RESUMO
OBJECTIVES: Phenylalanine hydroxylase (PAH) is predominantly a hepatic enzyme that catalyzes phenylalanine (Phe) into tyrosine, which is the rate-limiting step in Phe catabolism. Biallelic variants in the PAH gene cause PAH enzyme deficiency. Phenylketonuria (PKU) is an autosomal recessive disorder that causes neurologic, behavioral, and dermatological findings. PKU could be divided clinically into three types based on the blood Phe levels: classic phenylketonuria (cPKU), mild-moderate phenylketonuria (mPKU), and mild hyperphenylalaninemia (MHP). This study aimed to determine the phenotypic and genotypic characteristics of Turkish PKU patients in the eastern region of Türkiye. METHODS: Demographic characteristics, serum Phe levels, treatments, and PAH variants of 163 patients with PKU and hyperphenylalaninemia (HPA) were retrospectively evaluated. Blood Phe levels of the patients were analyzed with the high-performance liquid chromatography method. For PAH gene analysis, next-generation sequencing was performed. RESULTS: Of the 163 patients included in the study, 38 (23.3â¯%) had cPKU, 16 (9.8â¯%) had mPKU, and 109 (66.9â¯%) had MHP. Homozygous variants in the PAH gene were detected in 66 (40.5â¯%) of the patients, while compound heterozygous variants were detected in 97 (59.5â¯%) patients. Two novel and 35 recurrent variants in the PAH gene were detected. Of the two novel variants, one was missense (p.Phe351Leu) and the other was frameshift (p.Met276Cysfs*65). The most frequently detected variants were p.Thr380Met (18â¯%), p.Arg261Gln (16.8â¯%), and p.Ala300Ser (12.8â¯%). All patients with the homozygous c.1066-11G>A variant exhibited cPKU phenotype. The c.898G>T (p.Ala300Ser), c.1139C>T (p.Thr380Met), and c.1208C>T (p.Ala403Val) variants were statistically related to mild phenotype. On the other hand, c.592_613del (p.Tyr198Serfs*136), c.1028A>G (p.Tyr343Cys), and c.782G>A (p.Arg261Gln) variants were more frequently detected in the cPKU group. CONCLUSIONS: Our study, conducted with patients from the eastern region of Türkiye, demonstrates the genetic heterogeneity in the Turkish population. Simultaneously, our research contributes to genotype-phenotype correlation and expands the genotypic spectrum by identifying novel variants.
Assuntos
Fenilalanina Hidroxilase , Fenilcetonúrias , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Biomarcadores/sangue , Biomarcadores/análise , Seguimentos , Genótipo , Mutação , Fenótipo , Fenilalanina/sangue , Fenilalanina/genética , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/genética , Fenilcetonúrias/sangue , Prognóstico , Estudos Retrospectivos , Turquia/epidemiologiaRESUMO
Empagliflozin has been successfully repurposed for treating neutropenia and neutrophil dysfunction in patients with glycogen storage disease type 1b (GSD 1b), however, data in infants are missing. We report on efficacy and safety of empagliflozin in infants with GSD 1b. This is an international retrospective case series on 21 GSD 1b infants treated with empagliflozin (total treatment time 20.6 years). Before starting empagliflozin (at a median age of 8.1 months with a median dose of 0.3 mg/kg/day) 12 patients had clinical signs and symptoms of neutrophil dysfunction. Six of these previously symptomatic patients had no further neutropenia/neutrophil dysfunction-associated findings on empagliflozin. Eight patients had no signs and symptoms of neutropenia/neutrophil dysfunction before start and during empagliflozin treatment. One previously asymptomatic individual with a horseshoe kidney developed a central line infection with pyelonephritis and urosepsis during empagliflozin treatment. Of the 10 patients who were treated with G-CSF before starting empagliflozin, this was stopped in four and decreased in another four. Eleven individuals were never treated with G-CSF. While in 17 patients glucose homeostasis remained stable on empagliflozin, four showed glucose homeostasis instability in the introductory phase. In 17 patients, no other side effects were reported, while genital (n = 2) or oral (n = 1) candidiasis and skin infection (n = 1) were reported in the remaining four. Empagliflozin had a good effect on neutropenia/neutrophil dysfunction-related signs and symptoms and a favourable safety profile in infants with GSD 1b and therefore qualifies for further exploration as first line treatment.
