ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a ß1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

Is Celiac Disease an Etiological Factor in Children with Nonsyndromic Intellectual Disability?

To determine the prevalence of celiac disease in children and adolescents with nonsyndromic intellectual disability, we investigated serum levels of tissue transglutaminase antibody and total IgA from 232 children with nonsyndromic intellectual disability and in a healthy control group of 239 children. Study participants who were positive for tissue transglutaminase antibody underwent a duodenal biopsy. A total of 3 patients in the nonsyndromic intellectual disability group (5.45%) and 1 in the control group (0.41%) had positive serum tissue transglutaminase antibody (P > .05). Duodenal biopsy confirmed celiac disease in only 1 patient who had nonsyndromic intellectual disability. In this present study, children with nonsyndromic intellectual disability did not exhibit a higher celiac disease prevalence rate compared with healthy controls. Therefore, we suggest that screening test for celiac disease should not be necessary as a part of the management of mild and moderate nonsyndromic intellectual disability. However, cases of severe nonsyndromic intellectual disability could be examined for celiac disease.

West syndrome associated with a novel chromosomal anomaly; partial trisomy 8P together with partial monosomy 9P, resulting from a familial unbalanced reciprocal translocation.

West syndrome is classified according to the underlying etiology into an acquired West syndrome, a congenital/developmental West syndrome, and West syndrome of unknown etiology. Causes of a congenital/developmental West syndrome are extensive and include chromosomal anomalies. We report on a patient carrying a derivative chromosome originating from the reciprocal unbalanced translocation t (8;9) (p11.2;p22) and presenting with macrocephaly, West syndrome, severe mental motor retardation and hypotonia. As far as we know, this is a new chromosomal anomaly associated with West syndrome.

Superoxide Dismutase and Catalase Genotypes in Pediatric Migraine Patients.

This study compared superoxide dismutase (SOD) and catalase (CAT) alleles in 97 consecutive children and adolescents with migraine to 96 healthy children and adolescents. Isolated genomic DNA was used as a template for SOD1 (35 A/C), SOD2 16 C/T, and CAT2 [(-262 C/T) and (-21 A/T)] allele genotyping. The SOD2 16 C/T genotype and C allele frequency differed significantly between controls and migraine (P = .047; P = .038). CAT -21 AA genotype and A allele frequency were significantly higher in both migraine with aura patients (P = .013; P = .004) and migraine without aura patients (P = .003; P = .001) compared to controls. To our knowledge, this is the first demonstration of differences in SOD and CAT genotypes between pediatric migraine patients and age-matched controls. Further studies on the functional implications of these genetic variants on neural antioxidant capacity and the use of antioxidant modulators for migraine treatment are warranted.

Hyperventilation during routine electroencephalography: are three minutes really necessary?

OBJECTIVE: Hyperventilation induces absence seizures in children with absence epilepsy, and routine electroencephalography studies include three minutes of hyperventilation. We studied the duration of hyperventilation required to provoke a first absence seizure to determine whether three minutes of the procedure are indeed necessary. METHODS: Electroencephalography records of children who experienced absence seizures during hyperventilation were reviewed. The time from hyperventilation onset to a first and further seizure(s) was measured, and the occurrence of absences during the posthyperventilation phase was also noted. RESULTS: Sixty-two studies were evaluated. Mean time from hyperventilation onset to a first absence was 52 seconds (median 32 seconds). The vast majority (85.5%) had an absence within 90 seconds. Most (68%) children sustained a single event. All eight children with posthyperventilation seizures had experienced at least one event during hyperventilation. CONCLUSIONS: Our findings suggest that current guidelines for routine pediatric electroencephalography recording requiring three minutes of hyperventilation may not be clinically necessary. We found that the vast majority of children referred for suspected absence seizures experience a seizure less than 90 seconds after hyperventilation onset, and even more so by 120 seconds. Hence, a larger prospective study is warranted to establish more accurate hyperventilation duration parameters. We also suggest that once an absence seizure has been recorded at any time during hyperventilation, this procedure could be stopped, thus reducing the amount of discomfort for the child.

