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Aminoacyl-transfer RNA (tRNA) synthetases ligate amino acids to specific tRNAs and are essential for protein synthesis. Although alanyl-tRNA synthetase (AARS) is a synthetase implicated in a wide range of neurological disorders from Charcot-Marie-Tooth disease to infantile epileptic encephalopathy, there have been limited data on their pathogenesis. Here, we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity. Whole-exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp). A lymphoblastoid cell line developed from one of the affected individuals showed a strong reduction in AARS abundance. The mutations decrease aminoacylation efficiency by 70%-90%. The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation. Our study has extended potential mechanisms underlying AARS-related disorders to include destabilization of the protein, aminoacylation dysfunction, and defective editing activity., (© 2017 Wiley Periodicals, Inc.)

Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders.

Autism is associated with epilepsy in early childhood, with evidence suggesting that individuals with both autism and more severe cognitive impairment are at higher risk. However, the incidence of an abnormal electroencephalogram and/or epilepsy in the full range of pervasive developmental disorders (PDDs) is not well defined. This naturalistic study addresses the incidence of epilepsy and electroencephalographic abnormalities in children with PDDs. The clinical history and electroencephalograms of 56 children diagnosed with PDD-not otherwise specified, autism, or Asperger syndrome were retrospectively reviewed. Forty percent of children with autism were diagnosed with epilepsy. Abnormal electroencephalograms and epilepsy occurred at significantly higher rates in children in the more impaired range of the autism spectrum (P<0.05). These findings suggest that the use of neurological investigative techniques such as electroencephalography should be a consequence of careful clinical evaluation and should be considered routinely during evaluation of more impaired individuals.

A clinical and radiologic diagnosis of acute disseminated encephalomyelitis was made in two children: a 6-month-old female who presented with focal seizures and thalamic and cerebral white matter lesions, and a 4.5-year-old male who presented with tremor and dystonia and had bilateral basal ganglia lesions, without evidence of active brain infection. Serial clinical and laboratory evaluations were supplemented by neuroimaging including routine magnetic resonance imaging and (1)H magnetic resonance spectroscopy. They were treated symptomatically, without using steroids or intravenous immunoglobulin, and both children recovered. Single voxel (1)H magnetic resonance spectroscopy data were acquired from the involved areas and from normal-appearing white matter. Abnormalities in N-acetyl-aspartate, choline, and lactate peaks were evident during the symptomatic phase, and persistence of low N-acetyl-aspartate was observed during recovery. These spectroscopic findings are consistent with neuropathologic findings of neuronal dysfunction, cellular membrane turnover, cellular infiltration, and metabolic stress in the acute phase, and with neuronal loss in the chronic phase.

Vagus nerve stimulation (VNS) with the neuro cybernetic prosthesis (NCP) is an approved treatment of partial seizures for patients 12 years and older. Developmentally disabled or mentally retarded patients with epilepsy may also benefit from VNS; however, their evaluation and management pose greater problems. A retrospective chart review was conducted on all patients diagnosed with mild to severe mental retardation who had an NCP implanted. Records of these 21 patients, ranging in age from 3 to 56 years, were reviewed regarding VNS efficacy, side effects, behavioral changes, and alterations in antiepileptic drugs (AEDs). Seizure types included partial onset and generalized. Sixteen patients had clearly evaluable seizures both pre- and postimplant, with a greater than 50% reduction in seizures noted in 68% (11/16) after 6 months of implant. There were no adverse events that prevented chronic stimulation. Institutional staff and family members were provided with both pre- and postoperative education on VNS and magnet use. VNS appeared to be an effective and well-tolerated therapy in this group of developmentally disabled patients with refractory epilepsy.

Speech and language delay is a common developmental or acquired disorder. It can be a feature of the autistic spectrum, and if regression of language coincides with epilepsy, the diagnosis of Landau-Kleffner syndrome is considered. Slow acquisition of language without regression is called developmental dysphasia. A retrospective review of clinical and electroencephalographic (including video electroencephalographic) data on 138 children with speech/language delay, seen in a year's time, is presented. The electroencephalogram (EEG) was abnormal in 61% of children with a history of language regression. The EEG was abnormal in only 15% of children with developmental language disorder, most of whom also had clinical seizures. The difference between the two groups was highly significant (P = 0.004). Therefore obtaining an EEG in children with regression of language, especially if a history of clinical seizures is elicited, is indicated.

