Genetics and Disabilities Diagnostic Care Center
P.O. Box 4548
Virginia Beach, VA 23454
(757) 425-1969
|
Lawrence G. Leichtman, M.D., FAAP, FACMG Genetics and Disabilities Diagnostic Care Center P.O. Box 4548 Virginia Beach, VA 23454 (757) 425-1969 |
|
Reprinted with the permission of the author |
You may have been approached by one of your patients to discuss the issue of Targeted Nutritional Intervention and the use of Piracetam in Down syndrome. You may have, in most cases, drawn a blank or have self-referred back to the era of mega-vitamin therapy and drawn an immediate negative reaction. What is all of this and does it have any grounding in medical science or is it nothing but snake oil?
First of all, it isn't snake oil. The TNI formulation, NuTriVene-D, was designed originally by Dixie Lawrence Tafoya. All subsequent modifications were based on journal articles or research and reviewed and approved by the SAC (Scientific Advisory Committee) of Trisomy 21 Research Foundation, Inc. (TRI). Dixie Tafoya first developed this formula based on the work of Henry Turkel, M.D. carried out from the 1940s to the 1970s in which he used a formulation based on some educated guesses. These guesses were made without benefit of formal knowledge of the biochemistry or genetics of Trisomy 21. In fact, when Dr. Turkel first developed his formula, the correct number of human chromosomes was not known nor was it known that Down syndrome was produced by an extra chromosome 21. Today, the ongoing Genome Project in association with improved metabolic assaying techniques has afforded us a better view of the genetics and biochemistry of chromosome 21 in order to make more accurate estimations of what supplementation may help in the treatment of Trisomy 21.
Most recent gene mapping has sequence all of the genes on chromosome 21 This doesn't mean that they are all known, that process will take more time. But within a few years we should know all of the genes and their protein products. Already several gene families of developmental genes have been found. Some of these because they are turned on only prenatally cannot be influenced but some of them may be amenable to either metabolic or gene therapy in the future. This is exciting new work and has the potential for many new therapies but in the meantime what can be done?
Arguments have been made both pro and con for treating Trisomy 21 as a disease. It is unreasonable to expect that the genes that are present on the additional chromosome 21 are non-functional. In fact, gene dosage studies have shown for many years that many of the genes on 21 are quite functional and producing 40-50% increases of their gene products. Two of these, zinc/copper superoxide dismutase and cystathionine beta synthase are major sources of concern in Trisomy 21. Obviously genes that are developmental in nature such as DYRK and are only turned on in fetal life cannot be affected by any therapy that is begun postnatally but sufficient genes are active to cause a mix of biochemical problems in Trisomy 21.
Is there evidence of metabolic abnormalities in DS? Yes, numerous studies (see Bibliography below) have demonstrated biochemical abnormalities in DS. The first to find these was Jerome Lejeune, who is the physician who first discovered Trisomy 21 as the basis of Down syndrome. Lejeune found that single carbon chains were handled abnormally by people with Down syndrome. This, we now know, is caused by disruptions in the S-Adenosylmethionine cycle or SAM cycle mediated by the enzyme cystathionine beta synthase which is on chromosome 21. The result of these abnormalities is an increased cysteine pool, loss of homocysteine and and decreased methyl groups available for DNA methylation and other biomethylations. Secondary to this is a disruption of folic acid metabolism caused by trapping of folate as 5-methyltetrahydrofolate. Lejeune later demonstrated abnormalities in purine synthesis that produces high levels of uric acid, presumably caused by the gene GART (first 3 steps in purine synthesis) which is also triplicated.
The zinc/copper enzyme Super Oxide Dismutase (SOD) is well known to be over-functioning in Trisomy 21. It normally is the first step in metabolic conversion of superoxide. Superoxide is a free radical that may cause problems to both the cell membrane and the cell nucleus. SOD produces hydrogen peroxide which two other (not on chromosome 21) gene products, catalase and glutathione peroxidase, convert to nontoxic products. Neither catalase nor glutathione peroxidase are sufficiently upregulated to handle the excess hydrogen peroxide. Hydrogen peroxide is a potent oxidizer which on the cell surface produces lipid peroxidation and compromises the cell membrane, particularly in the presence of excess iron (Fenton reaction). At the organelle and nuclear level, hydrogen peroxide causes damage and stimulates apoptosis ("programmed" death) of the cell. In a study by de Haan et al in Human Molecular Genetics (5:283-292, 1996), it was found that the ratio of SOD to glutathione peroxidase led to increased hydrogen peroxide in the cells and cellular senescence. In a study from Nature (1995), Busciglio and Yankner demonstrated that fetal neuronal cells from non-DS and DS fetuses grew differently. The non-DS cells grew in culture in an orderly fashion but the DS cells grew for only 72 hours and began dying. When a second DS culture was incubated with powerful antioxidants these cells began growing normally. While not direct evidence of the role of reactive oxygen species in the production of symptomotology of DS it certainly provides useful information and a starting place for future studies. This is the logic behind using additional antioxidants in DS.
A recent paper by G. Lubec (2002) J. Neurol. 249: 1347-1356 proposes that molecular evidence of the role of reactive oxygen species and apoptosis of brain cells exists. This evidence is strong and points to antioxident treatment as a means of preventing future damage.
Numerous studies have documented immune dysfunction in Down syndrome including decreased IGA, low white cell counts, and low levels of T-cells. These deficits probably lead to the increased incidence of upper respiratory, ear, and gastrointestinal infection rate in Down syndrome most evident in children but even present in adults. The immune dysfunction seems to be related to zinc depletion but also may be an indirect result of the effects of hydrogen peroxide on immune cells. TNI seems to directly impact this parameter and significant improvement in the incidence of infections is one of the primary effects of TNI.
It has always been assumed that children and adults with Down syndrome will be short. This seems to be a case of self-fulfilling prophecy. Children who are supplemented throughout their lives show a significant increase in growth velocity. In addition, many studies demonstrate an increased incidence of growth hormone deficiency in this population. Looking for and treating growth hormone deficiency may also go towards increasing height in this population. In fact, endocrine dysfunction is not uncommon in Down syndrome. Certainly the connection with hypothyroidism as well as infertility in males with Down syndrome is well known.
Numerous studies have shown poor lipid metabolism in Down syndrome. Omega 3 and 6 fatty acids (ALA, AA) are decreased. Cholesterol is often increased without a concomitant increase in cardiovascular risk. Apolipoproteins E is abnormal and may contribute to the increased Alzheimer risk in Down syndrome. While DHA (docosohexaenoic acid) is not specifically decreased in Down syndrome it is normally low in the diets of nonbreast-fed and American-diet breast-fed infants and children. There is good data to show improvements in brain and retinal development in children supplemented with DHA. DHA has been added to infant formulas in Europe and is currently under consideration for a similar use in the US.
The risk for the development of Alzheimer disease in Down syndrome has been estimated as high as 40%. While these figures are hard to demonstrate, the risk is definitely both increased and also at an earlier age of onset. This does not necessarily translate into clinical symptoms. Alzheimer disease risk in Down syndrome is not related to any one factor but a host of factors including a gene for Alzheimer disease on chromosome 21, lipid handling abnormalities, increased hydrogen peroxide damage to the cells, endocrine abnormalities and reduced acetylcholine receptors in the brain. Current estimates are that over 50% of adults with Down syndrome will develop MRI evidence of Alzheimer disease by age 45.
