were enrolled in this study. 6/20 had neonatal and 14/20 late-onset presentation. 2/20 patients had positive family history for OTCD and one of them was diagnosed antenatally and received prospective treatment. All patients were managed with standard of care based on protein-restricted diet, ammonia scavengers and supplementation with arginine and/or citrulline before LT. 15/20 patients had neurodevelopmental problems before LT. The indication for LT was presence (or family history) of recurrent metabolic decompensations occurring despite standard medical therapy leading to neurodisability and quality of life impairment. Median age at LT was 10.5 months (6-24) and 66 months (35-156) in neonatal and late onset patients, respectively. 15/20 patients had deceased donor LT (DDLT) and 5/20 had living related donor LT (LDLT). Overall survival was 95% with one patient dying 6 h after LT. 13/20 had complications after LT and 2/20 patients required re-transplantation. All patients discontinued dietary restriction and ammonia scavengers after LT and remained metabolically stable. Patients who had neurodevelopmental problems before LT persisted to have difficulties after LT. 1/5 patients who was reported to have normal neurodevelopment before LT developed behavioural problems after LT, while the remaining 4 maintained their abilities without any reported issues. LT was found to be effective in correcting the metabolic defect, eliminates the risk of hyperammonemia and prolongs patients' survival.

2.
Biomedicines ; 11(8)2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37626723

RESUMO

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder with high unmet needs, as current dietary and medical treatments may not be sufficient to prevent hyperammonemic episodes, which can cause death or neurological sequelae. To date, liver transplantation is the only curative choice but is not widely available due to donor shortage, the need for life-long immunosuppression and technical challenges. A field of research that has shown a great deal of promise recently is gene therapy, and OTCD has been an essential candidate for different gene therapy modalities, including AAV gene addition, mRNA therapy and genome editing. This review will first summarise the main steps towards clinical translation, highlighting the benefits and challenges of each gene therapy approach, then focus on current clinical trials and finally outline future directions for the development of gene therapy for OTCD.

3.
Eur J Med Genet ; 66(6): 104764, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37061027

RESUMO

Gaucher disease (GD) is the most frequent lysosomal storage disorder due to biallelic pathogenic variants in GBA gene. Only homozygous D409H variant has been associated with the cardiovascular phenotype which is also known as Gaucher disease type 3c. In this descriptive study, we presented phenotypic heterogeneity and a novel clinical finding among 13 patients with GD type 3c. Patients presented with varying degrees of cardiac valve and/or aortic calcifications (84,6%) and corneal opacities (76,9%) in addition to visceral (100%), hematological (92,3%), neurological (92,3%), and skeletal (30%) manifestations. Also, cervical dystonia (38,4%) and psychiatric disorders (46,1%) were not infrequent entities with respect to neurological involvement in GD type 3c. In this report, we highlight transient neonatal cholestasis (38,4%) as a novel finding in GD type 3c. Neonatal cholestasis is a finding associated with Gaucher type 2, but transient neonatal cholestasis has not been reported in GD patients, so far. The clinical features of GD type 3c are highly heterogeneous, from disease severity or age of onset to disease progression. Also, we concluded that phenotypic spectrum may be associated with age at onset of clinical symptoms. As, patients presenting in infancy or childhood had mainly visceral and hematological involvement and patients presenting in adolescence and adulthood had mainly cardiac, neurological involvement, and psychiatric behavioral disorders. Identifying the heterogeneous clinical course of these patients in this fatal disease, may lead a sufficient understanding of the pathophysiology which will enable targeted therapeutic interventions.