Assuntos
Compostos Benzidrílicos , Glucosídeos , Doença de Depósito de Glicogênio Tipo I , Neutropenia , Neutrófilos , Humanos , Doença de Depósito de Glicogênio Tipo I/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo I/complicações , Neutropenia/tratamento farmacológico , Masculino , Feminino , Lactente , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/administração & dosagem , Estudos Retrospectivos , Neutrófilos/efeitos dos fármacos , Glucosídeos/uso terapêutico , Glucosídeos/farmacologia , Glucosídeos/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Resultado do Tratamento , Fator Estimulador de Colônias de Granulócitos/uso terapêuticoRESUMO
AIM: Phenylketonuria (PKU) is an inherited metabolic disorder in which accumulation of phenylalanine (Phe) leads to poor neurological outcomes without treatment. Dietary therapy is the main treatment and nonadherence is associated with elevated blood Phe levels and correspondingly poor neuropsychiatric outcomes. This study aimed to examine the effect of home visits on blood Phe levels in PKU patients. METHODS: Sixty-five paediatric PKU patients who were on low-phenylalanine diet were visited monthly at home for 6 months. At each visit, dietary education was provided, patients' height and weight were measured and blood samples were collected. RESULTS: Twenty-eight (43.1%) patients had classic PKU and 37 (56.9%) had moderate PKU. Blood Phe levels decreased statistically significant at first, second, fifth, and sixth months compared with screening visit. Blood Phe levels in moderate PKU patients decreased significantly at the last visit unlike classic PKU patients. A significant decrease in blood Phe levels was observed in patients older than 10 years. Anthropometric parameters improved. CONCLUSIONS: Dietary nonadherence is the main treatment failure in PKU. Home visits for education are a promising way to improve treatment outcomes by providing quality education, better assessment, and correction of mistakes but they should be ongoing and supported by different interventions that address patients' special needs.
Assuntos
Visita Domiciliar , Fenilcetonúrias , Criança , Humanos , Dieta , Estudos Longitudinais , FenilalaninaRESUMO
BACKGROUND: Ethylmalonic encephalopathy (EE) is a rare intoxication-type metabolic disorder with multisystem involvement. It is caused by mutations in ETHE1, which encodes the ETHE1 enzyme in the mitochondrial matrix that plays a key role in hydrogen sulfide (H2S) detoxification acting as a sulphur dioxygenase. RESULTS: This review focuses on the clinical, metabolic, genetic and neuroradiological features of 70 reported cases, including two new cases. The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively. A significant difference was found in EMA and C4 levels (p=0.003, p=0.0236) between classical and mild phenotypes. Urinary EMA, C4 and C5 levels were found to exhibit normal values in milder cases during attack-free periods. The most common ETHE1 gene homozygous state mutations were (p.R163Q) (c.488G>A), exon 4 deletion, (p.R163W)(c.487C>T), (p.Glu44ValfsTer62)(c.131_132delAG) and (p.M1I)(c.3G>T) mutations, respectively. Fifty-two patients underwent cranial MRI. Basal ganglia signal alterations were detected in 42 cases. Of the 70 cases, eight had a mild phenotype and slow neurological progression with low levels of ethylmalonic acid (EMA) and C4 acylcarnitine. The current age of alive patients in the published articles with mild phenotype was significantly higher than the classical phenotype. (p=0.002). Reducing the accumulation and inducing detoxification of sulfide is the main long-term treatment strategy for EE, including metronidazole, N-acetylcysteine (NAC), dietary modification, liver transplantation and continuous renal replacement therapy (CRRT). CONCLUSION: Measuring EMA and C4 acylcarnitine during metabolic attacks is critical to diagnosing EE, allowing for early treatment initiation to prevent further encephalopathic crises. Experience with liver transplantation, diet and CRRT, is currently limited. An early multidisciplinary approach with combination therapies is vital to prevent irreversible neurological damage.
