Lesch‐nyhan syndrome: A study of motor behavior and cerebrospinal fluid neurotransmitters

Jankovic, Joseph; Caskey, Thomas; Stout, J. Timothy; Butler, Ian J.

doi:10.1002/ana.410230507

Cited by 115 publications

(57 citation statements)

References 19 publications

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“…The abnormally low DHPG levels may thus represent an adaptive mechanism to spare NE levels, possibly mediated by reduced MAO activity. This finding is consistent with the report of low CSF MHPG in 5 LN boys (Jankovic et al 1988), and low to normal plasma levels of NE in 14 LN subjects compared to controls (Lake and Ziegler 1977). Of interest, central noradrenergic function was reported to be normal in postmortem biochemical analyses of NE concentration (Lloyd et al 1981), and in a genetic mouse model of LN (Jinnah et al 1994).…”

Section: Discussionsupporting

confidence: 89%

“…Notwithstanding, EPI concentrations have not been assessed in any of the published biochemical studies of LN disease (Rockson 1974;Lake and Ziegler 1977;Silverstein et al 1985;Jankovic et al 1988). In contrast, NE levels have been reported to be normal or reduced at baseline, and irresponsive to postural changes (Lake and Ziegler 1977;Rockson 1974), or to exposure to cold (Rockson 1974).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Adrenergic and Noradrenergic Plasma Levels in Lesch-Nyhan Disease

Ernst¹,

Zametkin²,

Pascualvaca³

et al. 2000

Neuropsychopharmacology

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“…In some of these disorders, dopamine metabolite disturbances have already been reported, such as the presence of low CSF HVA values in phenylketonuria 21,22 and Lesch-Nyhan disease. 23 In addition, these kinds of diseases that involve the brain in a diffuse manner are commonly associated with structural brain abnormalities. In our study we have observed that cortical atrophy disclosed by brain MRI tends to be related to low 5-HIAA concentrations.…”

Section: (3) Neurogenetic Conditionsmentioning

confidence: 99%

Secondary abnormalities of neurotransmitters in infants with neurological disorders

García‐Cazorla

Serrano

Pérez‐Dueñas

et al. 2007

Develop Med Child Neuro

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Neurotransmitters are essential in young children for differentiation and neuronal growth of the developing nervous system. We aimed to identify possible factors related to secondary neurotransmitter abnormalities in pediatric patients with neurological disorders. We analyzed cerebrospinal fluid (CSF) and biogenic amine metabolites in 56 infants (33 males, 23 females; mean age 5.8mo [SD 4.1mo] range 1d-1y) with neurological disorders whose aetiology was initially unknown. Patients were classified into three clinical phenotypes: epileptic encephalopathy, severe motor impairment, and non-specific manifestations. All patients showed normal results for screening of inborn errors of metabolism. We report clinical, neuroimaging, and follow-up data. Among the patients studied, 10 had low homovanillic acid (HVA) levels and in four patients, 5-hydroxyindoleacetic acid (5-HIAA) was also reduced. Patients with neonatal onset had significantly lower levels of HVA than a comparison group. HVA deficiency was also associated with severe motor impairment and the final diagnosis related to neurodegenerative disorders. 5-HIAA values tended to be decreased in patients with brain cortical atrophy. The possibility of treating patients with L-Dopa and 5-hydroxytryptophan, in order to improve their neurological function and maturation, may be considered.Brain neurotransmission is essential in young children, not only for interneuronal communication but also for differentiation, neuronal growth, and shaping and wiring of the nervous system. 1 Biogenic amines are the most representative group among brain neurotransmitters 2 and are composed of catecholamines (dopamine and norepinephrine) and serotonin. Within the central nervous system, the final metabolite for dopamine is homovanillic acid (HVA) and for serotonin, 5-hydroxyindoleacetic acid (HIAA). These metabolites can be measured in the cerebrospinal fluid (CSF). Low concentrations of biogenic amine metabolites in the CSF are mainly due to defects in their biosynthetic and catabolic pathways. Deficiencies of tyrosine hydroxylase, aromatic L-amino acid decarboxylase, guanosine triphosphate cyclohydrolase (GTPCH), and sepiapterin reductase, 3 (the last two enzymes contributing to the formation of tetrahydrobiopterin [BH4]), cause the main paediatric neurotransmitter diseases.Little is known about secondary causes of low CSF biogenic amine metabolites, and, to our knowledge, no study focusing on how diverse neurological disorders in infants could affect brain biogenic amines production has been described until now. There are a few studies that have looked at secondary reduction of HVA. It has been reported that epilepsy, 4,5 rapidonset dystonia-parkinsonism, 6 Huntington's disease, 7 and depression and dementia 8,9,10 are among those disorders characterized by secondary reduction of HVA. However, the results found in these studies are often contradictory and not specific to young children. Moreover, no study concerning possible factors that could be related to these secondary abnormalit...

