Manganese and Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of upper and lower motor neurons and sclerosis of motor pathways in the spinal cord, leading to widespread progressive skeletal muscle atrophy. ALS is typically fatal within 2–5 years of symptom onset. The incidence of ALS is largely uniform across most parts of the world.

Mn is an essential ubiquitous trace element required for normal growth, development and cellular homeostasis.

Mn functions as a required cofactor of several enzymes necessary for neuronal and glial cell function, as well as enzymes involved in neurotransmitter synthesis and metabolism.

Manganese crosses barrier systems at the choroid plexus and accumulates in the central nervous system, with a longer half-life in nervous tissue. Manganese (Mn) has been specifically implicated in ALS pathogenesis.

Mn levels in brain tissue average approximately 1–2 µg/g dry weight. The concentration of Mn in the brain varies across brain regions under excessive exposures. In the ALS, Mn contents were higher in the anterior horn and lateral fasciculus than in the posterior horn.

Mn overload has also been implicated in ALS. This link was first described by Voss, who documented a Mn smelter who developed occupational manganism and bulbar ALS in Germany
Manganese and Amyotrophic Lateral Sclerosis

Acrodermatitis enteropathica - disorder of zinc metabolism

Acrodermatitis enteropathica is a rare inherited disorder, transmitted as an autosomal recessive trait, which results in defective in absorption of zinc, an essential trace element required by more than one hundred enzymes and whose role in the metabolism of nucleic acid is important.

Characterized by a triad of clinical features - acral dermatitis, diarrhea and alopecia – it invariably presents in infancy and, in particular, at the time of weaning. Signs and symptoms in infancy can include diarrhea, mood changes, anorexia, and neurological disturbance.

The dermatological condition may mimic a cutaneous fungal infection or other pathogen related skin diseases.

The deficiency is caused by a defect of dietary zinc absorption in the duodenum and jejunum. The gene SLC39A4, located in chromosome 8q24.3, codifies the transmembrane protein required for zinc absorption, which is expressed in the duodenum and jejunum, and its mutation reduces the intestinal ability to absorb dietetic zinc. SLC39A4 is a specific protein for transporting zinc and iron.

Zinc is an essential co-enzyme in metal enzymes (like alkaline phosphatase); it is an important structural component of gene regulatory proteins (required, for example, for the intracellular binding of tyrosine kinase to T-cell receptors) and it has also a function in regulation (has the ability to regulate gene expression).

Acquired zinc deficiency is caused mainly by prolonged parenteral central venous nutrition, excision of the digestive tract, or severe diarrhea or vomiting.
Acrodermatitis enteropathica - disorder of zinc metabolism

Menkes syndrome: multisystemic disorder of copper metabolism

Menkes syndrome is a lethal multisystemic disorder of copper metabolism. Mutations in the ATP7A gene cause Menkes syndrome. The ATP7A (ATPase copper transporting alpha) gene provides instructions for making a protein that is important for regulating copper levels in the body. Copper is necessary for many cellular functions, but it is toxic when present in excessive amounts. The ATP7A protein is found throughout the body, except in liver cells. In the small intestine, this protein helps control the absorption of copper from food.

Mutations in the ATP7A gene result in poor distribution of copper to the body's cells. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels of copper.

Progressive neurodegeneration and connective tissue disturbances, together with the peculiar ‘kinky’ hair are the main manifestations. Menkes syndrome is inherited as an X-linked recessive trait, and as expected the vast majority of patients are males.

Menkes syndrome is characterized by physical and neurological alterations. In the neonatal period, these alterations can be nonspecific, which makes early diagnosis a challenge. Diagnosis can be suspected when there are low levels of ceruloplasmin and serum copper. Molecular analysis confirms the diagnosis.
Menkes syndrome: multisystemic disorder of copper metabolism