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Baraitser-Winter cerebrofrontofacial syndrome is caused by heterozygous missense mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1. Recently, we characterized the large cohort of 41 patients presenting with this condition. Our series contained 34 patients with mutations in ACTB and only nine with ACTG1 mutations. Here, we report on seven unrelated patients with six mutations in ACTG1-four novel and two previously reported. Only one of seven patients was clinically diagnosed with this disorder and underwent ACTB/ACTG1 targeted sequencing, four patients were screened as a part of the large lissencephaly cohort and two were tested with exome sequencing. Retrospectively, facial features were compatible with the diagnosis but significantly milder than previously reported in four patients, and non-specific in one. The pattern of malformations of cortical development was highly similar in four of six patients with available MRI images and encompassed frontal predominant pachygyria merging with the posterior predominant band heterotopia. Two remaining patients showed mild involvement consistent with bilaterally simplified gyration over the frontal lobes. Taken together, we expand the clinical spectrum of the ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome demonstrating the mild end of the facial and brain manifestations. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Chromosomal abnormalities involving deletions and duplications are known to cause severe developmental disorders, including mental retardation, dysmorphism, and seizures, in children. As the technique of array-based comparative genomic hybridization is being applied more frequently in the diagnostic evaluation of children with developmental disorders, novel pathologic chromosomal abnormalities are being identified. We report the case of a 9-year-old girl with a history of pervasive developmental disorder, growth delay, mild dysmorphic features, and intractable primary generalized epilepsy with a de novo microdeletion of approximately 0.73-0.94 Mb within chromosome 15q26.1. A much larger (5 Mb) but overlapping microdeletion has been previously reported in a 30-month-old child with similar phenotype including intractable myoclonic epilepsy, growth delay, and dysmorphic features. This leads us to propose that a potential candidate gene or genes within the deleted region involved in the pathogenesis of some forms of generalized intractable epilepsy, previously considered to be idiopathic., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Nonketotic hyperglycinemia (NKH) is an inborn error of metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. NKH is caused by deficiency of the glycine cleavage multi-enzyme system with three specific components encoded by GLDC, AMT, and GCSH. We undertook the first comprehensive screening for GLDC, AMT, and GCSH mutations in 69 families (56, six, and seven families with neonatal, infantile, and late-onset type NKH, respectively). GLDC or AMT mutations were identified in 75% of neonatal and 83% of infantile families, but not in late-onset type NKH. No GCSH mutation was identified in this study. GLDC mutations were identified in 36 families, and AMT mutations were detected in 11 families. In 16 of the 36 families with GLDC mutations, mutations were identified in only one allele despite sequencing of the entire coding regions. The GLDC gene consists of 25 exons. Seven of the 32 GLDC missense mutations were clustered in exon 19, which encodes the cofactor-binding site Lys754. A large deletion involving exon 1 of the GLDC gene was found in Caucasian, Oriental, and black families. Multiple origins of the exon 1 deletion were suggested by haplotype analysis with four GLDC polymorphisms. This study provides a comprehensive picture of the genetic background of NKH as it is known to date., ((c) 2006 Wiley-Liss, Inc.)

Occasionally, but more often than has been reported, true epileptic seizures are triggered by non-epileptic syncopes. This combination of syncope and epileptic seizure has been called an anoxic-epileptic seizure. A few examples of such anoxic-epileptic seizures, including the induction of status epilepticus, have been reported in books and medical journals, but no video-recordings have been published. We show here home video recordings of the first three known examples of the transition from the triggering syncope and anoxic seizure, to the subsequent epileptic seizure. In the first two children, a neurally-mediated syncope, probably mediated by prolonged expiratory apnoea (so-called breath-holding spells), induces a long, clonic epileptic seizure with some features of myoclonic absence. In the third example, a compulsive Valsalva in an older autistic child provokes a vibratory tonic epileptic seizure. In addition, we show two further video clips of the most usual type of epileptic seizure induced by syncopes in very young children. In one, the video recording begins after the end of the triggering syncope and shows a rhythmic clonic seizure that includes repetitive vocalizations. The final recoding is of a spontaneous epileptic seizure with features of myoclonic absence: this child had both epilepsy and identical episodes induced by syncopes, that is, anoxic- epileptic seizures. Not only paediatricians and paediatric neurologists, but also adult neurologists and epileptologists in general, should be aware of the important clinical scenario of true epileptic seizures induced by syncopes. This phenomenon is not considered in any international classification. (Published with videosequences)

