Acrodermatitis Enteropathica and Other Conditions Related to Zinc Deficiency and Associated With Mutations in Gene (SLC39A4)

The last trip Sandy; along with Georgie his “real true Mother” and myself: ever made was to Waterton Lakes National Park.

There is a broad spectrum of physiological signs of zinc deficiency given that zinc is involved in a great number of biochemical processes. Most commonly, zinc deficiency is associated with skin lesions, such as seen in Acrodermatitis enteropathica, an autosomal recessive metabolic disorder affecting the uptake of zinc. Additionally, growth retardation and hypogonadism in males were among the first and frequently reported clinical signs in zinc deficient patients. However, apart from several other symptoms caused by zinc deficiency, such as poor appetite, delayed wound healing, cell-mediated immune dysfunction, and abnormal neurosensory changes, behavioural alterations have been consistently reported.

Zinc deficiency may result in depression, emotional instability, increased anxiety and aggression, irritability and deficits in social behaviour. Additionally, or as consequence of some factors discussed above, impaired memory and capacity to learn may occur.

Zinc deficiency is associated with multiple disorders. In particular, patients suffering from neurological disorders often show zinc deficiencies. For example, low serum zinc levels have been reported in Autism Spectrum Disorders (ASD), Attention deficit hyperactivity disorder (ADHD), Mood Disorders, such as depression, Schizophrenia (SCZ), and Spinocerebellar ataxia type 2.

Furthermore, zinc deficiency has been observed in disorders of the gastro-intestinal (GI) tract, such as malabsorption syndrome, Crohn’s disease, regional ileitis and steatorrhea, as well as liver disease, renal diseases, ***alcoholism, and sickle cell disease***
{Sickle-cell disease is one of the most common severe monogenic disorders in the world. Haemoglobin polymerisation, leading to erythrocyte rigidity and vaso-occlusion, is central to the pathophysiology of this disease, although the importance of chronic anaemia, haemolysis, and vasculopathy has been established. Clinical management is basic and few treatments have a robust evidence base. One of the main problems of sickle-cell disease in children is the development of cerebrovascular disease and cognitive impairment, and the role of blood transfusion and hydroxycarbamide for prevention of these complications is starting to be understood. Recurrent episodes of vaso-occlusion and inflammation result in progressive damage to most organs, including the brain, kidneys, lungs, bones, and cardiovascular system, which becomes apparent with increasing age. Most people with sickle-cell disease live in Africa.}

It is therefore necessary to understand how zinc deficiency will influence the initiation and/or progression of such a disorder and modify the disease phenotype. Here, we will focus especially on the behavioural alterations that can be observed in zinc deficient subjects.

Acrodermatitis Enteropathica
Much of the information available about this disease comes from through the treatment (including DNA&GENETIC research) on Robert Alexander (Sandy) Cameron Girvan, my son. Sandy was born 9/03/1972.Acrodermatitis enteropathica (AE) is a disorder of zinc metabolism that can either be *inherited* or acquired. Both forms lead to the inability to absorb zinc from the intestine. The lack of zinc can cause skin inflammation with a rash (pustular dermatitis) around the mouth and/or anus; diarrhea; and abnormal nails (nail dystrophy). Irritability and emotional disturbances can also occur. 

The inherited form is caused by mutations in the SLC39A4 gene and inherited in an autosomal recessive pattern. The acquired form can result from diets lacking the appropriate amount of zinc. Supplemental zinc usually eliminates the symptoms of acrodermatitis enteropathica

