Micro-Nutrient Needs in Down Syndrome: A peer … 3-arm chromosome (trisomy) increases production by...

Micro-Nutrient Needs in Down Syndrome:

A peer-reviewed science base © 2014

Joan Jory, MSc, PhD, RD

Down Syndrome: the Implications

Down Syndrome results from a (third arm) on chromosome 21.

This trisomy is associated with changes in:

- neurological development

- physical growth

- muscle to fat ratio

- immunity and resistance to infection

- risk of leukemia

- risk of celiac disease

- risk of thyroid dysfunction

- risk of diabetes and blood sugar abnormalities

- precocious aging

- Alzheimer-like lesions

Down Syndrome: an Analogy

A 2-arm chromosome (normal) is like a recipe:

X volume of ingredients Y volume of product.

A 3-arm chromosome (trisomy) increases production by 50%:

Y + 50% volume of product requires X + 50% volume ingredients.

X + 50% ingredients faster depletion of ingredient stores

‘stealing’ ingredients from other functions

decreased ingredients for growth + development

decreased ingredients for disease prevention

decreased ingredients for healthy aging

Down Syndrome: the Functional Paradigm

1. 50% overproduction of products coded on Chromosome 21

(50% more products produced)

2. 50% increase in production causes a 50% increase in requirements for raw ingredients (vitamins, minerals, amino acids, etc)

(50% more ingredients needed)

3. There is also an increase in the byproducts (mess), requiring increased antioxidants to neutralize the excess byproducts

(50% more garbage produced + 50% more antioxidants needed).

Down Syndrome: Enzyme Overexpression

There are three well-documented enzymes coded on Chromosome 21 which increase requirements for zinc, selenium and vitamin B12 :

1) Cu-Zn SuperOxide Dismutase (SOD): a zinc dependent enzyme.

2) Glutathione Peroxidase: a selenium dependent enzyme

3) Cysteine Beta Synthase (CBS): a folate and B12 dependent enzyme

Additionally, there is an increased production of free radicals and consequently an increased requirement for anti-oxidants such as:

3) glutathione, vitamin A, vitamin C, vitamin E

Copper-Zinc Superoxide Dismustase (SOD) in Down

Syndrome

Down Syndrome: What Evidence of Excess SOD?

Superoxide Dismutase (SOD) levels can be normal in mosaic Down Syndrome

(Biol Trace Elem Res 2001)

Superoxide Dismutase (SOD) levels are increased in full expression Down

Syndrome

(Mayo Clin Proc 2005)

Overproduction of Superoxide Dismutase (SOD) increases oxidative stress and

increases oxidative damage to proteins in children with Down Syndrome .

(Clin Chem Lab Med 2006)

Consequences of Low Zinc in Down Syndrome

Down Syndrome: Implications of Low Zinc

Low zinc status in Down Syndrome is associated with:

1) decreased immune status

2) decreased growth and lean tissue ratios

3) thyroid dysfunction

4) celiac disease

5) altered taste perception and appetite

Zinc and Immunity

Down Syndrome: Zinc and Immunity

18 children with Down Syndrome

Hx respiratory, ear and skin infections

2 cycles of zinc supplementation 10 months apart

1 mg elemental zinc/kg/day x 2 months each

Decreased infections and increased school attendance

Despite normal plasma zinc before supplementation

No effect on copper status

Franceschi C et al. J Ment Defic Res 1988;32(Pt3):169-81. Oral zinc supplementation in Down

Syndrome: restoration of thymic endocrine activity and some immune defects.


12 children with Down’s Syndrome

Low serum zinc and immune deficiency

Zinc sulfate supplementation @ 135 mg zinc/d x 2 months

Immune improvements in 11/12 children

Bjorksten B et al. Acta Pediatr Scand 1990; .Zinc and Immune Function in Down’s Syndrome.



63.2% with low plasma zinc

Supplementation with zinc sulfate x 20 mg/kg/day x 2 months

Normalized immunity (lymphocyte response) x 6 months

But, immunity decreasing 22 months after supplementation ended

Stabile A et al. Clin Imunol Immunopathol 1991; 58(2): 207-16. Immunodeficiency and plasma

zinc levels in children with Down’s syndrome: a long-term follow-up of oral zinc

supplemenation.

