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Genetics of Metal Disorders (Excluding NBIA)

  • Chapter
Movement Disorder Genetics

Abstract

In this chapter, we describe genetic movement disorders arising from endogenous dysregulation of calcium, copper, and manganese homeostasis. In general, dysregulation of metal homeostasis may lead to regional brain metal accumulation, systemic metal accumulation affecting the whole brain and other organs, or brain metal deficiency.

Primary familial brain calcification leading to regional brain calcium deposits is caused by mutations in inorganic phosphate transporter 2 (PiT2), platelet-derived growth factor (PDGFβ), or platelet-derived growth factor receptor-β (PDGFRβ). Mutations in these three genes explain 50 % of cases and further causative genes are likely involved.

Systemic accumulation of copper is the hallmark of Wilson disease and MEDNIK syndrome caused by mutations in ATP7B and AP1S1 genes, respectively. Menkes disease, caused by mutations in ATP7A, is an example of disorder of systemic copper deficiency.

Systemic accumulation of manganese has been described in manganese transporter deficiency caused by SLC30A10 mutations. The brain and liver are the most affected organs in these systemic disorders. Kufor-Rakeb syndrome, caused by mutations in ATP13A2, is likely also related to manganese toxicity.

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Abbreviations

AP1S1:

Adaptor-related protein complex 1, subunit σ1A

AT1:

Acetyl-CoA transporter

ATOX1:

Antioxidant 1 copper chaperone

ATP:

Adenosine triphosphate

ATP7A:

ATPase, Cu2+ transporting, alpha polypeptide

ATP7B:

ATPase, Cu2+ transporting, beta polypeptide

BBB:

Blood-brain barrier

BCB:

Blood-cerebrospinal fluid barrier

BG:

Basal ganglia

Ca:

Calcium

CCS:

Copper chaperone for superoxide dismutase 1

Cd:

Cadmium

COMMD1:

Copper metabolism (Murr1) domain-containing 1 protein

COX17:

Cytochrome c oxidase copper chaperone

CP:

Ceruloplasmin

CSF:

Cerebrospinal fluid

CT:

Computerized tomography

Cu:

Copper

DHPG:

Dihydroxyphenylglycol

DMT1:

Divalent metal transporter 1

DOPAC:

Dihydroxyphenylacetic acid

ER:

Endoplasmic reticulum

Fe:

Iron

FPN1:

Ferroportin 1

GHS:

Glutathione

GP:

Globus pallidus

hCTR:

Human copper transporter protein

HEPH:

Hephaestin

ITPR:

Inositol 1,4,5-trisphosphate receptor

K-F ring:

Kayser-Fleischer ring

MBD:

Metal-binding domain

MCT1:

Monocarboxylic acid transporter

MD:

Menkes disease

Mn:

Manganese

MRI:

Magnetic resonance imaging

NBIA:

Neurodegeneration with brain iron accumulation

Ni:

Nickel

NMDA:

N-methyl D-aspartate

OHS:

Occipital horn syndrome

P2RX1:

Purinergic receptor type P2X1

Pb:

Lead

PD:

Parkinson’s disease

PDGF-B:

Platelet-derived growth factor-β

PDGFRβ:

Platelet-derived growth factor receptor-β

PFBC:

Primary familial brain calcification

PiT1:

Phosphate transporter 1

PiT2:

Phosphate transporter 2

RYR:

Ryanodine receptor

SCA:

Spinocerebellar ataxia

SERCA:

Sarcoplasmic/endoplasmic reticulum calcium ATPase

SLC:

Solute carrier family

SLC30A10:

Solute carrier family 30, member 10

T1w:

T1-weighted image

T2w:

T2-weighted image

TD:

Transmembrane domain

TFRC:

Transferrin receptor

TGN:

Trans-Golgi network

TRPM7:

TRP, subfamily M, member 7

TRPs:

Transient receptor potential cation channels

WD:

Wilson disease

ZDHHC17:

Zinc finger DHHC domain-containing protein 17

Zn:

Zinc

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Acknowledgements

This work was supported by the research grants PRVOUKP26/LF1/4, UNCE 204011/12, and RVO-VFN64165/2012.

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Authors and Affiliations

  1. Department of Neurology and Center of Clinical Neuroscience, Charles University, Prague, Czech Republic

    Petr Dusek MD, PhD

  2. 1st Faculty of Medicine, General University Hospital, Prague 2, 12000, Czech Republic

    Petr Dusek MD, PhD

  3. First Faculty of Medicine, Charles University, Prague 2, 12000, Czech Republic

    Daniela Zahorakova RNDr, PhD

  4. Department of Pediatrics and Adolescent Medicine, General University Hospital, Prague 2, 121 00, Czech Republic

    Daniela Zahorakova RNDr, PhD

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Correspondence to Petr Dusek MD, PhD .

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  1. Department of Neurology, University Hospital Kiel, Kiel, Germany

    Susanne A. Schneider

  2. Department of Molecular Neuroscience, University College London, Institute of Neurology, London, United Kingdom

    José M. Tomás Brás

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Dusek, P., Zahorakova, D. (2015). Genetics of Metal Disorders (Excluding NBIA). In: Schneider, S., Brás, J. (eds) Movement Disorder Genetics. Springer, Cham. https://doi.org/10.1007/978-3-319-17223-1_14

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