Zinc is an essential component of the diet. Zinc in human milk is more absorbable than that from infant formulas or cow's milk, hence the later onset of acrodermatitis enteropathica in breast-fed babies compared to formula-fed babies.
Happenings, Things That Allowed Sandy to Survive:
1. A mother from the La Leche League International (La Leche is Spanish for "the milk" is an international nonprofit advocacy group that distributes information on and promotes breastfeeding. It was founded in 1956 in Franklin Park, Illinois as "La Leche League" and has a presence in more than 85 countries.) came and breast fed him.
2. She continued to do so until it was discovered that mother’s milk can be kept in the frozen state for up to a year.
*The inherited form of acrodermatitis enteropathica* was usually fatal until the role of zinc was discovered in 1973 It should be treated with 1 mg/kg body weight of oral zinc supplementation per day for life. Zinc gluconate is better tolerated than zinc sulphate. Zinc can be given during pregnancy.
What is acrodermatitis enteropathica?
Acrodermatitis enteropathica is a rare *Inherited genetic* disorder characterised by diarrhoea, an inflammatory rash around the mouth and/or anus, and hair loss. It is also called acrodermatitis enteropathy, primary zinc malabsorption syndrome, Danbolt-Closs syndrome and Brandt syndrome.
What causes acrodermatitis enteropathica?
Acrodermatitis enteropathica is due to malabsorption of zinc through the intestinal cells. It is associated with mutations in a gene (SLC39A4) that codes the zinc transporter protein, ZIP4. It is thought that the missing protein may be responsible for decreased zinc uptake and abnormal zinc metabolism.
*To Have Congenital Acrodermatitis Enteropathica You Must Inherit Two Defective Genes (one from each parent) i.e. the inheritance is autosomal recessive.* If an individual receives one normal gene and one defective gene, the person will be a carrier for the disease, but usually will not show symptoms.
Who gets acrodermatitis enteropathica?
Symptoms usually occur in bottle-fed infants within a few days or weeks after birth and breast-fed infants soon after weaning. Both males and females are equally affected.
Zinc deficiency may also rarely arise in adults.
Causes include: Necrolytic migratory erythema (glucagonoma)
Inadequate zinc in the diet (especially in alcoholics and previously, with intravenous nutrition)
Intestinal malabsorption (inflammatory bowel disease, intestinal bypass surgery, pancreatic disease)
Excessive urinary loss of zinc (nephrotic syndrome)
Low levels of albulin and high catabolic states (trauma, burns, extensive surgery, and cirrhosis)
What are the clinical features?
Skin findings include:

Red and inflamed patches of dry and scaly skin, particularly around body openings such as the mouth, anus, and eyes, and the skin on elbows, knees, hands, and feet. It may look like atopic dermatitis.
Patches evolve into crusted, blistered, pus-filled and eroded lesions.
There is usually a sharp demarcation between the affected area and normal skin.
Skin around nails becomes inflamed (paronychia) and there may be nail ridging.
Diffuse hair loss on the scalp, eyebrows and, eyelashes.
Secondary infection with Candida albicans or Staphylococcus aureus
Red glossy tongue and mouth ulcers
Impaired wound healing
Other Symptoms Features Of Acrodermatitis Enteropathica Include:
Conjunctivitis
Sensitivity to light
Loss of appetite
Diarrhoea, mild or severe
Irritability (babies cry and whine incessantly)
Depressed mood
Growth failure
Zinc is an essential component of the diet. Zinc in human milk is more absorbable than that from infant formulas or cow's milk, hence the later onset of acrodermatitis enteropathica in breast-fed babies compared to formula-fed babies. Zinc is also found in meat, shellfish and wheat germ. Foods of plant origin are mostly low in zinc. Phytates present in cereals and soy, and high levels of calcium, can reduce the absorption of zinc through the duodenum.

Zinc is needed to assist metalloenzymes that are involved in many cellular processes throughout the body. These include the production of anti-inflammatory agents (cytokines and antioxidants) and the normal functioning of the brain.
After zinc replacement the skin lesions heal within one to two weeks, diarrhoea ceases and irritability and depression of mood improve within 24 hrs.
Secondary bacterial and/or fungal infection of lesions require appropriate antibiotic therapy.
Although zinc is usually non-toxic, high doses for a long period can result in gastrointestinal symptoms, dizziness and copper deficiency, leading to anaemia.©Al (Alex-Alexander) D Girvan. All rights reserved.