Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo.

Abstract

Dopamine (DA) deficiency has been implicated in Lesch-Nyhan disease (LND), a genetic disorder that is characterized by hyperuricemia, choreoathetosis, dystonia, and compulsive self-injury. To Several neurodevelopmental disorders are thought to involve the neuropathology of the basal ganglia. Among them, the best known are Lesch-Nyhan disease (LND) and Rett syndrome. In both of these conditions, there is evidence for the dysfunction of the dopaminergic neurotransmission.LND is an X-chromosome-linked disease with infantile onset characterized by hyperuricemia, choreoathetosis, dystonia, and compulsive self-injury (1). The underlying defect is a near absence of hypoxanthine-guanine phosphoribosyl transferase (HPRT) (2), an enzyme that is normally present in the brain in greater amounts than in other organs. Three lines of evidence suggest that HPRT deficiency is linked to abnormal dopamine (DA) function in LND: (i) an autopsy study of three LND subjects demonstrated a marked reduction in the DA content and in the activity of DA-synthesizing enzymes in the caudate and putamen (3); (ii) when neonatal rats are depleted of DA with the neurotoxin 6-hydroxydopamine, self-injurious behavior (similar to that seen in LND) occurs when the rats are challenged with 3,4-dihydroxyphenylalanine (L-dopa) as adults (4, 5); and (iii) in an HPRT-deficient mutant mouse strain, there is a reduction of striatal tyrosine hydroxylase and in the number of striatal dopamine transporters measured with 3H-N-[1-(2-benzo(,B)thiophenyl) cyclohexyl]piperidine (3H-BTCP) (6). The pertinence of the loss of brain DA in LND has been questioned due to the limited scope of the autopsy study and the fact that the HPRT-deficient mouse study showed only a modest reduction of DA with no self-injury, or other clinical symptoms of LND (6). Therefore the question of dopamine reduction in vivo remains unresolved.The availability of positron emission tomography (PET) ligands that bind to pre-or postsynaptic DA sites has made it possible to study the DA system in vivo in patients affected with disorders that involve the basal ganglia. For example, the DA transporter probe ,3-carbomethoxy-3,3-4-fluorophenyl-tropane (CFT; WIN-35,428) (7-11) has been used to detect the degeneration of DA nerve terminals in adult humans (12,13). It has also been used to measure the degeneration of nerve terminals in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates and in idiopathic Parkinson disease (14-16). In addition, 428 is suitable for evaluating the integrity of DAcontaining neurons in neurodevelopmental disorders.In the present investigation, the hypothesis-that HPRT deficiency in LND is associated with impaired development of dopaminergic projections to the striatum-was tested by determining the number of DA transporters in vivo by using PET with the radiolabeled DA transporter ligand 428. The measurement of the presynaptic DA sites of 428 using PET provides a relevant assessment of the degree of dopaminergic deficiency in LND.The binding of [1...

Commentary: Dopaminergic dysfunction in DYT1 dystonia

“…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).…”

“…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).…”

“…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.…”

Polymorphisms in the 3′-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression

“…DAT protein levels vary in normal subjects, particularly as a function of age, and deviate from the normal range in pathological states. [4][5][6][7][8] DAT protein is markedly reduced in Parkinson's disease, 9,10 Lesch-Nyhan syndrome 11 and reportedly is elevated in attention deficit hyperactivity disorder (ADHD), [12][13][14] Tourette's syndrome, 15 and major depression. 16 Chronic use of stimulant drugs such as cocaine leads to increases in DAT levels during withdrawal whereas methamphetamine results in DAT depletion, possibly a consequence of neurotoxicity.…”

Partial Volume Correction Strategies in PET

“…In epileptic foci, also, hypometabolism is larger than a mere atrophy effect [67]. Assessment of the dopaminergic system with PET has shown that dopamine transporters are noticeably reduced in Lesh-Nyhan disease; PVC highlights this finding [68]. Dopa-decarboxylase activity has been shown to be reduced greatly in patients who have Parkinson disease, compared with normal controls [69].…”