Ingeborg Krägeloh-Mann

Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) has recently been defined based on a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy. LBSL is an autosomal recessive disease, most often manifesting in early childhood. Affected individuals develop slowly progressive cerebellar ataxia, spasticity and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. We performed linkage mapping with microsatellite markers in LBSL families and found a candidate region on chromosome 1, which we narrowed by means of shared haplotypes. Sequencing of genes in this candidate region uncovered mutations in DARS2, which encodes mitochondrial aspartyl-tRNA synthetase, in affected individuals from all 30 families. Enzyme activities of mutant proteins were decreased. We were surprised to find that activities of mitochondrial complexes from fibroblasts and lymphoblasts derived from affected individuals were normal, as determined by different assays.

The role of magnetic resonance imaging in elucidating the pathogenesis of cerebral palsy: a systematic review.

The aim of this study was to show the role of magnetic resonance imaging (MRI) in elucidating the aetiology, or at least pathogenesis, of cerebral palsy (CP). A systematic review of studies using MRI in children with CP was performed according to pathogenetic patterns characterizing different timing periods of occurence of the lesions, and with respect to gestational age (term vs preterm) and CP subtypes. Out of the studies published since 1990 in English, six met all the inclusion criteria; they involved children with spastic and dyskinetic CP. Abnormal MRI was reported in 334 out of 388 (86%) patients and gave clues to pathogenesis in 83%. Fourteen studies met only part of the inclusion criteria and abnormal MRIs were reported even more frequently in these (91%; 930/1022). Periventricular white matter lesions were most frequent (56%) followed by cortical and deep grey matter lesions (18%); brain maldevelopments were rather rare, described in 9%. Brain maldevelopments and grey matter lesions were more often seen in term than in preterm‐born children with CP (brain maldevelopments: 16% vs 2.5%; grey matter lesions: 33% vs 3.5%); periventricular white matter lesions occurred significantly more often in preterm than in term‐born children (90% vs 20%). CP is mainly characterized by brain lesions which can be identified by MRI in around 75% of preterm infants; brain maldevelopments occur in around 10%.

Reorganization in congenital hemiparesis acquired at different gestational ages

It is well established that the reorganizational potential of the developing human brain is superior to that of the adult brain, but whether age‐dependent differences exist already in the prenatal and perinatal period is not known. We have studied sensorimotor reorganization in 34 patients with congenital hemiparesis (age range, 5–27 years), using transcranial magnetic stimulation and functional magnetic resonance imaging during simple hand movements. Underlying pathologies were brain malformations (first and second trimester lesions; n = 10), periventricular brain lesions (early third trimester lesions; n = 12), and middle cerebral artery infarctions (late third trimester lesions; n = 12). Of this cohort, eight patients with malformations and all patients with periventricular lesions have been published previously. In all three groups of pathologies, transcranial magnetic stimulation identified patients in whom the paretic hand was controlled via ipsilateral corticospinal projections from the contralesional hemisphere (n = 16). In these patients, the motor dysfunction of the paretic hand correlated significantly with the timing period of the underlying brain lesion. This demonstrates that the efficacy of reorganization with ipsilateral corticospinal tracts indeed decreases during pregnancy. Ann Neurol 2004

Cerebral palsy update

A common language on CP has been developed for the European registers by the SCPE (Surveillance of Cerebral Palsy in Europe) working group and the common database allows prevalence analyses on a larger basis. CP prevalence increases with lower birthweight and higher immaturity. Increase of survival after preterm birth has first also increased CP rates. But already in the 80s this trend was reversed for LBW infants, and in the 90 s also for VLBW or very immature infants. The outcome with respect to CP in the group of extremely LBW or immature infants remains a matter of specific concern, as prevalence seems to be rather stable on a high level. CP is caused in more than 80% by brain lesions or maldevelopments which can be attributed to different timing periods of the developing brain. Extent and topography determine the clinical subtype of CP and are related also to the presence and severity of associated disabilities. CP, thus, offers a model to study plasticity of the developing brain. Reorganisation following unilateral lesions is mainly interhemispheric and homotopic. In the motor system, it involves the recruitment of ipsilateral tracts; functionality seems to be limited and decreases already towards the end of gestation. There is no clear evidence for substantial reorganisation in the sensory system. The best compensatory potential is described concerning language function following left hemispheric lesions. Language function reorganized to the right hemisphere eventually seems not to be impaired, this occurs, however, on the expense of primary right hemispheric functions.