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“…Despite the absence of neurobehavioral deficits in these mice, several studies have demonstrated neurochemical abnormalities that are strikingly similar to those observed in Lesch-Nyhan disease. In particular, these animals have significant deficits in brain dopamine levels (Finger et al, 1988;Dunnett and Sirinathsinghji, 1989;Williamson et al, 199 1;Jinnah et al, 1993) similar to those that occur in Lesch-Nyhan patients (Lloyd et al, 198 1;Silverstein et al, 1985;Jankovic et al, 1988). The occurrence of this defect in the HPRTmice provides a unique tool for studying the relationship between HPRT deficiency and brain dopamine systems.…”

mentioning

confidence: 98%

Dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease

et al. 1994

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We have examined several aspects of neurotransmitter function in the brains of mice carrying a deletion mutation in the gene encoding the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). During the first 6 weeks of postnatal development, dopamine levels in whole-brain extracts from the mutant mice (HPRT-) failed to increase at rates comparable to normal animals, resulting in 40% lower dopamine levels throughout adulthood. Regional analysis in adult animals showed the caudoputamen to be the most severely affected region, with dopamine deficits of 48–64%. Dopamine levels in other regions were normal or less severely affected. The decrease in dopamine was accompanied by a decrease in tyrosine hydroxylase (TH) activity, the rate-limiting step in dopamine synthesis. Kinetic analysis of TH extracted from the caudoputamen of normal and HPRT- mice demonstrated a 45% decrease in Vmax with an increased affinity for the tetrahydropterin cofactor in the mutants. Labeling of midbrain dopamine neurons using TH immunohistochemistry revealed no obvious deficits in the number of midbrain dopamine neurons, but quantitative autoradiographic studies revealed significant reductions in the binding of 3H-N-[1-(2-benzo(beta)thiophenyl)cyclohexyl]piperidine (3H-BTCP) to dopamine uptake sites in the forebrain of the mutants. In contrast to these abnormalities of the dopamine systems in the mutant mice, other neurotransmitter systems appeared relatively unaffected. Norepinephrine, 5-HT, tryptophan hydroxylase, and glutamic acid decarboxylase were present at normal levels in the brains of the mutants. ChAT activity was slightly lower than normal in the caudoputamen of the mutant animals, but was normal in all other brain regions examined. These results indicate that HPRT deficiency is associated with a relatively specific deficit in basal ganglia dopamine systems that emerges during the first 2 months of postnatal development.

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Lesch‐nyhan syndrome: A study of motor behavior and cerebrospinal fluid neurotransmitters

Cited by 115 publications

References 19 publications

Adrenergic and Noradrenergic Plasma Levels in Lesch-Nyhan Disease

Adrenergic and Noradrenergic Plasma Levels in Lesch-Nyhan Disease

Secondary abnormalities of neurotransmitters in infants with neurological disorders

Dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease

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