RESUMO
AIM: In many countries, adult clinics specifically dedicated to adult patients with lysosomal storage diseases (LSDs) do not exist. In Turkey, these patients are managed either by pediatric metabolic specialists or adult physicians who do not specifically specialize in LSDs. In this study, we aimed to identify the unmet clinical needs of these adult patients and their suggestions. METHODS: The focus group participants were 24 adult LSD patients. Interviews were conducted in person. RESULTS: A total of 23 LSD patients and parents of a patient with mucopolysaccharidosis type-3b with intellectual deficit were interviewed, with 84.6% of patients diagnosed after the age of 18 years and 18% of patients diagnosed before the age of 18 years desiring management by adult physicians. Patients with particular physical characteristics or severe intellectual deficit declined the transition. Patients reported structural problems in the hospital and social problems associated with pediatric clinics. They made suggestions to facilitate the possible transition. CONCLUSION: With improved care, more patients with LSDs survive into adulthood or receive the diagnosis in adulthood. Children with chronic diseases need to transition to the care of adult physicians when they reach adulthood. Thus, there is an increasing need for adult physicians to manage these patients. In this study, most LSD patients accepted a well-planned and organized transition. Problems were related to stigmatization and social isolation in the pediatric clinic or adult issues with which pediatricians are not familiar. There is a need for adult metabolic physicians. Thus, health authorities should adopt necessary regulations for training of physicians in this field.
Assuntos
Doenças por Armazenamento dos Lisossomos , Humanos , Criança , Adulto , Adolescente , Turquia , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/terapia , Atenção à Saúde , Pais , PediatrasRESUMO
BACKGROUND: While thyroid dysfunction develops in about 50% of untreated children with cystinosis, there is no data about how the sonography of thyroid tissue appears in this disease. Therefore, the purpose of this study was to assess the sonographic appearance, color doppler findings in this disease and to evaluate how cystine crystal accumulation affect tissue stiffness using shear wave elastography (SWE). METHODS: Sixteen children diagnosed with cystinosis and a control group consisting of 34 healthy children were included in this study. B mode ultrasound, color doppler imaging and real-time SWE of thyroid tissue were performed. RESULTS: Ultrasound imaging revealed lower echogenicity and diffuse heterogeneous echotexture in 7 of the 16 cystinosis patients. Thyroid gland volumes were lower in cystinosis patients (p 0.005). Doppler ultrasound demonstrated increased flow in 8 patients. On SWE, the thyroid tissue stiffness was established to be lower in patients compared to healthy children (p 0.003). CONCLUSIONS: This is the first study evaluating thyroid gland B mode, color doppler ultrasonography, and SWE findings in cystinosis. Our findings indicate that cysteamine treatment still cannot completely prevent the disease infiltration process of thyroid gland. The other important finding-that thyroid tissue stiffness was established to be lower than that of the controls-also demonstrates the ongoing disease infiltration process.
Assuntos
Cistinose , Técnicas de Imagem por Elasticidade , Criança , Humanos , Glândula Tireoide/diagnóstico por imagem , Ultrassonografia , Ultrassonografia DopplerRESUMO
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 , HomozigotoRESUMO
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 JovemRESUMO
Gaucher disease type 2 is the most progressive and the rarest form of Gaucher disease, defined as the acute neuronopathic type. We presented two GD2 patients who died before three months of age due to severe septicemia, respiratory and liver failure. One was homozygous for a novel GBA variant c.590 T > A (p.197 K), and the second homozygous for the known GBA mutation c.1505G > A (p.R502H). Ichthyosis, hydrops fetalis, apnea, myoclonic seizures, and hepatosplenomegaly occurred in both patients, but hypertrophic cardiomyopathy was observed only in the second and unilateral cataract in the first patient. Due to the disease's early and rapid neurological progression, we did not administer ERT to our patients. It is strongly believed that early diagnosis is essential, and prenatal diagnosis makes genetic counselling possible for future pregnancies.
