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BACKGROUND: Benzodiazepines are the first-line anti-seizure medication (ASM) for generalized convulsive status epilepticus (GCSE), but they fail to end seizures in a third of cases. Combining benzodiazepines with another ASM that acts by a different pathway could be a potential strategy for rapid control of GCSE. OBJECTIVES: To evaluate the efficacy of adding levetiracetam to midazolam in the initial treatment of pediatric GCSE. DESIGN: Double-blind randomized controlled trial. SETTING: Pediatric emergency room at Sohag University Hospital between June, 2021 and August, 2022. PARTICIPANTS: Children aged between 1 month and 16 years with GCSE lasting more than 5 min. INTERVENTIONS: Intravenous levetiracetam (60 mg/kg over 5 min) and midazolam (Lev-Mid group) or placebo and midazolam (Pla-Mid group) as first-line anticonvulsive therapy. OUTCOME MEASURES: Primary: cessation of clinical seizures at 20-min study time point. Secondary: cessation of clinical seizures at 40-min study time point, need for a second midazolam dose, seizure control at 24-hr, need for intubation, and adverse effects. RESULTS: Cessation of clinical seizures at 20-min occurred in 55 children (76%) in Lev-Mid group compared with 50 (69%) in the Pla-Mid group [RR (95% CI) 1.1 (0.9-1.34); P=0.35]. No significant difference was found between the two groups regarding the need for a second midazolam dose [44.4% vs 55.6%; RR (95% CI) 0.8 (0.58-1.11); P=0.18] as well as cessation of clinical seizures at 40-min [96% vs 92%; RR (95% CI)1.05 (0.96-1.14); P=0.49] and seizure control at 24-hr [85% vs 76%; RR (95% CI) 1.12 (0.94-1.3); P=0.21]. Intubation was required for three patients in the Lev-Mid group and six patients in the Pla-Mid group [RR (95%CI) 0.5 (0.13- 1.92); P=0.49]. No other adverse effects or mortality were observed during the 24-hour study timeframe. CONCLUSION: Combined levetiracetam and midazolam for initial management of pediatric GCSE presents no significant advantage over midazolam alone in cessation of clinical seizures at 20-min.
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Midazolam , Estado Epiléptico , Humanos , Criança , Lactente , Levetiracetam/uso terapêutico , Midazolam/uso terapêutico , Anticonvulsivantes/efeitos adversos , Resultado do Tratamento , Estado Epiléptico/tratamento farmacológicoRESUMO
This study presents 46 patients from 23 unrelated Egyptian families with ALS2-related disorders without evidence of lower motor neuron involvement. Age at onset ranged from 10 months to 2.5 years, featuring progressive upper motor neuron signs. Detailed clinical phenotypes demonstrated inter- and intrafamilial variability. We identified 16 homozygous disease-causing ALS2 variants; sorted as splice-site, missense, frameshift, nonsense and in-frame in eight, seven, four, three, and one families, respectively. Seven of these variants were novel, expanding the mutational spectrum of the ALS2 gene. As expected, clinical severity was positively correlated with disease onset (p = 0.004). This work provides clinical and molecular profiles of a large single ethnic cohort of patients with ALS2 mutations, and suggests that infantile ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS) are belonged to one entity with no phenotype-genotype correlation.
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Fatores de Troca do Nucleotídeo Guanina , Humanos , Egito/epidemiologia , Fatores de Troca do Nucleotídeo Guanina/genética , Análise Mutacional de DNA , MutaçãoRESUMO
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic form of cerebral white matter disease whose clinicoradiologic correlation has not been completely understood. In this study, we investigated the association between clinical and brain magnetic resonance imaging (MRI) features in 22 Egyptian children (median age 7 years) with MLC. Gross motor function was assessed using the Gross Motor Function Classification System, and evaluation of brain MRI followed a consistent scoring system. Each parameter of extensive cerebral white matter T2 hyperintensity, moderate-to-severe wide ventricle/enlarged subarachnoid space, and greater than 2 temporal subcortical cysts was significantly associated (P < .05) with worse Gross Motor Function Classification System score, language abnormality, and ataxia. Having >2 parietal subcortical cysts was significantly related to a worse Gross Motor Function Classification System score (P = .04). The current study indicates that patients with MLC manifest signification association between certain brain MRI abnormalities and neurologic features, but this should be confirmed in larger studies.
