Nomenclature and classification of vitamins.

Vitamins is a collective name for a range of organic chemicals which are not related chemically . They differ in their physiological actions, being substances which the body requires in small amounts for metabolism, and is incapable of synthesizing, or does not synthesize in sufficient quantity for its overall needs.
Vitamins have been classified as water or lipid soluble. This is useful indicating the intestinal absorption systems used.
The water-soluble vitamins are vitamin C (ascorbic acid), vitamin B (thiamin), nicotinic acid (niacin) and nicotinamide, riboflavin, vitamin B6 (pyridoxine), pantothenic acid, biotin, folic acid and vitamin B12 (cyanocobalamin). The fat-soluble are vitamin A (retinol), vitamin D (cholecalciferol), vitamin K and vitamin E (tocopherols).

Vitamins may be single chemical entities, eg ascorbic acid, or form a family of closely related compounds, as are A, D, K, E and B12.

Vitamins may have actions which have blood-forming importance (folic acid and vitamin B12) anti-oxidant (ascorbic acid and vitamin E), energy metabolism (thiamin, riboflavin and pyridoxine), bone formation (vitamin D) and protein metabolism (vitamin K and A). Vitamins may also act in a general systemic manner as anti-oxidants, e.g. ascorbic acid and vitamin E.

Vitamins may also act as enzymatic cofactors or have hormone-like actions on receptors
Anti-vitamins

Anti-vitamins

These are present in natural food. Several synthetic analogues of vitamins are highly poisonous, e.g. aminopterin, tesoxypyridoxine. These substances inhibit the activity of true vitamins and enzyme systems.

Pro-vitamins

These, while not themselves being vitamins, can be converted to vitamins in the body. Carotenes are pro-vitamins of vitamin A and the amino acid tryptophan can be converted to nicotinic acid. Vitamin D is synthesized in the skin by the action of sunlight on a derivative of cholesterol.

Water Soluble Vitamins

VITAMIN C ( ASCORBIC ACID )

Chemistry
Ascorbic acid is a simple sugar.

Function
Ascorbic acid is a powerful reducing agent and an electron donor. As such it has a central role in the relative states of oxidation/reduction of other metabolically important water-soluble substances.
Enzyme reactions requiring ascorbic acid are hydroxylations utilizing oxygen with Fe2+ or Cu2+ as cofactors. The interaction between ascorbic acid and iron can increase the oxidative potential of iron, and iron acts as a pro-oxidant in the presence of ascorbic acid. The ascorbic acid utilising enzymes include the synthesis of hydroxyproline and hydroxylysine in pro-collagen, carnitine from lysine, and the hepatic microsomal mono-oxygenase system which is important for steroid hormones and xenobiotics.
Dietary source
Ascorbic acid is found in fresh fruit and juices, liver and milk
Recommended requirements
Adults. Recommended intakes range from 40 to 200 mg/day.
Pregnancy and lactation: should increase by 10 mg/day during the third trimester.
During lactation an intake of 70 mg/day is probably satisfactory.
Children: clinical scurvy has not been observed in fully breast-fed infants. The vitamin C content of breast milk varies from 170 to 450 μmol/l, which provides 25 mg/day.
Smokers: smokers have an increased turnover of vitamin C and their intake should be increased to over 80 mg/day.
Effects of dietary deficiency
A dietary deficiency of ascorbic acid results in scurvy. Haemorrhages, either large or microscopic, may occur anywhere in the body, including the gums, subcutaneous tissues, synovia of joints and beneath the periosteum of bones. There is failure of wound healing, and
old wounds which have healed break down. Osteoporosis may also occur in scurvy
Effects of dietary deficiency
Ascorbic acid in excess is metabolized to oxalic acid , excreted in the urine and has the potential for oxalic acid renal stone formation

