Sibylle Zotter

Predictive validity of attentional functions in differentiating children with and without ADHD: a componential analysis.

Aim  The objective of this study was to investigate which attentional components are of predictive utility in differentiating children with attention‐deficit–hyperactivity disorder, combined type (ADHD‐C) from their peers without ADHD.

Phenotypic variability of a deletion and duplication 6q16.1 → q21 due to a paternal balanced ins(7;6)(p15;q16.1q21)†‡

Constitutional insertional translocations are rare findings in clinical cytogenetics. Here, we report on the unbalanced segregation of a balanced paternal insertional translocation ins(7;6)(p15;q16.1q21) to three children. Investigations by conventional karyotyping, FISH with locus‐specific probes, microsatellite marker analysis, and SNP‐array based copy number analysis revealed a direct orientation of the inserted segment, a size of 11.3 Mb, and breakpoints between rs4370337 and rs12660854 and rs12110990 and rs4946730 on 6q16.1 and 6q21, respectively, as well as within BAC clone RP11–182J2 on 7p15. A 17‐year‐old daughter inherited the der(6) chromosome and was affected by severe mental retardation, obesity, and minor anomalies. Two further children inherited the der(7) chromosome. A daughter shows an almost unremarkable phenotype and only minor features in neuropsychological testing at 19 years of age. Her 14‐year‐old half‐brother demonstrates a mild delay in cognitive development most likely jointly caused by the chromosomal rearrangement and asphyxia during delivery. The patient with the deletion confirms the previously reported phenotype of severe mental retardation and obesity in patients with del(6)(q16.2), while both patients with partial trisomy for the same segment of chromosome 6 are further examples for a generally less severe phenotype associated with duplications than with deletions, and even for the recent insight that chromosomal aneusomies of several megabases may go without major clinical consequences.

Glucose transporter type 1 deficiency syndrome effectively treated with modified Atkins diet.

This is a report on the successful treatment of a 6-year-old girl with genetically proven glucose transporter type 1 deficiency syndrome (GLUT1-DS) with modified Atkins diet (MAD). GLUT1-DS is an inborn disorder of glucose transport across the blood-brain barrier, which leads to energy deficiency of the brain with a broad spectrum of neurological symptoms including therapy-resistant epilepsy. Usually classical ketogenic diet (KD) is the standard treatment for patients with GLUT1-DS. Treatment with MAD, a variant of KD, for an observation period of 17 months resulted in improvement of seizures, alertness, cognitive abilities, and electroencephalography in this patient.

Neurocognition and brain structure in pediatric patients with type 1 diabetes

Recent findings suggest that in addition to severe hypoglycemia, chronic hyperglycemia may also hamper the cognitive development of patients with type 1 diabetes. Executive and memory dysfunctions mediated by frontoparietal and temporal brain structures are frequently reported to be associated with type 1 diabetes. However, most studies investigating pediatric patients with diabetes focus on either brain function or brain structure. The current study combines neuropsychological and structural brain imaging methods (i.e., voxel-based-morphometry) to study the neurofunctional integrity of frontoparietal brain areas. We investigated 30 children with type 1 diabetes and 19 healthy controls. Children with diabetes were divided into two groups representing better (HbA1c ≤ 7.9%) and worse (HbA1c ≥ 8.0%) glycemic con- trol. Our findings were threefold: First, results revealed significant group differences with respect to neuropsychological performance (i.e. response accuracies on a marker task tapping frontoparietal brain functions). Second, structural imaging disclosed significant group differences between patients and controls regarding gray matter volume in frontal (anterior cingulate) and occipital (cuneus, bordering precuneus) brain regions and regarding white matter in middle temporal and occipital gyri as well as in the ventromedial temporal lobe (uncus). Third, disease duration, age at diagnosis and white matter volume in a hippocampal region-of-interest (but not HbA1c levels, intelligence, total gray/white matter or other white/gray matter regions-of-interest) explained 56% of neuropsycholo- gical performance variance. Taken together, our findings are among the first to provide evidence of a direct link between brain function and brain structure in pediatric patients with type 1 diabetes.

Chromosomal microaberrations in patients with epilepsy, intellectual disability, and congenital anomalies

Epilepsy is a common finding in patients with chromosomal macro‐ and micro‐rearrangements but only few aberrations show a constant pattern of seizures. DNA array‐based studies have reported causative copy number variations (CNVs) in 5–30% of patients with epilepsy with or without co‐morbidities. The interpretation of many of the detected CNVs remains challenging. In order to identify CNVs carrying epilepsy‐related genes we investigated 43 children with various patterns of epileptic seizures, intellectual disability (ID), and minor dysmorphism, using the Illumina® Infinium Human1M‐DuoV1 array. In three patients we found likely causative de novo CNVs, i.e. deletions in 1q41q42.12 (3.4 Mb) and 19p13.2 (834 kb), and a mosaic two‐segment duplication in 17p13.2 (218 kb) and 17p13.1 (422 kb). In six additional patients there were aberrations (a deletion in one and duplications in five patients) with uncertain clinical consequences. In total, the finding of causative chromosomal micro‐rearrangements in 3 out of 43 patients (7%) and potentially causative CNVs in 6 additional patients (14%) with epilepsy and ID but without major malformations confirms the power of DNA arrays for the detection of new disease‐related genetic regions.

Microdeletion 19p13.2 in an almost 5-year-old boy.