TNI is not a cure for Down syndrome. It is a treatment plan that provides additional nutrients and micro nutrients to promote:
Does it work? I have been observing patients for the last 7 years who were on this protocol as well as patients not on this protocol. A cohort study has been assembled consisting of 200 patients ranging from 1 month to 4 years of age, and a control group (all on multivitamins) has been followed consisting of 200 patients, ranging from 1 month to 4 years of age. Comparable figures for the two groups were noted for the incidence of congenital heart disease, cardiac surgery, hypothyroidism, day care or school attendance, breast feeding, sex, and race. These observations are subject to the bias that they were not blinded for investigator, patients or parents but still have validity.
Compared to multivitamin controls, the TNI group showed statistically significant differences (improvements) in:
Piracetam, one of a growing group of drugs known as nootropics (which means acting on the mind) is an important part of the TNI protocol. This drug has been used extensively in Europe and Russia originally for the treatment of Alzheimer disease but eventually in the late 1970s in Spain, Italy and Germany for the treatment of Down syndrome. A double-blind study published in 2001 by Lobough et al was a small study with serious methodological flaws. George Capone, M.D. at Johns Hopkins Kennedy Krieger Institute is doing ongoing research into the use of Piracetam. The only known study to date in Down syndrome was an unblinded study from Spain in 1978 that showed improvement in academic performance while taking Piracetam. No serious side-effects were seen and no serious side effects are reported in the very extensive literature that exists for Piracetam. In fact, the LD-50 for Piracetam in laboratory animals requires an IV dose of 8-10 gms/kg, and no oral LD-50 has been reported. The side-effects seen may include headache, gastrointestinal disturbance, fine papular rashes that are transient, and occasionally hyperactivity in children who already show some tendency towards hyperactivity.
Its action in Down syndrome is two-fold. One aspect is the return of membrane fluidity to cell membranes that have undergone lipid peroxidation. Lipid peroxidation is known to be significantly higher in Down syndrome and Alzheimer disease. This lack of fluidity tends to decrease signal intensity in neurons and actually decreases ion flow in and out of cells and thus decreases signal propagation as well. A second effect is the increase in acetylcholine receptors. Acetylcholine receptors have been shown to be decreased in both Down syndrome and Alzheimer disease. Piracetam has been shown by experimental studies to be most active in the corpus callosum of the brain. While no study has shown corpus callosum deficits in the brain of persons with Down syndrome it is an area that is susceptible to lipid peroxidation as is the basal ganglia and hippocampus. Piracetam seems to have its greatest effect in speech production and visual motor coordination/learning.
Piracetam may be prescribed under the Orphan Drug act. It is approved for use in progressive myoclonic epilepsy but to date not for Down syndrome. This, however, is not unusual for Pediatric drugs most of which have never been double-blind tested in children and most of which do not have Pediatric indications. Most pharmacies do not carry it but compounding pharmacies are allowed to make it from base ingredients. It can also be purchased from England or Mexico.
In addition, newer forms of Piracetam such as Pramacetam are coming on the market and may show more efficacy than Piracetam. Alzheimer medications such as Aricept (Donapezil) and Exelon (Rivastigmine) are currently or have been studied with promising results in cognitive improvement and behavior in the preteen, adolescent, and adult groups.
(Disclaimer: Neither I nor any member of the Scientific Advisory Committee of Trisomy 21 Research Foundation, Inc. has, to my knowledge, any financial interest in International Nutrition or any of the products listed below.)
7 grams will supply the following level of nutrients (As a reference, note that 1 teaspoon = 5 grams):
| Fat-Soluble Vitamins | |
| Vitamin A (as Beta Carotene, FCC) | 3000 IU |
| Vitamin A (as Palmitate, USP-FCC) | 5000 IU |
| Vitamin D3 (as Cholecalciferol, USP-FCC) | 200 IU |
| Vitamin E (as Succinate, USP-FCC) | 400 IU |
Water-Soluble Vitamins and Related Ingredients | |
| Biotin (FCC) | 0.2 mg |
| Folic Acid (USP-FCC) | 0.4 mg |
| Folinic Acid (USP-FCC) | 0.4 mg |
| Niacinamide (USP-FCC) | 125mg |
| Pantothenic Acid (as D-Calcium Pantothenate, USP-FCC) | 45 mg |
| Vitamin B1 (as Thiamin HC1, USP-FCC) | 55 mg |
| Vitamin B12 (as Cyanocobalamin, USP) | 90 mcg |
| Vitamin B2 (as Riboflavin, USP-FCC) | 45 mg |
| Vitamin B6 (as Pyridoxine HC1, USP-FCC) | 35 mg |
| Vitamin C (as Sodium Ascorbate, USP-FCC) | 1000 mg |
| Coenzyme Q10 | 30 mg |
| Inositol (FCC) | 75 mg |
| PABA (USP) | 75 mg |
| Alpha Lipoic Acid | 45 mg |
Minerals | |
| Calcium (as Calcium Citrate, FCC) | 100 mg |
| Chromium (as Chromium Chloride) | 75 mcg |
| Iodine (as Potassium Iodide, USP-FCC) | 7 mcg |
| Magnesium (as Magnesium Oxide, USP) | 150 mg |
| Manganese (as Manganese Gluconate, USP) | 1.5 mg |
| Molybdemun (as Sodium Molybdate) | 75 mcg |
| Potassium (as Potassium Chloride, USP-FCC) | 15 mg |
| Selenium (as Sodium Selenate) | 90 mcg |
| Zinc (as Optizinc) | 20 mg |
Amino Acids and Related Substances | |
| L- Citrulline | 70 mg |
| L-Glutithione | 150 mg |
| L-Histidine (FCC) | 25 mg |
| alpha-Ketoglutaric Acid (FCC) | 500 mg |
| L-Methionine (USP-FCC) | 150 mg |
| L-Ornithine | 100 mg |
| L-Proline (USP-FCC) | 100 mg |
| L-Serine (USP-FCC) | 150 mg |
| L-Tryptophan (FCC) | 50 mg |
| L-Tyrosine (FCC) | 100 mg |
| Betaine (Trimethylglycine) | 500 mg |
| Taurine | 200 mg |
Miscellaneous | |
| Choline Bitartrate (FCC) | 800 mg |
| Acetyl-L-Carnitine | 45 mg |
| Bioflavonoids | 150 mg |
| Bromelain (as 80 GDU or 50 MCU) | 5 mg |
| Papain (as 16,000 FCC PU/mg) | 5 mg |
| NightTime Formula Ingredients | |
| Two capsules supply: | |
| Vitamin B6 | 5 mg |
| L-Ornithine | 300 mg |
| L-Tryptophan | 250 mg |
Daily Enzyme Formula Ingredients | |
| Three capsules supply: | |
| Alpha-Amylase | 25 mg |
| Cellulase | 1 mg |
| Lactase | 1 mg |
| Lipase | 25 mg |
NuTriVene-D can be obtained from International Nutrition, Inc., by calling 1-800-899-3413. Dosage is by weight. Person over 16 years of age should request the adult formula. The package comes with 3 bottles: Daily formula, Enzyme capsules and Night-time formula. You can mix up the first two with the piracetam in the morning and give the 3 daily doses that way. The enzyme formula is the one part that can cause problems. If diarrhea occurs stop enzyme and restart with smallest amount you can give and work up to prescribed dose. If diarrhea restarts go back to last dosage without diarrhea. Do not give night-time formula less than 1 hour from bed time. Do night give night time formula closer than 2 hours from last daily supplement. If reflux develops stop the daily enzyme and call International Nutrition.