TGF-ß1 genotype in pediatric migraine patients.

There is no information about the role of transforming growth factor-beta 1 (TGF-ß1) in the pathogenesis of pediatric migraine. This study included 100 consecutive children and adolescents in whom migraine was diagnosed and 88 healthy children and adolescents. The isolated genomic DNA was used as a template for TGFß-1 (-800G/A, -509C/T, 869T/C [codon 10] and 915G/C [codon 25]) genotyping. The allelic frequency of 509C/T was significantly different between control and migraine without aura patients (P = .04). Codon 10 C/T genotypic and C10 C allelic frequency of TGF-ß1 polymorphisms were significantly higher in migraine and migraine without aura patients versus healthy controls (P = .00; P = .00). To our knowledge, this is the first report dealing with the relationship between TGF-ß1 genotype and migraine in the pediatric age group. Further studies related to this subject are needed, along with a search for new therapeutic agents with anti-inflammatory properties.

Novel deoxyguanosine kinase gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome.

Deoxyguanosine kinase (DGUOK) gene mutations have been identified in the hepatocerebral form of mitochondrial DNA depletion syndromes. We report here clinical and laboratory features of 3 infants with novel DGUOK gene mutations, c.130G>A (Glu44Lys), c.493G>A (Glu165Lys), and c.707+3_6delTAAG.

Cerebellar mutism caused by primary varicella infection in an immunocompetent child.

Varicella (chickenpox) is a common childhood infection caused by the varicella-zoster virus, which is often self-limiting and usually benign. Although uncommon, neurologic complications of varicella have been documented that include postinfectious cerebellar ataxia, meningoencephalitis, Reye syndrome, myelitis, optic neuritis, stroke, Guillain-Barré syndrome, seventh cranial nerve palsy, and Ramsay-Hunt syndrome. In this case study, the authors describe a 7-year-old girl who presented with varicella skin rash with unsteady gait and anarthria on day 2, and her condition was attributed to cerebellar mutism. To date, this complication has never been reported in a child with primary varicella infection. Therefore, this case study documents a rare but serious complication of childhood chickenpox.

Multidrug resistance 1 (MDR1) 3435C/T genotyping in childhood drug-resistant epilepsy.

INTRODUCTION: A mutation at nucleotide position 3435 in exon 26 of the multidrug resistance 1 (MDR1) gene is the most frequently studied polymorphism in relation to multidrug resistance. However, there are conflicting data as to whether the CC or TT genotype of the 3435C>T polymorphism is associated with drug resistance. METHODS AND RESULTS: We investigated the association between this polymorphism in drug-resistant childhood epilepsy by comparison with drug-responsive patients. In total, 59 patients with drug-resistant epilepsy, defined as having four or more seizures within a 12-month period while using three or more AEDs, 60 children with drug-responsive epilepsy who had remained seizure-free for 12months on their current AED regimen and 76 healthy children were involved in this study. Genotype frequencies in drug-resistant patients were as follows: 32.2% CC, 44.1% CT, 23.7% TT; in the drug-responsive group: 20.0% CC, 50.0% CT, 30.0% TT; in the control group: 24.3% CC, 50.0% CT, 25.7% TT. Comparison of drug-resistant and drug-responsive patients revealed no significant difference in genotype frequency. The findings of the epilepsy patients were not significantly different from those of the healthy control subjects. CONCLUSIONS: Our study does not support any significant association between the MDR1 polymorphism and drug-resistant childhood epilepsy.

Early clinical predictors of intractable epilepsy in childhood.

