Deficit vitamínu a jeho symptomy

Alpha-tocopherol deficiency due to mutations in the alpha-TTP gene

• Associated with neurological symptoms, including ataxia

Ataxia with vitamin E deficiency (AVED) - primární - dědičná vzácná choroba

• Progressive disease
• Affecting motor control and movement

Hlas

• Slurred speech (dysarthria)
• Scanning speech pattern [4]

Ataxie

• Difficulty coordinating movements (ataxia)
• Progressive ataxia
• Clumsiness of the hands
• A nodding movement of the head (titubation) - characteristic head tremor [4]
• Positive Babinski sign (upward movement of the big toe and fanning of the feet after the sole of the foot has been firmly stroked)
• Handwriting deteriorates [4]
• Rarely, AVED may manifest as arm or cervical dystonia [Becker et al 2016]. [4]
• Urinary urgency (22.4%) [4]

PNS

• Numbness in the hands and feet (peripheral neuropathy)
• Progressive leg weakness
• Loss of the ability to know where one's body is in space (proprioception)
• Absent reflexes (areflexia)
• A tendency to sway or fall while standing upright with the feet together, arms stretched out and the eyes closed (positive Romberg sign)
• Difficulty walking in the dark [4]
• Partial loss of the sense of touch or sensitivity to pain and temperature may also occur.
• With time, reflexes in the legs may slow or be absent (areflexia) [6]

Svalovina

• Urinary incontinence (4.0%) [4]

Držení těla

• Scoliosis
• Dystonia
• Involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). [6]

Klenba nohy

• Abnormally high-arched foot (pes cavus) may develop
• Overextension (hyperextension) of the big toe.

Srdce

• Cardiomyopathy (1.5%) [4]
• With progressing deficiency in humans, there is also muscle deterioration, and this deterioration can include the heart muscle. [7]

Throat muscles

• May lead to impaired swallowing and choking
• May cause difficulty in eating

Tendinopatie

• “fatty” deposits (xanthomas) affecting the Achilles tendon

Zrak

• Some affected individuals may experience
• Vision loss due to damage to the back of the eye (retinitis pigmentosa)[3]
• Decreased visual sharpness (acuity)
• Macular atrophy (wasting away of the cells that form the part of our eye responsible for central vision)
• Retinitis pigmentosa (RP)(eye disease in which there is damage to the retina) [3]
• Nystagmus (5.3%) [4]
• Retinitis pigmentosa (2.3%) [4]
• Yellow “fatty” deposits (xanthelasmata) in the retina [4]
• Visual impairment in a middle-age patient with AVED
• By both RP
• By early-onset macular degeneration [10]

Mentální funkce

• In rare individuals, school performance declines secondary to loss of intellectual capacities [4]
• In some persons, psychotic episodes, intellectual decline, and dystonic episodes have been described. [4]
• Intellect and emotions are rarely affected. [7]

Průběh ataxie with vitamin E deficiency (AVED) - dědičného onemocnění

• Symptoms typically begin during childhood or adolescence
• And worsen with age
• Resulting in the need for a wheelchair by early adulthood [3]
• Between ages 11 and 50 years [Harding et al 1985, Ouahchi et al 1995, Hentati et al 1996, Cavalier et al 1998, Gabsi et al 2001, Benomar et al 2002, Mariotti et al 2004]. [4]

Skolioza

• Abnormal curvature of the spine (scoliosis) [6]

Dif. dg. AVED - ataxie

• Diseases that cause fat malabsorption
• Abetalipoproteinemia [3]
• Friedreich ataxia,
• Sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO)
• Autosomal recessive cerebellar ataxias
• Refsum disease,
• Ataxia telangiectasia,
• Charcot-Marie-Tooth disease 1A
• Ataxia with oculomotor apraxia types 1 and 2 [3]

Ataxia

• vit. E below 8 µmol/L (IOM, 2000) in plasma/serum [2]
• Develop progressive weakness of the legs
• May appear as a staggering, lurching way of walking (gait)
• Or trembling when an affected individual is standing still. [6]
• Ataxia is defined as a failure of muscle coordination that generally results in an unsteady gait. [6]
• Spinocerebellar ataxia, which occurs as a result of a dying back of peripheral nerves, specifically sensory neurons [7]
• Degeneration of neurons, particularly peripheral axons and posterior column neurons [9]

