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1.
Hum Mol Genet ; 32(12): 1988-2004, 2023 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-36795052

RESUMEN

SURF1 deficiency (OMIM # 220110) causes Leigh syndrome (LS, OMIM # 256000), a mitochondrial disorder typified by stress-induced metabolic strokes, neurodevelopmental regression and progressive multisystem dysfunction. Here, we describe two novel surf1-/- zebrafish knockout models generated by CRISPR/Cas9 technology. While gross larval morphology, fertility, and survival into adulthood appeared unaffected, surf1-/- mutants manifested adult-onset ocular anomalies and decreased swimming activity, as well as classical biochemical hallmarks of human SURF1 disease, including reduced complex IV expression and enzymatic activity and increased tissue lactate. surf1-/- larvae also demonstrated oxidative stress and stressor hypersensitivity to the complex IV inhibitor, azide, which exacerbated their complex IV deficiency, reduced supercomplex formation, and induced acute neurodegeneration typical of LS including brain death, impaired neuromuscular responses, reduced swimming activity, and absent heartrate. Remarkably, prophylactic treatment of surf1-/- larvae with either cysteamine bitartrate or N-acetylcysteine, but not other antioxidants, significantly improved animal resiliency to stressor-induced brain death, swimming and neuromuscular dysfunction, and loss of heartbeat. Mechanistic analyses demonstrated cysteamine bitartrate pretreatment did not improve complex IV deficiency, ATP deficiency, or increased tissue lactate but did reduce oxidative stress and restore glutathione balance in surf1-/- animals. Overall, two novel surf1-/- zebrafish models recapitulate the gross neurodegenerative and biochemical hallmarks of LS, including azide stressor hypersensitivity that was associated with glutathione deficiency and ameliorated by cysteamine bitartrate or N-acetylcysteine therapy.


Asunto(s)
Deficiencia de Citocromo-c Oxidasa , Enfermedad de Leigh , Animales , Adulto , Humanos , Enfermedad de Leigh/tratamiento farmacológico , Enfermedad de Leigh/genética , Enfermedad de Leigh/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Acetilcisteína , Cisteamina/farmacología , Azidas/metabolismo , Muerte Encefálica , Proteínas de la Membrana/metabolismo , Proteínas Mitocondriales/metabolismo , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Glutatión/metabolismo , Lactatos
2.
Genet Med ; 25(2): 100332, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36520152

RESUMEN

PURPOSE: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities. METHODS: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells. RESULTS: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells. CONCLUSION: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities.


Asunto(s)
Trastornos del Movimiento , Trastornos del Neurodesarrollo , Animales , Humanos , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Células HEK293 , Complejo Cetoglutarato Deshidrogenasa/genética , Complejo Cetoglutarato Deshidrogenasa/metabolismo , Trastornos del Neurodesarrollo/genética
3.
Genet Med ; 25(6): 100314, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36305855

RESUMEN

PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.


Asunto(s)
Fallo Hepático Agudo , Fallo Hepático , Adolescente , Niño , Preescolar , Humanos , Lactante , Adulto Joven , Acetilcisteína/uso terapéutico , Fallo Hepático/tratamiento farmacológico , Fallo Hepático/genética , Fallo Hepático Agudo/tratamiento farmacológico , Fallo Hepático Agudo/genética , Proteínas Mitocondriales/genética , Mutación , Estudios Retrospectivos , ARNt Metiltransferasas/genética
4.
Clin Genet ; 101(2): 247-254, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34708404

RESUMEN

Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense changes, two variants predicted to result in complete protein loss through nonsense-mediated decay, and two frameshift changes that likely introduce a truncation. Our findings (i) independently confirm the role of ZNFX1 in primary genetic immunodeficiency, (ii) expand the genetic and clinical spectrum of ZNFX1-related disease, and (iii) illustrate the utility of large, well-curated, and continually updated genotype-phenotype databases in resolving molecular diagnoses of patients with initially negative genetic testing findings.