Assuntos
Doença de Gaucher , Hepatopatias , Humanos , Recém-Nascido , Doença de Gaucher/genética , Doença de Gaucher/patologia , Glucosilceramidase/genética , Mutação , Fenótipo , Homozigoto
4.
EMBO Mol Med ; 15(4): e17285, 2023 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-36846970

RESUMO

Over the last two decades, gene therapy has given hope of potential cure for many rare diseases. In the simplest form, gene therapy is the transfer or editing of a genetic material to cure a disease via nonviral or viral vehicles. Gene therapy can be performed either in vivo by injecting a vector carrying the gene or tools for gene editing directly into a tissue or into the systemic circulation, or ex vivo when patient cells are genetically modified outside of the body and then introduced back into the patient (Yilmaz et al, 2022). Adeno-associated viral vectors (AAV) have been the vectors of choice for in vivo gene therapy. There has been a lot of promising research on the development of novel tissue and cell-specific serotypes in order to improve efficacy and safety for clinical applications (Kuzmin et al, 2021). In this issue of EMBO Molecular Medicine, Boffa and colleagues present a novel AAV-based liver-directed gene therapy for ornithine aminotransferase deficiency.


Assuntos
Vetores Genéticos , Fígado , Humanos , Terapia Genética , Dependovirus/genética
5.
Life (Basel) ; 12(11)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36362876

RESUMO

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle defect. The disease severity ranges from asymptomatic carrier state to severe neonatal presentation with hyperammonaemic encephalopathy. We audited the diagnosis and management of OTCD, using an online 12-question-survey that was sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres responded and 495 patients were reported in total. A total of 208 French patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51 (25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%) males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic females. A total of 19%, 12% and 7% of the patients presented with a neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting, altered mental status and encephalopathy were the most common initial symptoms in all three countries. While 69% in France and 79% in Turkey were receiving protein restriction, 42% were on a protein-restricted diet in the UK. A total of 76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey, France and the UK, respectively. The findings of our audit emphasize the differences and similarities in manifestations and management practices in three countries.

6.
J Bone Miner Metab ; 40(3): 498-507, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35066680

RESUMO

INTRODUCTION: This study aimed to evaluate the relationship between clinical findings, height and weight standard deviation scores, 25-hydroxyvitamin D3 (25(OH)D3) level, and dual-energy X-ray absorptiometry (DXA) results in patients diagnosed with mucopolysaccharidosis (MPS), where effective current treatments such as enzyme replacement therapy (ERT) can be accessed. MATERIALS AND METHODS: 25(OH)D3 level was measured in 126 patients with MPS (17 with MPS I, 14 with MPS II, 18 with MPS III, 33 with MPS IVA, and 44 with MPS VI; 24-524 months). DXA was performed in 45 of these patients (8 with MPS I, 4 with MPS II, 4 with MPS III, 12 with MPS IVA, and 17 with MPS VI; 62-197 months; all patients were under 18 when DXA was performed) to assess bone mineral density (BMD) of the lumbar spine. RESULTS: In total, 67.5% patients had a short stature, and 50% of them were underweight for their age. Of the patients, 13.5% were immobile, 28.6% had 25(OH)D3 deficiency, and 30.2% had an insufficient level of 25(OH)D3. BMD z score of 45 patients was - 2.5 ± 1.7. In 40% patients, it was < - 2. However, after correction for height-for-age z score (HAZ), HAZ-adjusted BMD z score was - 0.1 ± 0.9. In 2.2% patients, it was < - 2. CONCLUSION: The low BMD z score prevalence reported with DXA was misleadingly higher in children with MPS and short stature. To prevent exposure to unnecessary antiresorptive treatments in these children, the effect of severe short stature and bone geometry on DXA measurements should be considered; further studies on bone health are warranted.