Primary or secondary alpha-tocopherol deficiency

• Concentrations of about 2.5–12 µmol/L have been reported [2]

RBC haemolysis

• Change in plasma/serum alpha-tocopherol concentration has also been related to the percentage of RBC haemolysis [2]
• Peroxidative damage resulting from oxidative stress can lead to shortening of RBC life
• Possibly precipitate haemolysis in alpha-tocopherol deficiency
• Measuring the degree of haemolysis induced by hydrogen peroxide (or dialuric acid) in vitro [2]
• In a depletion–repletion study of over eight years (Horwitt et al., 1956; Horwitt, 1960, 1962; Horwitt et al., 1963)
• 38 men received either
• Basal diet providing about 3 mg/day of alpha-tocopherol (‘depletion’, n = 19)
• Basal diet supplemented with RRR-alpha-tocopheryl acetate15 (n = 9)
• Hospital diet ad libitum (n = 10) [2]
• Depleted group (over 70 months), plasma ‘tocopherol’ concentration
• Decreased from about 23 µmol/L to about 4.5 µmol/L
• Haemolysis increased from about 0 % to remain at about 80 % after approximately 28 months [2]
• In the supplemented group
• Haemolysis remained close to 0 % for about 60 months (Horwitt, 1960)
• Some subjects who had been on the depleted diet for 54 months
• Haemolysis and plasma ‘tocopherol’ concentration responded to supplementation
• At varying doses between 7.5 and 320 mg/day RRR-alpha-tocopheryl acetate for 138 days (Horwitt, 1960) [2]
• In four subjects depleted for 72–76 months (Horwitt et al., 1963)
• Haemolysis was 80–97 %
• Plasma ‘tocopherol’ concentration was about 1.5–5 µmol/L [2]
• In one subject on the basal diet supplemented for 74 months
• Five subjects on the hospital diet for 74–76 months
• Haemolysis was 1–12%
• Plasma ‘tocopherol’ concentration was 11.5–21.5 µmol/L (average at about 16 µmol/L) [2]
• Haemolysis between 3 and 12 % should be considered as similar
• Increase in the percentage of RBC haemolysis up to ‘high’ values
• Took several months in depleted men receiving a basal diet providing about 3 mg/day of alpha-tocopherol
• Dose–response relationship between alpha-tocopherol intake and hydrogen peroxide-induced haemolysis remains unclear. [2]

Main symptoms of vitamin E deficiency

• Mild hemolytic anemia
• Nonspecific neurologic deficits [9]

Cigarette smoking, mortality and vit. E levels

• Increase the utilization of alpha-tocopherol
• Smokers might be at increased risk of deficiency compared with nonsmokers
• 19-year follow-up analysis of the Alpha-Tocopherol, Beta-Carotene cancer (ATBC) trial in older, male smokers
• Participants in the highest versus lowest quintile of serum alpha-tocopherol concentrations
• Nad 31 µmol/L vs. pod 23 µmol/L at baseline had reduced risks of total and cause-specific mortality [10]

Laboratory studies in ataxie with vitamin E deficiency (AVED) - dědičného onemocnění

• Reduced plasma vitamin E concentration but normal levels of lipoproteins [3]

May be useful

• Nerve conduction studies,
• Brain imaging,
• Studies of nerve tissues [3]

Neuroimaging

• Cerebellar atrophy [Mariotti et al 2004];
• Present in approximately half of reported individuals [4]
• Small T2 high-intensity spots in the periventricular region and the deep white matter [Usuki & Maruyama 2000];
• Inconsistent finding in some individuals [4]
• No radiologic findings are specific to or diagnostic of AVED. [4]

Histopathology findings

• [Larnaout et al 1997, Yokota et al 2000, El Euch-Fayache et al 2014, Ulatowski et al 2014]
• Spinal sensory demyelination with neuronal atrophy and axonal spheroids [4]
• Dying back-type degeneration of the posterior columns [4]
• Neuronal lipofuscin accumulation in the third cortical layer of the cerebral cortex, thalamus, lateral geniculate body, spinal horns, and posterior root ganglia [4]
• Fiber type grouping of the peroneus brevis muscle [4]
• Mild loss of Purkinje cells [4]

