Neurologists
43 years of experience

Accepting new patients
Choc Neurology Clinic
1120 W La Veta Ave
Ste 125
Orange, CA 92868
714-509-7601
Locations and availability (6)

Education ?

Medical School Score Rankings
The Ohio State University (1967)
  • Currently 3 of 4 apples
Top 50%

Awards & Distinctions ?

Awards  
Christian Pueschel Memorial Research Award, National Down Syndrome Congress
National Research Award, National Down Syndrome Society, 2004
Castle Connolly America's Top Doctors® (2002 - 2008, 2010 - 2014)
Castle Connolly's Top Doctors™ (2012 - 2013)
Associations
American Board of Pediatrics
American Board of Psychiatry and Neurology

Affiliations ?

Dr. Lott is affiliated with 11 hospitals.

Hospital Affilations

Score

Rankings

  • University of California, Irvine Medical Center *
    1310 W Stewart Dr, Orange, CA 92868
    • Currently 4 of 4 crosses
    Top 25%
  • Saddleback Memorial Medical Center-Laguna Hills
    24451 Health Center Dr, Laguna Hills, CA 92653
    • Currently 4 of 4 crosses
    Top 25%
  • Los Alamitos Medical Center
    3751 Katella Ave, Los Alamitos, CA 90720
    • Currently 4 of 4 crosses
    Top 25%
  • St. Joseph Hospital - Orange
    1100 W Stewart Dr, Orange, CA 92868
    • Currently 4 of 4 crosses
    Top 25%
  • Anaheim Memorial Medical Center
    1111 W La Palma Ave, Anaheim, CA 92801
    • Currently 4 of 4 crosses
    Top 25%
  • Children's Hospital of Orange County *
    455 S Main St, Orange, CA 92868
    • Currently 2 of 4 crosses
  • Children's Hospital at Mission
    27700 Medical Center Rd, Mission Viejo, CA 92691
    • Currently 1 of 4 crosses
  • Choc
  • UCI Medical Center
  • CHOC in Orange
  • University Of California
  • * This information was reported to Vitals by the doctor or doctor's office.

    Publications & Research

    Dr. Lott has contributed to 30 publications.
    Title Down Syndrome and Dementia: a Randomized, Controlled Trial of Antioxidant Supplementation.
    Date November 2011
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Individuals with Down syndrome over age 40 years are at risk for developing dementia of the Alzheimer type and have evidence for chronic oxidative stress. There is a paucity of treatment trials for dementia in Down syndrome in comparison to Alzheimer disease in the general (non-Down syndrome) population. This 2-year randomized, double-blind, placebo-controlled trial assessed whether daily oral antioxidant supplementation (900 IU of alpha-tocopherol, 200 mg of ascorbic acid and 600 mg of alpha-lipoic acid) was effective, safe and tolerable for 53 individuals with Down syndrome and dementia. The outcome measures comprised a battery of neuropsychological assessments administered at baseline and every 6 months. Compared to the placebo group, those individuals receiving the antioxidant supplement showed neither an improvement in cognitive functioning nor a stabilization of cognitive decline. Mean plasma levels of alpha-tocopherol increased ~2-fold in the treatment group and were consistently higher than the placebo group over the treatment period. Pill counts indicated good compliance with the regimen. No serious adverse events attributed to the treatment were noted. We conclude that antioxidant supplementation is safe, though ineffective as a treatment for dementia in individuals with Down syndrome and Alzheimer type dementia. Our findings are similar to studies of antioxidant supplementation in Alzheimer disease in the general population. The feasibility of carrying out a clinical trial for dementia in Down syndrome is demonstrated.

    Title Systemic Mitochondrial Dysfunction and the Etiology of Alzheimer's Disease and Down Syndrome Dementia.
    Date September 2010
    Journal Journal of Alzheimer's Disease : Jad
    Excerpt