Acute disseminated encephalomyelitis is a monophasic, immune-mediated disorder that produces multifocal demyelinating lesions within the central nervous system. It is characterized clinically by the acute onset of neurologic abnormalities, including varying degrees of mental state changes ranging from drowsiness to coma. It is unusual for the illness to present as an isolated acute psychosis. The case of a 14-year-old female with biopsy-confirmed acute disseminated encephalomyelitis, who was initially diagnosed with an acute psychiatric disorder, is presented, and published reports on this unusual manifestation are reviewed. A Medline database search was performed from 1965 to 1999, using the terms acute disseminated encephalomyelitis, postvaccinal encephalomyelitis, postinfectious encephalomyelitis, and measles encephalomyelitis, combined with the terms psychosis, psychiatric disorder, and behavioral disorder. Selected cross-referenced reports were also reviewed. Nine patients were identified who presented with acute psychosis. We conclude that, although rare, acute disseminated encephalomyelitis can present as an acute psychosis. This immune-mediated condition should be included in the differential diagnosis of neurologic disorders presenting as a psychiatric illness.

We report two patients with intractable partial seizures who developed generalized nonconvulsive status epilepticus (NCSE) after receiving tiagabine (TGB). Neither had a history of absence seizures or generalized epileptic discharges on prior EEG monitoring. Clinicians need to be aware of a possible association between TGB and NCSE.

This review highlights our understanding of episodic phenomena in children and adolescents that resemble epileptic seizures. Although the initial focus is on psychogenically determined nonepileptic seizures (NES; pseudoseizures), other forms of conversion symptoms are also discussed. We subsequently examine the diverse nonpsychogenic, nonepileptic paroxysmal disorders that may be encountered in this age group.

Purpose: We assessed rates of symptoms of anxiety and depression among pediatric patients with epilepsy., Methods: We administered the Revised Child Manifest Anxiety Scale (RCMAS), and Child Depression Inventory (CDI) to 44 epilepsy patients aged 7-18 years (mean age 12.4 years). Demographic, socioeconomic, and epilepsy-related information was examined in relation to depression and anxiety scores., Results: No patients had been previously identified to have depression or anxiety. However, 26% had significantly increased depression scores and 16% met criteria for significant anxiety symptomatology., Conclusions: Symptoms of depression and anxiety are common among pediatric patients with epilepsy and appear to be overlooked by care providers.

We prospectively investigated drug-induced headaches (HA) among 60 epileptic patients receiving felbamate (FBM). Twenty patients (33%) experienced HA. HA was pounding in 11 (55%), steady in 9 (45%), moderate or severe in 19 (95%), occurred at least once a week in all patients, and was relieved by nonnarcotic analgesics in 14 (70%). Mean duration on FBM before HA onset was 19 days. HA occurred with higher FBM doses and was relieved in 8 of 13 patients (62%) with FBM dose reduction. FBM was discontinued in most cases because of risks of anemia or hepatitis; not because of HA. Other side effects included insomnia (25%), gastrointestinal symptoms (27%), and agitation or restlessness (23%). HA is a common dose-related complication of FBM, occurs early after initiation of FBM treatment, and is relieved by dose reduction.

We report the case of an 18-month-old child with infantile spasms and a hypsarrhythmic electroencephalogram (EEG) pattern associated with a porencephalic cyst. Surgical removal of the cyst and its surrounding tissue was performed following failure of medical therapy. Postoperatively, the patient has been free of infantile spasms for 12 months and the EEG has normalized. He has been maintained on the same preoperative antiepileptic medications. This case suggests that surgical treatment is helpful in selected patients with infantile spasms and focal CNS lesions.

Analysis of computed tomograms of patients with adrenoleukodystrophy in the early disease phase reveals a dinstinct CT apperance. It is suggested that brain or adrenal biopsy may not be necessary for diagnosis of adrenoleukodystrophy when these particular CT features are correlated with the clinical course and other laboratory parameters.