Nezralí novorozenci s defic. vit. E

• Retinopathy of prematurity = retrolental fibroplasia
• In premature infants
• Some cases of intraventricular and subependymal hemorrhage in neonates
• Affected premature neonates have muscle weakness [9]

• A snaha dodývat jim kyslík, aby to jejich nezralé plíce udýchaly, toto může zhoršit, pokud se nepomylsí na vit. E

• Developing nervous system appears to be especially vulnerable to vitamin E deficiency
• At birth rapidly experience irreversible neurologic symptoms if not treated with vitamin E during defficiency [10]

Plasma alpha-tocopherol concentrations pod 12 µmol/L

Are associated with

• Increased infection,
• Anemia,
• Stunting of growth,
• Poor outcomes during pregnancy for both the infant and the mother [7]

Low dietary amounts of alpha-tocopherol are consumed

• Tissue alpha-tocopherol needs exceed amounts available
• Increased damage to target tissues [7]

Porucha svaloviny

• Impaired skeletal muscle function and accumulation of ceroid pigments in smooth muscle tissue
• Reported at plasma alpha-tocopherol concentrations below 12 µmol/L (Stamp and Evans, 1987) [2]
• Vitamin E deficiency ultimately results in death. [7]
• In severe vitamin E deficiency, cardiomyopathy was among the symptoms of a vitamin E–deficient child who died of hepatic and cardiac failure [7]

Potraty

• Nested case-control study in Bangladeshi women
• Inadequate vitamin E status during early pregnancy may be associated with an increased risk of miscarriage [10]

Preeklampsie

Podaří se mi něco najít ?

Trombotizace placenty / Placentární insufficience

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Primary alpha-tocopherol deficiency - familial isolated alpha-tocopherol deficiency

• Associated with neurological symptoms, including ataxia
• Mutations in the alpha-TTP gene (Ouahchi et al., 1995)
• Carriers of variant alleles in the alpha-TPP gene
• Serum alpha-tocopherol concentrations even lower than 2.3 µmol/L have been reported (Cavalier et al., 1998; IOM, 2000; Mariotti et al., 2004). [2]

Fetal resorption in pregnant rats

• Need for alpha-tocopherol in order to prevent [2]

Occurring in alpha-tocopherol-deficient individuals

• Alpha-tokopherol prevents
• Haemolytic anaemia
• Neurological symptoms
• Ataxia,
• Peripheral neuropathy,
• Myopathy,
• Pigmented retinopathy [2] (Muller, 1986)

Symptomatic alpha-tocopherol deficiency

• In individuals without any disease and who consume diets ‘low’ in alpha-tocopherol has not been reported (IOM, 2000) [2]
• Adults with malabsorption, vitamin E deficiency very rarely causes spinocerebellar ataxia because adults have large vitamin E stores in adipose tissue [9]
• Individuals who develop gastrointestinal disorders affecting vitamin E absorption in adulthood
• May not develop neurologic symptoms for 10-20 years [10]