    Increasing evidence is implicating mitochondrial dysfunction as a central factor in the etiology of Alzheimer's disease (AD). The most significant risk factor in AD is advanced age and an important neuropathological correlate of AD is the deposition of amyloid-beta peptide (Abeta40 and Abeta42) in the brain. An AD-like dementia is also common in older individuals with Down syndrome (DS), though with a much earlier onset. We have shown that somatic mitochondrial DNA (mtDNA) control region (CR) mutations accumulate with age in post-mitotic tissues including the brain and that the level of mtDNA mutations is markedly elevated in the brains of AD patients. The elevated mtDNA CR mutations in AD brains are associated with a reduction in the mtDNA copy number and in the mtDNA L-strand transcript levels. We now show that mtDNA CR mutations increase with age in control brains; that they are markedly elevated in the brains of AD and DS and dementia (DSAD) patients; and that the increased mtDNA CR mutation rate in DSAD brains is associated with reduced mtDNA copy number and L-strand transcripts. The increased mtDNA CR mutation rate is also seen in peripheral blood DNA and in lymphoblastoid cell DNAs of AD and DSAD patients, and distinctive somatic mtDNA mutations, often at high heteroplasmy levels, are seen in AD and DSAD brain and blood cells DNA. In aging, DS, and DSAD, the mtDNA mutation level is positively correlated with beta-secretase activity and mtDNA copy number is inversely correlated with insoluble Abeta40 and Abeta42 levels. Therefore, mtDNA alterations may be responsible for both age-related dementia and the associated neuropathological changes observed in AD and DSAD.

    Title Telemedicine, Dementia and Down Syndrome: Implications for Alzheimer Disease.
    Date December 2009
    Journal Alzheimer's & Dementia : the Journal of the Alzheimer's Association
    Excerpt

    Individuals with Down syndrome (DS) who are at risk for dementia of the Alzheimer type (DAT) often live at sites remote from major medical centers. Telemedicine (TM) is a modality for providing medical care at remote locations but is underutilized for populations with Alzheimer disease (AD).

    Title The Genetic Architecture of Down Syndrome Phenotypes Revealed by High-resolution Analysis of Human Segmental Trisomies.
    Date August 2009
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Down syndrome (DS), or trisomy 21, is a common disorder associated with several complex clinical phenotypes. Although several hypotheses have been put forward, it is unclear as to whether particular gene loci on chromosome 21 (HSA21) are sufficient to cause DS and its associated features. Here we present a high-resolution genetic map of DS phenotypes based on an analysis of 30 subjects carrying rare segmental trisomies of various regions of HSA21. By using state-of-the-art genomics technologies we mapped segmental trisomies at exon-level resolution and identified discrete regions of 1.8-16.3 Mb likely to be involved in the development of 8 DS phenotypes, 4 of which are congenital malformations, including acute megakaryocytic leukemia, transient myeloproliferative disorder, Hirschsprung disease, duodenal stenosis, imperforate anus, severe mental retardation, DS-Alzheimer Disease, and DS-specific congenital heart disease (DSCHD). Our DS-phenotypic maps located DSCHD to a <2-Mb interval. Furthermore, the map enabled us to present evidence against the necessary involvement of other loci as well as specific hypotheses that have been put forward in relation to the etiology of DS-i.e., the presence of a single DS consensus region and the sufficiency of DSCR1 and DYRK1A, or APP, in causing several severe DS phenotypes. Our study demonstrates the value of combining advanced genomics with cohorts of rare patients for studying DS, a prototype for the role of copy-number variation in complex disease.

    Title Alpha- and Beta-secretase Activity As a Function of Age and Beta-amyloid in Down Syndrome and Normal Brain.
    Date September 2007
    Journal Neurobiology of Aging
    Excerpt

    Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alpha-secretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Abeta) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Abeta degradation and clearance.

    Title Rapid Assessment of Severe Cognitive Impairment in Individuals with Developmental Disabilities.
    Date April 2007
    Journal Journal of Intellectual Disability Research : Jidr
    Excerpt

