Ira T. Lott

Vitamin B6‐dependent seizures Pathology and chemical findings in brain

A 131/2h-year-old child died with vitamin B6-dependent seizures in progress. Microscopic findings in brain included an abnormally sparse quantity of central myelinated fibers in the cerebral hemispheres. Glutamic acid concentrations were elevated and GABA concentrations reduced in the frontal and occipital cortices but not in the spinal cord. All other amino acid concentrations were normal, except for increased cystathionine in the occipital cortex. Pyridoxal-5-phosphate (PLP) was reduced in the frontal cortex. Glutamic acid decarboxylase activity comparable to that of controls was detected when the PLP concentration was greater than 0.05 mM. These findings suggest that pyridoxine-dependent seizures in man are associated with reduced GABA concentrations in the brain and with diminished central white matter structures.

Down's Syndrome, Aging, and Alzheimer's Disease: A Clinical Review*

This review has been directed towards those aspects of DS which bear upon pathological aging. Clinical dementia in DS has heretofore been studied largely by retrospective methods with variable findings. A prospective study utilizing techniques designed to measure cognitive performance in a poorly verbal, retarded population is badly needed. There is definitive evidence for Alzheimers disease changes in the brains of DS patients with some suggestion of altered topography compared to the general population. Immunological studies have established a T-cell deficiency in DS that may be linked to precocious aging of thymic-dependent processes. Both antiviral and nonantiviral effects of interferon are accentuated in cell culture systems utilizing DS tissue, presumably as a consequence of the localization of the interferon gene(s) on chromosome 21. Multiple endocrine studies confirm the high frequency of autoimmune disease, an abnormality that may be related to the problems of immune surveillance in DS. Precocious aging has been noted in regards to measures of skin elasticity, fenestration of cardiac valves, and premature cataracts. The 21st chromosome has been implicated in the elevated activity of superoxide dismutase, a finding of significance in regard to potential intracellular damage from increased levels of peroxide. Several studies have suggested a compensatory increase in glutathione peroxidase.

Down's Syndrome: Transport, Storage, and Metabolism of Serotonin in Blood Platelets

Extract: Serotonin (5HT) transport and metabolism were studied in platelets from 14 trisomy-21 patients who were matched with 12 sibling and 9 non-sibling control subjects with regard to age, sex, home environment, diet and weight. Endogenous 5HT content, in nanograms per milligram platelet protein, was reduced from 446 ± 66 in the sibling controls and from 492 ± 74 in the non-sibling controls to 158 ± 16 in the Downs syndrome group, a difference of 61% and 68% respectively (P < 0.001). Initial uptake of 14C-5HT measured after a 3-min incubation period was reduced 35% (P < 0.05) in the platelets from Downs syndrome patients, while the efflux of radiolabeled amine from platelets was not significantly altered in these patients. Since platelets do not synthesize 5HT, the decreased transport found may explain the lower 5HT levels in these patients. Mongols did not differ from control subjects in the activity of platelet monoamine oxidase.Speculation: Similarities in the uptake, storage, and release of 5HT between the human blood platelet and the serotonergic neuron suggest that the 5HT abnormality observed in mongol platelets may reflect disordered metabolism of the monoamine within the central nervous system.

Dementia in Down's syndrome: Observations from a neurology clinic

Clinical manifestations of dementia were reviewed in 15 Downs syndrome (DS) patients referred to a neurological clinic over a 24-month period for mental deterioration. The ages ranged from 32-64 years. One hundred percent showed personality changes and loss of independent daily living skills, the presenting symptoms in two-thirds of the cases. Other manifestations included seizures (53%), gait deterioration (73%), sphincteric incontinence (40%), and pathological release reflexes (67%). All 7 patients with CT-scans showed moderate or severe central and peripheral cortical atrophy. Detailed clinical information is presented for two patients, one of whom showed a temporary remission with imipramine. A characteristic dementia syndrome appears to be present in a subpopulation of aging DA patients with radiographic findings of Alzheimers disease.

Speech and Histidinemia: Methodology and Evaluation of Four Cases

Four unrelated children with histidinemia (histidase deficiency) were studied specifically for characteristics of speech and language. Two of the children with normal intelligence were also normal in all aspects of speech and language. The third child, who had subnormal intelligence and emotional immaturity, had normal speech but manifested poor use of syntax on language evaluation. The remaining child, who was mentally retarded and had a moderate hearing loss, also had normal speech but had poor auditory and speech discrimination as well as poor digit recall on language testing. Speech discrimination became normal in this latter child when the intensity of the auditory stimulus was increased.

Down's syndrome. Central monoamine turnover in patients with diminished platelet serotonin.

m Considerable evidence suggests that a disturbance in serotonin (5-hydroxytryptamine, 5-HT) metabolism attends Down’s syndrome. The 5-HT levels in blood and the urinary excretion of 5-hydroxyindoleacetic acid (5HIAA), the principal catabolite of 5-HT, are diminished in patients with this disorder. More recent studies indicate that the reduced 5-HT content of blood reflects a diminution in platelet levels of the a m h ~ e . ~ ? ’ Several tryptophan loading studies have revealed abnormal patterns of indole metabolites in the urine of Down’s syndrome patients compatible with a defect in the absorption or metabolism of this dietary precursor of 5-HT.6-9 A report of the ability of 5-hydroxytryptophan to modify muscle tone in patients with Down’s syndrome” suggests that abnormalities in 5-HT transport or metabolism may have relevance to the central nervous system defect in this disorder. Similarities in the uptake, storage, and catabolism of 5-HR between blood platelets and serotonergic neurons’ ‘ I 3 have led to the proposal that reduced 5-HT levels in the platelets of Down’s syndrome patients may reflect disordered indoleamine transport or metabolism within the central nervous ~ y s t e m . ~ 9’ In an attempt to examine this hypothesis as well as to study central monoaminergic function in mongolism, we have compared Down’s syndrome patients with nonmentally retarded controls with respect to platelet 5-HT levels and the concentration of two monoamine catabolites in cerebrospinal fluid (CSF) before and during the administration of probenecid. Since probenecid inhibits the transport of 5-HIAA and homovanillic acid (HVA), a major catabolite of dopamine, from the central nervous system without materially affecting their rate of formation, the rate of accumulation of these substances in CSF during kLobenecid administration may bear some relationship to the turnover of the parent amine.’ -’

Abnormal copper metabolism in Menke's steely-hair syndrome.