Is vitamin E deficiency an important cause of spontaneous embryonic death?
Vitamin E was discovered nearly 100 y ago because female rats fed a vitamin E–deficient diet resorbed their fetuses early in pregnancy (71); the cause of the embryonic failure has never been fully characterized. We investigated embryonic vitamin E deficiency in a vertebrate model, the zebrafish (Danio rerio), and discovered that ?-tocopherol and ?-TTP have critical roles in embryonic development. We based our research on the observation that ?-TTP is expressed in the human yolk sac (72), that zebrafish embryos abundantly express ?-TTP by 48 h postfertilization (hpf), and that ?-TTP increases with oxidative stress in zebrafish embryos (73). We discovered that ?-tocopherol–deficient adult zebrafish could spawn and produce viable fertilized eggs, but within days the embryos suffered developmental impairment and increased mortality (74). The impaired brain formation in ?-TTP knockdown zebrafish embryos raises the possibility that low vitamin E status has adverse events in early central nervous system development in other animals, including humans. Jishage et al. (75) showed that if the mother mouse did not express ?-TTP and was not vitamin E supplemented, embryos (regardless of ?-TTP status) developed neural tube defects and failed to come to term. Although the study by Jishage et al. focused on mouse maternal ?-TTP deficiency, the embryonic phenotype and link to central nervous system development are similar to our findings in the zebrafish. In support of this notion, previous studies showed a clear association between maternal vitamin E status during gestation and cognitive function of the offspring in experimental animal models (76, 77). [7]
Importantly, we found that in the zebrafish embryo, ?-TTP knockdown caused head malformation before 15 hpf (78). This phenomenon coincides with the timing for increased synthesis of highly peroxidizable lipids by the embryo, evidenced by increased gene expression in the head/brain of 2 FA elongase enzymes, elongation of very long-chain fatty acid (Elovl)4 (79) and Elovl5 (80). When we measured specific PUFA concentrations in zebrafish embryos between 24 and 72 hpf, we found that both ?-tocopherol and DHA concentrations decreased in vitamin E–deficient embryos but not in control embryos. Moreover, arachidonic acid concentrations decreased 3 times faster in ?-tocopherol–deficient embryos (21 pg/h) compared with vitamin E–sufficient E embryos (7 pg/h) (P < 0.0001) (81). At 36 hpf, vitamin E-deficient embryos contained double the 5-hydroxy-eicosatetraenoic acids and 7-hydroxy-DHA concentrations, whereas other detectable hydroxy-lipids remained unchanged (81). Thus, vitamin E deficiency during embryogenesis depleted both omega-3 and omega-6 FAs (DHA and arachidonic acid, respectively) and increased hydroxy-FAs derived from these PUFAs, suggesting that ?-tocopherol is necessary to protect these critical FAs during development of the nervous system. Our studies show that the target zone that is most sensitive to ?-tocopherol depletion is the head/brain/eye; without delivery of ?-tocopherol, the brain fails to develop properly (78). [7]
This absolute requirement for ?-tocopherol by the zebrafish embryo takes place during a time analogous to the first 20 d of human embryonic gestation, a time during pregnancy before a woman knows she is pregnant. This time frame is 10–15 hpf for the zebrafish embryo (82), 9.5 d for rats (83), and 17–19 d for humans (84–86). Thus, the requirement for vitamin E very early in human pregnancy is analogous to situations of inadequate folic acid status. [7]
The importance of ?-tocopherol for preventing neural tube defects in humans can be surmised from studies in which multivitamins were compared with folic acid supplements. Specifically, folic acid supplements were not as effective in preventing neural tube defects as folic acid/multivitamin combinations, as shown in a review of 5 human trials (87). In a Hungarian trial to evaluate neural tube defects, the multivitamin contained 15 mg vitamin E along with other vitamins (88). The importance of vitamin E in preventing neural tube defects is emphasized by the findings from a study of neural tube defects and maternal micronutrient intakes, including 954 cases (300 with anencephaly, 654 with spina bifida) and 6268 controls (89). A decreased risk of spina bifida was associated with increased intakes of preconception supplements containing antioxidant vitamins E and C, as well as other micronutrients (89). The importance of vitamin E in the nervous system was also supported by a study in China that showed that higher maternal and cord blood ?-tocopherol concentrations at birth were associated with improved cognitive function when the child was assessed at age 2 y (90). And conversely, low plasma ?-tocopherol concentrations were associated with poorer cognitive function in patients with cystic fibrosis at diagnosis (91, 92).Vitamin E in pregnancy. [7]
