Niels Geerdink

MECP2 analysis in mentally retarded patients: implications for routine DNA diagnostics

Rett syndrome (RTT) is one of the most common neurodevelopmental disorders in females. The disease is caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2), and various mutations have been reported. The phenotypic spectrum in both female and male patients is diverse, ranging from very mild to congenital encephalopathy and prenatal lethality. In this study, the question was addressed as to whether implementation of systematic screening of MECP2 in patients with an unexplained mental retardation in DNA diagnostics would be reasonable, and the spectrum of phenotypes resulting from mutations in this gene was further explored. Mutational analysis of MECP2 was performed in mentally retarded female patients who were negative for FMR1 CGG repeat expansion, in male and female patients with clinical features suggestive of either Angelman or Prader-Willi syndrome without methylation defects on chromosome 15q11–q13. In the cohort of females negative for the molecular Fragile-X studies (N=92), one nonsense mutation (p.Q406X) was found. In the cohort of Angelman-negative patients (N=63), two missense mutations (p.R133C in a female patient and a mosaic p.T158M in a male patient) were found, which have been reported many times in patients with classical RTT syndrome. In the Prader-Willi-negative group (N=98), no pathogenic mutations were found.The results support testing of patients with features suggestive of Angelman syndrome, but without methylation defects on chromosome 15q11–q13 for mutations in MECP2. In the remaining patients with unexplained mental retardation, additional clinical features should determine whether analysis of MECP2 is indicated.

Essential features of Chiari II malformation in MR imaging: an interobserver reliability study—part 1

PurposeBrain MR imaging is essential in the assessment of Chiari II malformation in clinical and research settings concerning spina bifida. However, the interpretation of morphological features of the malformation on MR images may not always be straightforward. In an attempt to select those features that unambiguously characterize the Chiari II malformation, we investigated the interobserver reliability of all its well-known MR features.MethodsBrain MR images of 79 children [26 presumed to have Chiari II malformation, 36 presumed to have no cerebral abnormalities, and 17 children in whom some Chiari II malformation features might be present; mean age 10.6 (SD 3.2; range, 6-16) years] were blindly and independently reviewed by three observers. They rated 33 morphological features of the Chiari II malformation as present, absent, or indefinable in three planes (sagittal, axial, and coronal). The interobserver reliability was assessed using κ statistics.ResultsTwenty-three of the features studied turned out to be unreliable, whereas the interobserver agreement was almost perfect (κ value > 0.8) for nine features (eight in the sagittal plane and one in the axial plane, but none in the coronal plane).ConclusionsThis study presents essential features of the Chiari II malformation on MR images by ruling out the unreliable features. Using these features may improve the assessment of Chiari II malformation in clinical and research settings.

Motor evoked potentials and compound muscle action potentials as prognostic tools for neonates with spina bifida

UNLABELLED MEPs and CMAPs as prognostic tools for spina bifida. AIM The aim of this prospective study was to determine the prognostic value of neurophysiological investigations compared to clinical neurological examination in infants with spina bifida. METHODS Thirty-six neonates born with spina bifida between 2002 and 2007 were evaluated and followed for 2 years. Lumbar motor evoked potentials (MEPs) and compound muscle action potentials (CMAPs) were obtained at the median age of 2 days old before surgical closure of the spinal anomaly. MEPs were recorded from the quadriceps femoris, tibialis anterior, and gastrocnemius muscles and CMAPs from the latter two muscles. Areas under the curve and latencies of the MEPs and CMAPs were measured. Clinical neurological outcome at the age of 2 years was described using Muscle Function Classes (MFCs) and ambulation status. RESULTS The areas under the curve of MEPs and CMAPs in the legs were associated with lower neonatal levels of motor and sensory impairment. Better muscle function class of the lower limbs at 2 years of age was associated with larger MEP and CMAP areas of the gastrocnemius and tibialis anterior muscles at neonatal age. DISCUSSION MEPs and CMAPs of the gastrocnemius and tibialis anterior muscles are of prognostic value for clinical neurological outcome in neonates born with spina bifida.

Interobserver reliability and diagnostic performance of Chiari II malformation measures in MR imaging--part 2.

PurposeBrain MR imaging is essential in the assessment of Chiari II malformation in clinical and research settings concerning spina bifida. However, the interpretation of MR images of the malformation is not always straightforward. Morphometric analyses of the extent of Chiari II malformation may improve the assessment. In an attempt to select appropriate morphometric measures for this purpose, we investigated the interobserver reliability and diagnostic performance of several morphometric measures of Chiari II malformation on MR images.MethodsBrain MR images of 79 children [26 with open spinal dysraphism, 17 with closed spinal dysraphism, and 36 without spinal dysraphism; mean age 10.6 (SD 3.2; range, 6–16) years] were evaluated. All children had been assessed for Chiari II malformation (defined as cerebellar herniation in combination with open spinal dysraphism; n = 23). Three observers blindly and independently reviewed the MR images for 21 measures of the cerebellum, brainstem, and posterior fossa in three planes. The interobserver reliability was assessed by an agreement index (AI = 1 − RRE) and the diagnostic performance by receiver operating characteristic analyses.ResultsReliability was good for most measures, except for the degree of herniation of the vermis and tonsil. Most values differed statistically significantly between children with and without Chiari II malformation. The measures mamillopontine distance and cerebellar width showed excellent diagnostic performance.ConclusionsMorphometric measures may reliably quantify the morphological distortions of Chiari II malformation on MR images and provide additional tools to assess the severity of Chiari II malformation in clinical and research settings.

Compound muscle action potentials in newborn infants with spina bifida.

The aim of this study was to investigate the relationship between compound muscle action potentials (CMAPs) and neurological impairment in newborn infants with spina bifida. Thirty‐one newborn infants (17 males, 14 females, mean gestational age 39wks [SD 2]; mean birthweight 3336g [SD 496]) with spina bifida were investigated at a median age of 2 days (range 1–18d). Motor and sensory impairment and muscle stretch reflexes were assessed and neuroimaging was performed. CMAPs were recorded from the tibialis anterior muscle and the gastrocnemius muscle after percutaneous electrical nerve stimulation. CMAPs were obtained in almost all infants. The area under the curve of the CMAP (CMAP‐area) was associated with motor and sensory impairment and with the presence of muscle stretch reflexes, but not with the morphological level of the spinal anomaly. These associations were stronger for the gastrocnemius muscle than for the tibialis anterior muscle. In conclusion, the CMAP‐area correlates with neurological impairment in neonatal spina bifida and provides an estimate of residual motor neuron function in affected spinal segments. The assessment of CMAPs after percutaneous electrical nerve stimulation is recommended as an additional instrument to the clinical neurological examination and imaging studies.

Reliability of the MRI diagnosis of the Chiari type2 malformation

Background Every clinician familiar with spina bifida knows what Chiari type2 malformation (C2M) is about. However, as soon as it concerns a single patient, the discussion starts whether or not it is justified to make the diagnosis in that particular case. This complicates the insight in the epidemiology and pathogenesis, complicates the indication for (fetal) surgery and complicates inferences on the effect of treatment. This was reason for us to investigate the reliability of the diagnosis of C2M.