Assuntos
Doença de Gaucher , Feminino , Doença de Gaucher/complicações , Doença de Gaucher/diagnóstico , Doença de Gaucher/genética , Homozigoto , Humanos , Hidropisia Fetal/etiologia , Hidropisia Fetal/genética , Mutação/genética , GravidezRESUMO
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/complicaçõesRESUMO
BACKGROUND: Cystinosis is a lysosomal storage disease that affects many tissues. Its prognosis depends predominantly on kidney involvement. Cystinosis has three clinical forms: nephropathic infantile, nephropathic juvenile and non-nephropathic adult. Proximal tubular dysfunction is prominent in the infantile form, whereas a combination of glomerular and tubular alterations are observed in the juvenile form. METHODS: Thirty-six children with nephropathic cystinosis were included in the study. Clinical features, molecular genetic diagnoses, and kidney outcomes of the patients were evaluated. RESULTS: Twenty-one children (58.3%) were male. The median age at diagnosis was 18.5 months. Twenty-eight patients (77.8%) had infantile nephropathic cystinosis, while eight (22.2%) had juvenile nephropathic cystinosis. An acute rapid deterioration of the kidney function with proteinuria, hypoalbuminemia, and nephrotic syndrome, was observed in 37.5% of patients with the juvenile form. The mean estimated glomerular filtration rate (eGFR) was 82.31 ± 37.45 ml/min/1.73m2 at diagnosis and 63.10 ± 54.60 ml/min/1.73m2 at the last visit (p = 0.01). Six patients (16.6%) had kidney replacement therapy (KRT) at the last visit. The median age of patients with kidney failure was 122 months. Patients with a spot urine protein/creatinine ratio < 6 mg/mg at the time of diagnosis had better kidney outcomes (p = 0.01). The most common allele was c.451A>G (32.6%). The patients with the most common mutation tended to have higher mean eGFR and lower leukocyte cystine levels than patients with other mutations. CONCLUSION: Glomerulonephritis may be a frequent finding in addition to the well-known tubular dysfunction in patients with cystinosis. Furthermore, our results highlight that the presence of severe proteinuria at the time of diagnosis is a relevant prognostic factor for kidney survival.
Assuntos
Cistinose , Síndrome de Fanconi , Nefropatias , Síndrome Nefrótica , Adulto , Criança , Cistinose/complicações , Cistinose/diagnóstico , Cistinose/genética , Síndrome de Fanconi/genética , Humanos , Rim , Nefropatias/diagnóstico , Nefropatias/etiologia , Nefropatias/terapia , Masculino , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/genética , Proteinúria/etiologiaRESUMO
Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders.
Assuntos
Aminas Biogênicas/metabolismo , Doenças Genéticas Inatas/patologia , Pré-Escolar , Parto Obstétrico , Feminino , Doenças Genéticas Inatas/diagnóstico , Humanos , Lactente , Recém-Nascido , Fenótipo , GravidezRESUMO
BACKGROUND: This case series includes longitudinal clinical data of ten patients with Morquio A syndrome from south and southeastern parts of Turkey, which were retrospectively collected from medical records. All patients received enzyme replacement therapy (ERT). Clinical data collected included physical appearance, anthropometric data, neurological and psychological examinations, cardiovascular evaluation, pulmonary function tests, eye and ear-nose-throat examinations, endurance in the 6-min walk test and/or 3-min stair climb test, joint range of motion, and skeletal investigations (X-rays, bone mineral density). RESULTS: At the time of ERT initiation, two patients were infants (1.8 and 2.1 years), five were children (3.4-7.1 years), and three were adults (16.5-39.5 years). Patients had up to 4 years follow-up. Most patients had classical Morquio A, based on genotypic and phenotypic data. Endurance was considerably reduced in all patients, but remained relatively stable or increased over time in most cases after treatment initiation. Length/height fell below normal growth curves, except in the two infants who started ERT at ≤ 2.1 years of age. All patients had skeletal and/or joint abnormalities when ERT was started. Follow-up data did not suggest improvements in skeletal abnormalities, except in one of the younger infants. Nine patients had corneal clouding, which resolved after treatment initiation in the two infants, but not in the other patients. Hepatomegaly was reported in seven patients and resolved with treatment in five of them. Other frequent findings at treatment initiation were coarse facial features (N = 9), hearing loss (N = 6), and cardiac abnormalities (N = 6). Cardiac disease deteriorated over time in three patients, but did not progress in the others. CONCLUSIONS: Overall, this case series with Morquio A patients confirms clinical trial data showing long-term stabilization of endurance after treatment initiation across ages and suggest that very early initiation of ERT optimizes growth outcomes.
