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Giant axonal neuropathy

Giant axonal neuropathy is a rare inherited condition that causes disorganization of neurofilaments. Neurofilaments form a structural framework that helps to define the shape and size of neurons and are essential for normal nerve function. more...

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Giant axonal neuropathy generally appears in infancy or early childhood, and slowly progresses as more cells become involved. Signs of giant axonal neuropathy usually begin in the peripheral nervous system, which controls the arms, legs and many other areas of the body. Most individuals with this disorder first have problems with walking. Later they may lose sensation, coordination, strength, and reflexes in their limbs. Hearing or vision problems may also occur. Extremely kinky hair is characteristic of giant axonal neuropathy, appearing in almost all affected people. As the disorder progresses, central nervous system become involves. This may cause a gradual decline in mental function, loss of control of body movement, and seizures.

Giant axonal neuropathy is caused by mutations in the GAN gene, which provides instructions for making a protein called gigaxonin. Some GAN mutations affect the shape of the protein, changing how it binds to others in organizing the structure of the neuron. Other mutations result in the absence of any functional gigaxonin protein.

Neurons affected by a mutated GAN gene accumulate excess neurofilaments in the axon, the long extension from the nerve cell that transmits its signal to other nerve cells and to muscles. These distended or giant axons do not transmit signals properly and eventually deteriorate, resulting in problems with movement and other nervous system functions. The disease is inherited in an autosomal recessive pattern which means both parents must have mutated GAN genes.

This article incorporates public domain text from The U.S. National Library of Medicine


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Highlights of the Surgeon General's Report on Nutrition and Health
From Alcohol Health & Research World, 6/22/89

Highlights of the Surgeon General's Report on Nutrition and Health

According to the Surgeon General's Report on Nutrition and Health (U.S. Department of Health and Human Services 1988), alcohol-related diseases include both the direct toxic effects of alcohol and the indirect effects caused by the nutritional deficiencies found in alcoholics.

This issue of Alcohol Health & Research World presents articles on the possible role of nutrition in conjunction with alcohol abuse in the development of such diseases as fetal alcohol syndrome, liver disease, and pancreatitis. The following sections, excerpted from the Surgeon General's Report on Nutrition and Health, present what is known about alcohol and nutritional interactions in the development of diseases not covered in this issue--namely, diseases of the nervous system and cardiovascular disease. The highlights also refer to the Surgeon General's "Implications for Public Health Policy."


Wernicke-Korsakoff's Syndrome

Wernicke's encephalopathy is characterized by weakness of eye movements, gait disturbance, and confusion, and Korsakoff's psychosis by amnesia, a disordered sense of time, and confabulation. The two conditions probably represent a continuum, and they usually occur together as Wernicke-Korsakoff's syndrome. In approximately one-fourth of patients, the memory disturbance is completely reversible. In half of the cases, improvement ranges from slight to significant although the memory loss can be incapacitating, but in the remaining one-fourth of the patients, the memory disturbance is completely irreversible (Dreyfus 1979). If Wernicke's encephalopathy goes unrecognized, the chances of preventing its progression to Korsakoff's psychosis and resolving its manifestations are reduced.

In alcoholics, Wernicke-Korsakoff's syndrome is caused more by thiamin deficiency than by the direct toxic effect of alcohol. The eye manifestations of Wernicke's encephalopathy respond rapidly to thiamin administration, although the associated ataxia and confusion respond more slowly. Brain lesions similar to those found in patients with Wernicke-Korsakoff's syndrome are found in the brains of animals that are deficient in thiamin (Victor et al. 1971). Alcohol may directly or indirectly affect thiamin intake, absorption, storage, metabolism, and excretion (Hoyumpa 1983). Another possible mechanism includes altered cerebral energy metabolism resulting from deficiencies in the function of thiamin-dependent enzymes; these deficits can affect energy production, diminish acetylcholine neurotransmission, and impair DNA syntheses (Reuler et al. 1985). Subclinical thiamin deficiency, as measured by the activity of the thiamin-dependent enzyme erythrocyte transketolase, may occur in as many as one-third of alcoholics suspected of having liver disease (Camilo et al. 1981). Because alcohol inhibits active rather than passive transport of thiamin, supplementation of the vitamin in amounts larger than the Recommended Dietary Allowance can overcome the thiamin malabsorption caused by alcohol (Lieber 1983).

