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GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18â years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12â months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3â months and 1â day before starting treatment and 1, 3, 6 and 12â months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8â years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.
Assuntos
Receptores de N-Metil-D-Aspartato , Serina , Humanos , Feminino , Masculino , Criança , Pré-Escolar , Adolescente , Serina/uso terapêutico , Serina/genética , Receptores de N-Metil-D-Aspartato/genética , Encefalopatias/genética , Encefalopatias/tratamento farmacológico , Resultado do Tratamento , Qualidade de VidaRESUMO
BACKGROUND: This retrospective cohort analysis highlighted neurodevelopmental outcome predictors of genetic developmental and epileptic encephalopathies (DEE). PATIENTS AND METHODS: Patients' demographic, clinical and molecular genetics data were collected. All patients underwent clinical, developmental, and neuropsychological assessments. RESULTS: We recruited 100 participants (53 males, 47 females) with a mean follow-up lasting 10.46 ± 8.37 years. Age at epilepsy-onset was predictive of poor adaptive and cognitive functions (VABS-II score, r = 0.350, p = 0.001; BRIEF control subscale, r = -0.253; p = 0.031). Duration of epilepsy correlated negatively with IQ (r = -0.234, p = 0.019) and VABS-II score (r = -0.367, p = 0.001). Correlations were found between delayed/lacking EEG maturation/organization and IQ (r = 0.587, p = 0.001), VABS-II score (r = 0.658, p = 0.001), BRIEF-MI and BRIEF-GEC scores (r = -0.375, p = 0.001; r = -0.236, p = 0.033), ASEBA anxiety (r = -0.220, p = 0.047) and ADHD (r = -0.233, p = 0.035) scores. The number of antiseizure medications (ASMs) correlated with IQ (r = -0.414, p = 0.001), VABS-II (r = -0.496, p = 0.001), and BRIEF-MI (r = 0.294, p = 0.012) scores; while age at the beginning of therapy with ASEBA anxiety score (r = 0.272, p = 0.013). The occurrence of status epilepticus was associated with worse adaptive performances. The linear regression analysis model showed that delayed/lacking EEG maturation/organization had a significant influence on the IQ (R2 = 0.252, p < 0.001) and the BRIEF-GEC variability (R2 = 0.042, p = 0.036). The delayed/lacking EEG maturation/organization and the duration of epilepsy also had a significant influence on the VABS-II score (R2 = 0.455, p = 0.005). CONCLUSIONS: Age at seizure-onset, EEG maturation/organization, duration of epilepsy, occurrence of status epilepticus, age at the introduction and number of ASMs used are reliable predictors of long-term outcomes in patients with genetic DEE.
Assuntos
Epilepsia , Estado Epiléptico , Masculino , Feminino , Humanos , Estudos Retrospectivos , Epilepsia/complicações , Epilepsia/genética , Estudos de Coortes , CogniçãoRESUMO
The purpose of this study is to investigate the diagnostic and prognostic role of cerebrospinal fluid (CSF) biomarkers in the diagnostic work-up of glucose transporter 1 (GLUT1) deficiency. Reported here is a systematic review according to PRISMA guidelines collecting clinical and biochemical data about all published patients who underwent CSF analysis. Clinical phenotypes were compared between groups defined by the levels of CSF glucose (≤ 2.2 mmol/L versus > 2.2 mmol/L), CSF/blood glucose ratio (≤ 0.45 versus > 0.45), and CSF lactate (≤ 1 mmol/L versus > 1 mmol/L). Five hundred sixty-two patients fulfilled the inclusion criteria with a mean age at the diagnosis of 8.6 ± 6.7 years. Patients with CSF glucose ≤ 2.2 mmol/L and CSF/blood glucose ratio ≤ 0.45 presented with an earlier onset of symptoms (16.4 ± 22.0 versus 54.4 ± 45.9 months, p < 0.01; 15.7 ± 23.8 versus 40.9 ± 38.0 months, p < 0.01) and received an earlier molecular genetic confirmation (92.1 ± 72.8 versus 157.1 ± 106.2 months, p < 0.01). CSF glucose ≤ 2.2 mmol/L was consistently associated with response to ketogenic diet (p = 0.018) and antiseizure medications (p = 0.025). CSF/blood glucose ratio ≤ 0.45 was significantly associated with absence seizures (p = 0.048), paroxysmal exercise-induced dyskinesia (p = 0.046), and intellectual disability (p = 0.016) while CSF lactate > 1 mmol/L was associated with a response to antiseizure medications (p = 0.026) but not to ketogenic diet.Conclusions:This systematic review supported the diagnostic usefulness of lumbar puncture for the early identification of patients with GLUT1 deficiency responsive to treatments especially if they present with co-occurring epilepsy, movement, and neurodevelopmental disorders. What is Known: ⢠Phenotypes of GLUT1 deficiency syndrome range between early epileptic and developmental encephalopathy to paroxysmal movement disorders and developmental impairment What is New: ⢠CSF blood/glucose ratio may predict better than CSF glucose the diagnosis in children presenting with early onset absences ⢠CSF blood/glucose ratio may predict better than CSF glucose the diagnosis in children presenting with paroxysmal exercise induced dyskinesia and intellectual disability. ⢠CSF glucose may predict better than CSF blood/glucose and lactate the response to ketogenic diet and antiseizure medications.