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Encefalopatias , Cistos , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Megalencefalia , Malformações do Sistema Nervoso , Encefalopatias/patologia , Criança , Cistos/diagnóstico por imagem , Cistos/genética , Cistos/patologia , Egito , Humanos , Idioma , Imageamento por Ressonância MagnéticaRESUMO
Ataxia Telangiectasia (AT) is a very rare autosomal recessive primary immune deficiency (PID) disease that affects 1 in 10,000-40,000 new births per year in the world. It is caused by biallelic mutations in ataxia telangiectasia mutated (ATM) gene and characterized by a progressive cerebellar ataxia. The clinical profile of AT children in Upper Egypt in missing. Herein, we evaluated the clinical characteristics and immunological profiles of patients with AT attending Sohag University Hospital. This was a cross-sectional study, included 21 AT patients attending the Neurological and Immunological Units, Pediatric Department, Sohag University Hospital, starting April 2018 to the end of March 2019. AT represented 20.5% of all PID patients attending the hospital. The most common type of humoral immune deficiency in patients with AT was specific IgA deficiency (52.3%) followed by hypogammaglobulinemia (23.8%). Recurrent sinopulmonary infection with different degrees of severity was the common immunological problem. The most common neurological manifestations in our studied patients, other than the ataxia, were language delay and eye movement abnormalities followed by developmental delay and head nodding. None of our patients had developed malignancy till the end of the study.
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Ataxia Telangiectasia , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Criança , Estudos Transversais , Egito/epidemiologia , Hospitais Universitários , Humanos , MutaçãoRESUMO
OBJECTIVES: To study the clinical and laboratory features, management, and outcome of pediatric non-diabetic ketoacidosis (NDKA). METHODS: Between May 2018 and April 2020, we prospectively collected children under 18 years who presented with ketoacidosis, defined as ketosis (urinary ketones ≥++ and/or serum ß-hydroxybutyrate level ≥3 mmol/L) and metabolic acidosis (pH <7.3 and HCO3 - <15 mmol/L). Children with HbA1c level ≥6.5% at initial presentation and those meeting the diagnostic criteria for DM during follow-up were excluded. Data were collected on demographics, clinical and laboratory features, management, and outcome. RESULTS: Eleven children with 19 episodes of NDKA were identified. The median age was 12 months (range from 5 months to 5 years). They manifested dehydration and disturbed conscious level (all cases), convulsions (n=6), hypoglycemia (n=6), hyperglycemia (n=2) and significant hyperammonemia (n=4). Most cases required intensive care management. Death or neurodevelopmental impairment occurred in six cases. Seven cases had inborn errors of metabolism (IEMs). Other cases were attributed to starvation, sepsis, and salicylate intoxication. CONCLUSIONS: This is the largest case series of pediatric NDKA. Ketoacidosis, even with hyperglycemia, is not always secondary to diabetes mellitus. IEMs may constitute a significant portion of pediatric NDKA. Increased awareness of this unfamiliar condition is important for prompt diagnosis, timely management, and better outcome.
