Gilbert Lyon

The mechanism of arrest of neuronal migration in the Zellweger malformation: An hypothesis based upon cytoarchitectonic analysis

SummaryThe brain from a clinically typical case of the Zellweger malformation, dying at 5 weeks of age, is studied in general histologic preparations and in Bielschowsky impregnations. Cytoarchitectonic abnormalities, typical of previously described cases and unique to the Zellweger malformation, are observed in the cerebral hemispheres, the cerebellum and the inferior olivary complex. Neocortical malformation is associated with neuronal heterotopia. The impediment to neuronal migration has affected, principally, neurons destined for the outer cortical layers. The impediment to migration appears to be only partially effective in that a portion of neurons destined for cortical layers II and III are in their normal laminar positions whereas others lie in heterotopic intra-cortical and subcortical positions. The cerebellar cortex in this malformation is distinctive for large Purkinje cell heterotopias, subjacent to intact Purkinje and granule cell cortical laminae. Bielschowsky preparations identify multiple primary dendritic processes extending from the somata of heterotopic Purkinje cells. Finally, there are laminar discontinuities, unique to this malformation, in the principal nucleus of the inferior olivary complex. By analogy with the cerebellar cortical malformation in the weaver mutant mouse, the Zellweger cortical malformation may result from incomplete disruption of neuronal migration caused by circulating toxic metabolites.

Symptomatology of Late Onset Krabbe's Leukodystrophy: The European Experience

The authors present a study of 50 patients with late onset Krabbes leukodystrophy (LOKL), including 27 from a pooled European Series collected in 1987, and 23 published between 1906 and 1987. In Europe, the disease appears to be relatively frequent in Sicily and exceedingly rare in Sweden. Most cases started before the age of 5 years. The initial signs consisted mainly of progressive motor impairment, although, characteristically, visual failure was the initial manifestation in 25% of patients. Low nerve conduction velocities and a high protein content in the CSF were only present in 50%. There was no age-linked symptomatic predominance. The pace and length of the disease was very variable, but in one-third of the children before the age of 3 the course was remarkably rapid. There was no difference in the residual activity of galactosylceramide galactosidase in LOKL compared to the early infantile form.

Neuropathological study of a case of autistic syndrome with severe mental retardation

Infantile autism is a syndrome of unknown aetiology and unknown neuro‐anatomic substrate. The authors report a histological study of the brain of a well‐documented 16‐year‐old female with autistic syndrome and severe mental retardation, using direct microscopic examination of the whole brain. The major findings are low brain weight, a thin corpus callosum and ventricular dilatation. No abnormalities were found in the hippocampus or cerebellum. Excessive axonal elimination during brain development is hypothesized. The relations of hypothetical developmental events with the clinical features of autistic syndrome are discussed.

Aqueductal Stenosis in X‐Linked Hydrocephalus: a Secondary Phenomenon?

Two cases of x‐linked hydrocephalus are reported. One underwent postmortem examination: serial sections of the brain stem failed to show stenosis of the aqueduct, the mean and minimal cross‐sectional areas of which were normal. However, there were some morphological changes which were compatible with a mechanical compression of the brain stem. It is postulated that in the Bickers and Adams syndrome of x‐linked hereditary hydrocephalus the primary defect is a communicating hydrocephalus leading usually, but not always, to aqueductal stenosis. The importance of electrophysiological investigations for the correct diagnosis of the characteristic clasped‐thumb deformity is also indicated.

A Golgi study of the brain malformation in Zellweger's cerebro-hepato-renal disease.

SummaryCharacteristic neuronal heterotopias in two cases of Zellwegers cerebro-hepato-renal disease were studied with the Golgi method.In the corona radiata, heterotopias consist of large fields of small or medium-sized radial pyramids, and of dense clusters containing larger, randomly oriented pyramidal cells and multipolar neurons, some of which resemble granule cells. The latter type of heterotopia could result from a focal destructive process at a relatively early stage of neuronal migration.In the cerebellar white matter, heterotopic masses contain Purkinje cells and possibly Golgi neurons but no granule or basket cells. The mispositioned Purkinje cells resemble the subcortical and intragranular Purkinje cells of the reeler mutant mouse and those of the weaver mutant. The morphology of neurons in the abnormally convoluted olivary nucleus is normal.

Disorder of cerebellar foliation in Walker's lissencephaly and neu-laxova syndrome.