Summary: Copper (Cu) metabolism was selectively studied in seven infants with Menkes steely-hair syndrome (SHS). A daily oral regimen of CuSO4 (584 μg Cu/kg) and l-histidine (100 mg/kg) in three infants produced an increase in serum Cu concentrations ranging from 33–95% of normal, but without the formation of ceruloplasmin. Cohn serum protein fractionation after oral Cu/l-histidine loading showed a disproportionate accumulation of Cu in the albumin fraction (V). The electron spin resonance spectrum of fraction V showed a heightened signal for the SHS patients, suggesting that an increased concentration of a radical Cu species is present after oral loading. The Sephadex G-150 chromatographic profile of serum fraction V in SHS did not differ significantly from controls. These results suggest that, in SHS, Cu absorbed in the presence of l-histidine is in an abnormal complex involving albumin, which does not allow for holoceruloplasmin biosynthesis. Cu and ceruloplasmin concentrations in the cord blood specimen of an infant who went on to develop SHS were normal, a finding which may account for the transient period of seemingly normal development after birth in SHS patients. An almost 6-fold difference in mean Cu concentration was observed in SHS fibroblasts compared to controls. Fibroblast Cu concentration was elevated in one of two possible maternal heterozygotes, a finding which may permit diagnosis of the carrier state for some SHS heterozygotes.Speculation: The basic defect in SHS may be an abnormality in an intracellular Cu binding or transport protein, which is present in multiple tissues. This suggestion is supported by data from intestine and skin fibroblasts and may, in part, explain the common failure of simple Cu replenishment to alter the clinical course of SHS.

Cognitive Profiles on the Severe Impairment Battery Are Similar in Alzheimer Disease and Down Syndrome With Dementia.

Previous research has revealed similarities in the neuropathology, clinical presentation, and risk factors between persons with Alzheimer disease from the general population (GP-AD) and those with Down syndrome (DS-AD). Less is known, however, about the extent of similarities and differences in the cognitive profiles of these 2 populations. Fifty-one moderate to severely demented GP-AD and 59 DS-AD individuals participated in this study which compared the cognitive profiles of these 2 populations on the Severe Impairment Battery (SIB), controlling for sex as well as level of functional ability using a modified version of the Bristol Activities of Daily Living Scale. Overall, the neuropsychological profiles of the higher-functioning individuals within the DS-AD and advanced GP-AD groups, as represented by mean difference scores on the SIB as a whole and across the 9 separate cognitive domains, were very similar to one another after adjusting for sex and functional impairment. To our knowledge, this is the first study to directly compare the cognitive profiles of these 2 populations on the SIB. Findings suggest that the underlying dementia in GP-AD and DS-AD may have corresponding and parallel effects on cognition.

1687 PERMANENT LIGATION OF THE RIGHT COMMON CAROTID ARTERY AT BIRTH: 18 CASES

Extra corporeal membrane oxygenation (ECMO) is a heart-lung bypass procedure which involves permanent ligation of the right common carotid artery and internal jugular vein. 18 children who received ECMO as neonates for severe cardiorespiratory insufficiency were studied neurologically 4-11 years after treatment. Cognitive and/or language impairments were noted in 5/18 whereas 72% had a normal neurodevelopmental status. Spastic motor impairment was mild in 3 and severe in 2 patients. Five children had paroxysmal discharges on the EEG but lateralizing findings were not seen in any child. In 10/11 patients studied by noninvasive carotid evaluation, the arterial occlusion could be identified by ultrasound. In these cases the internal carotid artery (ICA) was patent and forward flow in the ICA was achieved by retrograde channeling through the external carotid artery. The size and volume of flow in the right ICA was approximately 50% of that in the left. Asymmetrical auditory cortical evoked potentials were seen in 60% of the 12 cases studied to date with right sided preponderance in the majority. These preliminary findings suggest a possible subclinical effect upon right hemispherel function ipsilateral to the arterial ligation. We conclude that: 1)collateral retrograde flow is established after right common carotid artery ligation at birth and 2)in the majority of patients there are no apparent specific clinical symptoms of right hemispheral dysfunction following the ECMO procedure.

Familial amentia, unusual ventricular calcifications, and increased cerebrospinal fluid protein

A sibship originally reported by Friedman and Roy1 as showing severe mental retardation, strabismus, hyperactive tendon reflexes, lalling speech, and foot deformities was restudied. Three major additional findings were noted. The cerebrospinal fluid protein concentration was increased two to three times above normal in four siblings who were available for study. Radiographs of cranial structures in three siblings showed identical pathologic intracranial calcifications which corresponded in distribution to the choroid plexus. The choroid plexus was not demonstrable in one patient when radiolabeled 99m-Tc-pertechnetate was injected without perchlorate. Neuropathologic findings in one sibling included small subcortical heterotopias and atrophy of the choroid plexus with encasement by glial fibrils. These findings denote a new heredofamilial neurologic syndrome associated with mental retardation and a disorder of choroid plexus.