Zinc and Growth

Down Syndrome: Zinc, Growth, Body Composition

Meta-analysis of 33 zinc supplementation studies and childhood growth.

Highly significant improvements in height

Highly significant improvements in weight

Greatest improvements among children with lowest height-for-age scores.

Brown KH et al. Am J Clin Nutr 2002; 75(6): 1062-71. Effect of supplemental zinc on the growth and

serum zinc concentrations of preburtal children: a meta-analysis of randomized controlled trials.



No difference in protein intake, carb or fat intake

Zinc intake adequate in 40% of Down Syndrome and 67% controls

Lower plasma zinc in Down Syndrome.

Shorter height in Down Syndrome.

Lima AS et al. Biol Trace Elem Res 2010; 133(1): 20-8. Nutritional status of zinc in children with Down

Syndrome



Supplemented with zinc sulphate for 6-9 months.

Increased growth percentile and increased growth hormone levels

Increased growth velocity (23.84 -> 40.80 mm/6 months).

Napolitano G et al. Am J Med Genet 1990;37(S7):63-65. Growth delay in Down Syndrome and zinc

sulphate supplementation.

Zinc and Body Composition


9 female elite athletes

% fat mass is negatively associated with plasma zinc.

% fat mass is positive associated with the plasma copper/zinc ratio.

Koury JC et al. Biol Trace Elem Res 2007; 115(1): 23-30. Plasma zinc, copper, leptin, and body

composition are associated in elite female judo athletes.


30 adolescents with Down Syndrome

No difference in protein, fat, carb or zinc intake

No difference in plasma zinc

Greater zinc losses in urine in Down Syndrome.

Greater overweight (26.7%) and obesity (6.6%) in Down Syndrome.

Marques RC et al. Biol Trace Elem Res 2007; 120(1-3): 11-8. Zinc nutritional status in adolescents with

Down Syndrome.

Zinc and Thyroid

Down Syndrome: Zinc and Thyroid


Lower plasma zinc

Higher TSH

No difference in T3 or T4

4 months zinc sulphate supplementation

Plasma zinc normalized

TSH on par with control children

Licastro F et al. Int J Neurosci 1992; 65(1-4): 259-68 . Zinc affects the metabolism of thyroid hormones

in children with Down’s Syndrome: normalization of thyroid stimulating hormon and of reversal

triiodothyroinine plasmic levels by dietary zinc supplementation.

Down Syndrome: Zinc and Thyroid


4 months of zinc sulphate supplementation:

Normalized plasma zinc and TSH

1 year after zinc supplementation stopped:

Plasma zinc decreasing

TSH increasing

Licastro F et al. J Trace Elem Electrolytes Health Dis 1993; 7(4): 237-9. Modulation of the

neuroendocrine system and immune functions by zinc supplementation in children with Down’s

Syndrome.

Zinc and Celiac Disease

Down Syndrome: Zinc and Celiac Disease


Lower zinc

Lower immune function

Higher TSH

Higher coeliac disease

Zinc lowest in children with celiac disease and decreased immune status

Licastro F et al. Brain Res Bull 2001; 55(2): 313-7. Immune-endocrine status and coeliac disease in

children with Down’s Syndrome: relationship with zinc and cognitive efficiency.

Zinc and Taste/Appetite

Down Syndrome: Zinc and Taste Disorders

22 patients with altered taste acuity (hypogeusia)

Zinc acetate supplementation x 50 mg zinc/day

Improvement in plasma zinc

Improvement in taste perception for sweet, salt and bitter.

Mahaian SK et al. Am J Clin Nutr 1980’; 33(7): 1517-21. Improvement of uremic hypogeusia by zinc: a

double-blind study.

Zinc Safety

Down Syndrome: Zinc Safety

Meta-analysis of preventive zinc supplementation studies among infants,

preschoolers and older prepubertal children.

Decreased diarrhea x 20%

Decreased acute respiratory infections x 15%

Decreased mortality in children > 1 yr x 18%

Increased growth in height

No adverse effect on iron or copper status.

Brown KH et al. Food Nutr Bull 2009; 30(1 Supp): S12-40. Preventive zinc supplementaton among

infants, preschoolers and older prepubertal children.

