Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene therapy is a potential therapeutic strategy for treating hereditary movement disorders, including hereditary ataxia, dystonia, Huntington's disease, and Parkinson's disease. Genome editing is a type of genetic engineering in which DNA is inserted, deleted or replaced in the genome using modified nucleases. Recently, clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9 (CRISPR/Cas9) has been used as an essential tool in biotechnology. Cas9 is an RNA-guided DNA endonuclease enzyme that was originally associated with the adaptive immune system of Streptococcus pyogenes and is now being utilized as a genome editing tool to induce double strand breaks in DNA. CRISPR/Cas9 has advantages in terms of clinical applicability over other genome editing technologies such as zinc-finger nucleases and transcription activator-like effector nucleases because of easy in vivo delivery. Here, we review and discuss the applicability of CRISPR/Cas9 to preclinical studies or gene therapy in hereditary movement disorders.
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PMID:Applications of CRISPR/Cas9 for Gene Editing in Hereditary Movement Disorders. 2766 85

Wilson disease (WD) is a potentially treatable neurodegenerative disorder. In the majority of cases, treatment with drugs that induce a negative copper balance (usually chelators or zinc salts) leads to improvements in liver function and neurologic signs. However, some patients show severe neurologic symptoms at diagnosis, such as tremor, dystonia, parkinsonism, and chorea. In this patient group, some neurologic deficits may persist despite adequate treatment, and further neurologic deterioration may be observed after treatment initiation. Such patients may require additional treatment to alleviate neurologic symptoms. Apart from general recommendations for WD anticopper treatment, there are currently no guidelines for managing neurologic symptoms in WD. The aim of this chapter is to summarize possible treatments of neurologic symptoms in WD based on the presently available medical literature.
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PMID:Symptomatic treatment of neurologic symptoms in Wilson disease. 2843 5

SLC39A14 (also known as ZIP14), a member of the SLC39A transmembrane metal transporter family, has been reported to mediate the cellular uptake of iron and zinc. Recently, however, mutations in the SLC39A14 gene have been linked to manganese (Mn) accumulation in the brain and childhood-onset parkinsonism dystonia. It has therefore been suggested that SLC39A14 deficiency impairs hepatic Mn uptake and biliary excretion, resulting in the accumulation of Mn in the circulation and brain. To test this hypothesis, we generated and characterized global Slc39a14-knockout (Slc39a14-/- ) mice and hepatocyte-specific Slc39a14-knockout (Slc39a14fl/fl;Alb-Cre+ ) mice. Slc39a14-/- mice develop markedly increased Mn concentrations in the brain and several extrahepatic tissues, as well as motor deficits that can be rescued by treatment with the metal chelator Na2CaEDTA. In contrast, Slc39a14fl/fl;Alb-Cre+ mice do not accumulate Mn in the brain or other extrahepatic tissues and do not develop motor deficits, indicating that the loss of Slc39a14 expression selectively in hepatocytes is not sufficient to cause Mn accumulation. Interestingly, Slc39a14fl/fl;Alb-Cre+ mice fed a high Mn diet have increased Mn levels in the serum, brain and pancreas, but not in the liver. Taken together, our results indicate that Slc39a14-/- mice develop brain Mn accumulation and motor deficits that cannot be explained by a loss of Slc39a14 expression in hepatocytes. These findings provide insight into the physiological role that SLC39A14 has in maintaining Mn homeostasis. Our tissue-specific Slc39a14-knockout mouse model can serve as a valuable tool for further dissecting the organ-specific role of SLC39A14 in regulating the body's susceptibility to Mn toxicity.
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PMID:Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice. 2875 76

Copper is a required cofactor for enzymes in critical metabolic pathways. Mutations in copper metabolism genes or abnormalities in copper metabolism result in disease from copper excess or deficiency. Wilson disease (WD) is an autosomal-recessive disease caused by mutations in the ATP7B gene which encodes a copper-transporting ATPase. Over 500 different WD mutations throughout the ATP7B gene have been described, most of which are missense mutations. Mutations in both ATP7B alleles result in abnormal copper metabolism and subsequent toxic accumulation of copper. The clinical manifestations of neurologic WD include variable combinations of dysarthria, dystonia, tremor, and choreoathetosis. Misdiagnosis and delay in treatment are clinically relevant because untreated WD progresses to hepatic failure or severe neurologic disability and death. Treatment can prevent and cure WD. Mutations in a second, closely related copper-transporting ATPase, ATP7A, cause a spectrum of copper deficiency disorders that include Menkes disease, occipital horn syndrome, and ATP7A-related distal motor neuropathy. Two important, nongenetic causes of copper deficiency myeloneuropathy are copper deficiency following gastric bypass or due to excess zinc ingestion, both of which can cause a myeloneuropathy similar to vitamin B12 deficiency. Copper deficiency following gastric bypass is preventable, and identification and elimination of the excess zinc source, most commonly dental cream, can result in recovery.
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PMID:Wilson disease and related copper disorders. 2932 17

ZC4H2 encodes a C4H2 type zinc-finger nuclear factor, the mutation of which has been associated with disorders with various clinical phenotypes in human, including developmental delay, intellectual disability and dystonia. ZC4H2 has been suggested to regulate spinal cord patterning in zebrafish as a co-factor for RNF220, an ubiquitin E3 ligase involved in Gli signaling. Here we showed that ZC4H2 and RNF220 knockout animals phenocopy each other in spinal patterning in both mouse and zebrafish, with mispatterned progenitor and neuronal domains in the ventral spinal cord. We showed evidence that ZC4H2 is required for the stability of RNF220 and also proper Gli ubiquitination and signaling in vivo. Our data provides new insights into the possible etiology of the neurodevelopmental impairments observed in ZC4H2-associated syndromes.
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PMID:ZC4H2 stabilizes RNF220 to pattern ventral spinal cord through modulating Shh/Gli signaling. 3133 85


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