Asunto(s)
Alelos , Antígenos de Neoplasias/genética , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/genética , Mutación , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Mapeo Cromosómico , Biología Computacional/métodos , Análisis Mutacional de ADN , Bases de Datos Genéticas , Facies , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Linaje , Fenotipo
5.
Neurol Sci ; 42(3): 1103-1111, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33486620

RESUMEN

INTRODUCTION AND PURPOSE: Neuronal ceroid lipofuscinoses (NCLs) is a group of congenital metabolic diseases where the neurodegenerative process with the accumulation of ceroid and lipofuscin autofluorescent storage materials is at the forefront. According to the age of presentation, NCLs are classified as congenital, infantile (INCL), late infantile (LINCL), juvenile (JNCL), and adult (ANCL) NCLs. In our study, it was aimed to discuss the clinical and molecular characteristics of our patients diagnosed with NCL. MATERIAL AND METHOD: This is a descriptive cross-sectional study which was conducted in 14 patients from 10 unrelated families who were diagnosed with different types of NCL based on clinical presentation, neuroimaging, biochemical measurements, and molecular analyses, at the department of pediatric metabolism between June 2015 and June 2020. RESULTS: A total of 14 patients were diagnosed with different types of NCL. Of those, 4 patients were diagnosed with NCL7 (4/14; 30%), 3/14 (23%) with NCL1, 3/14 (23%) with NCL2, 2/14 (14.2%) with NCL13, and 1/14 (7.1%) with NCL10. Eleven pathogenic variants were detected, 5 of which are novel (c.721G>T [p.Gly241Ter] and c.301G>C [p.Ala146Pro] in MFDS8 gene; c.316C>T [p.Gln106Ter] in PPT1 gene; c.341C>T [p.Ala114Val] in TPP1 gene; c.686A>T [p.Glu229Val] in CTSD gene) CONCLUSION: This study is one of the pioneer comprehensive researches from Turkey that provides information about disease-causing variants and clinical presentation of different and rare types of NCLs. The identification of novel variants and phenotypic expansion is important for genetic counselling in Turkey and expected to improve understanding of NCLs.


Asunto(s)
Lipofuscinosis Ceroideas Neuronales , Adulto , Niño , Estudios Transversales , Humanos , Lipofuscinosis Ceroideas Neuronales/diagnóstico por imagen , Lipofuscinosis Ceroideas Neuronales/genética , Tripeptidil Peptidasa 1 , Turquía
6.
Pediatr Int ; 63(10): 1175-1179, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33600034

RESUMEN

BACKGROUND: In parallel with the increase in the number of children with life-limiting or life-threatening diseases, the need for and right to pediatric palliative care is also increasing. This study aimed to examine the metabolic diseases, evaluate the symptoms, and review the needs of children who were admitted to the pediatric palliative care service. METHODS: Following the approval of the local ethics committee (18/7/2019-107), the computer records of patients hospitalized in the pediatric palliative care service between December 1, 2018 and January 6, 2019 were reviewed retrospectively. Dr Behçet Uz Children's Hospital, Pediatric Palliative Care Center is third center in Turkey. Our pediatric palliative care center has one year of experience. RESULTS: In the study period, there were 101 patients who were hospitalized in the pediatric palliative care service. Eighteen patients (19.7%) diagnosed with inborn errors of metabolism were included in the study. The mean age was 3.2 ± 2.1 (0-8) years. Although it could not be shown statistically, the duration of hospitalization of patients with congenital malformation was long. CONCLUSION: Pediatric palliative care provides the best care with the control of various symptoms in neurodegenerative congenital metabolic diseases that do not have treatment or treatment, but progressive symptoms cannot be prevented.


Asunto(s)
Errores Innatos del Metabolismo , Cuidados Paliativos , Niño , Preescolar , Hospitalización , Hospitales Pediátricos , Humanos , Lactante , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/terapia , Estudios Retrospectivos
7.
Blood Cells Mol Dis ; 76: 1-6, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30473482

RESUMEN

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.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Gaucher/complicaciones , Neutropenia/congénito , Proteínas Adaptadoras Transductoras de Señales/genética , Médula Ósea/efectos de los fármacos , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Enfermedad de Gaucher/tratamiento farmacológico , Humanos , Lactante , Masculino , Mutación , Neutropenia/complicaciones
11.
Pediatr Cardiol ; 35(4): 596-600, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24633236

