Hyperkinetic movements are unwanted or excess movements that are frequently seen in children with neurologic disorders. They are an important clinical finding with significant implications for diagnosis and treatment. However, the lack of agreement on standard terminology and definitions interferes with clinical treatment and research. We describe definitions of dystonia, chorea, athetosis, myoclonus, tremor, tics, and stereotypies that arose from a consensus meeting in June 2008 of specialists from different clinical and basic science fields. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random-appearing sequence of one or more discrete involuntary movements or movement fragments. Athetosis is a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Myoclonus is a sequence of repeated, often non-rhythmic, brief shock-like jerks due to sudden involuntary contraction or relaxation of one or more muscles. Tremor is a rhythmic back-and-forth or oscillating involuntary movement about a joint axis. Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. Stereotypies are repetitive, simple movements that can be voluntarily suppressed. We provide recommended techniques for clinical examination and suggestions for differentiating between the different types of hyperkinetic movements, noting that there may be overlap between conditions. These definitions and the diagnostic recommendations are intended to be reliable and useful for clinical practice, communication between clinicians and researchers, and for the design of quantitative tests that will guide and assess the outcome of future clinical trials.

ABSTRACT. Objective. Between October and November 2003, several infants with encephalopathy were hospitalized in pediatric intensive care units in Israel. Two died of cardiomyopathy. Analysis of the accumulated data showed that all had been fed the same brand of soy-based formula (Remedia Super Soya 1), specifically manufactured for the Israeli market. The source was identified on November 6, 2003, when a 5.5-month-old infant was admitted to Sourasky Medical Center with upbeat nystagmus, ophthalmoplegia, and vomiting. Wernicke's encephalopathy was suspected, and treatment with supplementary thiamine was started. His condition improved within hours. Detailed history revealed that the infant was being fed the same formula, raising suspicions that it was deficient in thiamine. The formula was tested by the Israeli public health authorities, and the thiamine level was found to be undetectable (<0.5 g/g). The product was pulled from the shelves, and the public was alerted. Thiamine deficiency in infants is very rare in developed countries. The aim of this study was to report the epidemiology of the outbreak and to describe the diagnosis, clinical course, and outcome of 9 affected infants in our care.Methods. After the index case, an additional 8 infants were identified in our centers by medical history, physical examination, and laboratory testing. The group consisted of 6 male and 3 female infants aged 2 to 12 months. All were assessed with the erythrocyte transketolase activity assay, wherein the extent of thiamine deficiency is expressed in percentage stimulation compared with baseline (thiamine pyrophosphate effect [TPPE]). Normal values range from 0% to 15%; a value of 15% to 25% indicates thiamine deficiency, and >25% indicates severe deficiency. Blood lactate levels (normal: 0.5-2 mmol/L) were measured in 6 infants, cerebrospinal fluid lactate in 2 (normal: 0.5-2 mmol/L), and blood pyruvate in 4 (normal: 0.03-0.08 mmol/L). The diagnostic criteria for thiamine deficiency were abnormal transketolase activity and/or unexplained lactic acidosis. Treatment consisted of intramuscular thiamine 50 mg/day for 14 days combined with a switch to another infant formula.Results. Early symptoms were nonspecific and included mainly vomiting (n ‫؍‬ 8), lethargy (n ‫؍‬ 7), irritability (n ‫؍‬ 5), abdominal distension (n ‫؍‬ 4), diarrhea (n ‫؍‬ 4), respiratory symptoms (n ‫؍‬ 4), developmental delay (n ‫؍‬ 3), and failure to thrive (n ‫؍‬ 2). Infection was found in all cases. Six infants were admitted with fever. One patient had clinical dysentery and group C Salmonella sepsis; the others had mild infection: acute gastroenteritis (n ‫؍‬ 2); upper respiratory infection (n ‫؍‬ 2); and bronchopneumonia, acute bronchitis, and viral infection (n ‫؍‬ 1 each). Two infants were treated with antibiotics. Three infants had neurologic symptoms of ophthalmoplegia with bilateral abduction deficit with or without upbeat nystagmus. All 3 had blood lactic acidosis, and 2 had high cerebrospinal fluid lactate levels. Patient 1, our index case, wa...

Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.

BackgroundIn the management of hypertonicity in children with cerebral palsy (CP), goals should be clearly identified in order to evaluate the effectiveness of botulinum toxin A (BoNT-A) treatment, specifically in non-ambulatory children and adolescents, Gross Motor Function Classification System (GMFCS), level IV or V. A retrospective chart review (Mesterman et al., 2013) identified the need for the development of a set of specific and meaningful goals linked to the International Classification of Functioning, Disability and Health (ICF) for future goal setting and evaluation in this population. Our objective is to create an inventory of goals based on the ICF framework that captures the needs and values of families with children with CP.MethodsThis cross-sectional observational study recruited parents of twenty children and youths with CP in GMFCS levels IV or V (mean age 11.2 years, SD 4.3, 13 males) who were assessed for BoNT-A treatment at the Spasticity Management Clinic at McMaster Children’s Hospital (Hamilton, ON). A previous inventory of goals was developed by a group of experts at a national botulinum toxin conference held in January 2014 (Montreal, Canada). The inventory of goals was further refined by asking the parents to select goals from the inventory list that they would like their child to accomplish after receiving BoNT-A treatment, and asking healthcare professionals for clarity and phrasing of goals in the inventory list.ResultsAll parents identified body structure and function goals, with more than 75% of parents selecting reduction in muscle tone and increased range of movements in the upper and lower extremities. More than 50% of parents identified activity goals related to ease of caregiving. Two activity goals and three participation goals were missing from the inventory. Participation goals were identified by less than 5% of parents.ConclusionThe inventory may be a helpful tool to facilitate a discussion about goal setting between healthcare professionals and families in the context of BoNT-A treatment. A future study is needed to conduct qualitative interviews to better understand the information that families may require about setting goals during BoNT-A treatment and to evaluate the usefulness of the inventory.Electronic supplementary materialThe online version of this article (10.1186/s12887-017-0974-x) contains supplementary material, which is available to authorized users.

PurposeHemiplegia is a subtype of cerebral palsy (CP) in which one side of the body is affected. Our earlier study of unselected children with CP demonstrated de novo and clinically relevant rare inherited genomic copy-number variations (CNVs) in 9.6% of participants. Here, we examined the prevalence and types of CNVs specifically in hemiplegic CP.MethodsWe genotyped 97 unrelated probands with hemiplegic CP and their parents. We compared their CNVs to those of 10,851 population controls, in order to identify rare CNVs (<0.1% frequency) that might be relevant to CP. We also sequenced exomes of “CNV-positive” trios.ResultsWe detected de novo CNVs and/or sex chromosome abnormalities in 7/97 (7.2%) of probands, impacting important developmental genes such as GRIK2, LAMA1, DMD, PTPRM, and DIP2C. In 18/97 individuals (18.6%), rare inherited CNVs were found, affecting loci associated with known genomic disorders (17p12, 22q11.21) or involving genes linked to neurodevelopmental disorders.ConclusionWe found an increased rate of de novo CNVs in the hemiplegic CP subtype (7.2%) compared to controls (1%). This result is similar to that for an unselected CP group. Combined with rare inherited CNVs, the genomic data impacts the understanding of the potential etiology of hemiplegic CP in 23/97 (23.7%) of participants.