Mutations in the X‐linked gene doublecortin, which encodes a protein with no clear structural homologues, are found in pedigrees in which affected females show “double cortex” syndrome (DC; also known as subcortical band heterotopia or laminar heterotopia) and affected males show X‐linked lissencephaly. Mutations in doublecortin also cause sporadic DC in females. To determine the incidence of doublecortin mutations in DC, we investigated a cohort of eight pedigrees and 47 sporadic patients with DC for mutations in the doublecortin open reading frame as assessed by single‐stranded conformational polymorphism analysis. Mutations were identified in each of the eight DC pedigrees (100%), and in 18 of the 47 sporadic DC patients (38%). Identified mutations were of two types, protein truncation mutations and single amino acid substitution mutations. However, pedigrees with DC displayed almost exclusively single amino acid substitution mutations, suggesting that patients with these mutations may have less of a reproductive disadvantage versus those patients with protein truncation mutations. Single amino acid substitution mutations were tightly clustered in two regions of the open reading frame, suggesting that these two regions are critical for the function of the Doublecortin protein. Ann Neurol 1999;45:146–153

While disorders of neuronal migration are associated with as much as 25% of recurrent childhood seizures, few of the genes required to establish neuronal position in cerebral cortex are known. Subcortical band heterotopia (SBH) and lissencephaly (LIS), two distinct neuronal migration disorders producing epilepsy and variable cognitive impairment, can be inherited alone or together in a single pedigree. Here we report a new genetic locus, XLIS, mapped by linkage analysis of five families and physical mapping of a balanced X;2 translocation in a girl with LIS. Linkage places the critical region in Xq21-q24, containing the breakpoint that maps to Xq22.3-q23 by high-resolution chromosome analysis. Markers used for somatic cell hybrid and fluorescence in situ hybridization analyses place the XLIS region within a 1 cM interval. These data suggest that SBH and X-linked lissencephaly are caused by mutation of a single gene, XLIS, that the milder SBH phenotype in females results from random X-inactivation (Lyonization), and that cloning of genes from the breakpoint region on X will yield XLIS.

Introduction Currently, there is no consensus on the indication of prophylactic surgery of the nodal compartments in the treatment of medullary thyroid carcinoma (MTC). The aim of our study was to perform a correlation study between preoperative calcitonin (basalCT) values and lymph node involvement to establish a criterion on which to base prophylactic surgery in these patients. Material and Methods We conducted an observational, retrospective and multicentre study with 29 hospitals. Patients over 18 years of age with a diagnosis of MTC with a pre-surgical calcitonin registry were included. The minimum surgery in all patients had to have been total thyroidectomy (TT) with central compartment lymph node dissection (CCLND). Receiver operating characteristic (ROC) curve analysis was used to establish basalCT cut-off values as predictors of postoperative lymph node involvement. Results A total of 244 patients were included. Baseline calcitonin (basalCT) was a good predictor of nodal involvement (AUC 0.718 and 95%CI 0.66–0.978). Heritability was identified as a preoperative factor correlated with baseline tumour CT values (p = 0.000). With a probability of lymph node involvement below 10%, new cut-off points were established. A prophylactic bilateral lateral lymph node dissection in sporadic tumours should be performed at a basalCT > 600 pg/mL; in the case of RET-mutated tumours this value would be 200 pg/mL. Conclusion The baseline CT value is a good predictor of postoperative lymph node involvement in MTC, however, cut-off points should depent on the hereditary nature of the tumour.

Patients with severe biotinidase deficiency (BD), if untreated, may exhibit seizures, psychomotor delay, deafness, ataxia, visual pathology, conjunctivitis, alopecia, and dermatitis. Clinical features normally appear within the first months of life, between two and five. Seizures are one of the most common symptoms in these patients (55%), usually presented as generalized tonic-clonic, and improving within 24 h of biotin treatment. Treatment delay has been associated with irreversible neurological damage, mental retardation, ataxia, paraparesis, deafness, and epilepsy exceptionally.We report the case of a girl who was admitted at 2.5 months because of vomiting, failure to thrive, flexor spasms, dermatitis, and neurological depression for 1 month. BD was identified and was treated with biotin, stopping seizures and improving symptoms. Developmental delay, paraparesis, optic atrophy, and seizures during febrile illness were observed at follow-up. At the age of 8, she suffered hemigeneralized seizures despite appropriate biotin treatment, so levetiracetam was administered, and epilepsy was controlled. Organic acid measurement was performed to determine whether the child was receiving enough or no biotin.Even though BD is a rare condition, because the biotinidase screening is a reliable procedure and the disorder is readily treatable, the implementation of extended biotinidase screening will effectively help to prevent any acute and long-term neurological problems as well as the significant morbidity associated with untreated disease. In addition, neonatal screening and early treatment with biotin prevents severe neurological sequelae, such as epilepsy, which has not been thoroughly described in the literature.

IntroductionAutism is a complex neurodevelopmental disorder in which the interactions of genetic, epigenetic and environmental influences are thought to play a causal role. In humans, throughout embryonic and fetal life, brain development is exquisitely susceptible to injury caused by exposure to toxic chemicals present in the environment. Although the use of herbal supplements during pregnancy is relatively common, little information is available on their association with fetal neurodevelopment. This is, to the best of our knowledge, the first report in the literature to associate a new plausible mechanism of neurodevelopmental toxicity with a case of autism spectrum disorder through a vitamin deficiency potentiated by concomitant use of herbal supplements and ethanol exposure.Case presentationWe describe the pediatric environmental history of a three-year-old Caucasian girl with an autism spectrum disorder. We utilized her pediatric environmental history to evaluate constitutional, genetic, and environmental factors pertinent to manifestation of neurodevelopment disorders. Both parents reported prenatal exposure to several risk factors of interest. A year prior to conception the mother began a weight loss diet and ingested 1200 mg/day of 'horsetail' (Equisetum arvense) herbal remedies containing thiaminase, an enzyme that with long-term use can lead to vitamin deficiency. The mother reported a significant weight loss during the pregnancy and a deficiency of B-complex vitamins. Thiamine (vitamin B1) deficiency could have been potentiated by the horsetail's thiaminase activity and ethanol exposure during pregnancy. No other risk factors were identified.ConclusionsA detailed and careful pediatric environmental history, which includes daily intake, herbal remedies and ethanol exposure, should be obtained from all patients with autism spectrum disorder. Maternal consumption of ethanol and of herbal supplements with suspected or potential toxicity should be avoided during pregnancy. The prospective parents should perform preconception planning before pregnancy.