The variations in clinical presentation and the fact that most persons with thiamin deficiency do not have Wernicke-Korsakoff's syndrome raise the possibility that there may be genetic variants that predispose individuals to its development (Blass and Gibson 1977). For example, a variant of transketolase with a low affinity for the coenzyme thiamin pyrophosphate was found in all of four patients with Wernicke-Korsakoff's syndrome but in none of six control patients. There is considerable evidence that isoenzymes of human erythrocyte transketolase exist, but the significance of such heterogeneity and its relationship to differential susceptibility to Wernicke-Korsakoff's syndrome has not been determined (Nixon 1984).

Because the rate of long-term institutionalization for persons admitted for Korsakoff's psychosis is 30 to 40 percent, some experts have proposed that thiamin be considered for addition to alcoholic beverages (Centerwall and Criqui 1978).

Alcoholic Peripheral Neuropathy

Alcoholic peripheral neuropathy, a distal mixed motor sensory neuropathy primarily affecting the lower extremities, is probably the most common neurologic complication of alcoholism, and it occurs in over 80 percent of persons with severe neurologic problems such as Wernicke's encephalopathy (Victor et al. 1971). The predominant pathologic abnormality is a "dying back" degeneration of nerve axons that affects distal segments of the longest nerve fibers (Behse and Buchthal 1977). Recovery from alcoholic peripheral neuropathy is slow and often incomplete.

In the early part of this century, thiamin deficiency was considered to be the cause of alcoholic peripheral neuropathy (Shattuck 1928). That a nutritional deficiency plays a role in its development is supported by many factors: the clinical and pathologic features are similar to those seen in beri-beri, the classic thiamin deficiency disease; patients with alcoholic peripheral neuropathy have been shown to have deficiencies of thiamin, folic acid, and other B-complex vitamins; improvement may occur with vitamin supplementation; and thiamin deficiency alone can cause a similar type of peripheral neuropathy.

Some evidence suggests that the toxic effects of alcohol alone may cause peripheral nerve damage because some patients with alcoholic neuropathy show no evidence of any nutritional deficiency (Behse and Buchthal 1977). Other evidence suggests that both diet and alcohol toxicity are at fault. A heavy alcohol intake and a poor diet result in acute axonal degeneration; in persons with chronic neuropathy, a long history of alcohol intake, but a good diet, however, there is little evidence of nerve regeneration (Walsh and McLeod 1970). Supplementation with B-complex vitamins and an improvement in overall nutritional status are important in the treatment of this disease, but abstinence from alcohol may be the single most important factor.

Alcoholic Dementia

The toxic effects of alcohol on the brain have received greater attention since the development of computed tomography (CT). In young alcoholics, cerebral atrophy as measured by CT may be reversed with the cessation of excessive drinking (Ron et al. 1982), but the associated cognitive dysfunction, labeled as alcoholic dementia, may be due in part to nutritional deficiencies. In one study, pathologic examination of alcoholic persons showed changes in the brain consistent with Wernicke's encephalopathy, although clinical signs of the disease were absent (Torvik et al. 1982). The syndrome of alcoholic dementia is also probably due to a combination of thiamin deficiency and the direct toxic effects of alcohol on the brain (Nakada and Knight 1984).


Alcoholic Cardiomyopathy

The adverse effects of alcohol on the heart muscle, or myocardium, have been known since the 1700's when William Withering observed that 10 percent of the patients to whom he administered foxglove (containing digitalis) for heart failure were excessive users of alcohol. Similar observations relating alcohol abuse to heart failure were made by other scientists, such as Steell in the late 1800's and Osler in the early 1900's, but these early observations were all but forgotten when beriberi heart disease was described in thiamin-deficient alcoholics (Weiss and Wilkins 1937). As with many other alcohol-associated conditions, nutritional deficiencies were presumed to be responsible for heart failure in alcoholics, and it was not until the early 1960's that alcohol was recognized to have a direct toxic effect on the myocardium (Brigden and Robinson 1964). Beriberi heart disease and the congestive cardiomyopathy of alcoholism are now known to be distinctly different entities.

The theory that alcoholic cardiomyopathy is caused by the direct toxic effect of alcohol on the myocardium has strong support. The ultrastructural changes seen in the myocardial cells of a person with alcoholic cardiomyopathy, such as fragmentation of myofibrils, clusters of giant mitochondria with distorted membrane folds, dilated sarcoplasmic reticulum, and increased glycogen and fat deposits, are similar to those seen in the livers of persons with alcoholic liver disease. Furthermore, thiamin administration and other nutritional therapies alone have produced no benefit in persons with alcoholic cardiomyopathy. The only factor shown to affect recovery significantly is abstinence from alcohol (Demakis et al. 1984).

