Article Figures & Data
Figures
- Figure 1
MRI brain a) sagittal sequence, b) axial sequence. Total agenesis of the corpus callosum in a 7 days old boy with nonketotic hyperglycinemia
- Figure 2
MRI brain, axial T2-sequence. Cortical malformation (polymicrogyri) in a patient with Zellweger disease. Note also the abnormal white matter signal.
- Figure 3
MRI brain a) axial T2 weighted image of 5 months old patient with Canavan disease demonstrates diffuse abnormal white matter signal; and b) MR spectroscopy showing markedly elevated N-acetylaspartic acid peak.
Tables
Stage 1: Dorsal induction: Formation and closure of the neural tube - Occurs at 3-5 weeks of gestation - Three phases: neurulation, canalization, retrogressive differentiation - Malformations of dorsal induction: anencephaly, exencephaly, cephaloceles, Arnold-Chiari malformations and spinal dysraphism Stage 2: Ventral induction: Formation of the brain segments and face - Occurs at 5-10 weeks of gestation -Three vesicles (prosencephalon, mesencephalon, and rhombencephalon) form the cerebral hemispheres/thalamus, midbrain, and cerebellum/brain stem respectively. - Development of face - Malformations of ventral induction: holoprosencephaly, Dandy-Walker malformation, cerebellar hypoplasia/dysplasia, Joubert syndrome, rhombencephalosynapsis, optic dysplasia, pituitary abnormalities and facial anomalies. Stage 3: Migration and histogenesis - Occurs at 2-5 months of gestation - Neuronal migration from germinal matrix to the cortex - Cortical organization - Failure of migration: abnormal gyration patterns (heterotopias, simplified gyria, polymicrogyria), schizencephaly, corpus callosum agenesis/hypoplasia. - Failure of histogenesis: aqueductal stenosis, arachnoid cysts, megalencephaly, micoencephaly, neurocutaneous syndromes, congenital vascular malformation, and congenital neoplasms of the brain. Stage 4: Myelination - Begins at 6 months of gestation; matures by 3 years. - Myelination proceeds from caudal to rostral, from posterior to anterior regions; and from central to peripheral locations. - Failure: leukodystrophies, metabolic disorders. - Table 2
Mechanisms of malformation of the central nervous system in inborn errors of metabolism.
Energy deprivation and defective cell respiration Aerobic metabolism in the brain tends to increase during periods of rapid neuronal proliferation, differentiation, and migration. Examples: Pyruvate dehydrogenase deficiency, respiratory chain deficiencies Accumulation of neurotoxic metabolites Intracellular accumulation of metabolites, such as glycine, lactic acid, or sulfites can produce direct neurotoxic effects. Examples: nonketotic hyperglycinemia, sulfite oxidase deficiency Defects within cellular signaling pathways Inborn errors of metabolism may have regulatory effects on the molecules involved in cell-to-cell signaling, an essential phenomena for organogenesis. Example: Smith-Lemli-Opitz syndrome Alterations in the biophysical properties of cell membranes The biophysical properties of cell membranes has a key role in the regulation of the cell physiology. Membrane clustering of receptors and ligands allows the formation of concentration gradients that are critical for axonal guidance. Cholesterol deficiency within membranes affects fluidity, potentially interfering with efficient anchoring of tyrosine kinase receptors and diffusibility of signaling molecules, resulting in disruption of signaling gradients. Example : Glu-1 deficiency syndrome, Smith-Lemli-Opitz syndrome Interrelationships of subcellular organelle functions Several subcellular organelles participate in the cholesterol biosynthetic pathway: the cytosol, mitochondria, and peroxisomes. Sequential steps in the pathway are compartmentalized and distributed among these organelles. Disturbance in peroxisomal function affects cholesterol biosynthesis. Example: Zellweger syndrome Brain malformation Corpus Callosum Cerebrum Cerebellum Brainstem Germinolytic cysts Vessels Nonketotic hyperglycinemia25 CC dysgenesis Ventriculomegaly Vermis hypoplasia, mainly the inferior part Pyruvate dehydrogenase deficiency26 CC dysgenesis -Subcortical heterotopias
-Pachygyria
-Polymicrogyria-Cerebellar hypoplasia
-Hypoplastic dentate nuclei
-Mega cisterna magnaBrainstem hypoplasia ++ Mitochondriopathies21,27 CC dysgenesis Ventriculomegaly
Cortical dysplasia++ Congenital disorder of glycosylation (PMM2-CDG)28 Cerebellar hypoplasia Pontine hypoplasia ALG8-CDG29 CC hypoplasia Ventriculomegaly ALG3-CDG30 Pons hypoplasia Zellweger syndrome31 CC dysgenesis -Polymicrogyria
-Pachygyria
-Periventricular heterotopiasCerebellar hypoplasia +++ Smith-Lemli-Opitz syndrome18 Absent or hypoplastic CC Ventriculomegaly
Holoprosencephaly
Hippocampal hypoplasia
Frontal lobes hypoplasiaCerebellar hypoplasia Mucolipidosis32 CC dysgenesis Cerebellar hypoplasia Pontine hypoplasia Fumaric aciduria33 Polymicrogyria
Ventriculomegaly
Open operculaBifunctional enzyme deficiency34 Adenylosuccinate lyase deficiency35 Thin corpus callosum -wide sylvian fissures with operculum hypoplasia
-Lissencephaly++ Neu-laxova syndrome (inborn error of serine metabolism)24 Absence of CC Ventriculomegaly
Simplified gyriCerebellar hypoplasia Hypoplastic brain stem Carnitine palmitoyltransferase II deficiency36 Abnormal migration disorders Dandy-Walker malformation Menkes disease37 tortuous and elongated intracranial vessels Sulfite oxidase deficiency38 Cerebellar hypoplasia Glutaric aciduria type I39 -Widened operculum
-Dilatation of the subarachnoid spaces
-Underdeveloped frontotemporal lobes
-Incomplete hippocampal inversion
-Large cavum septum pellucidiGlutaric aciduria type II40 CC dysgenesis -Pachygyria
-Subcortical heterotopiasCerebellar hypoplasia Pyridoxine dependent epilepsy41,42 -Thinning of the isthmus of the CC-mega cisterna magna
-Ventriculomegaly
-Heterotopias-Cerebellar hypoplasia
-mega cisterna magnaKrabbe disease43 Thick optic nerve and chiasma Maternal phenylketonuria44 CC dysgenesis Asparagine synthetase deficiency45 Simplified gyri Pontine hypoplasia Pyruvate carboxylase deficiency46 Subcortical heterotopias ++ Mucopolysaccharidoses type I and II47 -Enlarged perivascular spaces
-Ventriculomegaly-Enlarged perivascular spaces
-Mega cisterna magna
-MacrocerebellumCC - corpus callosum
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