Assuntos
Mucopolissacaridoses , Mucopolissacaridose III , Mucopolissacaridose IV , Absorciometria de Fóton/métodos , Densidade Óssea , Osso e Ossos/diagnóstico por imagem , Criança , Humanos , Mucopolissacaridoses/complicações
7.
J Pediatr Endocrinol Metab ; 35(4): 535-541, 2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-34883004

RESUMO

OBJECTIVES: Niemann-Pick type C (NPC) disease is a rare progressive neurodegenerative condition that is characterized by the accumulation of cholesterol, glycosphingolipids, and sphingosine in lysosomes. Patients have various systemic and neurological findings depending on their age at onset. This disease is caused by the autosomal recessive transmission of mutations in the NPC1 and NPC2 genes; patients have mutations mainly in the NPC1 gene (95%) and the majority of them are point mutations located in the exonic regions. CASE PRESENTATION: Here, we presented three cousins with hepatosplenomegaly and progressive neurodegeneration who were diagnosed with visceral-neurodegenerative NPC disease. Their parents were relatives, and they had a history of sibling death with similar complaints. Bone marrow smear showed foamy cells in patient 1. Vertical supranuclear gaze palsy was not present in all cases. Sphingomyelinase (SM) activities were almost normal to exclude NPA or NPB. Filipin staining was performed in patient 2 and showed a massive accumulation of unesterified cholesterol The NPC1 gene analysis of the three patients showed a novel homozygous c.1553+5G>A intronic mutation. cDNA analysis was performed from the patient 3 and both parents. It was observed that exon 9 was completely skipped in the homozygous mutant baby. Both the normal and the exon 9-skipped transcripts have been detected in the parents. CONCLUSIONS: When combined with the filipin staining and the patients' clinical outcomes, this mutation is likely to be deleterious. Moreover, cDNA sequencing supports the pathogenicity of this novel variant.


Assuntos
Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C , Colesterol , Éxons , Humanos , Íntrons/genética , Mutação , Proteína C1 de Niemann-Pick/genética , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/genética , Turquia
8.
Neuropediatrics ; 52(5): 358-369, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578440

RESUMO

BACKGROUND: Glutaric aciduria type 1(GA-1) is an inherited cerebral organic aciduria. Untreated patients with GA-1 have a risk of acute encephalopathic crises during the first 6 years of life. In so far as GA-1 desperately does not exist in Turkish newborn screening (NBS) program, most patients in our study were late-diagnosed. METHOD: This study included 41 patients diagnosed with acylcarnitine profile, urinary organic acids, mutation analyses in the symptomatic period. We presented with clinical, neuroradiological, and molecular data of our 41 patients. RESULTS: The mean age at diagnosis was 14.8 ± 13.9 (15 days to 72 months) and, high blood glutaconic acid, glutarylcarnitine and urinary glutaric acid (GA) levels in 41 patients were revealed. Seventeen different mutations in the glutaryl-CoA dehydrogenase gene were identified, five of which were novel. The patients, most of whom were late-diagnosed, had a poor neurological outcome. Treatment strategies made a little improvement in dystonia and the frequency of encephalopathic attacks. CONCLUSION: All GA-1 patients in our study were severely affected since they were late-diagnosed, while others show that GA-1 is a treatable metabolic disorder if it is diagnosed with NBS. This study provides an essential perspective of the severe impact on GA-1 patients unless it is diagnosed with NBS. We immediately advocate GA-1 to be included in the Turkish NBS.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Encefalopatias Metabólicas , Erros Inatos do Metabolismo dos Aminoácidos/genética , Glutaratos , Glutaril-CoA Desidrogenase/deficiência , Humanos , Recém-Nascido , Triagem Neonatal
9.
Turk J Med Sci ; 51(3): 1220-1228, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-33453710