A diffuse disorder of cerebellar foliation was found in eight infants and one fetus with Walkers lissencephaly. The cerebellar cortex consisted of fused and irregularly distorted folia. In the white matter, trilaminated rings of cortex were concentrically arranged around blood vessels and mesenchymal tissue. The normal relative position of the different classes of cortical nerve cells was preserved. Cells of the external granular layer invaded the meninges and migrated along penetrating blood vessels. We believe that this foliation disorder is caused by a defect in the external basal lamina that allows adjacent folia to be fused and sulci obliterated by intrameningeal ectopias of external granule layer cells. Physical forces applied during development probably contribute to the distortion of the gyral pattern. There was a volumetric reduction of the neocerebellum, which might also be a consequence of the basal lamina defect. The cerebellum of a fetus with the Neu-Laxova syndrome showed the same abnormalities as in Walkers lissencephaly. It is postulated that these two conditions belong to a class of prenatal developmental disorders that involves a defect of the extracellular matrix.

Ependymitis, Leukoencephalitis, Hydrocephalus, and Thrombotic Vasculitis Following Chronic Infection By Mouse Hepatitis Virus-3 (mhv-3)

SummaryMouse hepatitis virus 3 (MHV 3) is either avirulent (resistant mice), hepatotropic (susceptible mice). or neurotropic (semisusceptible mice), depending on the strain of mice infected. In semisusceptible mice, infection led first to a transient meningitis, ependymitis, and leukoencephalitis, followed by a permanent communicating hydrocephalus and, later on, to a chronic thrombotic vasculitis affecting meningeal and parenchymal vessels at the brain stem level. Small foci of ischemic necrosis related to vascular occlusions were seen in the dorsal brain stem. Cyclophosphamide treatment of semisusceptible mice significantly reduced the meningeal infiltrates but did not prevent the development of hydrocephalus and other neuropathologic changes. Identical lesions occurred in fully susceptible mice infected with a low dose of virus, but no neurologic disorder could be induced in genetically resistant mice even following immunosuppression or intracranial inoculation. The leukoencephalitis differed from the demyelinating lesions observed with MHV4. Vascular lesions were of particular interest. More attention should be given to the possibifity of virus induced chronic cerebral vasculitis in man.

Prolonged dysphagia caused by congenital pharyngeal dysfunction.

We describe two patients with severe, isolated, congenital dysphagia caused by paralysis of the pharyngeal muscles, who recovered at the ages of 40 months and 20 months, respectively. No other evidence of neurologic or muscular dysfunction was present except for a transient paralysis of the adductors of the vocal cords in one child. Radiocinematographic studies showed paralysis of the pharyngeal stage of swallowing, with minimal involvement of the oral stage. One child refused oral feeding for several months after apparent radiologic recovery. Two other patients with a similar disorder died of tracheal aspiration at the ages of 8 months and 4 months, respectively. Autopsies showed no abnormality of the central nervous system, and the cranial nerves involved in swallowing were normal. Only five other well-studied cases of this syndrome have been reported. These observations demonstrate the existence of a type of severe, idiopathic, congenital dysphagia related to paralysis of the constrictor muscles of the pharynx, with a propensity to recover after several months or years if properly managed. The cause of the disorder is obscure, but it is probably related to a dysfunction of the central nervous system.

Liver Peroxisome Damage During Acute Hepatic-failure in Partial Ornithine Transcarbamylase Deficiency

Summary: A boy with ornithine transcarbamylase (OTC) deficiency was relatively symptom free for 9 months and then developed an acute episode with liver failure and metabolic imbalance. Subsequently there was severe cerebral atrophy.Liver ornithine transcarbamylase activity was 3% of the normal mean. Of considerable interest was the finding of an accelerated breakdown of liver peroxisomes during the acute phase.Speculation: The present observation suggests that damage to peroxisomes may be an element in acute liver dysfunction. Consequently, drugs that stimulate the production or regeneration of peroxisomes could possibly be of therapeutic interest in such conditions.

Formation of "neo-cortex" in a congenital human teratoma.

SummaryA congenital human teratoma contained a neuroectodermal mass with architectonic features similar to those of the normal developing neo-cortex. Surrounding a central cavity, a germinal, an intermediate and a cortical zone were clearly distinguishable from innermost to outermost. Glial fibers coursed radially through the intermediate and cortical zones. In the “cortical plate” neuronal elements were oriented radially with an inside out gradient of differentiation. Mesothelial tissue covered the outer surfaces of the “cortex”. Over limited sectors a gap in the integrity of the meso-glial barrier were associated with neuroglial ectopias.The following points are of neurobiologic importance: the formation of the “miniature cerebral cortex” occurred in the absence of any influence of afferent subcortical fibers. The radial alignment of glial fibers between the germinal pseudostratified epithelium and the outer surface occurred only in sectors of the neuro-ectodermal mass where a “neo-cortex” was present, and may therefore have been a critical determinant in the formation of the “cortical plate”. The integrity of the outer glial mesenchymal barrier may be necessary for the normal arrangement of cortical neurons.