Objectives: Mutations disrupting the interaction of extra-cellular ligands and alpha-dystroglycan are responsible for an etiologically heterogeneous group of autosomal recessive congenital muscular dystrophies (CMD) that can have associated brain and eye abnormalities. The objective is to develop a diagnostic test for one of these CMDs, Muscle-Eye-Brain disease (MEB), due to mutations in the gene encoding Protein O-Mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1)., Design and Methods: POMGnT1 enzyme activity was determined in extracts of muscle biopsies from four MEB patients and various controls using commercially available reagents., Results: All four MEB muscle samples showed a highly significant decrease in POMGnT1 activity relative to controls., Conclusions: The assay of POMGnT1 activity in MEB muscle provides a rapid and relatively simple diagnostic test for this disease. CMDs associated with brain malformations such as MEB, WWS and FCMD are heterogenous in clinical presentation and on radiologic examination, suggesting that POMGnT1 assays of muscle biopsies should be used as a screening procedure for MEB in all CMD patients associated with brain malformations.

Infantile- and juvenile-onset spinal cerebellar ataxia (SCA) is associated with expansion of 130 to more than 200 CAG-repeats in the SCA2 and SCA7 genes. Routine clinical assays for SCA2 and SCA7, which use polymerase chain reaction (PCR) and denaturing PAGE (polyacrylamide gel electrophoresis), will not reliably detect such large expansions. An assay based on separation of PCR products on an agarose gel, blotting, and hybridization with a (CAG)6 oligonucleotide probe was used to test DNA from individuals more than 10 years of age who had a possible diagnosis of SCA. Among 25 cases, the PCR-blot assay confirmed the presence of SCA2 expansions between 230 and 500 repeats in four unrelated individuals, but did not detect any cases of extreme expansion in the SCA7 gene. The PCR-blot assay provides reliable detection of extreme expansion mutations. Routine incorporation of this assay in clinical laboratories may reveal that infantile-juvenile forms of SCA2 and SCA7 are more prevalent than previously recognized., (Copyright 2002 Wiley-Liss, Inc.)

Carnitine transporter defect is characterized by severely reduced transport of carnitine into skeletal muscle, fibroblasts, and renal tubules. All children with dilated cardiomyopathy or hypoglycemia and coma should be evaluated for this transporter defect because it is readily amenable to therapy that results in prolonged prevention of cardiac failure. This article details the cases of 3 children who have carnitine transporter defect, 2 of whom had severe dilated cardiomyopathy. Plasma and skeletal muscle carnitine levels were extremely low and both children were treated with oral L-carnitine, resulting in resolution of severe cardiomyopathy and prevention of recurrence or cardiac enlargement for more than 5 years. The third child had hypoglycemia and coma as presenting findings of the transporter defect and had mild left ventricular hypertrophy but no cardiac failure. The prognosis for long-term survival in pediatric dilated cardiomyopathy is poor. Children with carnitine transporter defect can have a different outcome if their underlying condition is detected early and treated medically.

During an evaluation for complicated migraine, a 14-year-old adolescent female was found to have a left frontoparietal cortical infarction on magnetic resonance imaging study. A transthoracic echocardiogram was normal, but a transesophageal echocardiogram, with contrast study, showed occasional right to left shunting through a patent foramen ovale. The role of cardiac anomalies in the pathogenesis of migraine-associated stroke is discussed.

An 11-year-old girl presented with a syndrome of inappropriate antidiuretic hormone secretion, which was transitory and, initially, of obscure origin. Subsequently, the patient's hypothalamic disorder emerged as a component of a steroid-responsive relapsing encephalomyelitis with cerebral pathology restricted to the basal ganglia and brainstem. Where such a disorder fits in the spectrum from acute disseminating encephalomeylitis to multiple sclerosis is discussed.

Two patients with congenital lactic acidemia of unknown etiology developed striking and extensive cranial computed tomography abnormalities of acute or subacute onset. In addition to Leigh syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), other lactic acidemia disorders may produce evolving cerebral radiographic abnormalities. An aggressive effort should be made in such patients to obtain a specific diagnosis through biochemical and molecular genetic studies.