AIM: In this retrospective study, we evaluated the clinical responses to antiepileptic drug (AED) therapy in pediatric epilepsy patients treated at a single center. MATERIALS AND METHODS: We identified 28 children with intractable epilepsy and 213 patients with drug-responsive epilepsy. RESULTS: Univariate analysis showed that age at onset, high (daily) initial seizure frequency, infantile spasm, history of neonatal seizures, abnormal neurodevelopmental status, neurological abnormalities, mental retardation, remote symptomatic etiology, and abnormal brain imaging results were significant risk factors for the development of intractable epilepsy (P < 0.05). Multivariate logistic regression analysis revealed that high (daily) initial seizure frequency and remote symptomatic etiology were significant and independent risk factors for intractable epilepsy (P < 0.05). CONCLUSION: Our study suggests that the risk of developing intractable epilepsy in childhood may be predicted, to some extent, by the early clinical course. Early identification of patients at high risk of developing intractable epilepsy will guide appropriate therapy and reduce exposure to ineffectual treatments.

New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms.

Hyperekplexia is a syndrome of readily provoked startle responses, alongside episodic and generalized hypertonia, that presents within the first month of life. Inhibitory glycine receptors are pentameric ligand-gated ion channels with a definitive and clinically well stratified linkage to hyperekplexia. Most hyperekplexia cases are caused by mutations in the α1 subunit of the human glycine receptor (hGlyR) gene (GLRA1). Here we analyzed 68 new unrelated hyperekplexia probands for GLRA1 mutations and identified 19 mutations, of which 9 were novel. Electrophysiological analysis demonstrated that the dominant mutations p.Q226E, p.V280M, and p.R414H induced spontaneous channel activity, indicating that this is a recurring mechanism in hGlyR pathophysiology. p.Q226E, at the top of TM1, most likely induced tonic activation via an enhanced electrostatic attraction to p.R271 at the top of TM2, suggesting a structural mechanism for channel activation. Receptors incorporating p.P230S (which is heterozygous with p.R65W) desensitized much faster than wild type receptors and represent a new TM1 site capable of modulating desensitization. The recessive mutations p.R72C, p.R218W, p.L291P, p.D388A, and p.E375X precluded cell surface expression unless co-expressed with α1 wild type subunits. The recessive p.E375X mutation resulted in subunit truncation upstream of the TM4 domain. Surprisingly, on the basis of three independent assays, we were able to infer that p.E375X truncated subunits are incorporated into functional hGlyRs together with unmutated α1 or α1 plus ß subunits. These aberrant receptors exhibit significantly reduced glycine sensitivity. To our knowledge, this is the first suggestion that subunits lacking TM4 domains might be incorporated into functional pentameric ligand-gated ion channel receptors.

Acute disseminated encephalomyelitis in children and adolescents: a single center experience.

BACKGROUND: Acute disseminated encephalomyelitis is an immune-mediated disease that produces multiple inflammatory lesions in the brain and spinal cord. METHODS: This study retrospectively evaluated 15 children with acute disseminated encephalomyelitis in children and adolescents from a single institution in Adana, Turkey. RESULTS: The patients presented in a seasonal distribution, with 73.3%: (11/15) presenting in winter or spring. The majority of patients (13/15, 86.7%) had a history of acute febrile illness 2 to 40 days before presentation, and five children had serologic evidence of specific triggers: mycoplasma (2 children), influenza-A (H1N1) (1 child), or Epstein-Barr virus. All children were treated with a standard protocol of 3 to 5 days of intravenous administration of methylprednisolone and intravenous immunoglobulin for patients who continued to deteriorate. Oseltamivir and clarithromycin were administered in patients with influenza-A (H1N1) and mycoplasma according to the serology. In 13 patients, all neurologic signs and symptoms resolved after treatment. Only one patient was left with severe neurologic sequelae and another child had recurrent attacks and was ultimately diagnosed with possible multiple sclerosis. CONCLUSIONS: The present series demonstrates that acute disseminated encephalomyelitis in children occurs predominantly in winter or spring and often follows an upper respiratory tract illness for those along the southern coast of Anatolia (Mediterranean region). Early treatment with immunomodulative agents is recommended and is likely to result in a favorable outcome or full recovery. This study also suggests benefit from antiviral and antibiotic treatment initiated as soon as possible after the onset of illness.

