Report of a novel ATP7A mutation causing distal motor neuropathy

Gualandi, Francesca; Sette, Elisabetta; Fortunato, F.; Bigoni, Stefania; Grandis, D. De; Scotton, C.; Selvatici, Rita; Neri, Marcella; Incensi, Alex; Liguori, Rocco; Storbeck, Markus; Karakaya, Mert; Simioni, Valentina; Squarzoni, Stefano; Timmerman, Vincent; Wirth, Brunhilde; Donadio, Vincenzo; Tugnoli, V.; Ferlini, Alessandra

doi:10.1016/j.nmd.2019.08.008

Cited by 15 publications

(13 citation statements)

References 28 publications

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“…In rare cases, the activity of ATP7A protein is partially preserved and the symptoms milder (occipital Horn syndrome), with patients living as long as 50 [171]. The mutation in the ATP7A gene does not necessarily lead to Menkes disease; it has also been described in patients suffering from hereditary motor neuropathy which results in the weakness of the upper limbs that progresses with age [189]. Another disease leading to the disorder of Cu metabolism is Huppke-Brendel syndrome, resulting from the mutation of the SLC33A1 gene encoding the AT-1 protein, first described in 2012 [190].…”

Section: Copper (Cu)mentioning

confidence: 99%

The Role of Fe, Zn, and Cu in Pregnancy

2020

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Iron (Fe), copper (Cu), and zinc (Zn) are microelements essential for the proper functioning of living organisms. These elements participatein many processes, including cellular metabolism and antioxidant and anti-inflammatory defenses, and also influence enzyme activity, regulate gene expression, and take part in protein synthesis. Fe, Cu, and Zn have a significant impact on the health of pregnant women and in the development of the fetus, as well as on the health of the newborn. A proper concentration of these elements in the body of women during pregnancy reduces the risk of complications such as anemia, induced hypertension, low birth weight, preeclampsia, and postnatal complications. The interactions between Fe, Cu, and Zn influence their availability due to their similar physicochemical properties. This most often occurs during intestinal absorption, where metal ions compete for binding sites with transport compounds. Additionally, the relationships between these ions have a great influence on the course of reactions in the tissues, as well as on their excretion, which can be stimulated or delayed. This review aims to summarize reports on the influence of Fe, Cu, and Zn on the course of single and multiple pregnancies, and to discuss the interdependencies and mechanisms occurring between Fe, Cu, and Zn.

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Section: Copper (Cu)mentioning

confidence: 99%

The Role of Fe, Zn, and Cu in Pregnancy

2020

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“…To date, more than 350 mutations responsible for Menkes disease in the ATP7A gene have been reported (HGMD, 2018; http://www.hgmd.cf.ac.uk). It is characterized by the proper transport of copper into copper-containing enzymes, which results in low ceruloplasmin and copper serum levels [65][66][67][68][69]. The incidence of Menkes disease is approximately 10/25,000 live births [67].…”

Section: Menkes Diseasementioning

confidence: 99%

Genetic Disorders Associated with Metal Metabolism

Umair

Alfadhel

2019

Cells

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Genetic disorders associated with metal metabolism form a large group of disorders and mostly result from defects in the proteins/enzymes involved in nutrient metabolism and energy production. These defects can affect different metabolic pathways and cause mild to severe disorders related to metal metabolism. Some disorders have moderate to severe clinical consequences. In severe cases, these elements accumulate in different tissues and organs, particularly the brain. As they are toxic and interfere with normal biological functions, the severity of the disorder increases. However, the human body requires a very small amount of these elements, and a deficiency of or increase in these elements can cause different genetic disorders to occur. Some of the metals discussed in the present review are copper, iron, manganese, zinc, and selenium. These elements may play a key role in the pathology and physiology of the nervous system.

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“…The dHMN phenotype is a pure motor neuropathy in which, unlike MD and OHS, the copper-related biochemical parameters are normal. 2,3 Although copper is relevant to maintain the integrity of motor neurons (MNs), the precise mechanisms by which dysfunctional ATP7A leads to the specific length-dependent axonal degeneration observed in MNs of patients with ATP7A-related dHMN remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Copper Toxicity Associated With an ATP7A-Related Complex Phenotype

Benito

Sola

Sousa

et al. 2021

Pediatric Neurology

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Background: The ATP7A gene encodes a copper transporter whose mutations cause Menkes disease, occipital horn syndrome (OHS), and, less frequently, ATP7A-related distal hereditary motor neuropathy (dHMN). Here we describe a family with OHS caused by a novel mutation in the ATP7A gene, including a patient with a comorbid dHMN that worsened markedly after being treated with copper histidinate. Methods: We studied in detail the clinical features of the patients and performed a genomic analysis by using TruSight One Expanded Sequencing Panel. Subsequently, we determined the ATP7A and ATP7B expression levels, mitochondrial membrane potential, and redox balance in cultured fibroblasts of Patient 1. Results: We found a novel ATP7A late truncated mutation p.Lys1412AsnfsX15 in the two affected members of this family. The co-occurrence of OHS and dHMN in Patient 1 reveals the variable phenotypic expressivity of the variant. A severe clinical and neurophysiologic worsening was observed in the dHMN of Patient 1 when he was treated with copper replacement therapy, with a subsequent fast recovery after the copper histidinate was withdrawn. Functional studies revealed that the patient had low levels of both ATP7A and ATP7B, the other copper transporter, and high levels of superoxide ion in the mitochondria.

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Report of a novel ATP7A mutation causing distal motor neuropathy

Cited by 15 publications

References 28 publications

The Role of Fe, Zn, and Cu in Pregnancy

The Role of Fe, Zn, and Cu in Pregnancy

Genetic Disorders Associated with Metal Metabolism

Copper Toxicity Associated With an ATP7A-Related Complex Phenotype

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