Right-Hemispheric Organization of Language Following Early Left-Sided Brain Lesions: Functional MRI Topography

Left-hemispheric (LH) brain lesions acquired early in life can induce language organization in the undamaged right hemisphere (RH). This study addresses the anatomical correlates of language processing in the RH of such individuals. Five hemiparetic patients with left periventricular brain lesions of pre- and perinatal origin were included, in whom fMRI during a word generation task had yielded predominantly RH activation; five age- and sex-matched healthy right-handers served as controls. The patterns of activation in the RH of patients showed a striking similarity with the LH patterns of the normal controls, and voxel-wise comparison failed to detect significant differences. This demonstrates that in patients with early LH damage, RH recruitment for language occurs in brain areas homotopic to the LH regions involved in language processing under normal circumstances.

Imaging of early brain injury and cortical plasticity.

The human brain undergoes complex organizational changes during development in and ex utero. Pathogenic events affecting the developing brain cause abnormalities or lesions, the patterns of which depend on the stage of brain development. During the first and second trimester, cortical neurogenesis predominantly takes place, characterized by proliferation, migration, and organization of neuronal cells. Brain pathology is characterized by maldevelopments. During the third trimester, growth and differentiation events are predominant, which persist into postnatal life. Disturbances of brain development during this period mainly cause lesions. During the early third trimester, periventricular white matter is especially affected, whereas toward the end of the third trimester, gray matter, either cortical or deep gray matter, appears to be more vulnerable. These patterns of brain maldevelopments or lesions offer excellent models to study mechanisms of organization and reorganization in the developing brain. Evidence for superior brain plasticity is well established for language function after early left-sided lesions. Some evidence exists for higher compensatory potential within in the motor system; maintenance of ipsilateral tracts seems to play a certain, but only incomplete functional role after unilateral lesions in early and mid gestation. The visual system seems to have limited compensatory potential.

tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia

Pontocerebellar hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.

BILATERAL SPASTIC CEREBRAL PALSY‐MRI PATHOLOGY AND ORIGIN. ANALYSIS FROM A REPRESENTATIVE SERIES OF 56 CASES

MRI of the brain was performed on 56 children with bilateral spastic cerebral palsy (CP) at a mean age of 10.7 years. Specific pathology was found in 91 per cent; periventricular leukomalacia was present in 42 per cent of term‐ and H7 per cent of preterm‐born children. Parasagittal subeortico‐cortical injury, multicystie encephalomalacia and basal ganglia lesions were identified in 16 per cent, in all but one associated with severe peri‐/neonatal events at term or near term. Maldevelopment composed 9 per cent, all but one found in term‐born children. MRI morphology correlated strikingly with outcome. Periventricular leukomalacia was associated with more severe disability in term‐ than preterm‐born children.

A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate

We identified eight patients with a distinct magnetic resonance imaging pattern of inhomogeneous cerebral white matter abnormalities and selective involvement of brainstem and spinal tracts. Proton magnetic resonance imaging showed increased lactate in the abnormal white matter. Clinically, the patients had slowly progressive pyramidal, cerebellar, and dorsal column dysfunction. The uniform, highly characteristic magnetic resonance imaging pattern and the similarities in clinical and magnetic resonance spectroscopy findings provide evidence for a new disease entity. Autosomal recessive inheritance is likely.

Global and local development of gray and white matter volume in normal children and adolescents

Over the last decade, non-invasive, high-resolution magnetic resonance imaging has allowed investigating normal brain development. However, much is still not known in this context, especially with regard to regional differences in brain morphology between genders. We conducted a large-scale study utilizing fully automated analysis-approaches, using high-resolution MR-imaging data from 200 normal children and aimed at providing reference data for future neuroimaging studies. Global and local aspects of normal development of gray and white matter volume were investigated as a function of age and gender while covarying for known nuisance variables. Global developmental patterns were apparent in both gray and white matter, with gray matter decreasing and white matter increasing significantly with age. Gray matter loss was most pronounced in the parietal lobes and least in the cingulate and in posterior temporal regions. White matter volume gains with age were almost uniform, with an accentuation of the pyramidal tract. Gender influences were detectable for both gray and white matter. Voxel-based analyses confirmed significant differences in brain morphology between genders, like a larger amygdala in boys or a larger caudate in girls. We could demonstrate profound influences of both age and gender on normal brain morphology, confirming and extending earlier studies. The knowledge of such influence allows for the consideration of age- and gender-effects in future pediatric neuroimaging studies and advances our understanding of normal and abnormal brain development.