Bioavailable Trace Metals in Neurological Diseases

Abstract

Opinion statement  Medical treatment in Wilson's disease includes chelators (D-Penicillamine andTrientine) or zinc salts that have to be maintain all the lifelong. This pharmacological treatment is categorized into two phases; the first being a decoppering phase and the second a maintenance's one. The best therapeutic approach remains controversial, as only a few non-controlled trials have compared these treatments. During the initial phase, progressive increase of chelators' doses adjusted to exchangeable copper and urinary copper might help to avoid neurological deterioration. Liver transplantation is indicated in acute fulminant liver failure and decompensated cirrhosis; in cases of neurologic deterioration, it must be individually discussed. During the maintenance phase, the most important challenge is to obtain a good adherence to lifelong medical therapy. Neurodegenerative diseases that lead to a mislocalization of iron can be caused by a culmination of localized overload (pro-oxidant siderosis) and localized deficiency (metabolic distress). A new therapeutic concept with conservative iron chelation rescues iron-overloaded neurons by scavenging labile iron and, by delivering this chelated metal to endogenous apotransferrin, allows iron redistribution to avoid systemic loss of iron.

Neurological presentations revealing acquired copper deficiency: diagnosis features, aetiologies and evolution in seven patients

“…The association with a normal or decreased cupruria allows the main differential diagnosis of ACD, which is Wilson disease, characterised by an elevated 24‐h urinary copper excretion, to be ruled out . The other differential diagnoses of low cupraemia with normal or decreased cupruria in adults with neurological signs are aceruloplasminaemia, tardive form of Menkes disease and Niemann‐Pick C, but all three are extremely rare . Zincaemia and zincuria should be screened, along with the copper balance, to look for causes of excess intake of zinc that limits copper absorption .…”

Overview of iron metabolism in health and disease

“…In aceruloplasminemia, the loss of ceruloplasmin ferroxidase activity impairs astrocyte iron export and incorporation into extracellular transferrin for uptake by neurons. This leads to a combination of oxidative damage from iron overload in astrocytes and possibly also toxicity from neuronal iron deficiency . In neuroferritinopathy, mutations in ferritin light chain impair safe iron storage leading to iron‐mediated oxidative damage .…”

“…This leads to a combination of oxidative damage from iron overload in astrocytes and possibly also toxicity from neuronal iron deficiency . In neuroferritinopathy, mutations in ferritin light chain impair safe iron storage leading to iron‐mediated oxidative damage . Mutations in frataxin, a mitochondrial iron chaperone important for iron‐sulfur cluster assembly, heme biosynthesis, and mitochondrial iron storage, cause Friedrich's ataxia, characterized by a loss of nerve cells in the spinal cord, cerebellum, and dorsal root ganglia, which is thought to be a consequence of mitochondrial dysfunction, oxidative stress, and possibly induction of sphingolipid synthesis and other signaling pathways induced by iron accumulation …”

“…[99][100][101] In neuroferritinopathy, mutations in ferritin light chain impair safe iron storage leading to iron-mediated oxidative damage. [99][100][101] Mutations in frataxin, a mitochondrial iron Iron metabolism in health and disease Hemodialysis International 2017; 21:S6-S20 S13 chaperone important for iron-sulfur cluster assembly, heme biosynthesis, and mitochondrial iron storage, cause Friedrich's ataxia, characterized by a loss of nerve cells in the spinal cord, cerebellum, and dorsal root ganglia, which is thought to be a consequence of mitochondrial dysfunction, oxidative stress, and possibly induction of sphingolipid synthesis and other signaling pathways induced by iron accumulation. 99,101,102 Iron accumulation is also associated with more common neurodegenerative diseases including Parkinson's disease and Alzheimer's disease.…”

High genetic carrier frequency of Wilson’s disease in France: discrepancies with clinical prevalence

“…WD is an inherited metabolic disorder which results in excess copper levels, particularly in the liver and brain. The initial symptoms may vary; in more than half of patients they may include hepatic abnormalities such as chronic active hepatitis, cirrhosis and more rarely fulminant hepatic failure, whereas others might display different neuropsychiatric manifestations such as tremor, Parkinsonism, dystonia or psychiatric abnormalities [1, 2]. The clinical signs of WD can appear at different ages (usually between 8 and 30 years) but they may also occur at extreme ages (1 to 80 years) [3, 4].…”