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Although this isn't so popular medical subject- it is certain that everyone has at least heard about some of the many enzyme found in our body.
thumb_thumb_aldehyde.jpgWell, it is very important to know that aldehyde dehydrogenases are also a group of enzymes that catalyse the oxidation or dehydrogenation of aldehydes. They belong to the group of enzymes that are located in the cell, in different parts- the cytosol, mitochondria and endoplasmic reticulum. It is also proven that there are several different forms of this enzyme! They have been classified as:
  • Class 1 (cytosolic)
  • Class 2 (mitochondrial)
  • Class 3 (tumor and other isozymes)
There is no doubt- aldehyde dehydrogenases have broad substrate specificity. Oxidation of aldehydes is considered to be generally a detoxification reaction because it is based on removing the electrophilic products of alcohol oxidation.

Function of Aldehyde Dehydrogenases

Several researches done in the past have proven that Aldehyde Dehydrogenases are able to oxidize a wide range of endogenous and exogenous aldehydes. It is important to know that aldehydes are substances formed during the metabolism of amino acids, carbohydrates, lipids, biogenic amines, vitamins, and steroids. It is also proven that a large number of xenobiotics can generate aldehydes during their biotransformation. They are also highly reactive electrophilic compounds that interact with different chemical groups and these effects vary from:
  • physiologic and therapeutic to
  • Cytotoxic
  • Genotoxic
  • mutagenic or carcinogenic

Chemical reactions catalyzed by ALDH

Important thing to know is that ALDH oxidizes aldehydes to carboxylic acids. To be more precise - two acetaldehyde dehydrogenase isozymes, cytosolic (ALDH1) and mitochondrial (ALDH2), catalyze this reaction. Some researches indicate that there is even a third isozyme present in the stomach but acetaldehyde is not a substrate for this isozyme.
The overall reaction catalyzed by the aldehyde dehydrogenases is:
 
RCHO + NAD(P)+ + H2O ↔ RCOOH + NAD(P)H + H+
 
This enzyme catalyse some very important reactions in our body! Some examples are:
  • It is proven that alcohol dehydrogenase oxidizes ethanol to acetaldehyde, which is responsible for some hangover symptoms. Experts are saying that aldehyde dehydrogenase detoxifies this to acetic acid.
  • It is also proven that aldehyde dehydrogenase detoxifies acrolein, the hepatotoxic metabolite formed from allyl. That’s how- it protects liver from this toxin!
  • Some experts are saying that there is a great possibility that Aldehyde dehydrogenases can also behave as esterases, hydrolyzing esters such as para-nitrophenyl acetate.

Aldehyde dehydrogenase and Alcohol dehydrogenase

Experts are saying that Aldehyde dehydrogenase (ALDH) is functioning often in tandem with Alcohol dehydrogenase. It is proven that they both act in detoxifying a wide variety of organic compounds, toxins and pollutants. They both work in detoxifying the ethanol to acetaldehyde which definitely protects the liver from its toxicity! 

Aldehyde dehydrogenase deficiency - Sjogren-Larsson syndrome

Important thing to know is that defects in ALDH leads to Sjogren-Larsson syndrome in humans. This fatty aldehyde dehydrogenase deficiency is in fact a genetic disease. The reported incidence of this disease is very rare, about 1 in 200,000. The Sjogren-Larsson syndrome is also known as
  • SLS
  • the ichthyosis
  • spastic neurological disorder
  • oligophrenia syndrome
  • fatty alcohol: NAD+ oxidoreductase deficiency (FAO deficiency)
  • FALDH deficiency
  • fatty aldehyde dehydrogenase 10 deficiency (FALDH10 deficiency)
 
It is usually characterized by a triad of clinical findings consisting of:
1.    Ichthyosis – condition characterized by thickened fish-like skin
It is extremely important that all the skin changes in the Sjogren-Larsson syndrome are similar to those in congenital ichthyosiform erythroderma. This is also a genetic disease that results in fish-like, reddened skin. Thickening of the skin- condition called hyperkeratosis is also a regular feature. What's interesting- bruises are present at birth or soon after in the Sjogren-Larsson syndrome. Sweating is normal, although some problems could also occur because of hyperkeratosis!
2.    Spastic paraplegia- spasticity of the limbs
It is proven that this spasticity and rigidity can also affect the arms as well as the legs, resulting in spastic paraplegia. Bad thing is that most of the patients never walk in their life and about half the patients have seizures.
3.    Mental retardation and eye problems
Eye problems accompanied with mental retardation are also part of the syndrome. Unfortunately- we are talking very serious form of mental retardation. About half of cases have pigment degeneration of the retina.