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Biomarcadores , Erros Inatos do Metabolismo dos Carboidratos , Humanos , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Prognóstico , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Erros Inatos do Metabolismo dos Carboidratos/líquido cefalorraquidiano , Criança , Ácido Láctico/líquido cefalorraquidiano , Ácido Láctico/sangue , Glicemia/análise , Dieta Cetogênica , Pré-Escolar , Transportador de Glucose Tipo 1/genética , Glucose/líquido cefalorraquidiano , Proteínas de Transporte de Monossacarídeos/deficiênciaRESUMO
PURPOSE: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified. METHODS: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. RESULTS: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect. CONCLUSION: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.
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Síndrome de Angelman , Transtornos do Neurodesenvolvimento , Humanos , Síndrome de Angelman/genética , Ubiquitina/genética , Ubiquitina-Proteína Ligases/genética , Transtornos do Neurodesenvolvimento/genética , FenótipoRESUMO
PURPOSE: This study evaluated the impact of a newly established clinic for the diagnosis of pediatric epilepsy in a resource-limited center (Ifakara, Tanzania). METHODS: Patients aged 0-18 years referred to the Pediatric Epilepsy Unit of Saint Francis Referral Hospital were recruited. Demographic and clinical data were collected through Kobo Toolbox and analyzed through a descriptive analysis.. RESULTS: 143 patients were evaluated, and for 48 of them an EEG was recorded (abnormalities were detected in 80.85% of the cases). The diagnosis of epilepsy was confirmed in 87 patients. Focal epilepsy was diagnosed in 57 patients, generalized epilepsy in 24 patients, and forms of unknown onset in 6 patients. Epilepsy was excluded for 9 children. Etiologies included hypoxic-ischemic encephalopathy (39%), central nervous system infections (3.4%), and genetic diseases (3.4%). A specific epilepsy syndrome was diagnosed in 16 patients. 74 patients were under treatment; the most used antiseizure medication (ASM) was phenobarbital (43.36%), followed by carbamazepine (16.08%), sodium valproate (11.19%), phenytoin (2.8%), and lamotrigine (0.7%). Therapeutic changes were proposed to 95 patients, more frequently consisting of withdrawing phenobarbital (39.16%), switching to sodium valproate (27.97%), switching to or adjusting carbamazepine dosage (27.27%), and starting prednisone (2.8%). 76% of the patients with confirmed epilepsy achieved complete seizure freedom at the fourth follow-up consultation. CONCLUSIONS: Our data depicted the epilepsy spectrum and highlighted the prognostic implications of improving the availability of ASMs such as sodium valproate and second- and third-generation ones in resource-limited countries.
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Epilepsia , Ácido Valproico , Criança , Humanos , Ácido Valproico/uso terapêutico , Tanzânia/epidemiologia , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Fenobarbital/uso terapêutico , Benzodiazepinas/uso terapêuticoRESUMO
Inborn errors of metabolism causing stroke (ischemic or haemorrhagic) or stroke-like episodes (e.g., that are also called "metabolic strokes" and include acute brain lesions not related with alterations of blood flow) cover a wide range of diseases in which acute metabolic decompensations after trigger events (e.g., fever, dehydration, sepsis etc.) may have a variable frequency. The early diagnosis of these conditions is essential because, despite their rarity, effective symptomatic treatments may be available for acute settings (e.g., arginine for Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes- MELAS) while in other cases disease modifying therapies may be useful to prevent stroke occurrence, recurrence, or relapse (e.g., Fabry disease). The detection of a non-vascular distribution of lesions and the diffuse use of 1HMRS are often diriment in the differential of ischemic and metabolic strokes. This review summarized the main clinical features and the pathophysiological mechanisms of stroke and stroke-like episodes in inborn errors of metabolism presenting with stroke as part of natural history of the disease. These conditions belong to different etiological groups, such as organic acidurias, mitochondrial encephalopathies, homocystinuria and remethylation disorders, urea cycle disorders, lysosomal diseases (e.g. Fabry disease, glycogen storage disease), congenital disorders of glycosylation, neurotransmitter disorders, adenosine deaminase 2 deficiency and few other neurometabolic disorders.