RESUMEN

Neurocardiogenic syncope is the most frequent cause of fainting in childhood and adolescence. Although head-up tilt table testing (HUTT) was previously considered as the reference standard in the diagnosis of syncope, in children with a typical history of reflex syncope, normal physical examination, and electrocardiogram (ECG) are sufficient to cease investigation; however, according to recent reports, TT is indicated in patients in whom this diagnosis cannot be proven by initial evaluation. The hypothesis of this study is that P-wave dispersion (PWD) can be a useful electrocardiographic predictor of cardiac autonomic dysfunction in children with vasovagal syncope (VVS). The study was designed prospectively and included 50 children with positive and 50 children with negative HUTT who presented with at least two previous unexplained episodes of syncope as well as 50 sex- and age-matched healthy children as the control group. All standard 12-lead ECGs were obtained in patients and controls, and the difference between maximum and minimum durations of the P wave was defined as the PWD. A total of 100 children with VVS and 50 healthy controls were evaluated for the study. The P maximum values of HUTT-positive (HUTT[+]) patients were significantly greater than those in the HUTT-negative (HUTT[-]) and control groups(p < 0.05). In addition, mean PWD values were 50.2 ± 18.5, 39.6 ± 11.2 and 32.0 ± 11.2 ms in the HUTT(+), HUTT(-), and control groups, respectively. The difference between groups was statistically significant (p < 0.05). We suggest that PWD is an early sign of cardiac autonomic dysfunction in children with neurally mediated syncope and can be used as a noninvasive electrocardiographic test to evaluate orthostatic intolerance syndromes.


Asunto(s)
Sistema Nervioso Autónomo/fisiopatología , Electrocardiografía , Atrios Cardíacos/inervación , Frecuencia Cardíaca/fisiología , Síncope Vasovagal/diagnóstico , Niño , Femenino , Estudios de Seguimiento , Atrios Cardíacos/fisiopatología , Humanos , Masculino , Examen Físico , Pronóstico , Estudios Prospectivos , Síncope Vasovagal/fisiopatología , Pruebas de Mesa Inclinada
13.
Mol Genet Metab Rep ; 36: 100979, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37275239