Declining mortality from Down syndrome—No cause for complacency. Lancet 1990; 335:888-889.
Abalan F. (1984). Alzheimer's disease and malnutrition: a new etiological hypothesis. Medical Hypotheses, 15:385.
Ahlbom BE, Goetz P, Korenberg JR, et al. Molecular analysis of chromosome 21 in a patient with a phenotype of Down syndrome and an apparently normal karyotype. Am J Med Genet 1996; 63:566-572.
Agarwala KL, Nakamura S, Tsutsumi Y, Yamakawa K. Down Syndrome cell adhesion molecule DSCAM mediates homophilic intercellular adhesion. Molecular Brain Research 2000; 79:118-126.
Airaksinen EM. Tryptophan treatment of infants with Down syndrome. Annals of Clinical Research 1974; 6:33-38.
Al Gazali L, Padmonabhan R, Melnyk S, et al. Abnormal folate metabolism and genetic polymorphism of the folate pathway in children with Down Syndrone and neural tube defect. Am. J. Med. Genet. 2001; 103:128-132.
Allanson JE, Hughes-Benzie RM, Farkas L. Anthropometric craniofacial pattern profiles in Down syndrome. Proc Greenwood Genet Center 1992; 11:165.(abstract)
Allanson JE, O'Hara P, Farkas LG, Nair RC. Anthropometric craniofacial pattern profiles in Down syndrome. Am J Med Genet 1993; 47:748-752.
Anderson AJ, Stolzner S, Lai F, Nixon RA. Morphological and biochemical assessment of DNA damage and apoptosis in Down Syndrome and Alzheimer disease, and effects on postmortem tissue archival in TUNEL. Neurobiol. Again 2000; 21:511-524.
Annerén G, Erdman B. Down syndrome — a gene dosage disease caused by trisomy of genes within a small segment of the long arm of chromosome 21, exemplified by the study of the effects from the superoxide-dismutase type 1 (SOD1) gene. APMIS 1993; 40 Supp:71-79.(abstract)
Annerén G, Gustafsson J, Sara VR, Tuvemo T. Normalized growth velocity in children with Down syndrome during growth hormone therapy. J Intell Disabil Res 1993; 37:381-387.(abstract)
Annerén G, Gustavson K-H, Sara VR, Tuvemo T. Growth retardation in Down syndrome in relation to insulin-like growth factors and growth hormone. Am J Med Genet 1990; Supp. 7:59-62.
Annerén G, Tuvemo T, Carlsson-Skwirut C, et al. Growth hormone treatment in young children with Down Syndrome: effects on growth and psychmotor development. Arch. Pediatr. Adolesc. Med 1999; 80:334-338.
Annerén G, Tuvemo T, Gustafsson J. Growth hormone therapy in young children with Down Syndrome: creation of motor growth curves. Growth Hormone and IGF Research 2000; 10:87-91.
Arnold GL, Schultz EG, Richert V, Krogh J, Kearns GL. Effect of amantadine supplementation on dopamine and developmental outcome in Down syndrome. Am J Hum Genet 1995; 57:A82.(abstract)
Auld RM, Pommer AM, Houck IC, Burke F: Vitamin absorption in mongoloid children. A preliminary report. American Journal of Mental Deficiency Research, 63:1010, 1959.
Baird PA, Sadovnick AD. Life expectancy to the seventh decade in Down syndrome. Am J Hum Genet 1988; 43:3:A37.(abstract)
Baird PA, Sadovnick AD. Life tables for Down syndrome. Hum Genet 1989; 82:291-292.
Bambrick LL, Yarowsky PJ, Krueger BK. Glutamate as a hippocampal neuron survival factor: an inherited defect in the trisomy 16 mouse. Proc Natl. Acad Sci USA 1995; 92:9692-9696.(abstract)
Barkin RM, Weston WL, Humbert JR, Sunada K: Phagocytic function in Down syndrome. II. Bactericidal activity and phagocytosis. Journal of Mental Deficiency Research, 24: 251, 1980.
Barlow PJ, Sylvester PE, Dickerson JWT: Hair trace elements in Down's syndrome patients. Journal of Mental Deficiency Research, 25:161, 1981.
Barreca A, Rasore QA, Acutis MS, et al. Assessment of growth hormone insulin like growth factor-I axis in Down syndrome. J Endocrinol Invest 1994; 17:431-436.
Becker LE, Mito T, Takashima S, Onodera K, and Friend WC, Association of phenotypic abnormalities of Down Syndrome with an imbalance of the genes on chromosome 21. APMIS Suppl 40, Vol 101:57-70, 1993
Bedwal RS, Nair N, Sharma MP, Mathur RS. Selenium -- its biological perspectives. Med Hypotheses 1993; 41:150-159.(abstract)
Bell JA, Pearn JH, Firman D. Childhood deaths in Down's syndrome. Survival curves and causes of death from a total population study in Queensland, Australia, 1976 to 1985. J Med Genet 1989; 26:764-768.
Bidder RT, Gray P, Newcombe RG, Evans BK, Hughes M. The effects of multivitamins and minerals on children with Down syndrome. Dev Med Child Neurol 1989; 31:532-537.
Book L, Hart A, Black J, et al. Prevelance and clinical characteristics of celiac disease and Down Syndrome in US study. Am. J. Med. Genet. 2001; 98:70-74.
Borghi CBE, Rethoré MO, Lejeune J, Alperovitch A. Absence of familial association between dementia of Alzheimer type and Down syndrome. Am J Med Genet 1989; 33:545-550.
Bosman GJCGM, Visser FE, De Man AJM, Bartholomeus IGP, De Grip WJ. Erythrocyte membrane changes of individuals with Down's syndrome in various stages of Alzheimer-type dementia. Neurobiol Aging 1993; 14:223-228.
Brooksbank BW, Balazs R. Superoxide dismutase glutothione peroxiclase alipoperoxidetim in Down Syndrome fetal brain. Brain Res. 1984; 318-37-44.
Brugge K, Katzman R, Hill LR, Hansen LA, Saitoh T. Serological 1-antichymotrypsin in Down's syndrome and Alzheimer's disease. Ann Neurol 1992; 32:193-197.
Brugge KL, Nichols SL, Salmon DP, et al. Cognitive impairment in adults with Down's syndrome: Similarities to early cognitive changes in Alzheimer's disease. Neurology 1994; 44:232-238.
Brattstrom L, et al: Homocysteine, Factor VII and antithrombin with different gene dosage for CBS. J. Inherit. Metab. Dis., 12:475, 1989
Bugiani O, Giaccone G, Frangione B, Ghetti B, Tagliavini F: Alzheimer's patients: pre-amyloid deposits are more widely distributed than senile plaques throughout the central nervous system. Neurosci. Lett., 103:263-268, 1989
Bugiani O., Giaccone G, Verga L, Pollo B, Ghetti B, Frangione B, Tagliavini F: Alzheimer patients and Down patients: abnormal presynaptic terminals related to cerebral amyloid deposits. Neurosci. Lett., 119:56-59, 1990
Burger PC, Vogel FS: the development of the pathologic changes of Alzheimer's disease and senile dementia in patients with Down's syndrome. American Journal of Pathology, 73:457, 1973.
