Michael von Rhein

Rare Missense and Synonymous Variants in UBE1 Are Associated with X-Linked Infantile Spinal Muscular Atrophy

X-linked infantile spinal muscular atrophy (XL-SMA) is an X-linked disorder presenting with the clinical features hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and infantile death. To identify the XL-SMA disease gene, we performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132 (Xp11.3-Xq11.1). This resulted in detection of three rare novel variants in exon 15 of UBE1 that segregate with disease: two missense mutations (c.1617 G-->T, p.Met539Ile; c.1639 A-->G, p.Ser547Gly) present each in one XL-SMA family, and one synonymous C-->T substitution (c.1731 C-->T, p.Asn577Asn) identified in another three unrelated families. Absence of the missense mutations was demonstrated for 3550 and absence of the synonymous mutation was shown in 7914 control X chromosomes; therefore, these results yielded statistical significant evidence for the association of the synonymous substitution and the two missense mutations with XL-SMA (p = 2.416 x 10(-10), p = 0.001815). We also demonstrated that the synonymous C-->T substitution leads to significant reduction of UBE1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBE1 expression in humans. Our observations indicate first that XL-SMA is part of a growing list of neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway and second that synonymous C-->T transitions might have the potential to affect gene expression.

Brain volumes predict neurodevelopment in adolescents after surgery for congenital heart disease

Patients with complex congenital heart disease are at risk for neurodevelopmental impairments. Evidence suggests that brain maturation can be delayed and pre- and postoperative brain injury may occur, and there is limited information on the long-term effect of congenital heart disease on brain development and function in adolescent patients. At a mean age of 13.8 years, 39 adolescent survivors of childhood cardiopulmonary bypass surgery with no structural brain lesions evident through conventional cerebral magnetic resonance imaging and 32 healthy control subjects underwent extensive neurodevelopmental assessment and cerebral magnetic resonance imaging. Cerebral scans were analysed quantitatively using surface-based and voxel-based morphometry. Compared with control subjects, patients had lower total brain (P = 0.003), white matter (P = 0.004) and cortical grey matter (P = 0.005) volumes, whereas cerebrospinal fluid volumes were not different. Regional brain volume reduction ranged from 5.3% (cortical grey matter) to 11% (corpus callosum). Adolescents with cyanotic heart disease showed more brain volume loss than those with acyanotic heart disease, particularly in the white matter, thalami, hippocampi and corpus callosum (all P-values < 0.05). Brain volume reduction correlated significantly with cognitive, motor and executive functions (grey matter: P < 0.05, white matter: P < 0.01). Our findings suggest that there are long-lasting cerebral changes in adolescent survivors of cardiopulmonary bypass surgery for congenital heart disease and that these changes are associated with functional outcome.

Neurodevelopmental outcome, psychological adjustment, and quality of life in adolescents with congenital heart disease.

The aim of this study was to examine neurodevelopment, psychological adjustment, and health‐related quality of life (HRQoL) in adolescents after bypass surgery for congenital heart disease (CHD) during early childhood.

Mortality and neurodevelopmental outcome at 1 year of age comparing hybrid and Norwood procedures