    BACKGROUND: Most standardized intelligence tests require more than 1 hour for administration, which is problematic when evaluating individuals with intellectual disabilities and developmental disabilities (IDDD), because a significant proportion of these individuals can not tolerate lengthy evaluations. Furthermore, most standardized intelligence tests are of limited usefulness for individuals with severe cognitive deficits because of floor effects. METHODS: A number of low-difficulty items were selected from standardized tests. A total of 271 participants with profound, severe, moderate and mild levels of cognitive impairment took part in this study. In the formative phase, 68 participants were evaluated with the selected items, and those items that differentiated between levels of cognitive impairment were retained in the battery. The instrument was then modified and standardized with an additional 203 participants. RESULTS: The instrument, referred to as the Rapid Assessment for Developmental Disabilities (RADD), required 10-25 min for administration. Internal reliability estimates from the RADD total score and from individual subtests satisfied conventional and rigorous statistical criteria (median alpha r = 0.93). The RADD total score was strongly correlated with the level of cognitive impairment (rho = 0.86). The RADD total score and individual subtests differentiated between all levels of cognitive impairment ( Wilks Lambda = 0.135, F(42,525.832) = 12.075, P < 0.001). Receiver operating characteristic curves indicated the instrument was particularly sensitive to the cognitive abilities of the most seriously impaired participants. CONCLUSIONS: The RADD, composed of low-difficulty items from published tests, is rapidly administered, assesses a wide range of cognitive skills and differentiates among all levels of cognitive impairment. The battery has clinical utility with populations exhibiting short attention spans because of its ability to quickly assess a wide range of cognitive abilities. The RADD also has research potential for the documentation of cognitive function in studies of individuals with IDDD.

    Title Temporal Cortex Hypermetabolism in Down Syndrome Prior to the Onset of Dementia.
    Date February 2004
    Journal Neurology
    Excerpt

    BACKGROUND: Adults with Down syndrome (DS) are at increased risk for dementia and provide an opportunity to identify patterns of brain activity that may precede dementia. Studies of early Alzheimer's disease (AD) and risk of AD show decreased function in posterior cingulate and temporal cortex as initial indicators of the disease process, but whether the origin and sequence of predementia brain changes are the same in DS is unknown. METHODS: The regional cerebral glucose metabolic rates (GMR) among middle-aged nondemented people with DS (n = 17), people with moderate AD (n = 10), and age-matched control subjects (n = 24) were compared using PET during a cognitive task. RESULTS: Statistical parametric mapping conjunction analyses showed that 1) both DS and AD groups had lower GMR than their respective controls primarily in posterior cingulate and 2) compared with respective controls, the subjects with DS had higher GMR in the same areas of inferior temporal/entorhinal cortex where the AD subjects had lower GMR. The same results were replicated after 1 year of follow-up. CONCLUSIONS: As the DS subjects were not clinically demented, inferior temporal/entorhinal cortex hypermetabolism may reflect a compensatory response early in disease progression. Compensatory responses may subsequently fail, leading to neurodegenerative processes that the authors anticipate will be detectable in vivo as future GMR decreases in inferior temporal/entorhinal cortex are accompanied by clinical signs of dementia.

    Title Oxidation of Abeta and Plaque Biogenesis in Alzheimer's Disease and Down Syndrome.
    Date January 2002
    Journal Neurobiology of Disease
    Excerpt

    The processes involved with beta-amyloid (Abeta) degradation and clearance in human brain are not well understood. We hypothesized that the distribution of oxidatively modified Abeta, as determined by an affinity-purified antibody in the entorhinal and frontal cortices of Alzheimer's disease (AD), Down syndrome (DS), nondemented elderly control cases, and canine brain, would provide insight into the mechanisms of Abeta accumulation. Based upon plaque counts, oxidized Abeta was present within 46-48% of diffuse and primitive plaques and 98% of cored plaques. Dense punctate deposits of oxidized Abeta were distributed throughout the neuropil in AD and DS brains but were also present within controls with mild neuropathology and isolated cognitive impairments. Confocal studies indicate that punctate oxidized Abeta deposits were within activated microglia. Oxidatively modified Abeta may reflect the efforts of microglial cells to take up and degrade Abeta. Oxidative modification of Abeta may be an early event in Abeta pathogenesis and may be important for plaque biogenesis.