Burgio R, Ugazio A, Nespoli L, Marcioni AF, Bottelli AM, Pasquali F: Derangement's of immunoglobulin levels, phtyohemagglutinin responsiveness and T and B cell markers in Down's syndrome at different ages. European Journal of Immunology, 5:600, 1975.
Busciglio J and Yankner BA: Apoptosis and increased generation of reactive oxygen species in Down's Syndrome neurons in vitro. Nature, 378:776-779, 1995
Carmeliet G, David G, Cassimann JJ. Cellular aging of Alzheimer disease and Down syndrome cells in culture. Mutat Res 1991; 256:221-231.(abstract)
Capone G. Biology of Down Syndrome CNS development and neurobiology. Molecular Biology of Down Syndrome CNS Development and Neurobilogy. Bar Harbor, Maine : Jackson Laboratories, 2000.
Castells S, Torrado C, Bastian W. Growth hormone deficiency in Down's syndrome children. J Intell Disabil Res 1992; 36:29-43.(abstract)
Ceballos-Picot I. Transgenic mice overexpressing copper/zinc superoxide dismutase: a model for the study of radical mechanisms and aging. Seances Soc Biol Fil 1993; 187:308-323.(abstract)
Chadefaux, et al: Cystathionine beta synthase: Gene dosage effect of trisomy 21. Biochem. Biophys. Res. Comm., 128:40, 1988
Chadefaux, et al: Is absence of atheroma in Down syndrome due to decreased homocysteine levels? (letter) Lancet, 1:741, 1988
Chandra RK: Immunocompetence as a functional index of nutritional status. British Medical Bulletin, 37:89, 1981.
Chirocolo, M., et al. (1993) Enhanced DNA repair in lymphocytes of Down syndrome patients: the influence of zinc nutritional supplementation. Mutat. Res. 295: 105-111.
Cole G, Neal JW, Singhrao SK, Jasani B, Newman GR: The distribution of amyloid plaques in the cerebellum and brain stem in Down's Syndrome and Alzheimer's disease: a light microscopical analysis. Acta Neuropathol., 85:542-552, 1993
Cooley WC, Graham Jr JM. Common syndromes and management issues for primary care physicians; Down syndrome--An update and review for the primary Pediatrician. Clin Pediatr 1991; 30:4:233-253.
Cooper S-A, Collacott RA. Mania and Down's syndrome. Br J Psychiatry 1993; 162:739-743.
Cork LC. Neuropathology of Down syndrome and Alzheimer disease. Am J Med Genet 1991; Supp. 7:282-286.
Cossarizza A, Monti D, Montagnani G, et al. Precocious aging of the immune system in Down syndrome: Alteration of B lymphocytes, T-lymphocyte subsets and cells with natural killer markers. Am J Med Genet 1991; Supp. 7:213-218.
Crastes de Paulet A. Free Radicals and Aging. Laboratorie de Biochemi A, Institut de Biologie, Montpellier 1993; (abstract)
Cremers MJG, Ramos L, Bol E, Van Gijn J. Radiological assessment of the atlantoaxial distance in Down's syndrome. Arch Dis Child 1993; 69:347-350.
Crate N, Gosset Ph, Theophile D, et al. Mapping the Down syndrome chromosome region. Eur J Hum Genet 1993; 1:51-63.
Cunningham C, Turner S, Sloper P, Knussen C. Is the appearance of children with Down syndrome associated with their development and social functioning? Dev Med Child Neurol 1991; 33:285-295.
Dalton AJ, Crapper-McLachlan DR. Clinical expression of Alzheimer's disease in Down's syndrome. In: Psychiatric Perspectives in Mental Retardation: Psychiatric Clinics of North America 9:4 December 1986. New York, New York: W.B. Saunders, 1986:659-670.
Davisson MT, Schmidt C, Akeson EC. Segmental trisomy of murine chromosome 16: A new model system for studying Down syndrome. In: Progress in Clinical and Biologic Research V 360
Molecular Genetics of Chromosome 21 and Down syndrome. New York: Wiley-Liss, Inc., 1990:263-280.
De Berker DAR, Wilson CL, Millard PR. Reactive perforating collagenosis and Down's syndrome. Br J Dermatol 1992; 126:71-73.
de Haan JB, Cristiano F, Iannello R, Blandier C, Kelner MJ, Kola I. Elevation of the ratio of CU/Zn- superoxide dismutase to glutathione peroxidase activity induces features of cellular senescence and this effect is mediated by hydrogen peroxide. Hum Mol Genet 1996; 5:283-292.
De La Monte SM and Hedley-Whyte T: Small cerebral hemispheres in adults with Down's syndrome: contributions of developmental arrest and lesions of Alzheimer's Disease. J. Neuropathol. Exp. Neurol., 49:509-520, 1990
Delabar J-M, Theophile D, Rahmani Z, et al. Molecular mapping of twenty-four features of Down syndrome on chromosome 21. Eur J Hum Genet 1993; 1:114-124.
Dickinson MJ, Lekh S, Singh I, Langa A. Adaptive behaviour scale in Down's syndrome. Br J Psychiatry 1993; 162:423-424.
Ebadi M, Iversen PL, Hao R, et al. Expression and regulation of brain metallothionen. Neurochem Int 1995; 27:1-22.(abstract)
Epstein CJ. Down syndrome (trisomy 21). In: Scriver CR, Beaudet AL, Sly WS, Valle DL, eds. The Metabolic Basis of Inherited Disease. 15th ed. New York: McGraw Hill, 1989:291-326.
Epstein CJ. The consequences of chromosome imbalance. Am J Med Genet 1990; Supp 7:31-37.
Epstein CJ, Korenberg JR, Annerén G, et al. Protocols to establish Genotype-Phenotype correlations in Down syndrome. Am J Hum Genet 1991; 49:207-235.
Epstein CJ, Trsiomy 21 and the nervous system: From cause to cure. In Epstein CJ (ed): The neurobiology of Down Syndrome. Raven Press, New York 1986, pp1-15
Evans DA, Funkenstein HH, Albert MS, et al: Prevalence of Alzheimer's disease in a community of older person. Higher than previously reported. JAMA, 262:2551-2556, 1989
Evenhuis HM. The natural history of dementia in Down's syndrome. Arch Neurol 1990; 47:263-267.
Farrar G, Altmann P, Welch S, et al. Defective gallium-transferrin binding in Alzheimer disease and Down syndrome: Possible mechanism for accumulation of aluminum in brain. Lancet 1990; 335:747-750.
Ferrier LJ, Bashir AS, Meryash DL, Johnston J, Wolff P. Conversational skills of individuals with fragile-X syndrome: A comparison with autism and Down syndrome. Dev Med Child Neurol 1991; 33:776-788.
Fishler K, Koch R. Mental development in Down syndrome mosaicism. Am J Mental Retardation 1991; 96:345-351.