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Doença de Fabry , Síndrome MELAS , Miopatias Mitocondriais , Acidente Vascular Cerebral , Distúrbios Congênitos do Ciclo da Ureia , Doença de Fabry/complicações , Humanos , Síndrome MELAS/genética , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/complicaçõesRESUMO
CHD2 encodes the chromodomain helicase DNA-binding protein 2, an ATP-dependent enzyme that acts as a chromatin remodeler. CHD2 pathogenic variants have been associated with various early onset phenotypes including developmental and epileptic encephalopathy, self-limiting or pharmacoresponsive epilepsies and neurodevelopmental disorders without epilepsy. We reviewed 84 previously reported patients carrying 76 different CHD2 pathogenic or likely pathogenic variants and describe 18 unreported patients carrying 12 novel pathogenic or likely pathogenic variants, two recurrent likely pathogenic variants (in two patients each), three previously reported pathogenic variants, one gross deletion. We also describe a novel phenotype of adult-onset pharmacoresistant epilepsy, associated with a novel CHD2 missense likely pathogenic variant, located in an interdomain region. A combined review of previously published and our own observations indicates that although most patients (72.5%) carry truncating CHD2 pathogenic variants, CHD2-related phenotypes encompass a wide spectrum of conditions with developmental delay/intellectual disability (ID), including prominent language impairment, attention deficit hyperactivity disorder and autistic spectrum disorder. Epilepsy is present in 92% of patients with a median age at seizure onset of 2 years and 6 months. Generalized epilepsy types are prevalent and account for 75.5% of all epilepsies, with photosensitivity being a common feature and adult-onset nonsyndromic epilepsy a rare presentation. No clear genotype-phenotype correlation has emerged.
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Epilepsia , Transtornos do Neurodesenvolvimento , Proteínas de Ligação a DNA/genética , Eletroencefalografia , Epilepsia/genética , Humanos , Mutação , Transtornos do Neurodesenvolvimento/genética , FenótipoRESUMO
This review provides an updated analysis of the main aspects involving the diagnosis and the management of children with acute ischemic stroke. Acute ischemic stroke is an emergency of rare occurrence in children (rate of incidence of 1/3500 live birth in newborns and 1-2/100,000 per year during childhood with peaks of incidence during the perinatal period, under the age of 5 and in adolescence). The management of ischemic stroke in the paediatric age is often challenging because of pleomorphic age-dependent risk factors and aetiologies, high frequency of subtle or atypical clinical presentation, and lacking evidence-based data about acute recanalization therapies. Each pediatric tertiary centre should activate adequate institutional protocols for the optimization of diagnostic work-up and treatments.Conclusion: The implementation of institutional standard operating procedures, summarizing the steps for the selection of candidate for neuroimaging among the ones presenting with acute neurological symptoms, may contribute to shorten the times for thrombolysis and/or endovascular treatments and to improve the long-term outcome. What is Known: â¢Acute ischemic stroke has a higher incidence in newborns than in older children (1/3500 live birth versus 1-2/100,000 per year). â¢Randomized clinical trial assessing safety and efficacy of thrombolysis and/or endovascular treatment were never performed in children What is New: â¢Recent studies evidenced a low risk (2.1% of the cases) of intracranial haemorrhages in children treated with thrombolysis. â¢A faster access to neuroimaging and hyper-acute therapies was associated with the implementation of institutional protocols for the emergency management of pediatric stroke.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Adolescente , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/terapia , Criança , Humanos , Recém-Nascido , Hemorragias Intracranianas , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Terapia Trombolítica , Resultado do TratamentoRESUMO