RESUMO

Background/aim: Isolated methylmalonic acidemia (MMA) is caused by complete or partial deficiency of the enzyme methylmalonyl- CoA mutase (mut0 or mut­ enzymatic subtype), a defect of its cofactor adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. While onset of the disease ranges from the neonatal period to adulthood, most cases present with lethargy, vomiting and ketoacidosis in the early infancy. Major secondary complications are; growth failure, developmental delay, interstitial nephritis with progressive renal failure, basal ganglia injury and cardiomyopathy. We aimed to demonstrate clinical and molecular findings based on long-term follow up in our patient cohort. Materials and methods: The study includes 37 Turkish patients with isolated MMA who were followed up for long term complications 1 to 14 years. All patients were followed up regularly with clinical, biochemical and dietary monitoring to determine long term complications. Next Generation Sequencing technique was used for mutation screening in five disease-causing genes including; MUT, MMAA, MMAB, MMADHC, MCEE genes. Mutation screening identified 30 different types of mutations. Results: While 28 of these mutations were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T(c.752+1G>T) has been reported. The most common clinical complications were growth retardation, renal involvement, mental motor retardation and developmental delay. Furthermore, one of our patients developed cardiomyopathy, another one died because of hepatic failure and one presented with lactic acidosis after linezolid exposure. Conclusion: We have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. We confirm the genotype-phenotype correlation in the study population according to the long-term complications.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Proteínas de Transporte da Membrana Mitocondrial , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/genética , Humanos , Ácido Metilmalônico , Metilmalonil-CoA Mutase/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Mutação
10.
J Inherit Metab Dis ; 44(1): 129-147, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32944950

RESUMO

Mucopolysaccharidosis type III (MPS III) or Sanfilippo disease is an orphan inherited lysosomal storage disease and one of the most common MPS subtypes. The classical presentation is an infantile-onset neurodegenerative disease characterised by intellectual regression, behavioural and sleep disturbances, loss of ambulation, and early death. Unlike other MPS, no disease-modifying therapy has yet been approved. Here, we review the numerous approaches of curative therapy developed for MPS III from historical ineffective haematopoietic stem cell transplantation and substrate reduction therapy to the promising ongoing clinical trials based on enzyme replacement therapy or adeno-associated or lentiviral vectors mediated gene therapy. Preclinical studies are presented alongside the most recent translational first-in-man trials. In addition, we present experimental research with preclinical mRNA and gene editing strategies. Lessons from animal studies and clinical trials have highlighted the importance of an early therapy before extensive neuronal loss. A disease-modifying therapy for MPS III will undoubtedly mandate development of new strategies for early diagnosis.


Assuntos
Mucopolissacaridose III/terapia , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Terapia de Reposição de Enzimas , Edição de Genes/métodos , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Chaperonas Moleculares/uso terapêutico , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/fisiopatologia , RNA Mensageiro/genética
11.
Int J Mol Sci ; 21(14)2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32709131

RESUMO

Niemann Pick disease type C (NPC) is a neurovisceral disorder due to mutations in NPC1 or NPC2. This review focuses on poorly characterized clinical and molecular features of early infantile form of NPC (EIF) and identified 89 cases caused by NPC1 (NPC1) and 16 by NPC2 (NPC2) mutations. Extra-neuronal features were common; visceromegaly reported in 80/89 NPC1 and in 15/16 NPC2, prolonged jaundice in 30/89 NPC1 and 7/16 NPC2. Early lung involvement was present in 12/16 NPC2 cases. Median age of neurological onset was 12 (0-24) and 7.5 (0-24) months in NPC1 and NPC2 groups, respectively. Developmental delay and hypotonia were the commonest first detected neurological symptoms reported in 39/89 and 18/89 NPC1, and in 8/16 and 10/16 NPC2, respectively. Additional neurological symptoms included vertical supranuclear gaze palsy, dysarthria, cataplexy, dysphagia, seizures, dystonia, and spasticity. The following mutations in homozygous state conferred EIF: deletion of exon 1+promoter, c.3578_3591 + 9del, c.385delT, p.C63fsX75, IVS21-2delATGC, c. 2740T>A (p.C914S), c.3584G>T (p.G1195V), c.3478-6T>A, c.960_961dup (p.A321Gfs*16) in NPC1 and c.434T>A (p.V145E), c.199T>C (p.S67P), c.133C>T (p.Q45X), c.141C>A (p.C47X) in NPC2. This comprehensive analysis of the EIF type of NPC will benefit clinical patient management, genetic counselling, and assist design of novel therapy trials.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Doença de Niemann-Pick Tipo C/genética , Proteínas de Transporte Vesicular/genética , Progressão da Doença , Humanos , Lactente , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/patologia , Doença de Niemann-Pick Tipo C/fisiopatologia
12.
Turk J Pediatr ; 61(3): 330-336, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31916709