RESUMEN

Background: Cerebral organic acid disorders are progressive neurometabolic diseases characterized by neurologic dysfunction. Glutaric aciduria type I (GA-I) and L-2-hydroxyglutaric aciduria (L2HGA) are the main cerebral organic acid disorders. They are both classified as, and it is suggested that these two disorders may share a common metabolic pathway. Current treatment strategies are based on levocarnitine, vitamin B2, and diet. Recent guidelines recommend a lysine-restricted diet up to six years of age, but there is no consensus for patients over the age of six. Vitamin B2 is exists in the blood as riboflavin and its cofactors, flavin mononucleotide and flavin adenine dinucleotide (FAD). FAD, the cofactor of L2HGD, accelerates the conversion of L-2-hydoxy glutarate to alpha-ketoglutarate. Levocarnitine stimulates the formation and excretion of derivatives of glutaric acid. Also, lysine-associated organic acidurias some results provide principal proof for the beneficial effects of riboflavin in GA-I. It has been previously reported that combination therapy with riboflavin and levocarnitine is effective for L2HGA as well as GA-I. Riboflavin and levocarnitine have been reported to improve not only clinical symptoms but also urinary 2-HGA levels. In our study, we aimed to evaluate the effect of the current treatment strategies and genotype on urinary metabolites and IQ scores in GA-I and L2HGA patients. Methods: The presented retrospective multicenter study included patients followed up in Diyarbakir Children's Hospital and Izmir Katip Celebi University Faculty of Medicine, Division of Pediatric Metabolism. Between 2016 and 2021, we retrospectively evaluated 35 patients with confirmed diagnosis of GA-I and L-2HGA. We analyzed the clinical, biochemical, neuroradiological, molecular data and treatment of the patients. The follow-up period was every 2 months until 12 months old, every 3 months until 6 years of age, and every 6 months thereafter. Therapy monitoring was undertaken during follow-up visits that included evaluation of clinical parameters, laboratory parameters, and dietary consumption records. Denver II was applied in order to evaluate children aged 0-6 years in terms of development. Patients between 6 and 16 years of age were evaluated using the Wechsler Intelligence Scale for Children-Revised. Results: We identified 25 with GA-I and 10 with L2HGA. The most common clinical symptoms were developmental delay, intellectual disability, and movement disorders. Behavioural problems were more common in L2HGA than in GA-I patients. In the same family, there were patients with severe developmental delay despite early diagnosis and treatment and individuals with normal IQ scores. In our study group, we used diet (lysine restricted or protein controlled), levocarnitine and vitamin B2 for GA-I patients. The mean urinary glutaric acid levels were decreased with treatment in GA-I patients. Group I consisted of 14/25 patients receiving lysine restricted diet and levocarnitine, Group II (8/25) received protein-controlled diet and levocarnitine. Group III (3/25) patients whom had p.Pro248Leu (P248L) variant, received riboflavin in combination with protein-controlled diet and levocarnitine. When we evaluated according to the treatment groups, a significant decrease was observed in urinary glutaric acid levels in group I. But there were no significant difference in Group II and III. The patients with c.1018C > T variant in GCDH gene had higher pre-treatment urinary metabolites and significant reduction in urinary metabolites with treatment was detected. In L2HGA patients, we used levocarnitine and vitamin B2. In all L2HGA patients, there was a significant decrease in the mean urinary 2- hydoxy glutarate with treatment. However, there was no significant difference between the c.164G > A and c.1115delT variants. The mean pre- and post-treatment IQ scores of GA-I patients, no significant difference was observed. Relative neurologic improvement was seen in three L2HGA patients. We found two novel variants, including the c.221A > G (p.Tyr74Cys) in the GCDH gene and the c.738 + 5A > G splice variant in the L2HGDH gene. Conclusions: Glutaric aciduria type I and L2HGA are the most common cerebral organic acidurias. Early and correct diagnosis is crucial. Poor prognosis based on metabolic crises and progressive deterioration still appears. In countries where newborn screening is not performed, a clinical suspicion index is required for cerebral organic aciduria. GA-I and L-2HGA are difficult to examine by medical evidence standards because of the small sample size, regional differences in newborn screening, and medical care limits. More clinical studies are needed to identify effective treatments. However, the significant decrease in urinary glutaric acid levels after treatment in patients on lysine-restricted diet raises the question of whether lysine-restricted diet should be continued after six years of age. We also reported our experience in order to contribute to the literature.

14.
Turk J Pediatr ; 64(4): 747-753, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36082649

RESUMEN

BACKGROUND: Hypomyelinating leukodystrophy-14 (HLD14) is a rarely seen neurodevelopmental disease caused by homozygous pathogenic ubiquitin-fold modifier 1 gene variants. The disease has an autosomal recessive inheritance. All patients with this condition reported to date have drug-resistant epilepsy. The posttranslational modification of proteins with ubiquitin fold modifier 1 is defective in these patients and is thought to be responsible for severe neurodevelopmental problems. There is no previous report on the effectiveness of the ketogenic diet in the treatment of drug-resistant epileptic seizures in this disease. Therefore, we present a pediatric case diagnosed with HLD14 and whose drug-resistant epileptic seizures were controlled by ketogenic diet therapy. CASE: The patient was a three-year-old male with drug-resistant epilepsy and developmental delay. His brain magnetic resonance imaging revealed cerebellar atrophy, periventricular white matter hypomyelination, and ventricular enlargement. Whole-exome sequencing analysis identified a homozygous pathogenic variant in the ubiquitin-fold modifier 1 gene on chromosome 13q13. Ketogenic diet therapy was initiated for his drug-resistant seizures and subsequently reduced seizure frequency by more than 75%. The patient is still on ketogenic diet therapy. CONCLUSIONS: Ketogenic diet therapy may be beneficial for seizure control in HLD14 patients with drug-resistant seizures.