Magnetic resonance imaging of the spine in 45 patients with myelomeningocele revealed hydrosyringomyelia in 24 and diastematomyelia in two. No patient at initial imaging manifested symptoms referable to hydrosyringomyelia; both patients with diastematomyelia had flaccid lower extremities. One patient developed an upper extremity monoparesis which resolved with syringo-peritoneal shunt placement; no other patient manifested symptoms or required surgery. Ventriculoperitoneal shunt malfunction produced reversible distention of the syrinx in another patient who remained asymptomatic.

A defect in intracellular uptake of carnitine has been identified in patients with severe carnitine deficiency. To define the clinical manifestations of this disorder, the presenting features of 15 affected infants and children were examined. Progressive cardiomyopathy, with or without chronic muscle weakness, was the most common presentation (median age of onset, 3 years). Other patients presented with episodes of fasting hypoglycemia during the first 2 years of life before cardiomyopathy had become apparent. A defect in carnitine uptake was demonstrable in fibroblasts and leukocytes from patients. The defect also appears to be expressed in muscle and kidney. Concentrations of plasma carnitine and rates of carnitine uptake in parents were intermediate between affected patients and normal control subjects, consistent with recessive inheritance. Early recognition and treatment with high doses of oral carnitine may be life-saving in this disorder of fatty acid oxidation.

Muscle biopsy was used to attempt determination of carrier status in mothers and maternal relatives of patients with severe neonatal centronuclear (myotubular) myopathy, an X-linked recessive disorder. We report findings from muscle biopsies of 3 mothers, one an obligate carrier. All biopsies showed abnormalities of nonspecific character. Whether such abnormalities assist in defining carrier status is uncertain. A more specific tissue marker for this disorder is required before muscle biopsy will facilitate carrier identification.

Plasmapheresis is used for treating the complications of liver failure. We performed plasmapheresis on 6 children with hepatic encephalopathy resulting from acute hepatic failure and prospectively assessed its effects on neurologic and electrophysiologic (electroencephalography and evoked potentials) function. Clinical improvement was observed in 3 of 6 patients; changes in the serum ammonia value or the results of initial electrophysiologic tests did not predict the patient response. Two patients underwent transplantation after neurologic improvement was produced by plasmapheresis; however, despite plasmapheresis, 4 patients progressed to brain death. Our data demonstrate that plasmapheresis may transiently improve the encephalopathy of acute hepatic failure but is not curative alone. Therefore, plasmapheresis may be a useful adjunct in the treatment of liver failure, potentially improving the pretransplantation status of the patient.

Carnitine deficiency syndromes manifest as metabolic encephalopathy, lipid storage myopathy, or cardiomyopathy. Impairment of long-chain fatty acid metabolism and failure of energy production affect tissues reliant on oxidative metabolism. The accumulation of toxic fatty acyl derivatives impedes gluconeogenesis and urea cycle function which, in turn, causes hypoketotic hypoglycemia, transaminase elevations, and hyperammonemia. Oxidation of accumulated fatty acids through an alternative pathway, omega-oxidation, produces dicarboxylic aciduria. Carnitine must be transported into skeletal muscle. Myopathic carnitine deficiency occurs when this transport mechanism is defective. Most systemic carnitine deficiencies are secondary to other disorders that promote excretion of carnitine as acylcarnitine; however, primary systemic carnitine deficiency, likely due to impaired renal conservation of carnitine, also occurs.

Electroretinography (ERG) may provide laboratory support for the diagnosis of childhood myotonic dystrophy. The sensitivity of ERG may exceed that of electromyography for early detection of the disease. The electroretinographic abnormalities are not specific for myotonic dystrophy.

Though osseous abnormalities are associated with tuberous sclerosis, involvement of the skull base and orbit has not been reported. We describe a patient with superior displacement of the orbit and proptosis that were due to sphenoid hyperplasia and sclerosis characteristic of fibrous dysplasia. A pelvic osteosclerotic lesion suggested polyostotic involvement. The bony abnormalities implied neither concurrent neurofibromatosis nor McCune-Albright syndrome in this patient with tuberous sclerosis.