RESUMO

Kör D, Seker-Yilmaz B, Bulut FD, Kilavuz S, Öktem M, Ceylaner S, Yildizdas D, Önenli-Mungan N. Clinical features of 27 Turkish Propionic acidemia patients with 12 novel mutations. Turk J Pediatr 2019; 61: 330-336. Propionic acidemia (PA) is an inherited metabolic disease caused by the deficiency of one of the four biotin-dependent enzymes propionyl-CoA carboxylase (PCC), and is characterized by coma and death in unrecognized patients, additionally late diagnosis leads to severe developmental delay and neurological sequels. Manifestations of PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other rarely reported complications include optic atrophy, hearing loss, premature ovarian insufficiency, and chronic renal failure. Mutations in PCCA-PCCB genes cause the clinically heterogeneous disease of PA. In this study, we investigate the mutation spectrum of PCCAPCCB genes and phenotypic features of 27 Turkish patients with PA from the South and Southeast parts of Turkey. We report 12 novel PA mutations, five affecting the PCCA gene and 7 affecting the PCCB gene.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Metilmalonil-CoA Descarboxilase/genética , Mutação , Acidemia Propiônica/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fenótipo , Estudos Retrospectivos , Turquia
13.
Metab Brain Dis ; 33(4): 1223-1227, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29656334

RESUMO

Gaucher disease is the most common lysosomal storage disorder due to glucosylceramidase enzyme deficiency. There are three subtypes of the disease. Neurological involvement accompanies visceral and haematological findings only in type II and type III Gaucher patients. Type II is the acute progressive neuronopathic form which is the most severe and rare subtype. Clinical findings are recognized prenatally or in the first months of life and followed by death within the first two years of age. Among our 81 Gaucher patients, we identified 4 (4,9%) type II patients in our metabolic centre. This rate is significantly higher than the rate reported in the literature (<1%). Three of the patients had novel mutations, one of them was a collodion baby and the other one was mistyped as type III due to its atypical presentation at the beginning and he was treated with ERT for 8 months. In this report, we present our type II Gaucher patients with three novel mutations and one perinatal lethal form with generalized ichthyosis which is a very rare disorder. Additionally, we would like to highlight the phenotypic heterogeneity not only between the subtypes, also even in the same type.


Assuntos
Doença de Gaucher/genética , Glucosilceramidase/genética , Mutação , Análise Mutacional de DNA , Humanos , Lactente , Masculino , Turquia
14.
J Pediatr Endocrinol Metab ; 31(3): 339-343, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29353266

RESUMO

BACKGROUND: Biotinidase deficiency (BD) is an autosomal recessive inborn error of metabolism characterized by neurologic and cutaneous symptoms and can be detected by newborn screening. Newborn screening for BD was implemented in Turkey at the end of 2008. METHODS: In total, 203 patients who were identified among the infants detected by the newborn screening were later confirmed to have BD through measurement of serum biotinidase activity. We also performed BTD mutation analysis to characterize the genetic profile. RESULTS: Twenty-seven mutations were identified. The most commonly found variants were c.1330G>C (p.D444H), c.1595C>T (p.T532M), c.470G>A (p.R157H), and c.198_104delGCGGCTGinsTCC (p.C33Ffs ) with allele frequencies of 0.387, 0.175, 0.165 and 0.049, respectively. Three novel pathogenic and likely pathogenic variants were identified: p.W140* (c.419G>A), p.S319F (c.956C>T) and p.L69Hfs*24 (c.192_193insCATC). We also identified three mutations reported in just one patient in the past (p.V442Sfs*59 [c.1324delG], p.H447R [c.1340A>G] and p.198delV [c.592_594delGTC]). Although all of the patients were asymptomatic under the treatment of biotin, only one patient, who had the novel c.419G>A homozygous mutation became symptomatic during an episode of acute gastroenteritis with a presentation of ketosis and metabolic acidosis. Among the screened patients, 156 had partial and 47 had profound BD. CONCLUSIONS: We determined the mutation spectra of BD from the southeastern part of Turkey. The results of this study add three more mutations to the total number of mutations described as causing BD.