    Title Neurological Changes and Emotional Functioning in Adults with Down Syndrome.
    Date December 2001
    Journal Journal of Intellectual Disability Research : Jidr
    Excerpt

    This study was designed to examine emotional changes in adults with Down Syndrome (DS) over time and whether changes in these psychological variables were associated with brain atrophy on MRI scan and the presence of pathological reflexes on the neurological examination. Participants were 26 adults with DS and their caregivers. Caregivers completed a measure of emotional functioning about individuals with DS at two different time points (1 year apart). Levels of cognitive functioning were measured and neurological and MRI examinations were performed on all subjects at initial testing. Significant group effect separated those with and without pathological findings on MRI and neurological exam across three different scales: depression, indifference, and pragmatic language functioning. Problems of poor pragmatic language functioning appeared later in the course of suspected Alzheimer's disease (AD), as demonstrated by a significant group effect at time 2, but not at initial testing. In these subjects, the primary emotional change was a decline in social discourse (e.g. conversational style, literal understanding, verbal expression in social contexts). These emotional levels were stable over time, regardless of degree of cognitive decline. Specific emotional changes occur during the course of AD which were associated with abnormal findings from MRI and from neurological examination. These results, along with abnormalities in brain imaging and the presence of pathological reflexes, suggested that frontal lobe dysfunction is likely to be an early manifestation of Alzheimer's Disease in Down Syndrome.

    Title Molecular Dating of Senile Plaques in the Brains of Individuals with Down Syndrome and in Aged Dogs.
    Date June 2000
    Journal Experimental Neurology
    Excerpt

    beta-Amyloid (Abeta) is a constituent of senile plaques found with increasing age in individuals with Down syndrome (DS) and in the canine model of aging. Sections of DS and dog brain were immunostained using an affinity-purified polyclonal antibody for a posttranslationally modified Abeta with a racemized aspartate at position 7 (d7C16). The immunostaining characteristics of d7C16 Abeta in DS and dog brain indicate that it is present in all plaque subtypes, including the thioflavin-S-negative diffuse plaques that develop with age in dogs. The youngest DS case exhibited weak immunolabeling for d7C16 but the extent of d7C16-positive plaques increased with age. In addition, d7C16-positive plaques were initially found in clusters in the superficial layers of the frontal and entorhinal cortex but, with advancing age, increasing numbers appeared in deeper layers, suggesting a progression of Abeta deposition from superficial to deeper cortical layers. Ultrastructural studies in DS brain were confirmed using perfused dog brain and provided consistent results; thioflavin-S-negative diffuse plaques consist of fibrillar Abeta and racemized Abeta is associated with thicker and more highly interwoven fibrils than nonracemized Abeta. The use of antibodies to modified forms of the Abeta protein should provide insight into the progression of plaque pathology in DS and Alzheimer's disease brain.

    Title Premature Aging in Persons with Down Syndrome: Mr Findings.
    Date January 1997
    Journal Ajnr. American Journal of Neuroradiology
    Excerpt

    PURPOSE: To determine whether persons with Down syndrome have features of premature aging on routine MR imaging sequences. METHODS: Sixty MR studies (in 30 persons with Down syndrome and 30 age- and sex-matched control subjects) were reviewed retrospectively by two blinded examiners. Sagittal T1-weighted and axial T2-weighted spin-echo images were evaluated for the presence and severity of three markers of brain aging: atrophy, white matter lesions, and T2 hypointensity of the basal ganglia, referenced to the examiner's internal standard of normal for that age and sex. RESULTS: Persons with Down syndrome had higher prevalence and severity of the three markers studied than the control subjects. Atrophy and white matter lesions increased in prevalence with age; abnormal T2 hypointensity of the basal ganglia was more equally distributed with age. CONCLUSION: Persons with Down syndrome have features of premature aging detectable at routine MR imaging.

    Title Magnetic Resonance Imaging of the Aging Brain in Down Syndrome.
    Date February 1996
    Journal Progress in Clinical and Biological Research
    Excerpt

    MRI studies to date have confirmed and expanded upon findings of morphologic differences between the brains of subjects with DS and those of the general population found by CT and post-mortem examination. [table; see text] Hippocam pal and neocortical structures are smaller in DS while unexpectedly the parahippocampal gyrus was found to be larger. MRI has demonstrated that subjects with DS develop signs associated with [table; see text] brain aging at an earlier age. These findings include increased rate of dilatation of ventricles, increased peripheral atrophy, and increased deep white matter lesions. In addition, changes that are associated with AD occur earlier in the DS population. Functional studies reveal decreasing cerebral perfusion with age in adults with DS, a pattern similar to non-DS subjects with clinically progressive dementia, and provide evidence for altered blood-brain barrier permeability. Dynamic MRI studies have also shown adults with DS to have fluctuating cortical CSF volumes, similar to some elderly non-DS subjects and subjects with shunted hydrocephalus. This is a new finding in brain aging that suggests a relationship between aging in DS and edematous states of the brain.