Etiology of the condition

Scientist, who discovered this syndrome - Sjogren in 1956, suggested that all Swedes with the syndrome are descended from one ancestor in whom a mutation occurred about 600 years ago. This mutation is now present in at least 1% of the population in northern Sweden. This phenomenon is called “founder effect”. Several studies done in the past have proven that the gene for the Sjogren-Larsson syndrome has been found situated on chromosome number 17. It is also proven that the presence in a person of one copy of the gene is harmless. However, the problem is if two gene carriers mate, because in that case - the risk for each of their children is ¼  to receive both of their Sjogren-Larsson genes and to have the syndrome. Some experts are saying that clinical improvement has been reported to occur with fat restriction in the diet and supplementation with medium-chain triglycerides. The mechanism of this improvement is still unclear but – it is considered that using less fat will bypass and spear this enzyme!

Sjogren-Larsson syndrome and Sicca syndrome

Most patients are confused with the diagnosis because they don’t know the difference between the Sjogren-Larsson syndrome and Sjogren (sicca) syndrome. You see, the fact is that Sjogren-Larsson syndrome is sometimes called the T. Sjogren syndrome to distinguish it from the sicca syndrome, which was described by Henrick Sjogren, a Swedish ophthalmologist. This syndrome is about lack of tears in the eye and has nothing similar with Sjogren-Larsson syndrome. The Sjogren of the Sjogren-Larsson syndrome was Torsten Sjogren (1896-1974), professor of psychiatry at the celebrated Karolinska Hospital in Stockholm and a pioneer in modern psychiatry and medical genetics.

Laboratory findings

The fact is that the laboratory findings are critically important. Logically- there is a deficiency of an enzyme called fatty aldehyde dehydrogenase. The syndrome is due to a deficit of aldehyde dehydrogenase and the gene for the Sjogren-Larsson syndrome gene is synonymous with this enzyme gene.

Diagnosis

There is no doubt- Sjogren-Larsson syndrome can be diagnosed by demonstrating decreased activity of the deficient enzyme, or by identifying one of the genetic defects known to cause Sjogren-Larsson syndrome. It is proven that simple MRI of the brain will reveal problems with myelin allowing for quick conduction of nerve messages. Skin biopsies will reveal a variety of abnormalities characteristic of Sjogren-Larsson syndrome. An EEG will reveal disordered electrical patterns throughout the brain.

Treatment

Unfortunately - there are no treatments that can cure Sjogren-Larsson syndrome. Only symptomatic treatment is available! It is proven that there is a number of lotion or cream preparations may help improve itching and flaking, decrease the speed of skin turnover, and soften the skin. Sauna treatments and frequent showering and bathing may improve moisture levels in the skin. Spasticity is sometimes improved through various surgical procedures. It is also proven that Braces may help increase mobility.

Management of chronic alcoholics - Aldehyde Dehydrogenase Inhibitors

The famous aldehyde dehydrogenase inhibitor is called Disulfiram! This drug inhibits the enzyme aldehyde dehydrogenase, blocking oxidation of alcohol and allowing acetaldehyde to accumulate to concentrations in the blood 5-10 times higher than normally achieved during alcohol metabolism.   

Indications for Disulfiram

Several researches done in the past have shown that this drug can really help in the management of chronic alcoholics who want to remain in a state of enforced sobriety.

Contraindications for Disulfiram

Contraindicated in the presence of allergy to Disulfiram are:
  • severe myocardial disease
  • coronary occlusion
  • psychoses
  • current or recent treatment with Metronidazole, paraldehyde, alcohol, alcohol-containing preparations
Extreme caution
  • diabetes mellitus
  • hypothyroidism
  • epilepsy
  • cerebral damage
  • chronic and acute nephritis
  • hepatic cirrhosis or dysfunction

Possible side effects

Disulfiram-alcohol reaction:
  • Flushing
  • throbbing in head and neck
  • throbbing headaches
  • respiratory difficulty
  • nausea
  • copious vomiting
  • sweating
  • thirst
  • chest pain
  • palpitations
  • dyspnea
  • hyperventilation
  • tachycardia…