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Cetoacidose Diabética/complicações , Hiperglicemia/patologia , Hipoglicemia/patologia , Sepse/patologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Hiperglicemia/etiologia , Hipoglicemia/etiologia , Lactente , Masculino , Prognóstico , Sepse/etiologia , Taxa de SobrevidaRESUMO
PURPOSE: The misdiagnosis of non-epileptic seizures (NES) as epilepsy is one of the most common pitfalls in neuropsychiatric practice. This study aimed to describe the percentage and types of NES among children who were referred for a diagnosis of epilepsy in Upper Egypt. METHODS: We recruited a total of 876 patients who were referred to Sohag University Hospital, a tertiary referral centre in Upper Egypt, for the evaluation of suspected epilepsy. Relevant methods for the diagnosis of epilepsy, including medical history and examination, EEG, video-EEG, laboratory investigations, and brain imaging, were performed for all study participants. RESULTS: Among the 876 patients who were referred for the diagnosis of suspected epilepsy during the period from June 2017 to October 2018, 171 patients (19.5 %) were diagnosed as having NES. In general, we found that NES in the paediatric age groups did not differ from that reported in various studies across several different populations. The most prevalent NES in our study was breath-holding spells (32.2 %), followed by syncope (17.5 %), psychogenic nonepileptic seizures (12.3 %), motor tics (9.9 %), and benign sleep myoclonus (7.6 %). Other less frequent NES included infantile masturbation (7 %), spasmus nutans (5.3 %), migraine (2.9 %), benign paroxysmal torticollis (2.9 %), night terrors (1.8 %), and shuddering attacks (0.6 %). CONCLUSION: Ideally, neurologists should not misdiagnose NES as epilepsy, and whenever the diagnosis of NES is uncertain, an accurate diagnosis should be made using long-term video-EEG monitoring, especially in younger paediatric patients.
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Epilepsia , Criança , Diagnóstico Diferencial , Egito/epidemiologia , Eletroencefalografia , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Humanos , Transtornos Mentais , Convulsões/diagnóstico , Convulsões/epidemiologiaRESUMO
BACKGROUND: Glutaric acidemia type 1 (GA1) is an inherited neurometabolic disease with significant morbidity. However, neuro-radiological correlation is not completely understood. OBJECTIVE: The study aimed to characterize the neuroimaging findings and their association with neurological phenotype in GA1 children. METHODS: Twenty-six Egyptian children (median age = 12 months) diagnosed with GA1 underwent clinical evaluation and brain magnetic resonance imaging (MRI). We objectively assessed the severity of neurological phenotype at the time of MRI using movement disorder (MD) and morbidity scores. Evaluation of brain MRI abnormalities followed a systematic and region-specific scoring approach. Brain MRI findings and scores were correlated with MD and morbidity scores, disease onset, and presence of seizures. RESULTS: Fifteen (57.7%) cases had insidious onset, eight (30.8%) manifested acute onset, whereas three (11.5%) were asymptomatic. Ten (38.5%) cases had seizures, five of which had no acute encephalopathic crisis. Putamen and caudate abnormalities (found in all acute onset, 93.3 and 73.3% of insidious onset, and one of three asymptomatic cases) were significantly related to MD (p = 0.007 and 0.013) and morbidity (p = 0.005 and 0.003) scores. Globus pallidus abnormalities (50% of acute onset, 46.7% of insidious onset, and one of three of asymptomatic cases) were significantly associated with morbidity score (p = 0.023). Other MRI brain abnormalities as well as gray and white matter score showed no significant association with neurological phenotype. Younger age at onset, acute onset, and seizures were significantly associated with worse neurological manifestations. CONCLUSION: Patients with GA1 manifest characteristic and region-specific brain MRI abnormalities, but only striatal affection appears to correlate with neurological phenotype.
