Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4.

Charcot-Marie-Tooth disease is a genetically heterogeneous group of motor and sensory neuropathies associated with mutations in more than 30 genes. Charcot-Marie-Tooth disease type 4J (OMIM 611228) is a recessive, potentially severe form of the disease caused by mutations of the lipid phosphatase FIG4. We provide a more complete view of the features of this disorder by describing 11 previously unreported patients with Charcot-Marie-Tooth disease type 4J. Three patients were identified from a small cohort selected for screening because of their early onset disease and progressive proximal as well as distal weakness. Eight patients were identified by large-scale exon sequencing of an unselected group of 4000 patients with Charcot-Marie-Tooth disease. In addition, 34 new FIG4 variants were detected. Ten of the new CMT4J cases have the compound heterozygous genotype FIG4(I41T/null) described in the original four families, while one has the novel genotype FIG4(L17P/nul)(l). The population frequency of the I41T allele was found to be 0.001 by genotyping 5769 Northern European controls. Thirty four new variants of FIG4 were identified. The severity of Charcot-Marie-Tooth disease type 4J ranges from mild clinical signs to severe disability requiring the use of a wheelchair. Both mild and severe forms have been seen in patients with the same genotype. The results demonstrate that Charcot-Marie-Tooth disease type 4J is characterized by highly variable onset and severity, proximal as well as distal and asymmetric muscle weakness, electromyography demonstrating denervation in proximal and distal muscles, and frequent progression to severe amyotrophy. FIG4 mutations should be considered in Charcot-Marie-Tooth patients with these characteristics, especially if found in combination with sporadic or recessive inheritance, childhood onset and a phase of rapid progression.

Vagus nerve stimulation for the management of seizures in children: an 8-year experience.

BACKGROUND: Medication-resistant seizure disorder is a challenging, debilitating, and expensive condition. Although multiple interventions are now available, none is universally effective. In 1997, vagus nerve stimulation (VNS) was approved for treatment of refractory seizures in patients older than 12 years. Vagus nerve stimulation has shown some benefit for these individuals, but less is known about its use in patients younger than 12 years. This review analyzes the safety and efficacy of VNS in young children. METHODS: From March 2000 to February 2008, patients with medication-resistant seizures were implanted with a neurocybernetic prosthesis. Two weeks later, the device was activated. The children were followed for at least 3 months, and adjustments were made. Retrospective chart review was performed to collect data. RESULTS: Of 28 patients, the mean age at implantation was 8 years and 5 months. Twenty-one (75%) children were younger than 12 years. There were no surgical complications. Two children were reimplanted for lead malfunction, and 4 generators were replaced. Two children had transitory adverse effects (hoarseness and stridor). Mean follow-up was 3 years and 5 months. At 1 year, 52% of children had greater than 50% reduction in seizures. CONCLUSIONS: Although the effectiveness of VNS is variable and unpredictable, safety is high even in young children. Because of the potential benefit for these complex patients, the implantation of this nerve stimulation device should be included in the armamentarium of pediatric surgeons.