Copy number variation plays an important role in clinical epilepsy.

OBJECTIVE: To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. METHODS: We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. RESULTS: Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34% were >500kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or "hotspots." We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. INTERPRETATION: Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy.

Lambert-Eaton syndrome, an unrecognized treatable pediatric neuromuscular disorder: three patients and literature review.

BACKGROUND: Lambert-Eaton myasthenic syndrome, a presynaptic neuromuscular junction autoimmune disorder, rarely occurs in children. Patients typically present with proximal lower extremity weakness with areflexia. METHODS: We report three children presenting between ages 9 and 10 years diagnosed with Lambert-Eaton myasthenic syndrome 2 years, 1 year, and 5 months later, respectively. Their clinical attributes are correlated with nine other pediatric Lambert-Eaton myasthenic syndrome patients found in our literature review. RESULTS: These patients were identified as having Lambert-Eaton myasthenic syndrome during their evaluation for proximal weakness. Low-amplitude compound muscle action potentials classically facilitating >100% with voluntary exercise and/or 50 Hz stimulation were essential to diagnosis. Three of the 12 children had associated malignancies, two of them had lymphoproliferative disorders with onset of symptoms more rapid than the rest, and the third had neuroblastoma. The nine nonparaneoplastic Lambert-Eaton myasthenic syndrome patients responded to immunomodulatory therapy with close return to their baseline function. Complete remission no longer necessitating medication was reported in two patients. Follow-up up to 17 years was available on two patients previously reported. CONCLUSION: Lambert-Eaton myasthenic syndrome is a diagnosis that must be considered in children presenting with unidentified proximal muscle weakness. In most children, Lambert-Eaton myasthenic syndrome is a primary autoimmune disorder that is treatable. Nevertheless, a search for malignancy is recommended.

The spectrum of myotonic and myopathic disorders in a pediatric electromyography laboratory over 12 years.

This study assessed the spectrum of disorders associated with electrophysiologic myotonia in a pediatric electromyography laboratory. Records of 2234 patients observed in the Electromyography Laboratory at Boston Children's Hospital from 2000-2011 were screened retrospectively for electrophysiologic diagnoses of myotonia and myopathy. Based on electromyography, 11 patients manifested myotonic discharges alone, eight exhibited both myotonic discharges and myopathic motor unit potentials, and 54 demonstrated myopathic motor unit potentials alone. The final diagnoses of patients with myotonic discharges alone included myotonia congenita, paramyotonia congenita, congenital myopathy, and Pompe disease (acid maltase deficiency). The diagnoses of patients with both myotonic discharges and myopathic motor unit potentials included congenital myopathy and non-Pompe glycogen storage diseases. Myotonic discharges are rarely observed in a pediatric electromyography laboratory, but constitute useful findings when present. The presence or absence of concurrent myopathic motor unit potentials may help narrow the differential diagnosis further.

Spinal muscular atrophy: a clinical and research update.

Spinal muscular atrophy, a hereditary degenerative disorder of lower motor neurons associated with progressive muscle weakness and atrophy, is the most common genetic cause of infant mortality. It is caused by decreased levels of the "survival of motor neuron" (SMN) protein. Its inheritance pattern is autosomal recessive, resulting from mutations involving the SMN1 gene on chromosome 5q13. However, unlike many other autosomal recessive diseases, the SMN gene involves a unique structure (an inverted duplication) that presents potential therapeutic targets. Although no effective treatment for spinal muscular atrophy exists, the field of translational research in spinal muscular atrophy is active, and clinical trials are ongoing. Advances in the multidisciplinary supportive care of children with spinal muscular atrophy also offer hope for improved life expectancy and quality of life.

Muscle-Eye-Brain disease.

A term female infant was evaluated for global developmental delay, hypotonia, hyporeflexia, diffuse weakness including facial muscles, and visual impairment with optic nerve hypoplasia. In the absence of family history or perinatal concerns, an extensive investigation was performed, including lab studies, muscle biopsy, brain MRI and focused genetic testing. This revealed elevated serum CK, a structurally abnormal brain, and a dystrophic-appearing muscle biopsy with evidence of a glycosylation defect in the alpha-dystroglycan complex. Of the 6 known related genes, testing of the POMGnT1 gene showed three heterozygous missense mutations. Thus her history, examination, biopsy specimen, imaging, laboratory, and genetic studies are all consistent with the diagnosis of Muscle-Eye-Brain (MEB) disease. MEB is one of an emerging spectrum of congenital disorders that involve both central and peripheral nervous systems, described further in this case report.

Child neurology: chronic inflammatory demyelinating polyradiculoneuropathy in children.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disorder characterized by patchy demyelination of nerve roots and distal nerves. The course may be monophasic progressive or relapsing-remitting. CIDP is less common in children than in adults. As in adults, children with CIDP present with proximal and distal weakness and loss of deep tendon reflexes. Children are most often brought to medical attention due to gait disturbance and falling. As in adults, immunomodulatory treatment is the mainstay of therapy. Based on the small number of case series available, children with CIDP seem have a more favorable long-term course than adults.

Spinal muscular atrophy in the neonate.

Spinal muscular atrophy (SMA) type I is an autosomal recessive disorder characterized by loss of lower motor neurons in the spinal cord. This severe hereditary neurodegenerative disorder is an important cause of morbidity in the neonate and the leading hereditary cause of infant mortality. The characteristic degeneration of anterior horn cells in the spinal cord leads to progressive muscular weakness and atrophy of the skeletal muscles. In SMA type I, the most severe form of SMA, death usually ensues by 2 years of age from respiratory failure or infection. Accurate diagnosis is now available through genetic testing, and progress is being made toward the development of therapy based on understanding of the disease mechanism. The neonatal nurse plays a pivotal role in identifying and caring for these medically fragile infants and in providing support and education for parents and families.

Valproic acid increases SMN levels in spinal muscular atrophy patient cells.

Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1). Although a centromeric copy of the survival motor neuron gene (SMN2) is retained in all patients with SMA, it differs from SMN1 at a critical nucleotide such that the majority of SMN2 transcripts lack exon 7 and encode an unstable, truncated protein. Here, we show that valproic acid increases levels of exon 7-containing SMN transcript and SMN protein in type I SMA patient-derived fibroblast cell lines. Valproic acid may increase SMN levels both by activating the SMN promoter and by preventing exon 7 skipping in SMN transcripts. Valproic acid and related compounds warrant further investigation as potential treatment for SMA.

Ingestion of tea tree oil (Melaleuca oil) by a 4-year-old boy.

A 4-year-old boy ingested a small quantity of tea tree oil. Within 30 minutes, he became ataxic and shortly thereafter progressed to unresponsiveness; he was endotracheally intubated by paramedics. His neurologic status improved gradually over 10 hours, and he remains well on follow-up. Tea tree oil is an increasingly popular topical antiseptic that is available in a wide variety of products, often without warning labels. Healthcare providers should be aware of the common uses of tea tree oil, as well as its potential toxicity.