The manner in which alcohol produces its direct toxic effect on cardiac muscle is unclear, although acetaldehyde, the first product of alcohol oxidation, may induce myocardial damage (Schreiber et al. 1972) and has been shown to diminish myocardial protein synthesis (Bing 1978). Changes in cardiac metabolism may also be involved. Alcohol inhibits mitochondrial respiration and the activity of mitochondrial enzymes in the tricarboxylic acid cycle in addition to interfering with mitochondrial calcium binding and uptake. Alcoholics display blood levels of acetaldehyde high enough to inhibit the association of the muscle proteins actin and myosin in vitro and to interfere with mitochondrial protein synthesis (Rubin 1979).


Another manifestation of the ability of alcohol to produce cardiac toxicity is seen in persons with alcohol-induced dysrhythmia, dubbed "the holiday heart syndrome" because it occurs more frequently around holidays such as New Year's Eve when alcohol intake is generally highest (Ettinger et al. 1978). Individuals with unexplained acute atrial fibrillation have been shown to have a significantly higher rate of heavy alcohol consumption than control persons (Rich et al. 1985). Alcoholics with evidence of myocardial dysfunction are more sensitive to the depressant effects of alcohol on the heart and to atrial and ventricular dysrhythmias following the acute administration of alcohol. Serious dysrhythmias have been observed in patients consuming as little as 7 ounces of vodka (Singer and Lundberg 1972).

Hemodynamic Effects

Acute alcohol ingestion produces complex changes in cardiovascular physiology, including dilation of peripheral blood vessels and diminished blood return to the heart. Recent studies have shown that acute alcohol ingestion in normal subjects has a depressant effect on heart muscle action (Lang et al. 1985), but in one group of patients with congestive heart failure, a single intoxicating dose of alcohol significantly reduced pumping efficiency without causing any significant deterioration in cardiac performance (Greenberg et al. 1982). It is well established from both animal and human studies that chronic alcohol use injures the heart muscle, depresses ventricular function, and impairs cardiac performance. Over time, alcohol abuse may Over time, alcohol abuse may lead to irreversible damage to the heart muscle and cause congestive heart failure or cardiac arrhythmias.


Most studies have indicated that a self-reported average consumption of three to four alcoholic drinks per day causes a measurable increase in both the systolic and diastolic blood pressures. These studies suggest that as much as 11 percent of hypertension in men may be attributable to consumption of alcohol at this level (MacMahon 1986).


The most common lipid abnormality associated with alcohol abuse and alcoholism is hypertriglyceridemia. In such persons, the very low density lipoprotein (VLDL) levels are high, corresponding to what would traditionally be classified as hyperlipidemia type IV. In more severely affected individuals, there may be an accompanying elevation of chylomicrons, which is consistent with hyperlipidemia type V. Because VLDL particles contain some cholesterol, the serum cholesterol may also be elevated as a result.

The effect of alcohol intake on triglyceride levels is often overlooked. Among patients referred to lipid clinics, only diabetes is more important as a secondary cause of hyperlipidemia. Typically, persons with alcohol-induced hyperlipidemia do not respond to dietary or drug intervention unless alcohol intake is limited (Janus and Lewis 1978).

Indeed, the alcohol intake of all persons with hypertriglyceridemia should be assessed. In a light to moderate drinker especially, awareness of this effect of alcohol may provide sufficient motivation to lower intake. In the alcoholic person, this awareness might lead to the identification and treatment of the alcoholism.

Severe hypertriglyceridemia may cause and/or result from pancreatitis (Geokas 1984). Because pancreatitis is more common in alcoholics than in nonalcoholics, all individuals presenting with pancreatitis or otherwise unexplained recurrent upper abdominal pain should be evaluated for hypertriglyceridemia and history of alcohol use.

In alcoholics, extreme forms of hyperlipidemia have been described in which excessive alcohol intakes were associated with jaundice, severe hyperlipidemia, and hemolytic anemia (Zieve 1958). Liver biopsies in such patients showed fatty infiltration with minimal to moderate portal cirrhosis. Fortunately, this syndrome appears to be rare.