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Erros Inatos do Metabolismo dos Aminoácidos , Encefalopatias Metabólicas , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encefalopatias Metabólicas/diagnóstico por imagem , Egito , Glutaril-CoA Desidrogenase/deficiência , Glutaril-CoA Desidrogenase/genética , Humanos , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Until now, diabetes during pregnancy has been associated with a high risk of maternal, fetal, and neonatal morbidities and mortalities. The main aim of this study was to evaluate the risk factors of hypoglycemia in infants of diabetic mothers (IDMs) and to study the relationship between umbilical cord (UC) C peptide levels and the risk of developing hypoglycemia. MATERIAL AND METHODS: UC blood C-peptide and serial serum blood glucose measurements were done for all included singleton newborns born to diabetic mothers during the study period. Maternal and neonatal data such as gestational age, maternal age, maternal weight, types of diabetics and its control, maternal glycated hemoglobin (HbA1C), birth weight, Apgar score, and neonatal complete blood picture were collected. RESULTS: In total, 83 IDMs met the inclusion criteria. Fifty-four (65.06%) developed hypoglycemia and 29 (34.94%) remained normoglycemic. However, there were no significant differences between hypoglycemic and normoglycemic IDMs in terms of types of maternal diabetics (P value = 0.41), its duration (P value = 0.43). The hypoglycemia peak occurred within the first 3 h of life, with 33.11 ± 8.84 mg/dl for the hypoglycemia group and 54.10 ± 6.66 mg/dl for the normoglycemic group (P value < 0.0001). Most of the babies had no hypoglycemic manifestation (96.30%). Neonates with hypoglycemia their mothers had poor diabetes control in the last trimester (HbA1C 7.09 ± 0.96%) compared to normoglycemic babies (HbA1C 6.11 ± 0.38%), (P-value < 0.0001). The mean (SD) of UC C-peptide level in hypoglycemic neonates increased to 1.73 ± 1.07 ng/ml compared to normoglycemic ones with 1.08 ± 0.81 ng/ml (P value = 0.005). CONCLUSION: Poor diabetes control, especially in the last trimester, is associated with neonatal hypoglycemia. Increased UC C-peptide levels could be used as an early indicator for the risk of developing neonatal hypoglycemia and a predictor for babies need neonatal admission.
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Diabetes Mellitus , Diabetes Gestacional , Hipoglicemia , Gravidez em Diabéticas , Glicemia , Peptídeo C , Diabetes Gestacional/diagnóstico , Feminino , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/etiologia , Lactente , Recém-Nascido , Mães , Gravidez , Cordão UmbilicalRESUMO
PA and MAA have numerous nonspecific presentations, potentially leading to delayed diagnosis or misdiagnosis. In this paper, we present the clinical and biochemical characteristics of MMA and PA patients at initial presentation. Results. This is a retrospective review of 20 patients with PA (n = 10) and MMA (n = 10). The most observed symptoms were vomiting (85%) and refusing feeding (70%). Ammonia was 108.75 ± 9.3 µmol/l, showing a negative correlation with pH and bicarbonate and positive correlation with lactate and anion gap. Peak ammonia did not correlate with age of onset (r = 0.11 and p = 0.64) or age at diagnosis (r = 0.39 and p = 0.089), nor did pH (r = 0.01, p = 0.96; r = -0.25, p = 0.28) or bicarbonate (r = 0.07, p = 0.76; r = -0.22, p = 0.34). There was no correlation between ammonia and C3 : C2 (r = 0.1 and p = 0.96) or C3 (r = 0.23 and p = 0.32). The glycine was 386 ± 167.1 µmol/l, and it was higher in PA (p = 0.003). There was a positive correlation between glycine and both pH (r = 0.56 and p = 0.01) and HCO3 (r = 0.49 and p = 0.026). There was no correlation between glycine and ammonia (r = -0.435 and p = 0.055) or lactate (r = 0.32 and p = 0.160). Conclusion. Clinical presentation of PA and MMA is nonspecific, though vomiting and refusing feeding are potential markers of decompensation. Blood gas, lactate, and ammonia levels are also good predictors of decompensation, though increasing levels of glycine may not indicate metabolic instability.
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Blepharophimosis-ptosis-intellectual disability syndrome (BPID) is an extremely rare recognizable blepharophimosis intellectual disability syndrome (BID). It is caused by biallelic variants in the UBE3B gene with only 24 patients described worldwide. Herein, we report on the clinical, brain imaging and molecular findings of additional nine patients from six unrelated Egyptian families. Patients presented with the characteristic features of the syndrome including blepharophimosis, ptosis, upslanted palpebral fissures with epicanthic folds, hypertelorism, long philtrum, high arched palate, micrognathia, microcephaly, and intellectual disability. Other findings were congenital heart disease (5 patients), talipes equinovarus (5 patients), genital anomalies (5 patients), autistic features (4 patients), cleft palate (2 patients), hearing loss (2 patients), and renal anomalies (1 patient). New or rarely reported findings were spherophakia, subvalvular aortic stenosis and hypoplastic nails, and terminal phalanges. Brain MRI, performed for 7 patients, showed hypogenesis or almost complete agenesis of corpus callosum. Genetic studies revealed five novel homozygous UBE3B variants. Of them, the c.1076G>A (p.W359*) was found in three patients from two unrelated families who shared similar haplotype suggesting a likely founder effect. Our results strengthen the clinical, dysmorphic, and brain imaging characteristic of this unique type of BID and extend the mutational spectrum associated with the disorder.