Compound heterozygosis is the most diffuse and hardly to tackle condition in aromatic amino acid decarboxylase (AADC) deficiency, a genetic disease leading to severe neurological impairment. Here, by using an appropriate vector, we succeeded in obtaining high yields of AADC protein and characterizing two new heterodimers, T69M/S147R and C281W/M362T, detected in two AADC deficiency patients. We performed an extensive biochemical characterization of the heterodimeric recombinant proteins and of the related homodimers, by a combination of dichroic and fluorescence spectroscopy and activity assays together with bioinformatic analyses. We found that T69M/S147R exhibits negative complementation in terms of activity but it is more stable than the average of the homodimeric counterparts. The heterodimer C281W/M362T retains a nearly good catalytic efficiency, whereas M362T homodimer is less affected and C281W homodimer is recovered as insoluble. These results, which are consistent with the related phenotypes, and the data emerging from previous studies, suggest that the severity of AADC deficiency is not directly explained by positive or negative complementation phenomena, but rather depends on: i) the integrity of one or both active sites; ii) the structural and functional properties of the entire pool of AADC proteins expressed. Overall, this integrated and cross-sectional approach enables proper characterization and depicts the functional result of subunit interactions in the dimeric structure and will help to elucidate the physio-pathological mechanisms in AADC deficiency.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Descarboxilases de Aminoácido-L-Aromático/deficiência , Heterozigoto , Fenótipo , Adolescente , Adulto , Descarboxilases de Aminoácido-L-Aromático/genética , Biologia Computacional , Feminino , Humanos , Masculino , Mutação , Proteínas Recombinantes , Adulto JovemRESUMO
Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.
Assuntos
Neurotransmissores/deficiência , Fenótipo , Qualidade de Vida , Adolescente , Adulto , Comportamento , Criança , Pré-Escolar , Disfunção Cognitiva/etiologia , Feminino , Humanos , Lactente , Inteligência , Internacionalidade , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Adulto JovemRESUMO
Neurological emergencies account for about one-third of the highest severity codes attributed in emergency pediatric departments. About 75% of children with acute neurological symptoms presents with seizures, headache, or other paroxysmal events. Life-threatening conditions involve a minor proportion of patients (e.g., less than 15% of children with headache and less than 5% of children with febrile seizures). This review highlights updated insights about clinical features, diagnostic workup, and therapeutic management of pediatric neurological emergencies. Particularly, details will be provided about the most recent insights about headache, febrile seizures, status epilepticus, altered levels of consciousness, acute motor impairment, acute movement disorders, and functional disorders, as well as the role of diagnostic tools (e.g., neuroimaging, lumbar puncture, and electroencephalography), in the emergency setting. Moreover, the impact of the current novel coronavirus disease2019 (COVID-19) pandemic on the evaluation of pediatric neurologic emergencies will also be analyzed.
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Doença Aguda , Cefaleia/diagnóstico , Convulsões/diagnóstico , Estado Epiléptico/diagnóstico , COVID-19 , Criança , Emergências , Cefaleia/terapia , Humanos , Pandemias , Pediatria , Convulsões/terapia , Estado Epiléptico/terapiaRESUMO
Sleep-related hypermotor epilepsy (SHE) is a rare syndrome that presents with hyperkinetic asymmetric tonic/dystonic seizures with vegetative signs, vocalization, and emotional facial expression, mainly during light non-rapid eye movement sleep stages. The role of various genes (CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, NPRL2, NPRL3, and PRIMA1) has previously been reported, though genetic etiology is assessed in less than 10% of cases. We report the case of a 5-year-old female carrying the TSC1 variant c.843del p.(Ser282Glnfs*36) who presented with a mild phenotype of tuberous sclerosis, including carbamazepine-responsive SHE, normal neurocognitive functioning, hypomelanotic macules, no abnormalities outside the central nervous system, and tubers at neuroimaging. The presented case extends the list of SHE-related genes to include TSC1, thus suggesting a central pathogenic role of mammalian target of rapamycin (mTOR) cascade dysfunction in SHE and introducing a possible use of mTOR inhibitors in this epileptic syndrome.