BIOTIN —

Chemistry
Biotin contains a ureido group in a five-membered ring fused with a tetrahydrothiophene ring with a five-carbon side chain terminating in a carboxyl group.
Function
Biotin is a cofactor for the acetyl-CoA, propionyl-CoA and pyruvate carboxylase systems. These enzymes are involved in the synthesis of fatty acids and involved in gluconeogenesis and carboxylation in this metabolic pathway.
Biotin is a covalently bound cofactor in enzymes, as a site for formation of a carboxylated intermediate, being bound to the enzyme by amide linkage between e-amino groups of enzyme lysine and the carboxyl group of biotin’s valeric acid side chain.
The coenzyme function of biotin allows the carboxylation reactions to proceed by receiving the ATP-activated carboxyl group and transferring to the carboxyl acceptor substrate.
Dietary source
Biotin is found in yeast, liver, kidney, pulses, nuts, and some vegetables
The dietary requirement of biotin is not known with certainty. A biotin intake of between 10 and 200 ug/day is safe and adequate.
Effects of dietary deficiency
A dietary deficiency of biotin results in fatigue, depression, sleepiness, nausea and loss of appetite, muscle pain, hyperaesthesiae and paraesthesiae without reflex changes or other signs of neuropathy. The tongue becomes smooth with loss of papillae, the skin is dry with fine scaly desquamation, and anaemia and hypercholesterolaemia develop.
There are no indications that excess biotin is harmful or toxic

NIACIN —

Chemistry
also known as nicotinic acid or vitamin B3,
Nicotinic acid occurs as a pyridine derivative and is found in the body as the amide, nicotinamide.
Function
Nicotinamide is a component of the coenzymes nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+). These coenzymes are electron carriers. In the reaction NAD+ NADPH, two electrons and a proton are accepted from the substrate being oxidized.
Dietary source
Nicotinic acid is found in plants and animal foods in small amounts, with the exception of meat, fish, whole meal cereals and pulses. In many cereals, particularly maize and perhaps potatoes, the nicotinic acid is held in a bound, unabsorbable form.
Recommended requirements
Recommendations for niacin are associated with tryptophan ingestion. The median intake of protein in Britain is 84 g/day for men and 62 g/day for women, containing approximately 13 mg tryptophan per gram, equivalent to 17 mg/day of niacin for men and 13 mg/day for women.
Infants
Infant milk should provide not less than 3.3–3.85 mg pre-formed niacin per 1000 kcal. Because of the tryptophan present in cows’ milk protein, infants would have an intake similar to adults of niacin equivalent per 1000 kcal.
Pregnancy
Because of hormonal changes in tryptophan metabolism in late pregnancy, 30 mg of tryptophan is equivalent to 1 mg of dietary niacin.
Lactation
Mature human milk provides pre-formed niacin (2.7 mg/litre).
Effects of dietary deficiency
Dietary nicotinic acid deficiency leads to pellagra, characterized by dementia, diarrhoea and dermatitis.

Pantothenic Acid —

Chemistry
Pantothenic acid is the dimethyl derivative of butyric acid joined by a peptide linkage to the amino acid b-alanine. The biochemically active form of the vitamin is 4’-phosphopantetheine.
Function
Pantothenic acid is the precursor of coenzyme A.
Dietary source
Pantothenic acid is widely available in natural foods.
Recommended reqirements
Most human diets provide 3–10 mg derived from a variety of natural foods. Estimates in the British diet give values of the order of 5–6 mg/day.
The intake for children is of the order of 3 mg/1000 kcal.
Effects of dietary deficiency
No deficiency condition has been described in humans.

RIBOFLAVIN —

Chemistry
Riboflavin is a substituted alloxazine ring linked to ribotol, an alcohol derived from the pentose sugar ribose.
Function
Riboflavin links with phosphoric acid as flavin mononucleotide or riboflavin-5¢-phosphate (FMN) which with adenosine monophosphate, forms flavin adenine dinucleotide (FAD). These are the prosthetic groups of the flavoprotein enzymes. The functional part of the coenzyme is the isoalloxane ring.
These flavoproteins are strong oxidizing agents and are versatile redox coenzymes.
Dietary source
Dietary sources are liver, milk, cheese, eggs, some green vegetables and beer. Other sources are yeast extracts, e.g. Marmite and meat extracts, e.g. Bovril.
Recommended requirements
Adults
1.3 mg/day for men and 1.1 mg/day for women.
Infants
The average riboflavin content of breast milk in Britain is approximately 1.4 μmol/l. The range varies enormously, depending on the mother’s intake. An intake should be 0.4 – 1.0mg/day.
Pregnancy and lactation
Because of the extra demands for riboflavin the requirement should be increased by 0.3 mg/day during pregnancy and 0.5 mg/day during lactation.
Elderly
While the resting metabolism and riboflavin intake decreases with age, the recommended intake for elderly individuals should be the same as for young people.
Effects of dietary deficiency
Riboflavin deficiency is associated with cheilosis, angular stomatitis and superficial interstitial keratosis of the cornea.