Elevated Serum Cholesterol Levels

Several population studies have suggested that light to moderate drinkers (by self-report) have a lower risk for coronary artery disease than do nondrinkers (Yano et al. 1977; Blackwelder et al. 1980). The observation that alcohol intake tends to increase high density lipoprotein (HDL) cholesterol was originally thought to be consistent with these epidemiologic findings, especially because HDL cholesterol appears to be inversely related to the risk for coronary artery disease. However, more recent studies have shown that the HDL cholesterol can be subdivided into fractions. The [HDL.sub.2] fraction is thought to protect against coronary artery disease but is affected relatively little by moderate alcohol ingestion. Alcohol elevates the [HDL.sub.3] fraction, which appears to have no association with coronary artery disease. In alcoholics, however, the reports to date regarding HDL cholesterol level have been variable and appear to depend on a variety of factors such as level of alcohol intake, the degree of hepatic microsomal enzyme induction, and the severity of alcoholic liver disease (Hurt et al. 1986). Because of the association of reduced levels of apolipoproteins AI and AII (apo AI and AII) with coronary artery disease (Kottke et al. 1986), the effect of alcohol on apo AI and AII is also of interest and appears to parallel its effect on HDL cholesterol. In alcoholic men, however, the apo AI levels have been observed to be lower than in nonalcoholic controls (Hurt et al. 1986). The epidemiologic findings, therefore, await further confirmation as well as elucidation of a biologic mechanism to explain the apparent protective effect of alcohol.

Coronary Heart Disease

Some evidence suggests that the ingestion of two to three alcoholic drinks per day reduces the rate of nonfatal myocardial infarction and mortality from coronary heart disease (Yano et al. 1977; Blackwelder et al. 1980). Whether these epidemiologic observations are mediated by effects of alcohol on HDL levels is unknown at present (Ernst et al. 1980). The effects at various levels of alcohol intake, the presence of liver disease, and effects of exercise on HDL cholesterol levels in alcoholics require further study. It appears that the benefits of consuming two to three drinks per day do not increase in persons who drink more. On the contrary, mortality from other diseases increases markedly when alcohol consumption exceeds those levels (Blackwelder et al. 1980; Marmet et al. 1981).


Dietary Guidance

General Public. Alcohol has been identified as a dietary factor that increases the risk for diseases of the liver, nervous system, and heart. It also contributes to the development of certain cancers. Although consumption of up to one to two drinks per day has not been associated with disease among healthy male and nonpregnant female adults, evidence that 9 percent of the total population consumes two or more alcoholic drinks per day suggests that the risk for alcohol-related conditions could be reduced by an overall decrease in alcohol consumption among some segments of the general public. Special Populations. Because studies in pregnant women have been unable to identify a threshold level of safety for alcohol intake during pregnancy, and because the risk for fetal abnormalities increases with increased alcohol intake during pregnancy, pregnant women--and women planning to become pregnant--should be advised to avoid drinking alcohol.

Persons with alcohol-related liver, nervous system, and cardiovascular conditions (e.g., elevated blood cholesterol and blood pressure levels) should receive advice from health professionals to reduce or eliminate alcohol intake to reverse or to prevent progression of these conditions. Persons with diabetes should also receive counseling on the effects of alcohol on caloric intake and blood glucose control.

Adolescents and young adults should be counseled in schools and through the media on the relationship between alcohol intake and motor vehicle and other accidents, suicides, and homicides. Older individuals should be counseled on the relationship between alcohol intake, nutritional deficiencies, and drug interactions.

Nutrition Programs and Services

Food Labels. Evidence related to the role of alcohol in health suggests that if alcoholic beverage containers are required to bear health warning labels, these labels should carry information warning of hazards to the developing fetus as well as of other health hazards associated with alcohol consumption abuse. Legislation to require such labeling was passed by Congress in 1988. The law becomes effective in November 1989. Food Services. Aside from the special populations noted below, evidence related to the role of alcohol currently holds no special implications for change in policies related to food service programs. Food Products. There are no special implications for change in policy related to formulation of food products. Special Populations. Pregnant women, including those served by the Special Supplemental Food Program for Women, Infants, and Children (WIC) and other maternal and child health programs, should be provided with counseling on avoidance of alcoholic beverages. Persons with alcohol-related conditions should be provided with counseling and referrals on the benefits of abstinence.

Research and Surveillance

Research and surveillance issues of special priority related to the role of alcohol and health include investigations into: * The levels at which alcohol intake

increases risk for chronic diseases

and birth defects. * The mechanisms by which alcohol

induces fatty changes in the liver. * The mechanisms by which alcohol

increases blood pressure, blood

cholesterol, blood glucose levels, and

other risk factors for chronic

disease. * The mechanisms by which low

levels of alcohol may reduce risk for

coronary heart disease. * The mechanisms by which alcohol

increases cancer risk. * The mechanisms by which alcohol

damages the nervous system. * The mechanisms by which alcohol

intake interferes with nutritional

status. * Definition of the physiologic energy

value of alcoholic beverages. * The interaction of alcohol intake,

nutritional status, socioeconomic

status, and health.

COPYRIGHT 1989 U.S. Government Printing Office
COPYRIGHT 2004 Gale Group

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