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Síndromes Epilépticas/genética , Parassonias/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Esclerose Tuberosa/genética , Pré-Escolar , Síndromes Epilépticas/complicações , Feminino , Humanos , Parassonias/etiologia , Fenótipo , Índice de Gravidade de DoençaRESUMO
Inborn errors of neurotransmitter metabolism are ultrarare disorders affecting neurotransmitter biosynthesis, breakdown or transport or their essential cofactors. Neurotransmitter dysfunctions could also result from the impairment of neuronal receptors, intracellular signaling, vesicle release or other synaptic abnormalities. Epilepsy is the main clinical hallmark in some of these diseases (e.g. disorders of GABA metabolism, glycine encephalopathy) while it is infrequent in others (e.g. all the disorders of monoamine metabolism in exception for dihydropteridine reductase deficiency). This review analyzes the epileptogenic mechanisms, the epilepsy phenotypes and the principle for the clinical management of epilepsy in primary and secondary inherited disorders of neurotransmitter metabolism (disorders of GABA, serine and glycine metabolism, disorders of neurotransmitter receptors and secondary neurotransmitter diseases).
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Encefalopatias Metabólicas Congênitas/complicações , Epilepsia/terapia , Encefalopatias Metabólicas Congênitas/metabolismo , Epilepsia/etiologia , Epilepsia/metabolismo , HumanosRESUMO
Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurodevelopmental disorder characterized by impaired synthesis of dopamine, noradrenaline, adrenaline and serotonin, leading to a complex syndrome of motor, behavioral, and autonomic symptoms. This retrospective study assessed the symptoms and developmental outcome of a large international cohort of patients with AADCD via physician and/or caregiver responses to a detailed, standardized questionnaire. Sixty-three patients (60% female; ages 6 months-36 years, median 7 years; 58 living) from 23 individual countries participated. Common symptoms at onset (median age 3 months, range 0-12 months) were hypotonia, developmental delay, and/or oculogyric crises. Oculogyric crises were present in 97% of patients aged 2 to 12 years, occurred in the majority of patients in all age groups, and tended to be most severe during early childhood. Prominent non-motor symptoms were sleep disturbance, irritable mood, and feeding difficulties. The majority of subjects (70%) had profound motor impairment characterized by absent head control and minimal voluntary movement, while 17% had mild motor impairment and were able to walk independently. Dopamine agonists were the medications most likely to produce some symptomatic benefit, but were associated with dose-limiting side effects (dyskinesia, insomnia, irritability, vomiting) that led to discontinuation 25% of the time. The age distribution of our cohort (70% of subjects under age 13 years) and the observation of a greater proportion of patients with a more severe disease phenotype in the younger compared to the older patients, both suggest a significant mortality risk during childhood for patients with severe disease.
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Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Descarboxilases de Aminoácido-L-Aromático/deficiência , Agonistas de Dopamina/uso terapêutico , Distúrbios Distônicos/etiologia , Transtornos da Motilidade Ocular/etiologia , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Agonistas de Dopamina/efeitos adversos , Feminino , Terapia Genética , Humanos , Lactente , Internacionalidade , Masculino , Fenótipo , Estudos Retrospectivos , Adulto JovemRESUMO
The PRICKLE1 (Prickle Planar Cell Polarity Protein 1-MIM 608500) gene is involved in different phases of human development. The related diseases include autosomal recessive progressive myoclonus epilepsy - ataxia syndrome, neural tube defects associated with heterozygous mutations, agenesis of corpus callosum, polymicrogyria, and autistic spectrum disorder. Reported here is a young boy with a new variant (NM_153026.2:c.820G>A, p.Ala274Thr) presenting with an early infantile epileptic encephalopathy with developmental arrest.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas com Domínio LIM/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Proteínas Supressoras de Tumor/genética , Pré-Escolar , Análise Mutacional de DNA , Eletroencefalografia , Genótipo , Humanos , Masculino , Mutação , Linhagem , FenótipoRESUMO
The aim of our study was to describe the clinical, electroencephalogram, molecular findings and the diagnostic and therapeutic flow-chart of children with pyridoxine-dependent epilepsies (PDEs). We performed a retrospective observational study on children with PDEs, diagnosed and followed-up in Italian Pediatric Departments. In each centre, the authors collected data from a cohort of children admitted for intractable seizures, responsive to pyridoxine administration and resistant to other anticonvulsant therapies. Data were retrospectively analysed from January 2016 to January 2017. Sixteen patients (13 males, and 3 females) were included. We found that 93.75% of patients underwent conventional anticonvulsant therapy before starting pyridoxine administration and 62.5% had ex-juvantibus diagnosis, as specific serum diagnostic tests had been performed in only 37.5% of patients by alpha-AASA and pipecolic acid blood and urine dosage. The most common type of seizure was generalized tonic-clonic in 7 patients and the most common EEG pattern was characterized by a "burst suppression" pattern. Before pyridoxine administration, other anticonvulsant drugs were used in 93.75% of patients, with consequent onset of drug-resistance. Phenobarbital was the most frequently used drug as first-line treatment. The importance of our study relies on the need of a deeper knowledge of PDEs in terms of early diagnosis, avoiding incorrect treatment and related adverse events, clinical and EEG pathognomonic features, and genetic aspects of the disease.
Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Piridoxina/farmacologia , Convulsões/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/diagnóstico , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Convulsões/diagnóstico , Complexo Vitamínico B/uso terapêuticoRESUMO
BACKGROUND: Pyridoxal-5'-phosphate oxidase (PNPO) deficiency presents as a severe neonatal encephalopathy responsive to pyridoxal-5'-phosphate (PLP) or pyridoxine. Recent studies widened the phenotype of this condition and detected genetic variants on PNPO gene whose pathogenic role and clinical expression remain to be established. OBJECTIVE: This paper aims to characterize the functional effects of the c.347G>A (p.Arg116Gln) mutation in the PNPO gene in order to define its pathogenicity and describe the clinical features of new patients with epilepsy carrying this mutation. METHODS: Arg116Gln protein variant was expressed as recombinant protein. The mutant protein was characterized with respect to structural and kinetic properties, thermal stability, binding constants of cofactor (FMN) and product (PLP). We also reviewed clinical data of 3 new patients carrying the mutation. RESULTS: The Arg116Gln mutation does not alter the overall enzyme structure and only slightly affects its catalytic efficiency; nevertheless, this mutation affects thermal stability of PNPO, reduces its affinity for FMN and impairs transfer of PLP to PLP-dependent enzymes. Three boys with seizure onset between 8months and 3years of age, carrying the Arg116Gln mutation, are described. These three patients exhibited different seizure types associated with interictal EEG abnormalities and slow background activity. Mild/moderate intellectual disability was observed in 2/3 patients. A dramatic therapeutic response to pyridoxine was observed in the only patient who still had active seizures when starting treatment, while in all three patients interictal EEG discharges and background activity improved after pyridoxine treatment was initiated. CONCLUSIONS: The reported data support a pathogenic role of the c.347G>A (p.Arg116Gln) mutation in PNPO deficiency. The later onset of symptoms and the milder epilepsy phenotype of these expand the disease phenotype.
Assuntos
Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/fisiopatologia , Hipóxia-Isquemia Encefálica/genética , Hipóxia-Isquemia Encefálica/fisiopatologia , Monoéster Fosfórico Hidrolases/deficiência , Monoéster Fosfórico Hidrolases/genética , Piridoxaminafosfato Oxidase/deficiência , Convulsões/genética , Convulsões/fisiopatologia , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação , Fenótipo , Piridoxaminafosfato Oxidase/genética , Piridoxina/uso terapêutico , Convulsões/tratamento farmacológicoRESUMO
Lennox-Gastaut syndrome (LGS) is a severe age-dependent epileptic encephalopathy usually with onset between 1 and 8 years of age. Functional neuroimaging studies recently introduced the concept of Lennox-Gastaut as "secondary network epilepsy" resulting from dysfunctions of a complex system involving both cortical and subcortical structures (default-mode network, corticoreticular connections, and thalamus). These dysfunctions are produced by different disorders including hypoxic-ischemic encephalopathies, meningoencephalitis, cortical malformations, neurocutaneous disorders, or tumors. The list of etiologies was expanded to pathogenic copy number variants at whole-genome array comparative genomic hybridization associated with late-onset cases or pathogenic mutations involving genes, such as GABRB3, ALG13, SCN8A, STXBP1, DNM1, FOXG1, or CHD2. Various clinical trials demonstrated the usefulness of different drugs (including rufinamide, clobazam, lamotrigine, topiramate, or felbamate), ketogenic diet, resective surgery, corpus callosotomy, and vagus nerve stimulation in the treatment of epileptic manifestations. The outcome of LGS often remains disappointing regarding seizure control or cognitive functioning. The realization of animal models, which are still lacking, and the full comprehension of molecular mechanisms involved in epileptogenesis and cognitive impairment would give a relevant support to further improvements in therapeutic strategies for LGS patients.