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Blefarofimose/genética , Homozigoto , Deficiência Intelectual/genética , Mutação , Fenótipo , Anormalidades da Pele/genética , Ubiquitina-Proteína Ligases/genética , Anormalidades Urogenitais/genética , Blefarofimose/patologia , Criança , Pré-Escolar , Egito , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/patologia , Masculino , Linhagem , Anormalidades da Pele/patologia , Anormalidades Urogenitais/patologiaRESUMO
Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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Complexo 4 de Proteínas Adaptadoras/genética , Corpo Caloso/diagnóstico por imagem , Imageamento por Ressonância Magnética/tendências , Paraplegia Espástica Hereditária/diagnóstico por imagem , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Adulto JovemRESUMO
BACKGROUND: Phenylketonuria (PKU) is considered to be a rare inborn error of metabolism but one of the commonest causes of mental retardation if untreated. OBJECTIVES: The present study was done to characterize the clinical patterns of PKU and analyze various neuropsychiatric outcomes in PKU children in Sohag Province, Egypt. PATIENTS AND METHODS: A prospective cohort study was conducted on 113 PKU patients, diagnosed during the period from 2012 to 2017, at the Pediatric Neurology Clinic of Sohag University Hospital, Upper Egypt. One hundred and ten cases were diagnosed based on clinical suspicion combined with laboratory confirmation by measuring their plasma phenylalanine levels using amino acid analyzer, while 3 cases were detected during neonatal screening. With the exception of the 3 cases detected during neonatal screening, all patients were clinically diagnosed and treated late. Psychometric evaluations of PKU patients were done using intelligence quotient (IQ, Stanford- Binet V), Childhood Autism Rating Scale, and Children's Attention and Adjustment Survey. Dietetic management was applied. The results of neuroimaging (computed tomography or magnetic resonance imaging of the brain) and electroencephalography were included when available. RESULTS: The overall results showed that 15.9% had hyperphenylalaninemia, 35.4% had mild to moderate PKU, and classic PKU was diagnosed in 48.7%. Global developmental delay (54.9%) and delayed language (29.2%) were the most frequent presentations. Moderately impaired or delayed overall IQ was present in 77%. While, 83.2% had moderately impaired or delayed verbal IQ, autism was diagnosed in 50.4%. Super average and average probability of attention-deficit hyperactivity disorder was diagnosed in 88.5%. Abnormal neuroimaging (white matter abnormalities and brain atrophy) was the most important significant predictor for poor language and motor developmental outcome (P<0.05). CONCLUSION: PKU children had variable neuropsychological outcomes, mainly attention-deficit hyperactivity disorder and impaired verbal IQ, both of which were not related to the initial phenylalanine levels or to duration of dietary therapy, but were significantly related to early dietary intervention.
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Febrile seizures (FS) are frequent convulsive disorders, occurring in infants and young children. The present study aims to assess and compare the serum levels of oxidative stress markers and some essential trace minerals in FS with normal or abnormal EEG and evaluate the effect of antioxidant therapy on the clinical outcome. This study has been carried out on 80 children with FS (40 with simple FS and 40 with complex FS) and 40 febrile children without seizures. Clinical and EEG findings were recorded for the included patients. Biochemical assays of serum nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), copper (Cu), zinc (Zn) and selenium (Se), using colorimetric methods, were measured in the studied groups. The overall results showed an increased values of NO, MDA and Cu with decreased values of SOD, Zn and Se in patients with FS (simple and complex) in comparison with febrile children without seizures (p < 0.05 for all). Additionally, NO and MDA was increased in complex FS patients with EEG abnormalities in comparison with complex FS with normal EEG findings (p < 0.05); NO and MDA were also significantly decreased after valproate therapy in complex FS patients (p < 0.05 for all). In conclusions, oxidative stress, decreased Zn and Se with increased Cu may play a role in FS. Valproate improves the oxidative stress status in complex FS.