The role of vitamin E in pregnancy is of increasing concern because it is clear that adequate nutritional status for the first 1000 d of life is necessary for subsequent adult health and well-being, given that stunting cannot be reversed after this critical window (93). Moreover, a study in Egypt emphasized that vitamin E is a key missing micronutrient in stunted children (56). The authors showed that 78.2% of stunted children were vitamin E deficient, with plasma ?-tocopherol concentrations of 7.7 µmol/L compared with 14.1 µmol/L in control children (56). Fares et al. (94) reported that vitamin A, E, and D deficiencies were very common in very-low-birth-weight Tunisian neonates and were associated with pre-eclampsia (94). However, pre-eclampsia risk was not changed by vitamin E and C supplements in a number of studies in Western countries (95–99). The lack of benefit of vitamin E supplements in pre-eclampsia may be a result of the relative adequacy of vitamin E status of the women studied. For example, Poston et al. (99) reported that the circulating ?-tocopherol:cholesterol ratios were >6 µmol/mmol in the placebo group and >9 µmol/mmol in the vitamin E and C supplement group; these ratios indicate that even the placebo group was well nourished with respect to vitamin E. Taken together, these data indicate that low vitamin E status may increase pre-eclampsia risk, but women with adequate vitamin E status do not benefit further from vitamin E supplements. The definitions of what is “low” and “adequate” vitamin E status are not clearly delineated and merit further research. [7]
Worldwide, the adequacy of ?-tocopherol status during pregnancy is unclear and not frequently measured, and thus the utility of vitamin E supplements in improving outcomes has been variable. In situations in which ?-tocopherol status was documented to be low, vitamin E supplements had beneficial outcomes. For example, multivitamin supplements containing vitamin E reduced adverse pregnancy outcomes in HIV-positive women in Tanzania (100, 101). However, by using a cutoff of <11.6 µmol/L for plasma ?-tocopherol concentrations, the prevalence of low vitamin E status was 5.9% of nonpregnant women of reproductive age in the northern Persian Gulf region, leading the authors to conclude that most women had an adequate vitamin E status. Additionally, in a study in the United States (n = 9968; n = 4992 in the vitamin group and n = 4976 in the placebo group), where at baseline pregnant women were taking 22 IU vitamin E in a daily multivitamin (equal to the RDA), additional vitamin E supplements (400 IU) were not beneficial in reducing the risk of preterm births (102). By contrast, vitamin E supplements were associated with a decreased incidence of preterm births in a Hungarian population study (103). Although it is apparent that the vitamin E status of pregnant women must be adequate to successfully bear a child, these findings suggest that vitamin E supplements in excess of the RDA to adequately nourished women do not provide additional benefits.Neurologic disease and cognitive impairment with age. [7]
Given the importance of vitamin E in the developing nervous system and for the protection of peripheral nerves, as supported by studies in vitamin E–deficient humans and in experimental animals, it seems likely that vitamin E would also protect the nervous system with aging. There are some experimental data to support this hypothesis, especially with regard to Alzheimer disease. Vitamin E supplements were found to have benefit in slowing Alzheimer disease progression (104, 105), but they did not seem to prevent Alzheimer disease occurrence (106). A recent meta-analysis found that patients with Alzheimer disease compared with cognitively intact elderly controls had significantly lower plasma ?-tocopherol concentrations (P < 0.001) (107). Moreover, higher ventricular cerebrospinal fluid ?-tocopherol concentrations, measured postmortem in 230 participants from the Religious Orders Study, were associated with a lower density of neuritic plaques and with higher performance on tests of perceptual speed measured before death (108). Furthermore, compared with cognitively normal individuals, patients with either Alzheimer disease or mild cognitive impairment had lower circulating concentrations of all forms of vitamin E and both disorders were associated with increased oxidized vitamin E (109).
In experimental vitamin E deficiency in mice, axonal degeneration was observed in the hippocampus, an important area for memory and cognition (110). The combination of vitamin E deficiency and ?-TTP deficiency in mice caused atrophy and decreased branching of Purkinje neurons, which was associated with deficits in motor coordination and cognitive functions that were normalized upon vitamin E supplementation (111). Additionally in mice, impaired vitamin E delivery to the brain resulting from a knockout of the phospholipid transfer protein also resulted in increased memory impairment 1 wk after abeta25–35 peptide injection (112). This impairment could be prevented by vitamin E supplementation (112). These experimental findings are consistent with a report in elderly humans showing that a lifelong dietary pattern that results in nutrient intakes that provide increased circulating concentrations of vitamins B, C, D, and E is associated with a larger brain size (as assessed by MRI) and higher cognitive function (113). [7]