Zinc Testing

Zinc Assessment

1) Serum/plasma zinc

-> recent intake only

-> many confounding variables

2) Alkaline phosphatase (zinc enzyme)

-> functional zinc status

-> unreliable if recent growth as alk phos is mobilized into blood during growth

3) Best approach

-> combination of serum/plasma zinc AND alkaline phosphatase

Dietary Sources of Zinc

Zinc Sources in Diet

Absorption blocked by calcium, iron, fibre, phytate.

Richest food sources:

Seafood

Fish

Liver

Beef, Pork, Chicken

Beans

Cashews

Cheese

US National Institutes of Health, 2013

Glutathione Peroxidase (GPx) in Down Syndrome

Down Syndrome: What Evidence of Excess GPx?


RBC GPx was significantly increased.

Serum selenium was significantly decreased.

Meguid NA et al. Biol Trace Elem Res 2001; 81(1): 21-8.


RBC GPx in red cells was significantly increased

Plasma selenium was significantly decreased

Neve et al. Clin Chim Acta 1983

RBC GPx levels were significantly greater in the DS group

RBC GPx was significantly correlated with memory function.

Brugge K et al. Biol Psychiatry 1999; 46(12): 1682-9

Consequences of Low Selenium in Down Syndrome

Down Syndrome: Implications of Low Selenium

Low selenium levels in Down Syndrome are associated with:

1) impaired thyroid status

2) decreased immune status

Selenium and Thyroid

Down Syndrome: Selenium and Thyroid

109 healthy individuals

Decreased serum selenium

Decreased T3/T4 ratio

Decreased conversion of T4 to T3 because of low selenium status

Olivieri O et al. Biol Trace Elem Res 1996; 51(1): 31-41. Selenium, zinc, and thyroid hormones in health

subjects.

Down Syndrome: Selenium and Thyroid

18 adults with Down Syndrome

Decreased serum selenium

Decreased T4

Increased TSH

Kanavin OJ et al. Biol Trace Elem Res 2000; 78(1-3):35-42. Thyroid hypofunction in Down’s Syndrome:

is it related to oxidative stress?

Selenium and Immunity

Down Syndrome: Selenium and Immunity

1a) Natural Killer (NK) activity is low in Down Syndrome. Ugazio et al. Am J Med Genet Suppl 1990

1b) Supplementation with Se increases natural killer (NK) cell activity in the mouse. Kiremidjian-Schumacker & Roy. Z Ernarhrungswis 1998

2a) The T-lymphocyte activation response is patients with dysmorphic disorders. Cruz et al. Ann Allergy Ashtma Immunol 2009

2b) Selenoprotein deficiency suppresses T-lymphocyte response. Shrimali et al. J Biol Chemi 2008.

Selenium Testing

Selenium Assessment

1) Serum/plasma selenium -> only recent selenium intake

2) RBC selenium -> longer term selenium status

3) But, there are no established ‘normal ranges’ for either test

Thomson CD. Eur J Clin Nutr 2004; 58: 391-402. Assessment of requirements for selenium and adequacy

of selenium status: a review.

Dietary Sources of Selenium

Selenium Sources in the Diet

Richest food sources:

Brazil Nuts

Mixed Nuts and Seeds

Oysters

Fish

Liver

Beef, Pork, Lamb, Chicken

Eggs

Beans

Canadian Nutrient File 2012

Cystathione Beta Synthase (CBS) in Down Syndrome

Down Syndrome: What Evidence of Excess CBS?

Cystathione beta synthase (CBS) levels are increased by approximately three

times in the Down Syndrome brain.

High CBS causes homocysteinuria, which is characterized by mental retardation

and vascular disease.

The high CBS may explain the cognitive abnormalities in Down Syndrome, and

the vulnerability to Alzheimer’s Disease

Ichinohe A et al. Biochem Biophys Res Commun 2005; 338(3): 1547-50. Cystathione beta-synthase is

enriched in the brains of Down’s patients.

Down Syndrome: What Evidence of Excess CBS?


CBS overexpression in lymphoblasts altered homocysteine metabolism with

decreased homocysteine content, and decreased glutathione.