OBJECTIVES Neonates with hypoplastic left heart syndrome (HLHS) are at risk of high mortality and neurodevelopmental morbidity. As an alternative to Norwood-type stage I palliation, the hybrid procedure has been developed. It consists of bilateral pulmonary artery banding, catheter-based stenting of the arterial duct and balloon atrioseptostomy and delays open-heart surgery. Thus, it may be associated with a better outcome. The aim of this study was to determine the mortality and neurodevelopmental outcome in patients with HLHS and other univentricular heart (UVH) defects treated with hybrid or Norwood procedures. METHODS Thirty-one children (18 males) with HLHS and other UVH defects undergoing Norwood or hybrid procedure between 2004 and 2008 were consecutively enrolled. Mortality and neurodevelopmental outcome at 1 year of age were determined. RESULTS One-year mortality was 36% (31% in the hybrid vs. 39% in the Norwood group, P=0.71). Predictors of mortality were lower birth weight (P=0.02), older age at first procedure (P=0.02) and smaller size of ascending aorta (P=0.05). Overall, median psychomotor development index (PDI) and mental development index (MDI) of the Bayley Scales of Infant Development II were lower than the norm of 100 [PDI 57 (49-99), P<0.001; MDI 91 (65-109), P=0.002]. No effect of surgical treatment on neurodevelopmental outcome was found. Predictors of impaired motor outcome were length of hospital stay (LOHS) (P=0.01), lower body weight at second procedure (P=0.004) and female sex (P=0.01). Predictors of impaired cognitive outcome were longer mechanical ventilation time (P=0.03), intensive care unit stay (P=0.04) and LOHS (P<0.001), respectively. CONCLUSIONS Mortality at 1 year of age is comparable between patients undergoing hybrid and Norwood procedures. Early neurodevelopmental outcome is significantly impaired in patients with both HLHS and other UVH defects. Multicentre randomized studies are needed to determine the long-term neurodevelopmental outcome of children treated with the hybrid procedure.

Stable graphical model estimation with Random Forests for discrete, continuous, and mixed variables

Random Forests in combination with Stability Selection allow to estimate stable conditional independence graphs with an error control mechanism for false positive selection. This approach is applicable to graphs containing both continuous and discrete variables at the same time. Its performance is evaluated in various simulation settings and compared with alternative approaches. Finally, the approach is applied to two heath-related data sets, first to study the interconnection of functional health components, personal, and environmental factors and second to identify risk factors which may be associated with adverse neurodevelopment after open-heart surgery.

Structural Brain Lesions in Adolescents with Congenital Heart Disease

OBJECTIVES To assess long-term neurodevelopmental outcome of adolescents with congenital heart disease after open-heart surgery and to evaluate whether deficits are associated with cerebral injury detectable on magnetic resonance imaging (MRI). STUDY DESIGN We conducted a cohort study with longitudinal follow-up of 53 adolescents (mean age, 13.7 years; range, 11.4 to 16.9 years) who had undergone open-heart surgery with full-flow cardiopulmonary bypass during childhood and compared them with 41 age-matched controls. Assessment included conventional MRI and neurodevelopmental testing. RESULTS MRI abnormalities were detected in 11 of the 53 patients (21%), comprising predominately white matter abnormalities and volume loss. Neurodevelopmental outcome was impaired in several domains, including neuromotor, intellectual, and executive functions, as well as visuomotor perception and integration. Adolescents with cerebral abnormalities had greater impairment in most neurodevelopmental domains compared with those without cerebral abnormalities. CONCLUSIONS Cerebral abnormalities can be detected in a significant proportion of adolescents with corrected congenital heart disease. These abnormalities are found predominately in the white matter and are apparently of hypoxic-ischemic origin, most likely acquired during the neonatal period.

Severe Congenital Heart Defects Are Associated with Global Reduction of Neonatal Brain Volumes

OBJECTIVES To determine neonatal global and regional brain volumes in infants with congenital heart disease (CHD) in comparison with healthy controls and to determine brain growth. STUDY DESIGN Prospective cohort study in infants undergoing open-heart surgery for complex CHD. Global and regional volumetric measurements on preoperative cerebral magnetic resonance imaging were manually segmented in children without overt brain lesions. RESULTS Preoperative brain volumetry of 19 patients demonstrates reduction in total and regional brain volumes, without any specific regional predilection compared with 19 healthy control infants (total brain volume reduction: 21%, regional brain volume reduction 8%-28%, all P < .001). CONCLUSIONS Infants with CHD undergoing bypass surgery have smaller brain volumes prior to surgery without a specific regional predilection. This suggests a fetal origin of reduced brain growth.