Flickinger KS and Culp LA: Dermal fibroblasts from Down's syndrome. Exp. Cell Research, 189:189-201, 1990
Franchesi C, Licastro F, Paolucci P, Masi M, Cavicchi S, Sannotti M: T and B lymphocyte subpopulations in Down's syndrome. A study on non-institutionalized subjects. Journal of Mental Deficiency Research, 22:179, 1978.
Franceschi C, Monti D, Cossarizza A, Fagnoni F, Passeri G, Sansoni P. Aging, longevity, and cancer: Studies in Down's syndrome and centenarians. Ann NY Acad Sci 1991; 621:428-440.
Friedman DL, Kastner T, Pond WS, O'Brien DR. Thyroid dysfunction in individuals with Down syndrome. Arch Intern Med 1989; 149:1990-1993.
Galdzicki Z, Slarey R, Stoll J, Rapaport SI. On the cause of mental retardation in Down Syndrome: extrapolation from full and segmental trisomy 16 mouse models. Brain Res. 2001; 35-115-145.
Geggei RL, O'Brien JE, Feingold MF. Development of valve dysfunction in adolescents and young adults with Down syndrome and no known congenital heart disease. Journal of Pediatrics 1993; 122:5:1:821-823.
George EK, Mearin L, Bouquet J, et al. High frequency of celiac disease in Down syndrome. Journal of Pediatrics 1996; 128:4:555-557.
Gericke CS, Hesseling PB, Brink S, Tiedt FC: Leukocyte Utrastructure and folate metabolism in Down's syndrome. South African Medical Journal, 51: 369, 1977.
Gershwin ME, Crinella FM, Castles JJ, Trent JKT: Immunologic characteristics of Down's syndrome. Journal of Mental Deficiency Research, 21:237, 1977.
Goiffin B: Coprologie fonctionnelle. Encyclopedic Medic-chirugicale. Estoma-Intestin 90-10: A10 and A-20: 4, 1977
Golden JA and Hyman, BT: Development of the superior temporal neocortex is anomalous in trisomy 21. J Neuropath. Exp. Neuro., 53(5):513-520, 1994
Golden GS. Controversies in the therapies for children with Down syndrome. PIR 1984; 6:4:116-120.
Gradwohl RBH: Clinical laboratory methods and diagnosis. 5th edition, Vol. 2, PP 1261-1314. The CV Mosby Company St. Louis, 1956
Greenberger NJ, Toskes PP: Approche d'un patient porteur d'une maladie pancratique. P.1607 in Harrison's Principels de medicine interne. Med Francaise, Vol. 2 (Isselbacher et al, eds.) Flammarion, Paris, 1982
Gregor P, Gaston SM, Yang X, et al. Genetic and physical mapping of the GLUR5 glutamate receptor gene on chromosome 21. Hum Genet 1994; 94:565-570.(abstract)
Hardy J, Crook R, Perry R, Raghavan R, Roberts G. ApoE genotype and Down's syndrome. Lancet 1994; 343:979-980.
Hassin-Baer S, Wertman E, Raphael M, Stark V, Chapman J, Michaelson DM. Antibodies from Down's syndrome patients bind to the same cholinergic neurofilament protein recognized by Alzheimer's disease antibodies. Neurology 1992; 42:551-555.
Heblein S and Klein LV: National Association Down Syndrome News, 11:1-3, 1994
Hemdal P, Corwin J, Oster H. Olfactory identification deficits in Down's syndrome and idiopathic mental retardation. Neuropsychologia 1993; 31:977-984.
Hestnes A, Borud O, Lunde H, Gjessing L. Cystathionuria in Down syndrome. J Ment Def Res 1989; 33:261-265.(abstract)
Hestnes A, Stovner LJ, Husoy O, Folling I, Fougner KJ, Sjaastad O. Hormonal and biochemical disturbances in Down's syndrome. J Ment Def Res 1991; 35:179 193.(abstract)
Hestnes A, Stovner LJ, Husoy O, Folling I, Sjaastad O. Somatomedin C (insulin-like growth factor I) in adults with Down syndrome. J Ment Def Res 1991; 35:204-208.(abstract)
Hilhorst MI, Brink M, Wauters EAK, Houwen RHJ. Down syndrome and coeliac disease: Five new cases with a review of the literature. Eur J Pediatr 1993; 152:884-887.
Hobbs CA, Sherman SL, Hopkins SE, et al. Polymorphisms in genes involving folate metabolism as maternal risk factors in Down Syndrome. Am. J. Hum. Genet. 2000; 67:623-630.
Howell SJL, Foster KJ, Rechless J: Protracted survival in patients with Down's syndrome. British Medical Journal, 287:1429m 1983
Hsiang YH, Berkovitz GD, Bland GL, Migeon CJ, Warren AC. Gonadal function in patients with Down Syndrome. Am J Med Genet 1987; 27:449-458.(abstract)
Hultcrantz E, Svanholm H. Down syndrome and sleep apnea—A therapeutic challenge. Int J Pediatr Otorhinolaryngol 1991; 21:263-268.
Huret JL, Delabar JM, Marlhens F, Aurias A, Nicole A, Berthier M, Tanzer J, Sinet PM: Down syndrome with duplication of a region of chromosome 21 containing the CuZn superoxide dismutase gene without detectable karyotypic abnormality. Hum. Genet., 75:251-257, 1987
Jenkins EC, Schupf N, Genovese M, et al. Increased low-level chromosome 21 mosaicism in older individuals with Down syndrome. Am J Med Genet 1997; 68:147-151.
Jernigan TL, Bellugi U, Sowell E, Doherty S, Hesselink JR. Cerebral morphologic distinctions between Williams and Down syndromes. Arch Neurol 1993; 50:186-191.
Kishnani P, Sullivan JA, Walter BK, et al. Cholinergic therapy for Down Syndrome. Laucet 1999; 353:1064-1065.
Kishnani PS, Spiridigliozz GA, Heller J, et al. Donepzil for Down Syndrome. Am. J. Psych 2001; 158:143-144.
Kohen D, Wise PH. Autoantibodies in Down's syndrome. Lancet 1992; 340:430.
Korenberg JR et al: Down syndrome phenotypes. The consequence of chromosomal imbalance. Proc. Natl. Acad. Sci. USA, 91:4997-5001, May, 1994
Korenberg JR. Toward a molecular understanding of Down syndrome. Prog Clin Biol Res 1993; 384:87-115.
Korenberg JR, Bradley C, Disteche CM. Down syndrome: Molecular mapping of the congenital heart disease and duodenal stenosis. Am J Hum Genet 1992; 50:294-302.
Korenberg JR, Kawashima H, M.-Pulst S, Allen L, Magenis RE, Epstein CJ. Down syndrome: Toward a molecular definition of the phenotype. Am J Med Genet 1991; Supp. 7:91-97.
Korenberg JR, Kawashima H, Pulst SM, et al. Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype. Am J Hum Genet 1990; 47:236-246.
Lai F, Williams RS. A prospective study of Alzheimer disease in Down syndrome. Arch Neurol 1989; 46:849-853.
LaPerchia P. Behavioral disorders, learning disabilities and megavitamin therapy. Adolescence 1987; XXII 87:729-738
Lejeune J, Pathogenesis of Mental Deficiency in Trisomy 21. Am.J.Med.Genet. 7:20-30, 1990
Lejeune J, et al: Homocysteine and the methotrexate toxicity in trisomy 21. Cancer Chemother. Pharmacol., 27:331, 1991
Lejeune J, Peeters M, Rethoré MO, De Blois MC. Down syndrome and 3,3',5'-triiodothyronine. Am J Dis Child 1990; 144:1:19.