Addition of methyl-folate, methyl-B12 or dimethylglycine improved this profile

Progribna M et al. Am J Hum Genet 2001; 69(1): 88-95 Homocystein metabolism in children with Down

Syndrome: in vitro modulation

Folate in Down Syndrome

Down Syndrome: Folate Status

Canadian Health Measures Survey

5248 people 6-79 years + 1162 women 15-45 years

‘Folate deficiency is virtually nonexistent in the Canadian population’

Very high folate among 40% of the Canadian population

New reference range for ‘normal’ RBC folate: 305-1360 nmol/L

Colapinto CK et al. CMAJ 2011; 183(13): 1519. Folate status of the population in the Canadian Health

Measures Survey.


Following folate fortification of flour in US :

Significant increase in maternal folate status

Normal serum and RBC folate in infants with Down Syndrome

Significant decrease in neural tube defects and cleft palate

7% increase in Down Syndrome (where no prenatal DS testing)

Canfield MA et al. Birth Defects Res A Clin Mol Teratol 2005; 73(10): 679-89. Changes in the birth

prevalence of selected birth defects after grain fortification with folic acid in the United States: findings

from a multi-state population based study.



No difference in serum and RBC folate between Down Syndrome and controls

Roizen and Amarose. Am J Med Genet 1993; 46(5): 510-2. Hematological abnormalities in children with

Down Syndrome


No difference in serum or RBC folate between Down Syndrome and controls

Onorata D et al. Pediatr Hematol-Oncol 1996; 13(3): 271-275. Hematological studies in children with

Down Syndrome

113 patients with Down Syndrome

No difference in serum of RBC folate between Down Syndrome and controls

Howell A et al. Scand J Haematol 1973; 11: 140-147. Red cell size and uric acid in Down Syndrome.

Folate Assessment

1) Serum/plasma folate -> only recent folate intake

2) RBC folate -> longer term folate status

Reference range for Canadians: 305-1360 nmol/L

Caution if RBC folate > 1360 nmol/L

Colapinto CK et al. CMAJ 2011; 183(13): 1519. Folate status of the population in the Canadian Health

Measures Survey.

Folate Sources in the Diet

All flour and flour products in Canada are fortified with flour

All multi-B, multivitamin and prenatal vitamins contain folate

Many protein powders and alternate non-dairy milks are folate fortified.

Richest unfortified dietary sources:

Liver

Beans and lentils

Dark green vegetables

Sunflower seeds

Potatoes

Fruit


B12 Status in Down Syndrome

Down Syndrome: B12 Status


Increased hemoglobin

Increased mean cell volume (MCV)

No difference in serum or RBC folate

No difference in serum iron or ferritin

No difference in serum B12 (but no test for functional B12 status)

‘Macrocytosis (is) an expression of an altered folate remethylation

pathway, secondary to enhance CBS activity, the gene for which is present

on chromosome 21’

Onorata D et al. Pediatr Hematol-Oncol 1996; 13(3): 271-275. Hematological studies in children with

Down Syndrome




Decreased serum B12

No difference in serum of RBC folate

Howell A et al. Scand J Haematol 1973; 11: 140-147. Red cell size and uric acid in Down Syndrome.


Increased hematocrit


Decreased white blood cells (WBC)

No B12 testing

No difference in serum and RBC folate

Roizen and Amarose. Am J Med Genet 1993




Increased mean platelet volume (MPV)

De Alarcon PA et al. Ped Res 1984; 18: 235A. Down’s Syndrome and increased mean corpuscular

volume (MCV) , mean platelet volume (MPV) and neutrophil alkaline phosphatase (NAP).



Decrease red cell survival

Wachtel TJ and SM Pueschel. AJMR 1991; 95(4):417-420. Macrocytosis in Down Syndrome


Increased mean cell volume (MCV) in 48%

Decreased white blood cells (WBC) and neutrophils in 20%

Prasher VP. Down Syndrome Research and Practice 1994; 2(2): 59-66. Screening of medical problems in

adults with Down Syndrome.

B12 deficiency and Abnormal Hematology

Down Syndrome: B12 and Hematology

Vitamin B12 deficiency can cause profound alterations in the bone marrow.

These alterations can mimic the more serious diagnosis of acute leukemia.