THIAMIN —

Chemistry
Thiamin hydrochloride is a substituted pyrimidine ring linked by a methylene group to a sulphur-containing thiazole ring
Function
Thiamin is the precursor of the coenzyme thiamin pyrophosphate. This is an essential coenzyme involved in the action of enzymes that catalyse the cleavage of C-C and C-X bonds, e.g. in many a-keto acid decarboxylations.
Dietary source
All animal and plant tissues contain thiamin. The important sources are plant seeds and the germ of cereals, nuts, peas, beans, pulses and yeasts.
Recommended requirements
Adults and children
Thiamin requirements are related to energy metabolism. The average requirement is 0.3 mg/1000 kcal, and a minimum of 0.4 mg/day.
Infants
The thiamin concentration in human milk is of the order of 0.5 μmol/l, which is equivalent to 0.3 mg/1000 kcal. The recommendation for infants is at least 0.3 mg/ 1000 kcal.
Pregnacy and lactation
There is no evidence of any increased need during normal pregnancy or lactation.
Effects of dietary deficiency
Thiamin deficiency causes beri-beri.
wet beri-beri (oedema and high output cardiac failure)
dry beri-beri (polyneuropathy) infantile form
Thiamin deficiencies are also found in chronic alcoholics:
alcoholic neuropathy, which is similar to that of dry beri-beri
thiamin-responsive cardiomyopathy
encephalopathy (the Wernicke-Korsakoff syndrome)

VITAMIN B6 —

Chemistry
Vitamin B6 is found in several forms; pyridoxal, pyridoxamine and pyridoxine, as the free form in plants and the phosphorylated form, pyridoxamine phosphate, in animal tissues.
Function
Pyridoxal-5’-phosphate is a coenzyme with a major role in the intermediary metabolism of amino acids, in a-decarboxylation, aldolization, transamination reactions, and the B-carboxylation of aspartic acid.
The aldehyde group of pyridoxal-5’-phosphate forms a Schiff base with the a-amino acid group of amino acids. Pyridoxal-5’-phosphate catalyses several different types of bond cleavage by stabilizing the electron pairs at the a- or μ-carbon atoms of a-amino acids.
Dietary source
Found in cereals, meat (particularly liver), fruits, leafy and other vegetables. Cereals, meat, fruits, leafy and other vegetables contain vitamin B6 in the range of 0.1–0.3 mg/ 100 g, and liver contains 0.5 mg/100 g.
Recommended requirements
Infants
0–12 months 0.1 -0.3 mg/day
Children 1-3 yrs. 0.5-0.6 mg / day
Adults. 1.5 mg / day
Pregnancy. 1.9 mg / day
Breast feeding mothers 2.0mg / day
Effects of dietary deficiency
Dietary pyridoxine deficiency has not been demonstrated in humans.

CARNITINE —

Chemistry
l-Carnitine [(b-hydroxy-)-g-N-trimethylaminobutyrate] is a natural constituent of higher animals.
Carnitine is derived from lysine which is a limiting amino acid in diets. The precursors of carnitine are lysine and methionine. S-Adenosylmethionine provides the methyl groups for enzymatic trimethylation of peptide-linked lysine.
Function
Carnitine plays a role in the transport of long-chain fatty acids into the mitochondrial matrix. Fatty acid acyl-CoAs only cross the inner membranes of mitochondria, after they are converted into the acyl carnitine derivative. The enzymes involved are carnitine acyltransferases.
Effects of dietary deficiency
Carnitine deficiency syndromes in humans result from inborn errors of metabolism. Clinical symptoms of dietary carnitine deficiency in infants are rarely seen.
INOSITOL ( Myo-inositol) —

Chemistry
Myo-inositol occurs as a 6 fold alcohol of cyclohexane, and can occur in one of 9 possible isomeric forms.
Function
Myo-inositol functions as an essential growth factor in many cells and also has an important cell structural role.
Myo-inositol functions in the cell in membrane phosphoinositides by stimulating the release of the second messengers 1,2-diacylglycerol and inositol triphosphate in stimulated cells.
Dietary source
Myo-inositol is found in the diet in the free form, as inositol-containing phospholipid and as phytic acid (inositol hexaphosphate). The cyclitols include the inositols of which there are nine possible isomers of hexahydroxycyclohexane.
Effects of dietary deficiency
Myo-inositol is not an essential nutrient