Lejeune J, Peeters M, Rethoré MO, De Blois MC. Homocsyteine and the methotrexate toxicity in trisomy 21. Cancer Chemotherapy Pharmacology 1991; 27:331-332.(abstract)
Lejeune J, Rethoré MO, De Blois MC, Peeters M. Psycose infantile, syndrome pseudo-Alzheimer, et trisomie 21: Essai de medication par l'acide folinique: rapport preliminaire. Therapie 1989; 44:115-121.
Lejeune J, Rethoré MO, De Blois MC, et al. Amino acids and trisomy. Ann Genet 1992; 35:8-13.
Levine OR. Down's syndrome, fetal alcohol syndrome, and upper airway obstruction. Am J Dis Child 1987; 14:478.
Levitt GA, Stiller CA, Chessells JM. Prognosis of Down's syndrome with acute leukaemia. Arch Dis Child 1990; 65:212-216.
Levo Y, Green P: Down's syndrome and autoimmunity. The American Journal of Medical Sciences, 273:95, 1977
Limbrock GJ, Fischer-Brandies H, Avalle C. Castillo-Morales Orofacial therapy: Treatment of 67 children with Down syndrome. Dev Med Child Neurol 1991; 33:296-303.
Lockitch G, Puterman M, Godolphin W, Sheps S, Tingle AJ, Quigley G. Infection and immunity in Down syndrome: A trial of long-term low oral doses of zinc. Journal of Pediatrics 1989; 114:5:781-787. Lott IT, Head E. Down Syndrome and Alzheimer disease: a link between development and again. Mental Retardation and Disabilities Research Reviews 2001; 7172:178-185.
Mann DMA, Royston MC, Ravindra CR. Some morphometric observations on the brains of patients with Down's syndrome: Their relationship to age and dementia. J Neurol Sci 1990; 99:153-164.
Marcus CL, Keens TG, Bautista DB, von Pechmann WS, Ward SLD. Obstructive sleep apnea in children with Down syndrome. Pediatrics 1991; 88:1:132-139.
Marino B, Corno A, Guccione P, Marcelletti C. Ventricular septal defect and Down's syndrome. Lancet 1991; 337:245-246.
Marino B, Papa M, Guccione P, Corno A, Marasini M, Calabro; R. Ventricular septal defect in Down syndrome. Am J Dis Child 1990; 144:544-545.
Marino B, Vairo U, Corno A, et al. Atrioventricular canal in Down syndrome. Am J Dis Child 1990; 144:10:1120-1122.
Maroudias N, Economides J, Christodoulou P, Helidonis E. A study on the otoscopical and audiological findings in patients with Down's syndrome in Greece. Int J Pediatr Otorhinolaryngol 1994; 29:43-49.
Martich V, Ben-Ami T, Yousefzadeh DK, Roizen NJ. Hypoplastic posterior arch of C-1 in children with Down syndrome:? A double jeopardy. Radiology 1992; 183:125-128.
Mastroiacovo P, Bertollini R, Corchia C. Survival trends in Down syndrome. Lancet 1990; 335:1278-1279.
Matin MA, Sylvester PE, Edwards D, Dickerson JWT: Vitamin and zinc status in Down's syndrome. Journal of Mental Deficiency Research, 25:121, 1981.
McCoy EE, Sneddon JM: Decreased calcium content and CAa2+ uptake in Down's syndrome blood platelets. Pediatric Research, 18:914, 1984.
Mattson MP, Barger SW, Cheng B, Lieberburg I. beta-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer disease. Trends Neurosci 1993; 16:409-414.(abstract)
McCormick MK, Schinzel A, Petersen MB, et al. Molecular genetic approach to the characterization of the "Down syndrome region" of chromosome 21. Genomics 1989; 5:325-331.
McQuillan CI, Choo KH. Comparison of total cellular DNA, mRNA, and rRNA levels between normals and Down syndrome patients. J Inherited Metab Dis 1992; 15:112-120.
Merrick J. Incidence and mortality of Down Syndrome. Isreal Medical Association Journal 2000; 2:25-26.
Mirochhnitchenko O and Inouye M: Effect of overexpression of human Cu,Zn superoxide dismutase in transgenic mice on macrophage functions. Department of Biochemistry. J. Immunol., 156(4):1578-86, Feb, 1996
Moore J, Englert E, Bigler AM, Clark RW: Simple fecal tests of absorption. A prospective study and critique. American Journal of Digestive Diseases,? 16:97, 1971.
Muenke M, Bone LJ, Mitchell HF, et al. Physical mapping of the holoprosencephaly critical region in 21q22.3, exclusion of SIM2 as a candidate gene for holoprosencephaly, and mapping Sim2 to a region of chromosome 21 important for Down syndrome. Am J Hum Genet 1995; 57:1074-1079.
Murdoch JC, Gray CA, McLarty DG, Ratcliffe JG. Pituitary function in Down syndrome. J Ment Def Res 1978; 22:273-275.(abstract)
Murphy EJ, Schapiro MB, Rapoport SI, Shetty HJ. Phospholipid composition and levels are altered in Down Syndrome brain. Brain Res. 2000; 867:8-19.
Napolitano G, Palka G, Grimaldi S, et al. Growth delay in Down syndrome and zinc sulphate supplementation. Am J Med Genet 1990; 7 Supplement:63-65.(abstract)
Norstrom M, Kjellstrom T. Age dependency of cystathionine beta-synthetase activity in human fibroblasts in homocystinemia and atherosclerotic vascular disease. Atherosclerosis 1992; 94:213-221.(abstract)
Nowak TV, Gjishan FK, Schulze-Delrieu K: Celiac sprue in Down's syndrome: considerations on a pathogenic link. American Journal of Gastroenterology, 78:385, 1983
Novo E, Garcia MI, Laverge J. Nonspecific immunity in Down syndrome: A study of chemotaxis, phagocytosis, oxidative metabolism, and cell surface marker expression of polymorphonuclear cells. Am J Med Genet 1993; 46:384-391.
Negrave J, Vertongen F, Cauchie P, Gnat D, Molle L. Selenium and glutathione peroxidase in plasma and erythrocytes of Down's syndrome (trisomy 21) patients. J Ment Defic Res 1984; 28:261-268.
O'Brien JM, Geggel R, Feingold MF. Mitral valve prolapse in Down syndrome. Proc Greenwood Genet Center 1990; 9:96-97.
O'Dwyer J, Holmes J, Collacott RA. Two cases of obsessive-compulsive disorder in individuals with Down's syndrome. J Nerv Ment Dis 1992; 180:603-604.
Olson JC, Bender JC, Levinson JE, Oestreich A, Lovell DJ. Arthropathy of Down syndrome. Pediatrics 1990; 86:6:931-936.
OMIM (1997). Online Mendelian Inheritance in Man. Victor A. McKusick, et al. URL: http://www.ncbi.nlm.nih.gov/omim/.
Opitz JM, Gilbert-Barness EF. Reflections on the pathogenesis of Down syndrome. Am J Med Genet 1991; Supp. 7:38-51.