Two patients were suspected of having acute leukemia or myelodysplasia

on the basis of bone marrow smear.

They were both found to have vitamin B12 deficiency

Parenteral vitamin B12 resulted in normalization of the bone marrow.

Aitelli C et al. South Med J 2004; 97(3): 295-7. Pernicous anemia: presentations mimicking acute

leukemia.


205 children with pancytopenia (decreased red cells, white cells and/or platelets)

Hematological malignancies = 24%

Megaloblastic anemia = 20 %

‘Leukemia and bone marrow failure are the most common causes.’

But ‘megaloblastic anemias are treatable and reversible causes of pancytopenia

Zeb Jan A et al. Pak J Med Sci 2013; 29(5): 1153-7. Pancytopenia in children.: a 6 year spectrum of

patients admitted to Pediatric Department of Rehman Medical Institute, Peshawar


Plasma concentrations of methycobalamin was significantly lower in CML

patients than the reference population.

Low methylcobalamin was associated with a poor prognosis.

Gimsing P. Br J Haematol 1995; 89(4): 812-9. Cobalamin forms and analogues in plasma and myeloid

cells during chronic myelogenous leukaemia related to clinical condition.

In the mouse model of L1210 leukemia, vitamin B12 + C inhibited cell growth

and increased survival

Pydock ME. Am J Clin Nutr 1991; 54 (6 Suppl): 1261S-1265S. Effect of combined ascorbic acid and

B12 on survival of mice with implanted Ehrlich carcinoma and L1210 leukemia.

B12 and Myelination

Down Syndrome: B12 and Myelination

14 cases of early-onset cobalamin deficiency

Mental retardation was identified in most cases

A variable degree of white matter atrophy was detected

Selective white matter involvement seems to be the most consistent finding of

cobalamin deficiency

The white matter atrophy may be related to a reduced supply of methyl groups,

possibly caused by the dysfunction of the methyl-transfer pathway.

Biancheri et al. Neuropediatr 2001

Down Syndrome: B12 and Myelination

1)The brain of a child with Down Syndrome develops differently from a normal

one, attaining a form reduced in size and altered in configuration.

2) Directly related to the mental retardation are neuronal modifications manifest as

alterations in cortical lamination (myelination)

Becker et al. Prog Clin Biol Res 1991


Delayed myelination in 22.5%

Wisniewski & Schmidt-Sidor. Clin Neuropath 1989

18 month old infant with Down Syndrome

Brain myelination equivalent to an 11-month infant.

Koo et al. J Child Neurol 1992

B12 Assessment

1) No gold standard has emerged for the diagnosis of cobalamin deficiency.

2)Therapeutic trials with pharmacologic doses of cobalamin are suggested when

findings consistent with cobalamin deficiency are present regardless of the results

of diagnostic tests. Solomon LR. Blood Rev 2007

Normal serum B12 can be repeatedly normal in the presence of haematological

and neurological symptoms of B12 deficiency.

Mar N et al. Open J of Hematol 2012; 3: DOI-10.13055/ojhmt_3_1_2.120920. Pitfalls in the diagnosis of

B12 deficiency.

There is concern that high intakes of folic acid from fortified food and dietary

supplements might mask the macrocytic anemia of vitamin B12 deficiency,

thereby eliminating an important diagnostic sign.

Johnson MA. Nutr Rev 2007

Occult cobalamin deficiency could become a common disorder. Ray et al. Clin Biochem 2000

B12 Assessment

1) Serum B12

Recent intake -> will show high if supplementation

Caution if < 400 (Japanese cutoff for serum B12)

2) MCV and MCH

If high, may indicate folate or B12 deficiency.

Test for RBC folate to differentiate

3) White cell count (WBC) and subsets, red cell count (RBC) and platelets

If low, may indicate B12 deficiency.

Consider testing response to high dose B12 before considering leukemia

4) Homocysteine

Will be low in Down Syndrome because of CBS overexpression on chromosome 21

B12 Sources in the Diet

Only 1% of dietary B12 is passively absorbed.

99% requires intrinsic factor production in the gut

Best dietary sources:

Clams

Liver

Seafood

Trout and Salmon

Beef and wild game


US National Institutes of Health 2011

Down Syndrome: Importance of Iron

Human infants with iron deficiency anemia test lower in cognitive, motor, social-

emotional, and neurophysiologic development than comparison group infants.