Assuntos
Condroitina Sulfatases , Mucopolissacaridose IV , Adulto , Criança , Terapia de Reposição de Enzimas , Humanos , Mucopolissacaridose IV/tratamento farmacológico , Estudos Retrospectivos , TurquiaRESUMO
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 NeonatalRESUMO
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 , MutaçãoRESUMO
Gangliosidoses (GM1 and GM2 gangliosidosis) are rare, autosomal recessive progressive neurodegenerative lysosomal storage disorders caused by defects in the degradation of glycosphingolipids. We aimed to investigate clinical, biochemical and molecular genetic spectrum of Turkish patients with infantile gangliosidoses and examined the potential role of serum aspartate transaminase levels as a biomarker. We confirmed the diagnosis of GM1 and GM2 gangliosidosis based on clinical findings with specific enzyme and/or molecular analyses. We retrospectively reviewed serum aspartate transaminase levels of patients with other biochemical parameters. Serum aspartate transaminase level was elevated in all GM1 and GM2 gangliosidosis patients in whom the test was performed, along with normal alanine transaminase. Aspartate transaminase can be a biochemical diagnostic clue for infantile gangliosidoses. It might be a simple but important biomarker for diagnosis, follow up, prognosis and monitoring of the response for the future therapies in these patients.
Assuntos
Aspartato Aminotransferases/metabolismo , Biomarcadores/análise , Gangliosidoses/tratamento farmacológico , Doença de Sandhoff/tratamento farmacológico , Aspartato Aminotransferases/efeitos dos fármacos , Feminino , Gangliosidoses GM2/tratamento farmacológico , Gangliosidose GM1/tratamento farmacológico , Humanos , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: The causes for intrinsic tooth discoloration can be separated into two categories as systemic and local. Systemic causes are either genetic or drug-induced effects. The development of dentition can also be affected by a number of systemic factors and metabolic diseases such as porphyria. Congenital erythropoietic porphyria (CEP), also known as Gunther's disease, is a metabolic disease caused by a transformation in the gene that codifies uroporphyrinogen-3 synthesis, leading to porphyrin aggregation in urine, skin, bone, and dentin. CASE REPORT: A 21-month-old girl with erythrodontia was referred to Paediatric Dentistry Department in September 2017. A physical examination revealed blisters on her face, nose, hands, and feet. Laboratory findings showed highly elevated urine total uroporphyrin and total coproporphyrin I and III levels. Next-generation sequencing multigene panel testing for porphyria demonstrated a homozygous c.10C>T (p.L4F) mutation in the UROS gene. For curative therapy, the patient was admitted to the allogeneic bone marrow transplantation program. CONCLUSION: Congenital erythropoietic porphyria most commonly presents in the first few years of life. Manifestations can include reddish-colored urine, skin blistering, scarring, and erythrodontia. A timely diagnosis can prevent undesirable skin findings of the disease and death due to hematological involvement before a curative allogeneic bone marrow transplantation is performed.
Assuntos
Porfiria Eritropoética , Descoloração de Dente , Dente , Criança , Feminino , Humanos , LactenteRESUMO
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 , TurquiaRESUMO
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 , TurquiaRESUMO
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.