Neurodevelopmental Disorders and Array-Based Comparative Genomic Hybridization: Sensitivity and Specificity using a Criteria Checklist for Genetic Test Performance.

BACKGROUND: Array-based comparative genomic hybridization (aCGH) is a molecular analysis method for identifying chromosomal anomalies or copy number variants (CNVs) correlating with clinical phenotypes. The aim of our study was to identify the most significant clinical variables associated with a positive outcome of aCGH analyses to develop a simple predictive clinical score. METHODS: We conducted a cross-sectional study in a tertiary center comparing the genotype and phenotype of the cases. A score was developed using multivariate logistic regression. The best score cutoff point, sensitivity, specificity, positive and negative predictive values, and area under the curve were calculated with the receiver operating characteristic curve. RESULTS: aCGH identified structural chromosomal alterations responsible for the disorder in 13.7% (95% confidence interval [CI]: 10.9-16.5) of our sample (570 patients analyzed by aCGH). Based on the most frequent phenotypic characteristics among patients with a pathogenic CNV, we have created a checklist with the following items: alteration of the cranial perimeter, stature < percentile (p) 3, weight < p3, presence of brain malformations, ophthalmological malformations, two or more dysmorphic features in the same patient, and autism spectrum disorder diagnosis. Using a score ≥1.5 as the cutoff point for the test, we obtained a sensitivity of 82.4% (95% CI: 73.1-91.8) and a specificity of 54.2% (95% CI: 49.7-58.7). CONCLUSION: All individuals with a score of 1.5 or higher should be genetically screened by aCGH. This approach can improve clinical indications for aCGH in patients with neurodevelopmental disorders, but the scoring system should be validated in an external group.

Respiratory chain complex I deficiency in an infant with Ohtahara syndrome.

We report an infant with complex I deficiency of the mitochondrial respiratory chain whose most conspicuous symptom at presentation was an Ohtahara syndrome. Review of the literature suggest that association of these two conditions is extremely rare. Despite the few cases reported, in our view Ohtahara syndrome should be considered as one of the forms of presentation of mitochondrial dysfunction.

Treatment of mitochondrial encephalomyopathies with a xanthine oxidase inhibitor.

Five females with mitochondrial encephalomyopathies were treated for 3 to 7 years with a xanthine oxidase inhibitor (allopurinol, oral route, 20 mg/kg/day, in 2 or 3 doses daily). Clinical course was monitored in all patients. In addition, various metabolic variables, namely blood lactic acid, blood adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate were monitored, as well as energy charge. Data obtained were compared with data for an age-matched control group of 10 healthy children. Four of the five patients manifested clinical improvement, and the remaining patient exhibited slower disease progression. Three of the four patients who exhibited clinical improvement also had normalization of blood lactic acid level. All five patients had an increase in blood adenosine triphosphate levels and a decline in blood adenosine monophosphate; four of the five manifested a decline in blood adenosine diphosphate and increased energy charge. Mean blood adenosine triphosphate was significantly increased with respect to pretreatment levels and with respect to the control group; mean energy charge displayed an increase, though this was not statistically significant. In one patient, reduction of the allopurinol dose to 10 mg/kg/day was followed by a decline in both blood adenosine triphosphate level and energy charge, and by clinical worsening. In conclusion, the xanthine oxidase inhibitor allopurinol appears to have had beneficial effects in these patients in terms of both energy metabolism and clinical course.

Evolution of serum lipids and lipoprotein (a) levels in epileptic children treated with carbamazepine, valproic acid, and phenobarbital.

The concentration levels of serum lipids and lipoprotein (a) were measured in 20 children receiving carbamazepine, 25 children receiving valproic acid, and 5 children receiving phenobarbital at the following times: (1) during chronic treatment while eating a normal diet, (2) during chronic treatment while eating a low-fat diet (children treated with carbamazepine and phenobarbital with high levels of total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), and (3) 3 months after the end of treatment with antiepileptic drugs. Patients during chronic treatment and eating a normal diet revealed significant changes in lipids, but when we reevaluated the groups of children treated with carbamazepine and phenobarbital when they were eating a low-fat diet and reevaluated the three groups of children 3 months after the end of treatment, a complete return to normal of all parameters was observed. These data demonstrate that the changes induced by these drugs are transient, reversible, and influenced by a low-fat diet. (J Child Neurol 2006;21:48-53).

Neurogenic arthrogryposis multiplex congenita and velopharyngeal incompetence associated with chromosome 22q11.2 deletion.

We report a case of neurogenic arthrogryposis multiplex congenita and velopharyngeal incompetence in association with a chromosome 22q11.2 deletion in a 5-month-old boy, the only child of a non-consanguineous couple without relevant antecedents. Specifically, polymerase chain reaction amplification of microsatellite markers revealed a noninherited microdeletion in position D22S306. This phenotype has not been reported previously in association with chromosome 22q11.2 deletions, and these findings raise the possibility that at least some cases of neurogenic arthrogryposis multiplex congenita might be due to genetic defects of this type.