    Title Cortical Csf Volume Fluctuations by Mri in Brain Aging, Dementia and Hydrocephalus.
    Date February 1995
    Journal Neuroreport
    Excerpt

    Dynamic MR imaging has revealed dramatic fluctuations in the appearance of CSF in the cortical sulci and cortical subarachnoid spaces in aging individuals and patients with hydrocephalus, dementia and Down syndrome in contrast to young healthy volunteers. The changes have been interpreted as volume fluctuations that represent undamped CSF hydrodynamics and have implications with respect to the origin of CSF in the cortical regions and with respect to the similarity between aging and dementia and edematous states of the brain.

    Title Mr Imaging of Cavitary Lesions in the Brain with Hurler/scheie.
    Date October 1989
    Journal Ajnr. American Journal of Neuroradiology
    Title Plasticity of Hippocampal Circuitry in Alzheimer's Disease.
    Date December 1985
    Journal Science (new York, N.y.)
    Excerpt

    Two markers of neuronal plasticity were used to compare the response of the human central nervous system to neuronal loss resulting from Alzheimer's disease with the response of rats to a similar neuronal loss induced by lesions. In rats that had received lesions of the entorhinal cortex, axon sprouting of commissural and associational fibers into the denervated molecular layer of the dentate gyrus was paralleled by a spread in the distribution of tritiated kainic acid-binding sites. A similar expansion of kainic acid receptor distribution was observed in hippocampal samples obtained postmortem from patients with Alzheimer's disease. An enhancement of acetylcholinesterase activity in the dentate gyrus molecular layer, indicative of septal afferent sprouting, was also observed in those patients with a minimal loss of cholinergic neurons. These results are evidence that the central nervous system is capable of a plastic response in Alzheimer's disease. Adaptive growth responses occur along with the degenerative events.

    Title Long-term Follow-up of Infants and Children Treated with Extracorporeal Membrane Oxygenation (ecmo): a Preliminary Report.
    Date November 1985
    Journal Journal of Pediatric Surgery
    Excerpt

    Extracorporeal Membrane Oxygenation (ECMO) has been used clinically as a life-saving treatment modality in infants and children who are dying of respiratory insufficiency. From 1973 to 1980 47 children less than 10 years of age were treated in a study to determine the feasibility and effectiveness of ECMO in the pediatric population. Despite a predicted mortality of 90% or greater, 24 patients survived. Eighteen of those patients have been seen in long-term follow-up. Thirteen patients (72%) demonstrate basically normal growth and development. Five patients (28%) have definite handicaps which are severe in two. Despite ligation of one common carotid artery and systemic heparinization, the risk of intracranial hemorrhage and/or neurodevelopmental problems appears to be no higher in this ECMO group and may even be lower than in the high-risk population treated with conventional therapy. The incidence of chronic respiratory problems, especially bronchopulmonary dysplasia, is zero in this group of patients. Only one patient (4%) has a defect that lateralizes to the right hemisphere which may have been affected by ligation of the carotid artery. Further study is required; however, it appears that ECMO offers life-saving intervention without increasing morbidity in select children with severe respiratory insufficiency.

    Title Retinoic Acid Embryopathy.
    Date October 1985
    Journal The New England Journal of Medicine
    Excerpt

    Retinoic acid, an analogue of vitamin A, is known to be teratogenic in laboratory animals and has recently been implicated in a few clinical case reports. To study the human teratogenicity of this agent, we investigated 154 human pregnancies with fetal exposure to isotretinoin, a retinoid prescribed for severe recalcitrant cystic acne. The outcomes were 95 elective abortions, 26 infants without major malformations, 12 spontaneous abortions, and 21 malformed infants. A subset of 36 of the 154 pregnancies was observed prospectively. The outcomes in this cohort were 8 spontaneous abortions, 23 normal infants, and 5 malformed infants. Exposure to isotretinoin was associated with an unusually high relative risk for a group of selected major malformations (relative risk = 25.6; 95 per cent confidence interval, 11.4 to 57.5). Among the 21 malformed infants we found a characteristic pattern of malformation involving craniofacial, cardiac, thymic, and central nervous system structures. The malformations included microtia/anotia (15 infants), micrognathia (6), cleft palate (3), conotruncal heart defects and aortic-arch abnormalities (8), thymic defects (7), retinal or optic-nerve abnormalities (4), and central nervous system malformations (18). The pattern of malformation closely resembled that produced in animal studies of retinoid teratogenesis. It is possible that a major mechanism of isotretinoin teratogenesis is a deleterious effect on cephalic neural-crest cell activity that results in the observed craniofacial, cardiac, and thymic malformations.