B Lozoff and MKGeorgieff. Sem in Pediatr Neurol 2006; 13(3): 158-165. Iron Deficiency and Brain

Development.

Increased likelihood of mild or moderate mental retardation associated with

anemia, independent of birth weight, maternal education, sex, race-ethnicity,

the mother’s age, or the child’s age at entry into the US WIC (Women, Infants

and Children Supplementation program.

EK Hurtado et al. Am J Clin Nutr 1999; 69(1): 115-119; Early Childhood Anemia and Mild or Moderate

Mental Retardation

Down Syndrome: Iron


Iron deficiency in 10%

Iron deficiency anemia in 3%

”Screening should include CBC, transferrin saturation and ferritin”

Dixon NE et al. J Pediatr 2010; 157(6): 967-971. Prevalence of iron deficiency in children with Down

Syndrome.


Anemia in 8.1%

Iron deficiency in 50% with iron tests (19/38)

Tenenbaum et al. Int J Pediatrics 2011; ID 813541. doi: 10.1155/2011/813541.

Iron Assessment

Serum Ferritin

An acute phase reactant -> can be falsely high if infection or inflammation

Can be increased if insufficient B12 for red cell production

Caution if < 30

Mean Cell Volume (MCV) and Mean Cell Hemoglobin

Low MCV and MCH in uncomplicated iron deficiency

May be normal or high if co-existing B12 or folate deficiency

Caution if <75-80 or >90-95

Iron Assessment

Iron Saturation

May be low if low iron or B12

May be high if macrocytosis (swollen cells) from B12 or folate deficiency

Serum iron

Recent iron intake; not functional iron status

Hemoglobin and hematocrit

If low, may be due to iron, B12 or folate deficiency

Need to test ferritin and RBC folate to determine which deficiency

Iron Sources in the Diet

Heme iron has a higher absorption, and comes from animal products

Non-heme iron absorption may be compromised by the presence of fibre and

phytate.

Iron absorption is enhanced by vitamin C and decreased by calcium

Richest dietary sources:

Seafood

Fish

Liver and kidney

Red meat

Beans and Soybeans

Spinach and dark greens

Fortified cereals


Vitamin A in Down Syndrome

Down Syndrome: Vitamin A


Serum retinol deficiency (<20mg/dL) in 18.4%

Chavez CJ et al. An Pediatr (Barc) 2010; 72 (3): 185-90.


Lower plasma and red cell retinol.

Shah SN and RD Johnson. Nutr Res 1989; 9(7): 709-715. Antioxidant vitamin (A and E) status of

Down’s Syndrome subjects.


No difference in vitamin A intake, serum vitamin A or Vitamin A absorption

But skin symptoms of hypovitaminosis A

Pueschel SM et al. J Met Defic Res 1990; 34(Pt 3) : 269-75. Vitamin A gastrointestinal absorption in

persons with Down’s Syndrome.

Vitamin A

Testing

Serum Vitamin A (retinol): recent intake only

Vitamin A Sources in the Diet

Liver

Cod Liver Oil

Eggs

Goat cheese

Cow cheese

Orange vegetables (sweet potato, pumpkin, carrots)

Green vegetables (spinach, kale, swiss chard)


Nutrient-Rich Diet for Down Syndrome

High animal protein (liver, fish, beef, lamb) (unfortified non-GMO whey protein)

High intake of colourful vegetables (dark greens and dark oranges)

High intake of nuts and seeds and lentils

Minimally processed grains

Minimal fruit

Dairy x 2-3 servings/day

Cod liver oil (without Vitamin A and D removed)

¼ tsp of iodized salt/day

Baseline Bloodwork for Children with Down Syndrome

CBC

Serum ferritin -> separate test for serum iron and iron saturation if abnormal

RBC folate

AST & ALT

Alkalinine phosphatase

TSH & T4

Ammonia

Fasting blood sugar & triglycerides

HDL and LDL cholesterol (if older than 12 years)

Urinalysis (for occult urinary tract infections or dysurias)

Consider also: vitamin A, serum zinc and serum selenium if appropriate

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