Presynaptic Dopaminergic Deficits in Lesch–Nyhan Disease

Ernst, Monique; Zametkin, Alan J.; Matochik, John A.; Pascualvaca, Daisy M.; Jons, Peter H.; Hardy, Kristina K.; Hankerson, James G.; Doudet, Doris J.; Cohen, Robert M.

doi:10.1056/nejm199606133342403

Cited by 175 publications

(89 citation statements)

References 25 publications

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“…Over 2000 mutations have been described [61] which reduce or abolish HPRT function by several mechanisms including aberrant protein folding and reduced substrate affinity or enzyme synthesis. There is evidence of degeneration of dopaminergic midbrain neurons LND [62] which is likely to be the cause of the dystonic motor phenotype. However, the exact pathogenesis by which disrupted purine metabolism may cause death of mesencephalic dopaminergic and other neurons is not known.…”

Section: Lesch-nyhan Diseasementioning

confidence: 99%

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

Casper

Kalliolia²,

Warner³

2013

Current Neuropharmacology

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The majority of studies investigating the molecular pathogenesis and cell biology underlying dystonia have been performed in individuals with primary dystonia. This includes monogenic forms such as DYT1and DYT6 dystonia, and primary focal dystonia which is likely to be multifactorial in origin. In recent years there has been renewed interest in non-primary forms of dystonia including the dystonia-plus syndromes and heredodegenerative disorders. These are caused by a variety of genetic mutations and their study has contributed to our understanding of the neuronal dysfunction that leads to dystonia These findings have reinforced themes identified from study of primary dystonia including abnormal dopaminergic signalling, cellular trafficking and mitochondrial function. In this review we highlight recent advances in the understanding of the dystonia-plus syndromes and heredodegenerative dystonias.

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Section: Lesch-nyhan Diseasementioning

confidence: 99%

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

Casper

Kalliolia²,

Warner³

2013

Current Neuropharmacology

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“…These patients respond dramatically to treatment with low doses of the dopamine precursor L-DOPA. Another inherited disease in which dystonia is possibly due to a disturbance of dopamine synthesis is Lesch-Nyhan disease (Ernst et al, 1996;Wong et al, 1996;Visser et al, 2004), a condition in which a defect in purine synthesis gives rise to numerous medical problems, as well as neurologic symptoms including dystonia. Positronemission tomography (PET) studies in Lesch-Nyhan disease show reductions in [ 18 F]-DOPA uptake, and in labeling with WIN-35,428, a marker of dopamine transporter, in the basal ganglia and other regions of the brain (Ernst et al, 1996;Wong et al, 1996).…”

Section: The Role Of Dopamine In Dystoniamentioning

confidence: 99%

“…Another inherited disease in which dystonia is possibly due to a disturbance of dopamine synthesis is Lesch-Nyhan disease (Ernst et al, 1996;Wong et al, 1996;Visser et al, 2004), a condition in which a defect in purine synthesis gives rise to numerous medical problems, as well as neurologic symptoms including dystonia. Positronemission tomography (PET) studies in Lesch-Nyhan disease show reductions in [ 18 F]-DOPA uptake, and in labeling with WIN-35,428, a marker of dopamine transporter, in the basal ganglia and other regions of the brain (Ernst et al, 1996;Wong et al, 1996). Mutations in the gene that codes for the rate-limiting enzyme in dopamine metabolism, tyrosine hydroxylase, also give rise to dystonias (Knappskog et al, 1995), as do mutations within the dopamine D2 receptor gene (myoclonus-dystonia, DYT11, Klein et al, 1999), or polymorphisms within the dopamine D5 receptor gene (Placzek et al, 2001).…”

Section: The Role Of Dopamine In Dystoniamentioning

confidence: 99%

“…Further evidence that altered dopaminergic transmission plays a role in dystonia comes from PET imaging studies, which have demonstrated abnormalities of dopaminergic transmission in many dystonia patients (Ernst et al, 1996;Wong et al, 1996;Black et al, 1997;Perlmutter et al, 1997a,b;Brashear et al, 1999;Perlmutter and Mink, 2004). Specifically, reduced striatal dopamine receptor binding (Perlmutter et al, 1997a,b;Naumann et al, 1998), or [ 18 F]-DOPA uptake, suggestive of reduced DOPA decarboxylase activity (Playford et al, 1993), have been observed.…”

Section: The Role Of Dopamine In Dystoniamentioning

confidence: 99%

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Commentary: Dopaminergic dysfunction in DYT1 dystonia

Wichmann

2008

Experimental Neurology

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A three-base-pair deletion in the torsinA gene leads to generalized torsion dystonia (DYT1) in humans, an often devastating movement disorder in which voluntary movements are disrupted by sustained muscle spasms and abnormal limb posturing. In a recent issue of Experimental Neurology, Zhao et al. (2008) have provided a thorough behavioral, anatomic, and biochemical characterization of a mouse line that over-expresses human mutant torsinA, with particular emphasis on the possible role of dopaminergic dysfunction in these animals. This commentary provides an overview of the clinical and genetic features of the human disease and of the available transgenic mouse models for DYT1 dystonia, and discusses the evidence favoring the role of dopamine in the clinical manifestations of the disease.

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“…Although studies of brain function based on postmortem examination, functional neuroimaging, and animal models of LN disease (Goldstein 1986;Breese 1984;Dunnett et al 1989;Jinnah et al 1994;Ernst et al 1996;Wong et al 1996) have found abnormalities in the dopaminergic system and not in the adrenergic and noradrenergic systems in LN disease, the contribution of the latter cannot be ruled out. The proposition of the adrenergic and noradrenergic involvement in LN disease is based on three types of evidence.…”

mentioning

confidence: 99%

Adrenergic and Noradrenergic Plasma Levels in Lesch-Nyhan Disease

Ernst¹,

Zametkin²,

Pascualvaca³

et al. 2000

Neuropsychopharmacology

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Noradrenergic dysfunction and abnormality in monoamine oxidase (MAO) enzyme activity have been reported previously in Lesch-Nyhan (LN) Lesch-Nyhan disease (LN), a rare X-linked recessive disorder of purine synthesis, is characterized by the virtual absence of hypoxanthine guanine phosphoribosyl transferase (HPRT), one of the major enzymes of the salvage pathway of purine synthesis. Although HPRT activity is found in all tissues, highest levels are found in the brain and in the basal ganglia in particular. The human HPRT gene lies on the X chromosome (Xq26-27) and contains nine exons distributed over 40kb of DNA. The majority of the genetic lesions are point mutations, which affect the ability of the enzyme to catalyze the conversion of hypoxanthine and guanine to their respective nucleotides, inosinic acid and guanylic acid. In the absence of HPRT activity, de novo purine synthesis is increased, leading to the overproduction of uric acid. The clinical presentation includes hyperuricemia and a neuropsychiatric syndrome of choreoathetosis, dystonia, and compulsive aggression against self and others

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Presynaptic Dopaminergic Deficits in Lesch–Nyhan Disease

Cited by 175 publications

References 25 publications

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

Commentary: Dopaminergic dysfunction in DYT1 dystonia

Adrenergic and Noradrenergic Plasma Levels in Lesch-Nyhan Disease

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