and Emanual Maverakis3
(1)
University of British Columbia, Vancouver, British Columbia, Canada
(2)
New York Medical College, Valhalla, NY, USA
(3)
University of California Davis, Sacramento, CA, USA
3.1 Clinical Forms of AE
There are two main forms of AE identified that are clinically distinguishable from each other. The first form of the disorder is an acquired form resulting from a dietary zinc deficiency that resolves upon zinc repletion. The other form is an inheritable disease caused by a mutation in the SLC39A4 gene, which codes for the hZip4 Zn transporter protein, and it is inherited in an autosomal recessive pattern. One or more of its symptoms are often observed in the later stages of the disorder [1].
3.2 Nomenclature of Zinc Deficiencies
AE was identified for the first time by Brandt in 1936 [2]. In 1942, Danbolt and Closs categorized a group of symptoms as AE [3].
Furthermore, it was discovered that AE, which is an autosomal recessive inheritable disorder caused by a mutation in the gene coding for the hZip4 Zn transporter, which is necessary for zinc absorption in the intestine [4]. There have been reports of AE from all around the world and it is not specific to any gender or age [5].
There are two known types of zinc deficiency disorders which have AE-like symptoms: these disorders can either be hereditary or acquired.
Hereditary Acrodermatitis Enteropathica : this hereditary disorder is autosomal recessive and exclusively affects infants. It diminishes the intestinal uptake of zinc due to the absence of a zinc transporter called hZip4. Skin eruptions (dermatitis), alopecia, and persistent diarrhea are its distinctive symptoms. It can be fatal for infants if it is not diagnosed and treated early and properly [4, 6, 7]. Adult cases are rare and are chronic cases of AE that appear during early infancy of the patient [3].
Acquired Non-hereditary Zinc disorders :
Acquired zinc deficiency in newborns is often caused by insufficient zinc levels in maternal breast milk. One example is mutation of SLC30A2 [8, 9].
Pseudo-Acrodermatitis Enteropathica disorder is often not associated with a primary deficiency of zinc. Rather, it is caused by metabolic disorders such as methylmalonic acid productivity disorder, multiple carboxylase disorder, and fatty acid and amino acid deficiencies like Hartnup disease [10–13]. Other conditions such as prolonged total parenteral nutrition, excessive alcohol ingestion, and penicillamine therapy have also been reported to have caused zinc deficiency [14].
There have been rare reports of spontaneous improvement of zinc deficiency patients who reach puberty [15], which is likely not true AE but AE-like cases therefore not due to SLC39A4 mutations.
3.3 Acquired Non-hereditary Zinc Deficiency
As researchers conduct more studies on the biochemical role of zinc in human physiology, they are beginning to discover that zinc deficiency disorders are not simple genetic problems. Because of the researches and studies conducted on hereditary AE, the diagnosis of other diseases and disorders associated with zinc deficiency have become less complicated. Acquired zinc deficiency has been reported mainly in two different forms. One form is reported to occur in infants feeding on zinc deficient maternal milk and the other form is seen in individuals that are suffering from a metabolic deficiency that has zinc deficiency as a side effect. It is important to note that any chronic catabolic disorder can cause zinc deficiency: a few examples are methylmalonic acid productivity disorder, multiple carboxylase disorder, and fatty acid and amino acid deficiencies. Individuals with alcoholism are particularly prone to zinc deficiency and the clinical condition of these patients depends on the severity and duration of their zinc deficiency as well as their age [13]. The mechanism by which alcohol consumption induces hyperzincuria is not fully understood, but it may be as a result of alcohol’s direct effect on the renal tubules [16, 17]. Studies show significant increase in renal clearance of zinc in alcoholics, which resulted in reduction of the individuals’ serum zinc levels. It is important for clinicians to note that excessive ingestion of alcohol may cause severe zinc deficiency [18].
One main clinical differentiation between Hereditary AE and acquired zinc deficiency is that it is possible to stop zinc supplementation in patients with acquired zinc deficiency without the disease recurring. In contrast, in AE, the zinc supplementation is usually given for life because of the defective zinc absorption in the small intestine [19, 20].
3.3.1 Zinc Deficient Maternal Breast Milk
Acquired zinc deficiency in newborns is often caused by insufficient zinc levels in the maternal breast milk resulting in hypozincemia in the newborns. Because of their rapid rate of growth, normal infants require large amounts of zinc compared to adults. This is accentuated in premature infants who require even more zinc [20]. As a result, premature infants are more susceptible to acquired zinc deficiency. These transient forms of zinc deficiency may be due for instance to mutations in SLC30A2 [21].
Maternal milk is normally a good source of zinc; however, in these cases the maternal milk has a low zinc concentration that cannot be corrected by oral zinc supplementation. This is because the zinc-secreting mechanism of the mammary glands is defective. For instance in a literature case, a nursing mother, whose milk zinc level was low at 6 μmol/L while her serum zinc level was normal at 15 μmol/L, was subjected to 220 mg of zinc sulfate three times a day for a week and no change was observed in her milk zinc level [20]. This case is evident of a defective zinc-secreting mechanism since the maternal breast milk zinc concentration should be higher than those of the maternal serum for the purpose of meeting the infant’s growth and developmental requirements [8]. Moreover, this zinc deficiency condition can be clinically distinguished from AE since its symptoms only develop during breast feeding and do not recur after weaning [22].
Recent genetic studies have indicated that mutations in the SLC30A2 gene, which codes for the ZnT2 transporter protein, could be the cause for this defective zinc secretion. When functional, the transporter, located in mammary epithelial cells, is responsible for secretion of zinc into breast milk during lactation [23, 24]. Figure 3.1 illustrates the predicted molecular structure of the hZnT2 protein. As illustrated by the figure the transporter is predicted to have 6 transmembrane domains with a long histidine loop between transmembrane domains IV and V, which is likely to be a zinc-binding region [8, 25, 26].
Figure 3.1
Predicted structure of ZnT2 protein. The dark grey barrels represent the transmembrane domains. It is characterized by 6 transmembrane domains organized into two blocks of 4 and 2 separated by a histidine-rich cytoplasmic metal-binding site
When defective, it results in low zinc secretion into breast milk causing the infant who feeds on the milk to develop zinc deficiency. Interestingly, it was found that lactating mothers that were homozygous for the SLC30A2 mutation or heterozygous carriers of the SLC30A2 mutations also had low milk zinc levels, which is suggestive of haploinsufficiency [8]. In mouse, homozygous mutations of SLC30A4 in lactating mothers cause zinc deficiency in their pups resulting in the lethal milk phenotype [27], which was previously discussed in the etiology section. These infants were successfully treated with the addition of zinc to their diets. It is important to note that as these infants grew up and discontinued breast milk, they no longer needed supplemental zinc since they were not actually suffering from a hereditary zinc disorder and their symptoms were attributed to purely dietary deficiency during infancy.
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