Acute cerebellar ataxia in a pediatric case of Lyme disease and a review of literature.

A broad range of neurologic disorders have been described in children with Lyme disease, of which peripheral facial nerve palsy and aseptic meningitis are among the most common. In contrast, there are few reports of cerebellar involvement in pediatric Lyme disease patients. We report the case of a 5-year-old girl seropositive for antibodies against the causative Lyme disease pathogen Borrelia burgdorferi presenting with severe acute cerebellar ataxia from the in southern coast of Anatolia (Mediterranean region).

Chloral hydrate versus hydroxyzine HCL for sedation prior to pediatric sleep EEG recording.

OBJECTIVE: The sleep electroencephalogram (EEG) can reveal certain epileptiform activity patterns and facilitate localization of the focus. Sedation is often required for sleep EEG recording in pediatric patients, but there is no consensus on the optimal sedative. Hydroxyzine HCL (HH) and chloral hydrate (CH) are popular sedatives, but HH is rarely used for pediatric sleep EEG recording. The goal of this prospective study was to compare CH to HH for sleep induction efficacy, safety and effects on pediatric sleep EEG pattern. RESEARCH DESIGN AND METHODS: A total of 282 children (age 4-9 years) referred to our sleep EEG laboratory and requiring sedation were randomly assigned to two groups: the CH Group (n = 141) received 50 mg/kg CH and the HH group (n = 141) received 1 mg/kg HH. If sedation was unsatisfactory, a second equal dose of the same sedative was administered 30 min later. RESULTS: Sleep induction was less successful in the HH group compared to the CH group (p < 0.001). Sleep onset latency was significantly longer in the HH group (p < 0.01) and the proportion of HH group patients requiring a second sedative dose significantly higher (p < 0.01). There was no significant difference in the proportion of patients exhibiting epileptiform activity on the EEG or in adverse event rate between groups. CONCLUSION: CH was a superior sedative compared to HH owing to more rapid and successful sleep induction with no increase in adverse events.

Acute transverse myelitis in a child with Lyme disease and a review of literature.

Acute transverse myelitis is a rare Borellia burgdorferi-related neurologic complication in childhood. We present a 12-year-old girl who was diagnosed with acute transverse myelitis associated with a borreliosis infection. We also review clinical features in all five cases of Borellia burgdorferi-related transverse myelitis in children. We describe here the sixth child with borreliosis-related transverse myelitis.

A randomized trial comparing amitriptyline versus topiramate for the prophylaxis of chronic daily headache in pediatric patients.

OBJECTIVE: the goal of this prospective and double-blind study was to compare the efficacy of amitriptyline and topiramate for the prevention of pediatric chronic daily headache (CDH). RESEARCH DESIGN AND METHODS: fifty-seven children (aged 9-16 yr) diagnosed with CDH were randomly assigned to two groups: group A (n = 29 patients) received amitriptyline 0.5 mg/kg/d and group B (n = 28 patients) received topiramate 25 mg/d increasing up to 100 mg/d according to patient response. Treatment response was monitored for at least 4 months. RESULTS: fifty-five percent of the patients in group A responded to amitriptyline and 61% of patients in group B responded to topiramate as defined by a reduction of more than 50% in monthly headache frequency. There was no significant difference in responder rate or adverse event rate between the two groups (p > 0.05). By the end of the 4-month treatment period, there were no significant differences in the final average severity and monthly frequency of headaches between treatment groups. CONCLUSION: these results suggest that the efficacy and tolerability of topiramate is equivalent to that of amitriptyline for reducing the frequency of headache in pediatric CHD patients.