Orlicek SL, Walker MS, Kuhls TL. Severe mycoplasma pneumonia in young children with Down syndrome. Clin Pediatr (Phila ) 1992; 31:409-412.
Palmer CGS, Cronk C, Pustule SM, et al. Head circumference of children with Down syndrome (0-36 months). Am J Med Genet 1992; 42:61-67.
Palmer S. Influence of Vitamin A nurtiture on the immune response: Findings in Children with Down's syndrome. Internat J Vit Nutr Res 1978; 48:188-216.
Pary RJ, Strauss D, White JF. A population survey of bipolar disorder in persons with and without Down syndrome. Down Syndrome Quarterly 1996; 1:1-4.
Pearlson GD, Warren AC. Aging and brain weight in Down's syndrome. Neurology 1989; 39:1407.
Page LB and Culver PJ: A syllabus of laboratory examinations in clinical diagnosis. Revised Ed PP 374-380 Harvard University Press, Cambridge MA, 1961.
Peeters MA, et al: In vivo folic acid supplementation partially corrects methotrexate toxicity in patients with Down syndrome. Brit. J. Haematol., 89:678, 1995
Peeters MA, Megarbane A, Cattaneo F, Rethoré MO, Lejeune J. Differences in purine metabolism in patients with Down syndrome. J Intell Disabil Res 1993; 37:491-505.(abstract)
Peled-Kamar M, Lotem J, Okon E, Sachs L, Groner Y: Thymic abnormalities and enhance apoptosis of thymocytes and bone marrow cells in transgenic mice overexpressing CU/Zn-superoxide dismutase: Implications for Down syndrome. Department of Molecular Genetics and Virology, Weizman Institute of Science, Rehovot, Israel. EMBO J, Oct 16:14(20):4985-4931 1995.
Pierotti AR, Harmar AJ, Simpson J, Yates CM. High-molecular weight forms of somatostatin are reduced in Alzheimer disease and Down syndrome. Neurosci Lett 1986; 63:141-146.(abstract)
Pogribina M, Melynk S, Pogribina I, et al. Homocysteine metabolism in children with Down Syndrome: In vitro modulation. Am. J. Hum. Genet. 2001; 69:88-95.
Popovitch ER, Wisniewski HM, Barcikowska M, Silverman W, Bancher C, Sersen E, Wen GY: Alzheimer neuropathology in non-Down's syndrome mentally retarded adults. Acta. Neuropathol., 80:362-367, 1990
Prasad M, Moodie D, Sterba R, Murphy D, Rosenkranz E, Homa A. Long term follow-up of children with Down syndrome with cardiac lesions. Clin Pediatr 1990; October:569-574.
Prasher VP, Krishnan VHR. Mental disorders and adaptive behaviour in people with Down's syndrome. Br J Psychiatry 1993; 162:848-849.
Prince J, Jia S, Bave U, Annerén G, Oreland L. Mitochondrial enzyme deficiencies in Down syndrome. J Neural Trans Park Dement Sect 1994; 8:171-181.(abstract)
Pruess JB, Fewell RR, Bennett FC. Vitamin therapy and children with Down syndrome: A review of research. Exceptional Children 1989; 55:336-341.
Pueschel SM. Growth, thyroid function, and sexual maturation in Down syndrome. Growth, Genetics, & Hormones 1990; 6:1:1-5.
Pueschel SM. Clinical aspects of Down syndrome from infancy to adulthood. Am J Med Genet 1991; Supp. 7:52-56.
Pueschel SM, Louis S, McKnight P. Seizure disorders in Down syndrome. Arch Neurol 1991; 48:318-320.
Pueschel SM, Reed RB, Cronk CE, Goldstein BI. 5-Hydroxytryptophan and pyridoxine: Their effects in young children with Down's syndrome. Am J Dis Child 1980; 134:838-844.
Pueschel SM, Scola FH, Pezzullo JC. A longitudinal study of atlanto-dens relationships in asymptomatic individuals with Down syndrome. Pediatrics 1992; 89:6:1194-1198.
Querfurth HW, Wijsman EM, St George-Hyslop PH, Selkoe DJ. Beta APP mRNA transcription is increased in cultured fibroblasts from the familial Alzheimer disease -1 family. Brain Res Mol Brain Res 1995; 28:319-337.(abstract)
Rahmani Z, Blouin J-L, Creau-Goldberg N, et al. Down syndrome critical region around D21S55 on proximal 21q22.3. Am J Med Genet 1991; Supp. 7:98-103.
Ravindranath Y, Abella E, Krischer JP, et al. Acute myeloid leukemia (AML) in Down's syndrome is highly responsive to chemotherapy: Experience on Pediatric Oncology Group AML Study 8498. Blood 1992; 80:2210-2214.
Reddy VN, Aughton DJ, DeWitte DB, Harper CE. Down syndrome and omphalocele: An underrecognized association. Pediatrics 1994; 93:514-515.
Regland B, Gottfries CG. Slowed synthesis of DNA and methionine is a pathogenetic mechanism common to dementia in Down syndrome, AIDS, and Alzheimer disease? Med Hypotheses 1992; 38:11-19.(abstract)
Reilly J, Klima ES, Bellugi U. Once more with feeling: Affect and language in atypical populations. In: Development and Psychopathology, 2. 2nd ed. Boston: Cambridge University Press, 1990:367-391.
Ridgway D, Benda GI, Magenis RE, et al. Transient myeloproliferative disorder of the Down type in the normal newborn. Am J Dis Child 1990; 144:10:1117-1119.
Reading CM, McLEay A, Nobile S: Down's syndrome and thiamine deficiency. Journal of Orthomolecular Psychiatry, 8: 4, 1979
Roberts GW, Gentleman DM, Lynch A, Graham DI: Beta A4 amyloid protein deposition in brain after head trauma. Lancet, 338:1422-1423, 1991
Robinson LL, Neglia JP. Epidemiology of Down syndrome and childhood acute leukemia. In: Oncology and Immunology of Down Syndrome. New York: Alan R. Liss, 1987:19-32.
Robson WLM, Leung AKC. Down's syndrome and renal abnormalities. Pediatr Nephrol 1993; 7:775.
Roizen NJ, Mets MB, Blondis TA. Ophthalmic disorders in children with Down syndrome. Dev Med Child Neurol 1994; 36:594-600.
Rothman MM, Katz AB: Analysis of feces in Gastroenterology. 2nd edition vol. 2 p694 HL Bockus ed. WB Saunders Company. Philadelphia, 1964
Rowe IF, Ridler MAC, Gibberd FB. Presenile dementia associated with mosaic trisomy 21 in a patient with a Down syndrome child. Lancet 1989; 2:229.
Roy A, Roy M, Butler AC. Atlantoaxial instability in monozygotic twins with Down's syndrome. J R Soc Med 1993; 86:296.
Russell BG, Kjær I. Tooth agenesis in Down syndrome. Am J Hum Genet 1995; 55:466-471.
Sacchi N, Nalbantoglu J, Sergovich FR, Papas TS. Human ETS2 gene on chromosome 21 is not rearranged in Alzheimer disease. Proc Natl Acad Sci USA 1988; 85:7675-7679.
Sansone R, Pierluigi M, Carobbi S, Cominetti M, Strigini P. Disomic homozygosity and leukemia in Down's syndrome. Hum Genet 1990; 85:386.
