Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy.

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.

Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.

BACKGROUND: Early infantile Krabbe disease is rapidly fatal, but hematopoietic stem cell transplantation (HSCT) may improve outcomes if performed soon after birth. New York State began screening all newborns for Krabbe disease in 2006. METHODS: Infants with abnormal newborn screen results for Krabbe disease were referred to specialty-care centers. Newborns found to be at high risk for Krabbe disease underwent a neurodiagnostic battery to determine the need for emergent HSCT. RESULTS: Almost 2 million infants were screened. Five infants were diagnosed with early infantile Krabbe disease. Three died, two from HSCT-related complications and one from untreated disease. Two children who received HSCT have moderate to severe developmental delays. Forty-six currently asymptomatic children are considered to be at moderate or high risk for development of later-onset Krabbe disease. CONCLUSIONS: These results show significant HSCT-associated morbidity and mortality in early infantile Krabbe disease and raise questions about its efficacy when performed in newborns diagnosed through newborn screening. The unanticipated identification of "at risk" children introduces unique ethical and medicolegal issues. New York's experience raises questions about the risks, benefits, and practicality of screening newborns for Krabbe disease. It is imperative that objective assessments be made on an ongoing basis as additional states begin screening for this disorder.Genet Med 18 12, 1235-1243.

Newborn screening for Krabbe disease: the New York State model.

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.

Vagus Nerve Stimulation in the Developmentally Disabled.

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.

The Electroencephalogram in Children with Developmental Dysphasia.

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: an MRI/MRS longitudinal study.

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.

A practical review and approach to poststroke seizures.

Much confusion still exists about when to treat seizures related to stroke and what agents to use. Seizures may occur in the setting of ischemic stroke, intracranial hemorrhage, subarachnoid hemorrhage, and other cerebrovascular lesions. The epidemiology of poststroke seizures and patients at higher risk for developing poststroke epilepsy are identified. The utility of electroencephalography (EEG), continuous and video EEG monitoring, and management and treatment of those patients who develop epilepsy are discussed.

Autism and epilepsy: cause, consequence, comorbidity, or coincidence?

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.