LIPOTROPES —

The lipotropes include choline, methionine, vitamin B12 and folic acid.
These are a group of biologically active compounds with a major role in cellular metabolism. They are essential to the synthesis and methylation of DNA, the metabolism of lipids, red blood cell biology and the maintenance of tissue integrity. The lipotropes interact with each other and with other nutrients. The role of folate, vitamin B12 and methionine are important in the transfer of one-carbon units as methyl groups. Methyl groups are involved in purine ring formation, pyrimidine biosynthesis, amino acid interconversions and formate metabolism.
The methylation of homocysteine to methionine is the metabolic link between vitamin B12, folate and methionine metabolism. The enzyme transmethylase containing vitamin B12 is required for the conversion of homocysteine to methionine. By this process tetra hydrofolate (THF) is regenerated, which is central to folic co-enzymes carrying single carbon units , ie methyl group transfer a metabolic building brick.e.g. DNA synthesis.

FOLIC ACID —

Chemistry
Folates are found in many forms throughout nature. Folic acid (pteroylglutamic acid) is a pterin ring (2-amino, 4-hydroxy pteridine) attached to p-aminobenzoic acid conjugated to l-glutamic acid (PteGlu). The variations on folic acid include di- and tetrahydro- forms of the pteridine ring; a single-carbon substitution (methyl –CH2, formyl –CHOH, methylenyl = CH–, methylene = CH2 or formimino –CHNH) at N-5 or N-10 and a chain of four to six glutamates attached to the l-glutamate.
Function
The tetra hydrofolates function as co-substrates for enzymes involved in one-carbon (1-C) metabolism, eg amino acid inter conversions and DNA synthesis .
Dietary source
Sources of folate include liver, yeast extract and green leafy vegetables. Folic acid is found in diets which contain other B vitamins
Recommended requirements
Adults and the elderly 300 μ/day
Infants and Chilren 50 μ /day for formula-fed infants.
Pregnant women and those planning a pregnancy should increase their intake of folic acid to 0.4 mg by capsule supplement.
Lactation. Breast milk contains 40 μ /day, to replace this, from the diet, an intake of 60 μ/day has been suggested.
Effects of dietary deficiency
Dietary folic acid deficiency is a cause of megaloblastic anaemia. Supplementation of dietary folic acid before conception and during pregnancy reduces the incidence of neural tube defects in the child.

VITAMIN B12 —

Chemistry
Vitamin B12 contains cobalt and has a molecular weight of approximately 1350 Da. The structure of vitamin B12 is complex, consisting of four linked pyrrole rings (a corrin) co-ordinating with a cobalt atom at the centre. The naturally occurring forms of the vitamin B12 are methylcobalamin and adenosylcobalamin.
Function
Vitamin B12 has two enzymatically active derivatives, Co-5’-deoxyadenosylcorrinoid and aquacorrinoids (methyl B12). Co-5’-deoxyadenosylcorrinoid accounts for 80% of tissue cell stores, principally in the mitochondria.
Only three reactions require vitamin B12:
1. isomerization of methylmalonyl-CoA to succinyl-CoA (enzyme methylmalonyl-CoA mutase; coenzyme Co-5¢-deoxyadenosylcorrinoid);
2. isomerization of a-leucine to b-leucine;
3.. methyl transferase reactions homocysteine to methionine.
The enzyme methyltetrahydrofolate homocysteine methyltransferase requires methyl cobalamin in the transfer of a methyl group from N-5-methyl-THF to homocysteine, which converts homocysteine to methionine.
Dietary source
In nature, vitamin B12 is combined with a protein. At the pH of the stomach, cobalamin is separated from the dietary protein-cobalamin complex by acid and pepsin.. The cobalamin is released from the haptocorrin by pancreatic enzymes and binds to intrinsic factor. Intrinsic factor is a glycoprotein secreted by the parietal cells of the stomach
Yeast is a source of cobalamin which is also found in several forms in meat, primarily as adenosyl- and hydroxycobalamin, of which one-third or one-half respectively are absorbed. Methyl cobalamin is found in egg yolk and cheese, and sulphitocobalamin in some foods. Little or no cyanocobalamin occurs in food, except for cows’ milk which contains 3 μ/ litre.
Recommended requirements
Adults 1 μ/day.
Pregnancy 1.5 μ/day during pregnancy.
During lactation an increment of 0.5 μ/day
Infants 0.1 μ/day.
Effects of dietary deficiency
A vegetarian diet free of eggs, milk and other foods of animal origin leads to the risk of vitamin B12 deficiency.
A deficiency of vitamin B12 results in megaloblastic anaemia and neurological disorders, especially in the posterolateral columns of the spinal cord. Vitamin B12 has a role in the synthesis of fatty acids in the myelin of nerve tissue.
The tape worm, Diphyllobothrium latum, can infect humans and competes with the host for vitamin B12 , Similarly, bacteria can modify vitamin B12 absorption, as in enteric colonisation which occurs spontaneously in the elderly or also in conjunction with a surgical blind loop, or small-bowel diverticuli. Some drugs, e.g. p-aminosalicylic acid, biguanides, slow-release potassium and colchicine, can also interfere with the absorption of vitamin B12.