Assuntos
Deficiência de Biotinidase/genética , Biotinidase/genética , Mutação , Biotina/administração & dosagem , Biotinidase/sangue , Deficiência de Biotinidase/tratamento farmacológico , Frequência do Gene , Homozigoto , Humanos , Recém-Nascido , Triagem Neonatal , Turquia
15.
Metab Brain Dis ; 33(3): 977-979, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29159724

RESUMO

Ethylmalonic encephalopathy is a very rare autosomal recessively inherited inborn error of metabolism; characterized by encephalopathy, recurrent petechiae without bleeding diathesis, chronic diarrhea, and orthostatic acrocyanosis. Here, we describe a case of ethylmalonic encephalopathy with late onset neurologic symptoms and a confusing family history of two deceased brothers with the wrong suspicion of short chain acyl-CoA dehydrogenase deficiency.


Assuntos
Acil-CoA Desidrogenase/deficiência , Encefalopatias Metabólicas Congênitas/diagnóstico , Erros de Diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Púrpura/diagnóstico , Humanos , Lactente , Masculino
16.
Turk J Pediatr ; 59(3): 311-314, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29376577

RESUMO

Seker-Yilmaz B, Kör D, Tümgör G, Ceylaner S, Önenli-Mungan N. p.Val452Ile mutation of the SLC25A13 gene in a Turkish patient with citrin deficiency. Turk J Pediatr 2017; 59: 311-314. Citrin deficiency is an autosomal recessive metabolic disorder, which is caused by pathogenic mutations in the SLC25A13 gene on chromosome 7q21.3, as the causative gene that encodes the liver type aspartate/glutamate carrier isoform 2 (AGC2). One of the main clinical presentations is neonatal intrahepatic cholestatic hepatitis caused by citrin deficiency. We report a Turkish child presented with prolonged neonatal jaundice associated with elevated plasma citrulline and galactosuria. NICCD was suspected at this point and mutation study of SLC25A13 showed that she was homozygous for the missense NM_014251.2:c.1354G > A (NP_055066.1:p.Val452Ile) (dbSNP: rs143877538) mutation. Dramatic response was observed to the dietary treatment with medium-chain triglycerides containing formula, ursodeoxycholic acid and fat-soluble vitamin supplementation. The minor allele frequency of this variant was given as nearly as 0.01 in the South Asian population; it seems like a disease causing variant. This is the first report of this variant in the Turkish and European population.


Assuntos
Citrulinemia/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Criança , Citrulina/sangue , Citrulinemia/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Fórmulas Infantis , Icterícia Neonatal/etiologia , Masculino , Mutação de Sentido Incorreto , Serina/sangue , Treonina/sangue , Turquia
17.
Turk J Pediatr ; 59(4): 434-441, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29624224