    Title Communicating Hydrocephalus and Lysosomal Inclusions in Mannosidosis.
    Date July 1984
    Journal Archives of Neurology
    Excerpt

    A 32-year-old man with mannosidosis had a gait disorder develop that was associated with communicating hydrocephalus. The gait disorder improved with ventriculoperitoneal shunting, but proximal muscle weakness remained. Biopsy specimens of muscle and nerve disclosed typical lysosomal inclusions in both tissues, as well as selective loss of unmyelinated axons.

    Title Pancytopenia in Mannosidosis.
    Date July 1983
    Journal Archives of Internal Medicine
    Excerpt

    A case of autoimmune pancytopenia is described in a patient with mannosidosis who developed anti-platelet and anti-neutrophil antibodies and a low haptoglobin level. Bone marrow biopsy and 111InCl3 bone marrow scanning demonstrated hypoplasia of the marrow with a paucity of "storage cells." Pathogenic mechanisms and implications for other inborn errors of metabolism are discussed.

    Title Dementia in Down's Syndrome: Observations from a Neurology Clinic.
    Date January 1983
    Journal Applied Research in Mental Retardation
    Excerpt

    Clinical manifestations of dementia were reviewed in 15 Down's 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 Alzheimer's disease.

    Title Neuroaxonal Dystrophy and Down's Syndrome. Report of a Case.
    Date October 1982
    Journal Archives of Neurology
    Title Liver in the Cerebro-hepato-renal Syndrome: Defective Bile Acid Synthesis and Abnormal Mitochondria.
    Date February 1981
    Journal Gastroenterology
    Excerpt

    Two infants with the cerebro-hepato-renal syndrome (Zellweger's disease) exhibited cholestasis and progressive liver damage. Because abnormalities of mitochondrial structure and function have been reported in this condition, we examined the bile acids for evidence of defects in the mitochondrial phase of bile acid synthesis, namely, oxidation of the cholesterol side chain to form C-24 bile acids. The presence of increased amounts of the C-27 bile acid intermediates (trihydroxycoprostanic acid, varanic acid, and dihydroxycoprostanic acid) were noted and identified by gas-liquid chromatography-mass spectrosocopy confirming that a defect in the mitochondrial pathways for bile acid side chain cleavage is involved in this entity. The clinical course, liver histopathology, and hepatocyte ultrastructural abnormalities suggest that these bile acids may reflect an underlying mitochondrial dysfunction in this disease and possibly may contribute to the progressive hepatic lobular fibrosis observed in these patients.

    Title Familial Amentia, Unusual Ventricular Calcifications, and Increased Cerebrospinal Fluid Protein.
    Date January 1980
    Journal Neurology
    Excerpt

    A sibship originally reported by Friedman and Roy 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 correspond 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.

    Title Abnormal Copper Metabolism in Menke's Steely-hair Syndrome.
    Date November 1979
    Journal Pediatric Research
    Excerpt

    Copper (Cu) metabolism was selectively studied in seven infants with Menke's steely-hair syndrome (SHS). A daily oral regimen of CuSO4 (584 microgram 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 to two possible maternal heterozygotes, a finding which may permit diagnosis of the carrier state for some SHS heterozygotes.

    Title The Cellular Pathology of Menkes Steely Hair Syndrome.
    Date July 1978
    Journal Neurology
    Excerpt

    The principal neuropathologic abnormality observed in three autopsy cases of Menkes steely hair syndrome was widespread nerve cell loss and gliosis, especially severe in the cerebral and cerebellar cortex and in the relay nuclei of the thalamus. Granular stellate cells of neocortical layer IV and the granule cells of the cerebellum are cell classes which were particularly severely depopulated. The degree of reduction of myelinated axons is consistent with axonal degeneration secondary to nerve cell loss. There are also prominent abnormalities in the patterns of dendritic arborization of surviving cortical pyramids and cerebellar Purkinje cells as seen in Golgi impregnations. The deviant neuronal forms are probably due, in part, to failure of innervation by afferent fiber systems during the fetal as well as postnatal epochs.