FAT SOLUBLE VITAMINS —

VITAMIN A —

Chemistry
Vitamin A consists of a group of biologically active compounds closely related to the plant pigment carotene. The carotenoid family consists of approximately 100 naturally occurring pigments, which provide the yellow-red colour of vegetables and some fruits.
The retinol molecule consists of a hydrocarbon chain with a beta-ionone ring at one end and an alcohol group at the other. The usual form is the all-trans stereoisomer.
Function
Vitamin A is essential for growth and normal function of the retina and development of epithelial surfaces in the retina. The photopigment rhodopsin is a receptor protein which is found in the retinal rod cells. Rhodopsin consists of a membrane-embedded protein, opsin, and a light-sensitive pigment group, retinal.
Vitamin A and the retinoids act through nuclear receptor proteins which regulate gene transcription.
Dietary source
The retinol form is found in milk, butter, cheese, egg yolk and fatty fish. Liver oils of fish are good sources of vitamin A
Recommended requirements
Adults and children
For the average adult 300-500 μg/day for a male and 250-400 μg/day for a female.
Infancy
The recommendations for infants are usually based on the vitamin A provided by breast milk. A daily intake of 350 μ retinol equivalents meets a young child’s requirements, allowing for growth and maintaining liver stores.
Pregnancy
An increment of 100 μ/day during the pregnancy should meet all requirements.
Lactation
The diet of mothers who are breast feeding should contain an increment of 300 μ/day
Effects of dietary deficiency
Vitamin A deficiency is an important cause of eye malfunction, night blindness and xerophthalmia , a lesion of the conjunctiva and cornea. Other epithelial tissues, e.g. skin, are affected.
Large intakes of vitamin A are poisonous

VITAMIN D —

Chemistry
Compounds with vitamin D activity occur in several forms, including vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Most of the vitamin D3 required by humans is produced in the skin by the ultra-violet irradiation of 7-dehydrocholesterol (pro-vitamin D) which comes in animal fats
Function
Both vitamin D2 and vitamin D3 are biologically inactive. The active form of vitamin D is 1,25-dihydroxycholecalciferol (1,25(OH)2 vitamin D); this is formed in the kidney by a specific mitochondrial hydroxylase acting on 25(0H) vitamin D and is regulated by parathyroid hormone and plasma phosphate concentration.
The actions of the vitamin D family include calcium homeostasis (an interaction of parathyroid hormone and 1,25(OH)2 vitamin D), steroid hormone action (1,25(0H)2 vitamin D functions through nuclear receptors) and as a more general hormone.
1,25(OH)2 vitamin D may be a developmental hormone inhibiting proliferation and promoting differentiated function in cells
Dietary source
Vitamin D3 is produced in the skin from 7-dehydrocholesterol. Cholecalciferol is also found in fatty fish. Cholecalciferol may be regarded primarily as a hormone rather than a vitamin.
A major dietary source of vitamin D in humans is ergocalciferol. This differs from cholecalciferol in having an extra methyl group at C-24 and a double bond at C-22.
Cholecalciferol is also found in those fatty fish which eat the plankton that live near the surface of the sea
Recommended requirements
Adults
Plasma 25(OH) vitamin D concentrations range from 15–35 ng/ml in summer and 8–18 ng/ml in winter.
Infants and children
Breast milk vitamin D concentration varies through the year ; with winter milk containing very little vitamin D.
Pregnancy and lactation
Pregnant and lactating women should receive supplementary vitamin D to ensure an intake of 10 μ/day, despite seasonal variations.
Elderly
The elderly may have reduced stores because of insufficient exposure of skin for an adequate time in the summer. A daily 30-minute exposure of the face and legs will raise 25(OH) vitamin D levels at 37° latitude, whereas 1–2 hours may be necessary in the north of Britain.
Effects of dietary deficiency
The most important consequence of vitamin D deficiency is rickets, in which there is a failure to mineralise the bony skeleton. The site of the consequent bony deformities depends upon weight-bearing on the softened bones.