Asunto(s)
Dieta Cetogénica , Epilepsia Refractaria , Epilepsia , Niño , Preescolar , Dieta Cetogénica/métodos , Epilepsia Refractaria/genética , Humanos , Masculino , Convulsiones , Resultado del Tratamiento , Ubiquitinas
15.
Brain Dev ; 44(9): 640-644, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35680490

RESUMEN

BACKGROUND: Folate metabolism disorders can affect various organ systems, including the nervous system. 5,10-methenyltetrahydrofolate synthetase deficiency is a rare cerebral folate deficiency in which MTHFS activity is disrupted with low-normal cerebrospinal fluid (CSF) 5,10-methenyltetrahydrofolate levels, while peripheral folate levels are normal. CASE REPORT: We present here a female patient with developmental delay, microcephaly, hypotonia, nystagmus, and seizure in which a distinct brain MRI and CT showed restricted diffusion in the bilateral parietal and occipital lobes, and calcifications of the bilateral putamen, globus pallidus, and caudate nucleus, and the bilateral parietal and occipital lobes. Laboratory tests revealed macrocytic anemia, increased homocysteine, low-normal CSF 5,10-methenyltetrahydrofolate, and low CSF folate, but normal serum vitamin B12 and folate levels. A whole exome sequencing analysis verified the diagnosis of 5,10-methenyltetrahydrofolate synthetase deficiency. CONCLUSIONS: We have added novel knowledge which is nystagmus and hypotonia in the clinical findings, the involvement and restriction of bilateral putamen, globus pallidus, parietal and occipital lobes, and calcification of the bilateral putamen, globus pallidus, caudate nucleus, and parietal and occipital lobes in neuroimaging images and also low CSF folate in the metabolic investigation with the patient in 5,10-methenyltetrahydrofolate synthetase deficiency.


Asunto(s)
Ligasas de Carbono-Nitrógeno , Deficiencia de Ácido Fólico , Enfermedades Metabólicas , Deficiencia de Vitamina B 12 , Ligasas de Carbono-Nitrógeno/metabolismo , Femenino , Receptor 1 de Folato , Ácido Fólico , Humanos , Hipotonía Muscular , Deficiencia de Vitamina B 12/diagnóstico
16.
Turk J Pediatr ; 64(2): 210-220, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35611409

RESUMEN

BACKGROUND: We aimed to investigate the effectiveness of ketogenic diet (KD) in children with various types of refractory epilepsy. METHODS: A total of 91 children (49 females) aged 3 to 193 months (median, 52 months) with drug resistant epilepsy who received KD treatment for at least 12 months were enrolled in the study. Seizure frequency, adherence to diet, reason for discontinuation of KD, and adverse effects were recorded. Response was defined as ≥50% improvement in seizure frequency compared to baseline. We also searched for influences of different variables on the outcome. RESULTS: Intent-to-treat analysis revealed an improvement in seizure frequency for ≥50% in 73.6%, 80.2%, 75.8%, 73.6%, and 70.3% of patients at month-1, -3, -6, -9, and month-12, respectively. Overall, 32 (35.2%) patients remained seizure-free at month-12. There was no significant differences between responders and nonresponders in terms of age at onset of epilepsy, age at onset of KD, gender, or etiology. Mild hyperlipidemia was associated with a higher response rate. At the last follow-up (median: 20 months), 38 (41.8%) patients were still maintained on KD. While 15.4% of patients completed the diet with a success in seizure control, remainder discontinued KD due to lack of efficacy (23.1%), non-adharence to diet (11%), intercurrent infection (4.4%), adverse effects (3.3%), and death (1.1%). CONCLUSION: Ketogenic diet treatment appears to be effective in about two-thirds of children with various types of drug-resistant epilepsy, including one-third remaining seizure free. Mild hyperlipidemia seems to be associated with a higher response rate. Discontinuation of KD is mostly due to lack of efficacy or nonadherence, and rarely side effects.


Asunto(s)
Dieta Cetogénica , Epilepsia Refractaria , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Epilepsia , Hiperlipidemias , Niño , Dieta Cetogénica/efectos adversos , Femenino , Humanos , Lactante , Estudios Retrospectivos , Convulsiones , Resultado del Tratamiento
17.
Life (Basel) ; 12(11)2022 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-36362876

RESUMEN

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.