Deletions of the short arm of chromosome 19 are rarely found by conventional cytogenetic techniques. This region has a high gene density and this is likely the reason why deletions in this region are associated with a severe phenotype. Since the implementation of modern high‐resolution SNP‐ and CGH‐array techniques more cases have been reported. Here, we present an almost 5‐year‐old boy with intellectual disability, minor dysmorphisms, febrile seizures, and a de novo deletion of 834.2 kb on 19p13.2 encompassing 32 genes. The deletion was found by the Illumina® Infinium HD Human1M‐Duo v1 BeadChip SNP‐array and confirmed by the NimbleGen Human CGH 2.1M Whole Genome Tiling v2.0D oligonucleotide array. PCR amplification of the junction fragment and subsequent sequencing defined the breakpoints and indicated that formation was mediated by non‐allelic homologous recombination (NAHR). The phenotype of our patient shows that microrearrangements even at gene‐dense chromosomes may result in mild clinical consequences.

Very preterm children are at increased risk of reduced processing speed at 5 years of age, predicted by typical complications of prematurity and prenatal smoking

Very little is known about risk predictors for the development of reduced processing speed, which can cause intellectual problems in later life. This study identified risk predictors at 5 years of age in a population‐based cohort of very preterm infants.

Neuropsychological profile of children after an episode of neuroborreliosis.

BACKGROUND In the majority of patients with Lyme neuroborreliosis (LNB), neurological symptoms are transient. The extent of neuropsychological and neuropsychiatric problems in children is not well researched. OBJECTIVES The study aimed to investigate cognitive functions and behavioral problems in children after LNB. PATIENTS AND METHODS A total of 20 children between 6 and 16 years of age with an episode of LNB at least 4 month before neuropsychological testing were enrolled in the study and compared with 20 healthy controls. Children with LNB had cranial nerve palsies or meningoencephalitis, immunoglobulin G and immunoglobulin M antibodies for Borrelia burgdorferi in the peripheral blood, pleocytosis in the cerebrospinal fluid (leukocytes > 10 cells/μL) and/or an intrathecal synthesis of antibodies for B. burgdorferi.Neuropsychological tests assessing intellectual skills, memory, and executive functions were used. Two parental questionnaires assessing behavior, psychiatric problems, and executive functions were administered. RESULTS Intellectual skills, memory, and executive functions of children after an episode of LNB were within the normal range. In the subcategory of working memory, children after an episode of LNB performed worse than controls. The questionnaires did not reveal behavior or psychiatric problems, although there was a tendency that children after an episode of LNB had more physical complaints. CONCLUSION Neuropsychological deficits resulting from LNB in childhood are rare. Most children had a good cognitive, emotional, and behavioral outcome.

Don't miss patients with atypical FMR1 mutations: dysmorphism and clinical features in a boy with a partially methylated FMR1 full mutation.

Fragile X syndrome characterized by intellectual disability (ID), facial dysmorphism, and postpubertal macroorchidism is the most common monogenic cause of ID. It is typically induced by an expansion of a CGG repeat in the fragile X mental retardation 1 (FMR1) gene on Xq27 to more than 200 repeats. Only rarely patients have atypical mutations in the FMR1 gene such as point mutations, deletions, or unmethylated/partially methylated full mutations. Most of these patients show a minor phenotype or even appear clinically healthy. Here, we report the dysmorphism and clinical features of a 17-year-old boy with a partially methylated full mutation of approximately 250 repeats. Diagnosis was made subsequently to the evaluation of a FMR1 premutation as the cause for maternal premature ovarian failure. Dysmorphic evaluation revealed no strikingly long face, no prominent forehead/frontal bossing, no prominent mandible, no macroorchidism, and a head circumference in the lower normal range. Acquisition of a driving license for mopeds and unaccompanied rides by public transport in his home province indicate rather mild ID (IQ = 58). Conclusion: This adolescent demonstrates that apart from only minor ID, patients with a partially methylated FMR1 full mutation present less to absent pathognomonic facial dysmorphism, thus emphasizing the impact of family history for a straightforward clinical diagnosis.

Funktionelle Neuroplastizität bei zwei Jugendlichen mit ausgeprägten frühkindlichen strukturellen Hirnschädigungen

Zusammenfassung. Ziel der Studie war die detaillierte neurokognitive Untersuchung der funktionellen Neuroplastizitat bei zwei 17-jahrigen Madchen, welche trotz groser posteriorer Substanzdefekte gute Schulleistungen und unauffalliges Verhalten aufwiesen. Unsere Ergebnisse zeigen, dass die neuropsychologischen Beeintrachtigungen nach fruhkindlich erworbenen Substanzdefekten zwar gering, aber spezifisch sind. Relativ zu 10 gesunden Kontrollpersonen waren bei TB eine reduzierte verbale Lernleistung, jedoch gute sprachliche Leistungen feststellbar. MG demonstrierte defizitare visuell-raumliche Fahigkeiten und zusatzlich - uberraschenderweise - eine reduzierte verbale sowie nonverbale Merkfahigkeit. Insgesamt weisen die Ergebnisse darauf hin, dass die Mechanismen der neurofunktionellen Plastizitat nicht auf Sprache und visuo-konstruktive Prozesse beschrankt sind, sondern sich auch in anderen kognitiven Domanen (z. B. Lesefertigkeiten und Merkfahigkeit) manifestieren konnen.