Schapiro MB, Luxenberg JS, Kaye JA, Haxby JV, Friedland RP, Rapoport SI. Serial quantitative CT analysis of brain morphometrics in adult Down's syndrome at different ages. Neurology 1989; 39:1349-1353.
Schapiro MB, Rapoport SI. Aging and brain weight in Down's syndrome. Reply. Neurology 1989; 39:1407-1408.
Schmid F Von, Christeller S, Rehm W: Untersuchungen zum Status von Vitamin B1, B2 und B6 bein Down Syndrom. Fortschritte Der Medizin, 93:1-170, 1975
Schwaiger H, Weirich HG, Brunner P, et al. Radiation sensitivity of Down's syndrome fibroblasts might be due to overexpressed Cu/Zn-superoxide dismutase (EC 1.15.1.1). Eur J Cell Biol 1989; 48:79-87.
Schwartz PJ, Berger UV, Coyle JT. Mice transgenic for copper/zinc superoxide dismutase exhibit increased markers of biogeneic amine function. J Neurochem 1995; 65:660-669.(abstract)
Schweber MS. Alzheimer's disease and Down syndrome. Prog Clin Biol Res 1989; 317:247-267.
Shapiro BL. The environmental basis of the Down syndrome phenotype. Dev Med Child Neurol 1994; 36:84-90.
Sharav T, Collins RM, Baab PJ. Growth studies in infants and children with Down's syndrome and elevated levels of thyrotropin. Am J Dis Child 1988; 142:1302-1306.
Silverman W, Popovitch ER, Schupf N, Zigman WB, Rabe A, Sersen E, Wisniewski HM: Alzheimer neuropathology in mentally retarded adults: statistical independence of regional amyloid plaque and neurofibrillary tangle densities. Acta Neuropathol., 85:260-266, 1993
Sinet P-M, Theophile D, Rahmani Z, et al. Molecular mapping of the Down syndrome phenotype on chromosome 21. Prog Clin Biol Res 1993; 384:63-86.
Smith GF, Spiker D, Peterson CP, Cicchetti D, Justine P. Use of megadoses of vitamins with minerals in Down syndrome. Journal of Pediatrics 1984; 105:228-234.
Smith ML, Golitz LE, Morelli JG, Weston WL, Markewich G. Milialike idiopathic calcinosis cutis in Down's syndrome. Arch Dermatol 1989; 125:1586-1587.
Snow AD, Mar IL, Nochlin D. Gkiguchi RT, Kimata K, Koiko Y, Wight TN: Early accumulation of heparin sulphate in neurons and in the beta-amyloid protein containing lesions of Alzheimer's Disease and Down syndrome. Am. J. Pathol., 137:1253-1267, 1990
Sobel AE, Straluzza M, Sherman BS, Elkan B, Morgenstern SW, Marius N, Meisel A: Vitamin absorption and other blood composition studies in mongolism. American Journal of Mental Deficiency Research, 62:642, 1958
Solitare GB. Aging and brain weight in Down's syndrome. Neurology 1990; 40:729.
Spencer K, Carpenter P. Estimating risk of Down's syndrome. Br Med J 1991; 302:1536-1537.
Stafstrom CE, Konkol RJ. Infantile spasms in children with Down syndrome. Dev Med Child Neurol 1994; 36:576-585.
Stafstrom CE, Patxot OF, Gilmore HE, Wisniewski KE. Seizures in children with Down syndrome: Etiology, characteristics and outcome. Dev Med Child Neurol 1991; 33:191-200.
Stebbens VA, Dennis J, Samuels MP, Croft CB, Southall DP. Sleep related upper airway obstruction in a cohort with Down's syndrome. Arch Dis Child 1991; 66:1333-1338.
Strigini P, Sansone R, Carobbi S, Pierluigi M. Radiation and Down's syndrome. Nature 1990; 347:717.
Sullivan TJ, Clarke MP, Brazel S, Morin JD, Pashby RC. Congenital lacrimal fistula associated with Down's syndrome. Am J Ophthalmol 1992; 113:215-216.
Sutnick AL, London WT, Blumberg BS, Gertsley BJ: Susceptibility to leukemia: immunologic factors in Down's syndrome. Journal of the National Cancer Institute, 47:923, 1971.
Symon DNK, Stewart L, Russel T: Abnormally high sweat osmolality in children with Down's syndrome. Journal of Mental Deficiency Research, 29:202, 1985
Takanashi J, Sugita K, Honda A, Niimi H. Moyamoya syndrome in a patient with Down syndrome presenting with chorea. Pediatr Neurol 1993; 9:396-398.
Thase ME: Longevity and mortality in Down's syndrome. Journal of Mental Deficiency Research, 26: 117, 1982.
Ugazio AG, Maccario R, Notarangelo LD, Burgio GR. Immunology of Down syndrome: A review. Am J Med Genet 1991; Supp. 7:204-212.
Van Camp G, Stinissen P, Van Hul W, et al. Selection of human chromosome 21-specific DNA probes for genetic analysis in Alzheimer's dementia and Down syndrome. Hum Genet 1989; 83:58-60.
Van Dyke DC, Lang DJ, van Duyne S, Heide F, Chang H. Cell therapy in children with Down syndrome: A retrospective study. Pediatrics 1990; 85:79-84.
Verga L, Frangione B, Tagliavini F, Giaccone G, Migheli A, Bugiani O. Alzheimer patients and Down patients: Cerebral preamyloid deposits differ ultrastructurally and histochemically from the amyloid of senile plaques. Neurosci Lett 1989; 105:294-299.
Wang PP, Bellugi U. Williams syndrome, Down syndrome, and cognitive neuroscience. Am J Dis Child 1993; 147:1246-1251.
Weathers C. Effects of nutritional supplementation on IQ and certain other variables associated with Down syndrome. Am J Ment Defic 1983; 88:214-217.
Webb N, Hebert D, Arbus G. Renal replacement therapy in Down's syndrome. Pediatr Nephrol 1993; 7:771.
Wilcox WD. Abnormal serum uric acid level in children. Journal of Pediatrics 1996; 128: June:731-741.
Williams CA, Quinn H, Wright EC, Sylvester PE, Gosling PJH, Dickerson JWT: Xylose absorption in Down's syndrome. Journal of Mental Deficiency Research, 29:173, 1985.
Wisniewski KE and Schmidt-Sidor K, Postnatal delay of myelin formation in brains from Down Syndrome infants and children. Clin Neuropathol 8:55-62, 1989
Wisniewski HM, Wegiel J, Popovitch ER: Age-associated development of diffuse and thioflavin-s-positive plaques in Down syndrome. Devel. Brain Dysfunction, in press
Wisniewski KE. Down syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesis. Am J Med Genet 1990; Supp. 7:274-281.
Wolraich ML, Siperstein GN, Reed D. Doctors' decisions and prognostications for infants with Down syndrome. Dev Med Child Neurol 1991; 33:336-342.
Zipursky A, Doyle J. Leukemia in newborn infants with Down syndrome. Leuk Res 1993; 17:195.
Zori RT, Schatz DA, Ostrer H, Williams CA, Spillar R, Riley WJ. Relationship of autoimmunity to thyroid dysfunction in children and adults with Down syndrome. Am J Med Genet 1991; Supp. 7:238-241.