Given the importance of vitamin E in protecting unsaturated FAs, it is not surprising that patients with Alzheimer disease have increased concentrations of circulating lipid peroxidation products (114). Importantly, phosphatidylcholine 16:0/22:6 (DHA-PC 38:6), which contains the highly oxidizable FA DHA, was identified as 1 of 10 phospholipids that were depleted in the plasma of human participants who went on to develop Alzheimer disease (115). By contrast, individuals who were in the top quartile of plasma DHA-PC concentrations among the Framingham Heart Study participants had a significant 47% reduction in the risk of developing all-cause dementia (116). Taken together, these findings suggest that vitamin E protects critical FAs in the brain from lipid peroxidation and that improved brain vitamin E status is protective for cognitive function. Interestingly, vitamin E supplements (300 mg daily for 615 d compared with 30 mg for 361 d) were found to double brain ?-tocopherol concentrations in a study carried out in 2 terminally ill patients (117). [7]Conclusions and Speculations
This review evaluated the information available on the adverse consequences of inadequate ?-tocopherol status. In general, plasma ?-tocopherol concentrations <12 µmol/L are associated with increased infection, anemia, stunting of growth, and poor outcomes during pregnancy for both the infant and the mother. When low dietary amounts of ?-tocopherol are consumed, tissue ?-tocopherol needs exceed amounts available, leading to increased damage to target tissues. Hypothetically, these low ?-tocopherol intakes in humans lead first to anemia because of the relatively rapid turnover of erythrocytes and their exposure to oxygen and their high iron contents. Further damage might be expected in other tissues with rapid turnover. Potentially, intestinal cells are spared because they are exposed to other dietary antioxidants, as well as to low oxygen concentrations. The nervous system is a special case because ?-tocopherol is retained in the brain, likely as a result of brain expression of ?-TTP (111). With continued extrahepatic tissue ?-tocopherol depletion, peripheral nerves are at risk (5), likely due to their high PUFA contents compared with surrounding tissues. Sensory compared with motor neurons are likely more at risk because the information flow in sensory neurons is from the periphery to the brain, whereas in motor neurons the flow is in the opposite direction, potentially moving ?-tocopherol toward the periphery. Severe, or perhaps chronic, vitamin E depletion ultimately decreases brain ?-tocopherol, leading to damage and, in the elderly, cognitive impairment. [7]
The adequacy of the middle range of ?-tocopherol intakes is difficult to define. Plasma ?-tocopherol concentrations between 12 and 20 µmol/L can be raised with increases in dietary intake, suggesting that hepatic ?-TTP is not saturated. Studies in experimental animals suggested that hepatic ?-TTP maintains circulating ?-tocopherol, redistributing it and potentially allowing tissue ?-tocopherol depletion (118). In this case, ?-tocopherol returning from the periphery to the liver is not metabolized but is salvaged by hepatic ?-TTP and returned to the plasma (119), where it could be taken up by tissues with lipoprotein receptors. This process tends to increase circulating ?-tocopherol concentrations and normalize them at the expense of depletion of tissue ?-tocopherol. [7]
Hepatic ?-tocopherol trafficking, disposition, and metabolism are not well understood or characterized. The well-known lack of correlation between dietary vitamin E intakes and circulating ?-tocopherol [for examples, see (58, 120, 121)] in this middle range of intakes speaks to the efficiency of the regulatory controls governing circulating ?-tocopherol concentrations. These processes serve to protect circulating lipids, which are readily oxidized and potentially exposed to higher oxygen concentrations, as well as reactive oxygen species and free metals. Here the special case of fatty liver disease is of interest because the progression of this disorder to more serious forms of the disease is dependent on oxidative damage to lipids (122), suggesting that inadequate vitamin E intakes may promote disease progression. [7]
Supplements providing vitamin E intakes in excess of 100-fold dietary intakes increase plasma concentrations by ~2- to 4-fold above baseline values (123–126). The limitation on plasma concentrations appears to be a result of increased hepatic vitamin E metabolism and excretion, as discussed previously (40). Intakes of 12–15 mg ?-tocopherol/d are sufficient in normal healthy adult individuals to provide adequate vitamin E status on the basis of the health benefits associated with these intakes (127) [7]