RESUMO

Seker-Yilmaz B, Kör D, Bulut FD, Yüksel B, Karabay-Bayazit A, Topaloglu AK, Ceylaner G, Önenli-Mungan N. Impaired glucose tolerance in Fanconi-Bickel syndrome: Eight patients with two novel mutations. Turk J Pediatr 2017; 59: 434-441. Fanconi-Bickel syndrome (FBS) is a rare, autosomal recessive disorder of carbohydrate metabolism caused by defects in the facilitative glucose transporter 2 (GLUT2 or SLC2A2) gene. Prominent findings are failure to thrive, renal tubular acidosis, hypoglycemia and postprandial hyperglycemia even mimicking diabetes mellitus. Eight patients from 6 families with FBS were included in this study. c.482_483insC homozygous mutation was detected in six patients from four different families. Mutation analysis of SLC2A2 gene revealed two novel homozygous mutations; c.1069delGinsAATAA and c.575A > G. Standard oral glucose tolerance test with 1.75 g/kg oral glucose was performed in six of the patients who were older than 3-years of age. Impaired glucose tolerance was found in all patients as expected and two of them had overt diabetes. None of the antidiabetic medications were given to them in order to avoid significant hypoglycemia. Beside the conservative treatment, follow up with frequent oral glucose tolerance tests are planned. We report these cases of FBS, as GSD XI is rare, two novel mutations were detected and also to highlight the risk of diabetes mellitus; although there is not a consensus about the treatment.


Assuntos
Síndrome de Fanconi/genética , Intolerância à Glucose/genética , Transportador de Glucose Tipo 2/genética , Adolescente , Pré-Escolar , Análise Mutacional de DNA , Síndrome de Fanconi/complicações , Feminino , Intolerância à Glucose/etiologia , Teste de Tolerância a Glucose/métodos , Homozigoto , Humanos , Lactente , Masculino , Mutação
18.
Turk J Pediatr ; 58(4): 362-370, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28276207

RESUMO

We have conducted this study for the purposes of demonstrating the spectrum of mutations and of identifying their effects on the phenotype, with a particular focus on the clinical course, prognosis and response to treatment. A total of 25 patients from 20 families, who have been treated and followed up after being diagnosed with cystinosis. Nine patients were identified with mutations of homozygous c.451A > G, 7 patients with homozygous c.681G > A, 6 patients with homozygous c.834_842del, 2 patients with homozygous c.18_21delGACT and 1 patient with compound heterozygous for c.451A > G/ c.1015G > A. The c.834_842del mutation identified in six patients from four families has not been previously identified. Progression to renal failure occurred earlier in the patients identified with the new mutation, despite treatment. Larger patient series are required to demonstrate the genotypic properties of the patients with cystinosis and their relationship with the clinical course.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinose/genética , Adolescente , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação , Linhagem , Fenótipo , Turquia , Adulto Jovem
19.
Pediatr Neurol ; 48(1): 52-5, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23290021

RESUMO

Our study sought to identify early predictive factors of medically intractable childhood epilepsy. A cohort of epileptic children from the city of Mersin was retrospectively investigated. All patients received care from the same Department of Pediatric Neurology. The epileptic cohort was divided into a drug-responsive epilepsy group and an intractable epilepsy group. Intractable epilepsy is defined as continued seizures in children despite adequate therapy with two or more antiepileptic drugs for more than 18 months. Strong univariate association was observed between intractability and several factors: age of onset, high initial seizure frequency, symptomatic etiology, mixed seizure types, previous history of status epilepticus, febrile and neonatal seizures, mental and motor developmental delay, multiple seizures in 1 day, electroencephalogram abnormalities, magnetic resonance imaging findings, and specific epileptic syndromes. Logistic regression analysis revealed that a previous history of epilepticus status, abnormal electroencephalogram results, and multiple seizures in 1 day comprise independent predictors of medically intractable childhood epilepsy. We suggest that medical intractability in childhood epilepsy can be predicted by monitoring these factors. Along with early prediction, alternative therapies may be designed to provide patients better seizure control and quality of life.


Assuntos
Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Adolescente , Anticonvulsivantes/uso terapêutico , Encéfalo/patologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/classificação , Epilepsia/tratamento farmacológico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Prontuários Médicos , Análise Multivariada , Valor Preditivo dos Testes
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