18.
Eur J Med Genet ; 64(1): 104117, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33248288

RESUMEN

VAC14 related childhood-onset striatonigral degeneration was first defined in 2016 in two unrelated children with sudden onset neurological disease and regression of developmental milestones. Up to now, 11 cases have been reported. VAC14 is a component of a trimolecular complex that tightly regulates the level of phosphatidylinositol 3,5-bisphosphate (PI (3, 5)P2) and PI (3, 5)P2 is critical for the survival of neural cells. Pathogenic VAC14 variants result in striatonigral degeneration chacterised by prominent vacuolation of neurons in basal ganglia. Here, we present a patient with a homozygous pathogenic VAC14 variant, whose symptoms started at an early age and who had both basal ganglia and brain stem involvement. Our case is one of the youngest patients in literature and involvement of the brain stem is defined for the first time in VAC14 related neurological disease.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Degeneración Estriatonigral/genética , Edad de Inicio , Ganglios Basales/diagnóstico por imagen , Femenino , Homocigoto , Humanos , Lactante , Mutación , Fenotipo , Degeneración Estriatonigral/diagnóstico por imagen , Degeneración Estriatonigral/patología , Sustancia Negra/diagnóstico por imagen
19.
Seizure ; 91: 99-107, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34147890

RESUMEN

BACKGROUND: Ketogenic diet (KD) is a valuable treatment option for patients with medication-resistant epilepsy. It is associated with a number of side effects. However limited data are available for the long-term effects of KD on serum lipid levels. PURPOSE: The aim of this study was to investigate the long-term effects of KD on serum lipid concentrations in children with medication-resistant epilepsy in daily clinical practice. METHOD: A total of 73 children (40 girls) aged 3 to 193 months (median, 53 months) with medication-resistant epilepsy who received a KD treatment for at least 12 months between 2014 and 2019 years were enrolled in the study. All children were started on a KD with 3:1 ratio which was then adjusted between 2:1 to 4:1 after the onset of KD as clinically necessary. Serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride concentrations and body mass index-standard deviation scores (BMI-SDS) were measured at onset and at 1, 6 and 12 months of treatment, and also in 40 of these patients they were measured at 18 and 24 months of treatment. RESULTS: Dyslipidemia was observed in 71.2, 63, 63, 50, and 52.5% of the patients, at 1, 6, 12, 18, and 24 months, respectively. Median total cholesterol and triglyceride concentrations increased significantly at month-1, and although these high levels persisted for 24 months, the increase did not continue and showed a downward trend. However, this increase did not occur in the subset of patients with pre-existing dyslipidemia. Compared to baseline values, total cholesterol and triglyceride concentrations were higher at all time points, except 24-month cholesterol values. During the 24-month treatment period, BMI-SDS increased and the number of antiepileptic drugs decreased significantly. CONCLUSION: Total cholesterol and triglyceride concentrations appear to increase during the first month of KD treatment, and although these high values persist for 24 months, the increase does not continue, on the contrary, it approaches the normal values by drawing a downward trend. However, cholesterol and triglyceride concentrations do not increase in the subset of patients with pre-existing dyslipidemia.


Asunto(s)
Dieta Cetogénica , Epilepsia Refractaria , Anticonvulsivantes/uso terapéutico , Niño , Colesterol , Epilepsia Refractaria/tratamiento farmacológico , Femenino , Humanos , Triglicéridos
20.
J Pediatr Endocrinol Metab ; 34(7): 957-960, 2021 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-33823103

RESUMEN

OBJECTIVES: Childhood osteoporosis is often a consequence of a chronic disease or its treatment. Lysinuric protein intolerance (LPI), a rare secondary cause of the osteoporosis, is an autosomal recessive disorder with clinical features ranging from minimal protein intolerance to severe multisystemic involvement. We report a case diagnosed to have LPI using a Next Generation Sequencing (NGS) panel and evaluate the utility of reverse phenotyping. CASE PRESENTATION: A fifteen-year-old-boy with an initial diagnosis of osteogenesis imperfecta, was referred due to a number of atypical findings accompanying to osteoporosis such as splenomegaly and bicytopenia. A NGS panel (TruSight One Sequencing Panel) was performed and a novel homozygous mutation of c.257G>A (p.Gly86Glu) in the SLC7A7 gene (NM_001126106.2), responsible for LPI, was detected. The diagnosis was confirmed via reverse phenotyping. CONCLUSIONS: Reverse phenotyping using a multigene panel shortens the diagnostic process.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Osteoporosis/etiología , Adolescente , Errores Innatos del Metabolismo de los Aminoácidos/genética , Sistema de Transporte de Aminoácidos y+L/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Osteogénesis Imperfecta/genética , Fenotipo
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