Movement disorders developed in five children, ages 6 to 21 months, during the course of bacterial meningitis caused by Hemophilus influenzae (one), Streptococcus pneumoniae (one), Neisseria meningitidis (one), or Mycobacterium tuberculosis (two). Athetosis, choreoathetosis, and hemiballismus occurred, ranging in duration from hours to months. Cranial computed tomography, performed in four cases, showed no lesion of the basal ganglia. The movements were of such abrupt onset and severity that in four cases they were initially misinterpreted as seizures, and anticonvulsant therapy was contemplated. It is important to recognize the potential development of movement disorders during the acute phase of bacterial meningitis to preclude the inappropriate administration of anticonvulsant medication.

Cardiac rhabdomyoma occurs frequently in patients with tuberous sclerosis (TS). Although there have been case reports of detection of cardiac rhabdomyoma by 2-dimensional echocardiography, no study has examined the frequency of cardiac rhabdomyoma detected by cardiac ultrasound in patients with TS. Echocardiography was performed in 16 consecutive patients with TS. Physical examination revealed normal cardiac findings in each. Discrete areas of increased acoustic density were found in 8 of the 16 patients (50%). The maximum diameters ranged from 3 to 20 mm. Multiple areas were found in 3 of 8. The left ventricle was involved in 5 of the 8. Six masses were intracavitary and 8 were intramyocardial. No atrial masses were seen. Left ventricular size and function were normal. Although other tumors cannot be excluded, the diagnosis of cardiac rhabdomyoma is almost certain in these young patients with TS. The male predominance and the high incidence of intracavitary and left ventricular masses are similar to those in reported autopsy series, also supporting the diagnosis of cardiac rhabdomyoma. The prognosis and potential for growth of these masses are not known, but can be determined by longitudinal follow-up. Cardiac ultrasound should be considered for all patients with TS regardless of physical findings.

Electrophysiologic studies, echocardiograms, cardiac catheterizations and histologic and biochemical analyses of skeletal muscle biopsies were performed in 10 patients (aged 10 to 37 years, mean 21) who had dysrhythmias as the initial manifestation of cardiomyopathy. Presenting symptoms and signs attributable to dysrhythmias included sudden cardiac arrest in 2 patients, syncope in 3, presyncope in 3 and palpitations in 2. There was no clinical evidence of skeletal muscle weakness in any patient. Multicatheter electrophysiologic evaluation established diagnoses of ventricular tachycardia in 6 patients, primary atrial tachycardia in 2 and third degree infra-Hisian heart block in 1 patient. One patient presenting with palpitations had no inducible arrhythmia or conduction disturbance. Echocardiographic, angiographic and hemodynamic studies demonstrated previously unsuspected dilated cardiomyopathy in 7 patients and restrictive cardiomyopathy in 3. Skeletal muscle histologic characteristics were abnormal in all 10 patients; increases in lipid droplets and endomysial fibrosis were the characteristic findings. Serum free carnitine and short- and long-chain acylcarnitine were normal in 9 patients. However, skeletal muscle long-chain acylcarnitine was reduced in 9 patients. These findings support the concept that in certain patients presenting with dysrhythmias, the dysrhythmia may be a manifestation of cardiac and skeletal (that is, generalized) myopathy.

This article reviews the neurologic manifestations of hyperammonemic disorders. A variety of inborn errors of metabolism, as well as transient neonatal or acquired hepatic dysfunctions, are identified as causes of hyperammonemia. The pathogenesis of hyperammonemia in these disorders is outlined. Catastrophic hyperammonemia and hyperammonemic coma are described; algorithms to establish specific diagnosis are suggested. Symptoms of less severe ammonia intoxication, which also occur in more common diseases, are described. The need to consider hyperammonemia as a potential etiology for these symptoms is emphasized. Finally, the neurotoxicity of ammonia is discussed.

One hundred ninety-nine infants (birth to 15 weeks) were administered an impedance battery to describe emerging characteristics of the acoustic reflex in this age range. Tympanometry results suggest that the middle ear system changes from a highly flaccid state at birth to a relatively normal compliance by 15 weeks. Acoustic reflexes were observed infrequently in the newborn population and gradually increased as a function of age, but never exceeding 43% of the ears tested. A conservative approach regarding the relevance of the presence of the reflex in young children is warranted.

Two patients are reported with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes in whom CT documented massive focal brain swelling with midline shift concurrent with exacerbations of their conditions. Brain swelling producing mass effect should be recognized as a feature of MELAS.