Risk factors for neurodevelopmental impairments in school-age children after cardiac surgery with full-flow cardiopulmonary bypass

OBJECTIVE To determine the risk factors for adverse neurodevelopmental outcomes in school-age children after full flow open-heart surgery for congenital heart disease. METHODS The outcome was assessed in 117 children without a genetic comorbidity at a mean age of 10.4 ± 2.5 years. Intelligence was assessed using the Ravens Progressive Matrices and neuromotor function using the Zurich Neuromotor Assessment. Risk factors were retrieved from detailed chart review. RESULTS The mean intelligence score was 89 ± 16, significantly lower than the norm (P < .001). Cerebral palsy was diagnosed in 10% of patients. Poor neuromotor performance (less than p10) was present in 15% to 20% of the children, depending on the motor task (all P < .001). Pure motor and static balance performance was also significantly impaired when patients with cerebral palsy were excluded (P < .01). Intelligence was only related to socioeconomic status (P = .006), and neuromotor outcome was related to the length of hospital stay and postoperative neurologic abnormalities (P < .03). The extracorporeal circulation time was related to adaptive fine motor performance (P = .05). All other variables were not related to outcome. CONCLUSIONS Children without a genetic comorbidity are at risk of long-term intellectual and motor impairments also after full-flow cardiac repair. Surgery-related parameters play a less important role for adverse outcomes than postoperative complications. Our findings stress the importance of specialized follow-up assessments for all children with CHD undergoing open heart surgery.

Cerebral lesions on magnetic resonance imaging correlate with preoperative neurological status in neonates undergoing cardiopulmonary bypass surgery

OBJECTIVES To determine the prevalence, spectrum and course of cerebral lesions in neonates with congenital heart disease (CHD) undergoing full flow cardiopulmonary bypass (CPB) surgery using magnetic resonance imaging (MRI) and to examine the correlation between cerebral lesions and clinical neurological abnormalities. METHODS Prospective cohort study of neonates with d-transposition of the great arteries (n = 22), univentricular heart malformation with hypoplastic aortic arch (n = 6) and aortic arch obstructions (n = 2) undergoing CPB. Neonates underwent cerebral MRI and blinded standardized neurological examination before (median day 6) and after surgery (day 13). The MRI findings were compared with those of 20 healthy controls. RESULTS Preoperative cerebral lesions were present in 7 of 30 patients (23%) with isolated mild or moderate white matter injury (WMI) (n = 4), isolated small cerebral stroke (n = 1) and combined WMI and stroke (n = 2). None of the healthy controls had cerebral lesions on MRI. CHD neonates with preoperative cerebral lesions had more neurological abnormalities (P = 0.01) than neonates without cerebral lesions. Low arterial oxygen saturation (P = 0.03) was a risk factor for preoperative cerebral lesions, while balloon atrioseptostomy (P = 0.19) was not. After surgery, preoperative cerebral lesions persisted in 5 of 7 neonates, and 2 neonates (7%) showed signs of additional WMI in their postoperative MRI. CONCLUSIONS In neonates with severe CHD, WMI was the predominant preoperative finding, while cerebral strokes were less frequent. New postoperative lesions were rare. Preoperative neurological abnormalities correlated with the presence of cerebral lesions on MRI.

Hippocampal volume reduction is associated with intellectual functions in adolescents with congenital heart disease

Background:Adolescents undergoing early cardiopulmonary bypass surgery for congenital heart disease (CHD) may demonstrate a variety of neurocognitive impairments. These impairments can affect overall intellectual functions, but also specific memory deficits, language, and executive functions. As the hippocampus is a critical structure involved in these functions, we sought to determine whether hippocampal volume was reduced in adolescents with CHD and whether altered volumes were related to functional outcome.Methods:At a mean age of 13.8 y, 48 adolescent survivors of childhood cardiopulmonary bypass surgery for CHD and 32 healthy controls underwent neurocognitive testing and cerebral magnetic resonance imaging. Images were quantitatively analyzed using an automated regional segmentation tool (FSL-FIRST).Results:Adolescents with CHD had 10% lower total hippocampal volumes compared with controls. After controlling for total brain volume, total hippocampal volume correlated with total IQ, with working memory, and verbal comprehension in CHD patients, but not in controls.Conclusions:In adolescent survivors of cardiopulmonary bypass surgery for CHD, specific brain regions such as the hippocampus may show long-term persistent alteration and correlate with intellectual deficits, particularly with verbal and memory functions.