    Title The Cellular Pathology of Neuronal Ceroid-lipofuscinosis. A Golgi-electronmicroscopic Study.
    Date June 1977
    Journal Archives of Neurology
    Excerpt

    A cerebral biopsy specimen from a 4-year-old girl with a moderately advanced stage of the late infantile form of neuronal ceroid-lipofuscinosis was observed in routine cell and fiber stains and in Golgi and electronmicroscopic preparations. There was no evidence of neuronal degeneration or loss. Golgi impregnations identified a fusiform enlargement of proximal axon segments of most pyramidal neurons and some polymorphic neurons but not of other cortical neuronal classes. Typical curvilinear inclusions were found in all cells and appeared to be impacted within the dilated proximal axon segments of pyramidal neurons. The numbers of type II synapses on the axon hillock and dilated proximal axon segments of pyramidal neurons were much reduced, whereas type I synapses remained abundant in the neuropil.

    Title Mannosidosis. New Clinical Presentation, Enzyme Studied, and Carbohydrate Analysis.
    Date February 1977
    Journal Archives of Neurology
    Excerpt

    Mannosidosis is a rare inborn error of metabolism characterized by deficiency of the lysosomal enzyme alpha-mannosidase and widespread storage of complex carbohydrate, which is enriched in mannose. Two affected unrelated males, aged 6 and 26 years, are reported. Both had a nonprogressive encephalopathy with moderately severe mental retardation. The older patient showed several unique features, including massive gingival hyperplasia associated with histiocytes containing large amounts of a material with the staining characteristics of glycoprotein. The best determinant of mannose storage proved to be the ratio of mannose to other carbohydrates in urinary polysaccharides. The enzyme deficiency in this disease is most convincingly demonstrated at pH values below 4.0. The ability of zinc to activate the mutant enzyme in vitro offers a possible mode of therapy for this disease. Retarded individuals with a Hurler-like appearance and gum hyperplasia of unknown cause should be screened for alpha-mannosidase deficiency.

    Title Apparent Biochemical Homozygosity in Two Obligatory Heterozygotes for Metachromatic Leukodystrophy.
    Date October 1976
    Journal The Journal of Pediatrics
    Title Urinary Noradrenaline and Playroom Behaviour in Hyperactive Boys.
    Date January 1971
    Journal Lancet
    Title Association Between Frontal Cortex Oxidative Damage and Beta-amyloid As a Function of Age in Down Syndrome.
    Date
    Journal Biochimica Et Biophysica Acta
    Excerpt

    Down syndrome (DS) is the most common genetic cause of intellectual disability in children, and the number of adults with DS reaching old age is increasing. By the age of 40 years, virtually all people with DS have sufficient neuropathology for a postmortem diagnosis of Alzheimer disease (AD). Trisomy 21 in DS leads to an overexpression of many proteins, of which at least two are involved in oxidative stress and AD: superoxide dismutase 1 (SOD1) and amyloid precursor protein (APP). In this study, we tested the hypothesis that DS brains with neuropathological hallmarks of AD have more oxidative and nitrosative stress than those with DS but without significant AD pathology, as compared with similarly aged-matched non-DS controls. The frontal cortex was examined in 70 autopsy cases (n=29 control and n=41 DS). By ELISA, we quantified soluble and insoluble Aβ40 and Aβ42, as well as oligomers. Oxidative and nitrosative stress levels (protein carbonyls, 4-hydroxy-2-trans-nonenal (HNE)-bound proteins, and 3-nitrotyrosine) were measured by slot-blot. We found that soluble and insoluble amyloid beta peptide (Aβ) and oligomers increase as a function of age in DS frontal cortex. Of the oxidative stress markers, HNE-bound proteins were increased overall in DS. Protein carbonyls were correlated with Aβ40 levels. These results suggest that oxidative damage, but not nitrosative stress, may contribute to the onset and progression of AD pathogenesis in DS. Conceivably, treatment with antioxidants may provide a point of intervention to slow pathological alterations in DS.


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