VITAMIN K —

Chemistry
Vitamin K is a naphthoquinone. There are two forms: vitamin K1 is from the plant lucerne, a phytylmenaquinone (phylloquinone); vitamin K2 is produced by bacteria and has 4 to 13 isoprenyl units in its side chain.
Function
Vitamin K is involved in the synthesis of blood coagulation proteins, prothrombin and Factors VII, IX and X. Vitamin K is necessary for the post-translational carboxylation of glutamic acid to Y-carboxyglutamate in the coagulation proteins which allows the binding of calcium and phospholipids in the formation of thrombin.
When warfarin, an anticoagulant, is prescribed, conversion to g-carboxyglutamate does not occur and the coagulation proteins are ineffective in clotting mechanisms.
Dietary source
Vitamin K1 is present in fresh green vegetables, e.g. broccoli, lettuce, cabbage and spinach. Beef liver is a good source. Vitamin K2 as menaquinones is produced by intestinal bacteria.
Adults
The dietary requirements of phylloquinone are between 0.5 and 1.0 μ /kg body weight per day.
Infants
Vitamin K in human milk is almost entirely in the form of phylloquinone and may vary between 1 and 10 μ /litre. A reasonable provision for an infant fed on breast milk would be approximately 8.5 μ phylloquinone.
Vitamin K is given in haemorrhagic disease of the newborn. In approximately 1 in 800 newborn babies, bleeding into the tissues occurs (including skin, peritoneal cavity, alimentary tract or central nervous system) between the second and fifth day. In some countries, e.g. Britain, vitamin K is given routinely at delivery.
Effects of dietary deficiency
When there is vitamin K deficiency, the activities of Factors VII, IX and X are reduced and the blood clotting time is prolonged.

VITAMIN E —

Chemistry
Vitamin E is a term for any mixture of biologically active tocopherols. Eight tocopherols and tocotrienols with vitamin E activity are known, the differences being in the number and positions of the methyl groups around the ring of the molecule.
Function
Vitamin E acts as antioxidant or a free-radical scavenger in chemical systems and is associated with membranous organelles, miscible with lipids of the biological membrane.
Vitamin E is the only known lipid-soluble anti-oxygant in plasma and in red cell membranes.
Ascorbic acid may reduce tocopheroxyl radicals formed by the scavenging of free radicals during metabolism. This enables the single molecule of tocopherol to scavenge many radicals. Vitamin C is therefore protective in membranes against free-radical damage.
Dietary source
Abundant sources are vegetable oils, wheatgerm, sunflower seed, cottonseed, safflour, palm, rape seed and other oils
Recommended requirements
Adults
The average intake in Britain is 6 mg/day, of which 26% is derived from fats and oils and 9% from cereals.
Intakes of 4–10 mg and 3–8 mg of a-tocopherol equivalents per day respectively for men and women have been recommended .
Infants
Human milk has a varied vitamin E content, up to concentrations of 1 mg a-tocopherol equivalents/ 100 ml in colostrum, which may reduce to 0.32 mg/100 ml at 12 days and remains constant thereafter. This would give the infant consuming 850 ml of breast milk a daily intake of 2.7 mg.
Effects of dietary deficiency
Deficiency may show with neurological disabilities, ataxia, lost reflexes, decreased vibration sensation, and oculomotor weakness.