Vici syndrome associated with sensorineural hearing loss and laryngomalacia.

The phenotypically heterogeneous, autosomal recessive Vici syndrome was first described in 1988 in a sister and brother with oculocutaneous albinism, agenesis of the corpus callosum, cataract, cardiomyopathy, cleft lip, and immunodeficiency. Only 14 cases of Vici syndrome have yet been reported, several involving morphologic and functional defects in addition to those described in the initial case. We report on a 3-month-old Turkish girl with Vici syndrome associated with laryngomalacia, further expanding the clinical spectrum. We also review clinical features in all 15 Vici syndrome patients, to distinguish general from less common signs. To the best of our knowledge, this report is the first of a Turkish patient with Vici syndrome.

Involvement of the globus pallidus in giant axonal neuropathy.

Giant axonal neuropathy is a rare autosomal recessive disorder commonly characterized by chronic, progressive dysfunction in the peripheral nervous system. Lesions also can occur in the central nervous system, especially in the brainstem and cerebellum. We present cranial magnetic resonance imaging and magnetic resonance spectroscopy findings in a 5-year-old Turkish girl with giant axonal neuropathy. This study is the second to describe involvement of the globus pallidus on T(2)-weighted imaging in giant axonal neuropathy. Magnetic resonance spectroscopy of cerebellar white matter lesions and globus pallidus revealed metabolic changes, including increased choline/creatine ratios, increased lactate, and reduced N-acetyl aspartate/creatine ratios. Thus, magnetic resonance spectroscopy did not produce findings specific to giant axonal neuropathy, but indicated progressive neuronal loss, demyelination, and gliosis in the cerebellar white matter.

Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy gene.

BACKGROUND: The progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous disorders characterised by myoclonus, epilepsy, and neurological deterioration. This study aimed to identify the underlying gene(s) in childhood onset PME patients with unknown molecular genetic background. METHODS: Homozygosity mapping was applied on genome-wide single nucleotide polymorphism data of 18 Turkish patients. The potassium channel tetramerisation domain-containing 7 (KCTD7) gene, previously associated with PME in a single inbred family, was screened for mutations. The spatiotemporal expression of KCTD7 was assessed in cellular cultures and mouse brain tissue. RESULTS: Overlapping homozygosity in 8/18 patients defined a 1.5 Mb segment on 7q11.21 as the major candidate locus. Screening of the positional candidate gene KCTD7 revealed homozygous missense mutations in two of the eight cases. Screening of KCTD7 in a further 132 PME patients revealed four additional mutations (two missense, one in-frame deletion, and one frameshift-causing) in five families. Eight patients presented with myoclonus and epilepsy and one with ataxia, the mean age of onset being 19 months. Within 2 years after onset, progressive loss of mental and motor skills ensued leading to severe dementia and motor handicap. KCTD7 showed cytosolic localisation and predominant neuronal expression, with widespread expression throughout the brain. None of three polypeptides carrying patient missense mutations affected the subcellular distribution of KCTD7. DISCUSSION: These data confirm the causality of KCTD7 defects in PME, and imply that KCTD7 mutation screening should be considered in PME patients with onset around 2 years of age followed by rapid mental and motor deterioration.

Acute disseminated encephalomyelitis associated with influenza A H1N1 infection.

Acute disseminated encephalomyelitis is an immune-mediated inflammatory disorder of the central nervous system, characterized by demyelination. Acute disseminated encephalomyelitis predominantly involves the white matter of the brain and spinal cord, and often follows upper respiratory tract infection. We describe a case of acute disseminated encephalomyelitis associated with the influenza A (H1N1) virus. The H1N1 virus usually causes febrile respiratory signs, e.g., fever, cough, and sore throat. Although these signs exhibit a self-limited course, the frequencies of severe complications and death are increasing. To date, only a few reports of acute disseminated encephalomyelitis secondary to the H1N1 virus have been published.