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Metaboloma , Estresse Oxidativo/fisiologia , Convulsões Febris/metabolismo , Oligoelementos/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Cobre/sangue , Feminino , Humanos , Lactente , Masculino , Malondialdeído/sangue , Óxido Nítrico/sangue , Estudos Prospectivos , Convulsões Febris/sangue , Selênio/sangue , Superóxido Dismutase/sangue , Zinco/sangueRESUMO
AIM: Molybdenum cofactor deficiency (MoCD) and Sulfite oxidase deficiency (SOD) are rare autosomal recessive conditions of sulfur-containing amino acid metabolism with overlapping clinical features and emerging therapies. The clinical phenotype is indistinguishable and they can only be differentiated biochemically. MOCS1, MOCS2, MOCS3, and GPRN genes contribute to the synthesis of molybdenum cofactor, and SUOX gene encodes sulfite oxidase. The aim of this study was to elucidate the clinical, radiological, biochemical and molecular findings in patients with SOD and MoCD. METHODS: Detailed clinical and radiological assessment of 9 cases referred for neonatal encephalopathy with hypotonia, microcephaly, and epilepsy led to a consideration of disorders of sulfur-containing amino acid metabolism. The diagnosis of six with MoCD and three with SOD was confirmed by biochemical tests, targeted sequencing, and whole exome sequencing where suspicion of disease was lower. RESULTS: Novel SUOX mutations were detected in 3 SOD cases and a novel MOCS2 mutation in 1 MoCD case. Most patients presented in the first 3 months of life with intractable tonic-clonic seizures, axial hypotonia, limb hypertonia, exaggerated startle response, feeding difficulties, and progressive cystic encephalomalacia on brain imaging. A single patient with MoCD had hypertrophic cardiomyopathy, hitherto unreported with these diseases. INTERPRETATION: Our results emphasize that intractable neonatal seizures, spasticity, and feeding difficulties can be important early signs for these disorders. Progressive microcephaly, intellectual disability and specific brain imaging findings in the first year were additional diagnostic aids. These clinical cues can be used to minimize delays in diagnosis, especially since promising treatments are emerging for MoCD type A.
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Erros Inatos do Metabolismo dos Aminoácidos , Erros Inatos do Metabolismo dos Metais , Sulfito Oxidase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Coenzimas/genética , Egito , Humanos , Recém-Nascido , Doenças do Recém-Nascido , Masculino , Erros Inatos do Metabolismo dos Metais/genética , Erros Inatos do Metabolismo dos Metais/fisiopatologia , Metaloproteínas/genética , Cofatores de Molibdênio , Molibdoferredoxina/genética , Mutação , Fenótipo , Pteridinas , Sulfito Oxidase/genéticaRESUMO
Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.
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Doenças Cerebelares/genética , Cerebelo/patologia , Lisossomos/metabolismo , Fagossomos/metabolismo , Nexinas de Classificação/genética , Ataxias Espinocerebelares/genética , Animais , Atrofia/genética , Autofagia , Pré-Escolar , Feminino , Frequência do Gene , Humanos , Lactente , Escore Lod , Doenças por Armazenamento dos Lisossomos/genética , Masculino , Mutação , Síndrome , Peixe-ZebraRESUMO
Autism spectrum disorders (ASDs) are a group of heterogeneous neurodevelopmental disorders that show impaired communication and socialization, restricted interests, and stereotypical behavioral patterns. Recent advances in molecular medicine and high throughput screenings, such as array comparative genomic hybridization (CGH) and exome and whole genome sequencing, have revealed both novel insights and new questions about the nature of this spectrum of disorders. What has emerged is a better understanding about the genetic architecture of various genetic subtypes of ASD and correlations of genetic mutations with specific autism subtypes. Based on this new information, we outline a strategy for advancing diagnosis, prognosis, and counseling for patients and families.