Cerebrospinal fluid values for monoamine metabolites, γ-aminobutyric acid, and other amino compounds in Rett syndrome

Perry, Thomas L.; Dunn, Henry G.; Ho, Helena H.; Crichton, John U.

doi:10.1016/s0022-3476(88)80060-x

Cited by 54 publications

(26 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, the first study that examined neurotrans- mitter abnormalities in RTT supported such a hypothesis (11). Subsequent studies ranged from inconclusive to contradictory (13)(14)(15). Murine models of MECP2 disorders recapitulated behavioral features that could be linked to neurotransmitter abnormalities (28-32, 22, 33), providing at last the opportunity to address the question in a controlled fashion.…”

Section: Discussionmentioning

confidence: 99%

“…Although clinical studies have explored the hypothesis that the aminergic neurotransmitter systems might be altered in RTT, no solid conclusions have been reached. Early work suggested decreased aminergic metabolite levels in the spinal fluid of individuals with RTT (11, 12), but subsequent reports failed to identify such changes (13,14). More recently, one study reported instances of both decreased and increased aminergic metabolite levels in a few individuals with RTT (15).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities

Samaco¹,

Mandel‐Brehm²,

Chao

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

227

214

View full text Add to dashboard Cite

Rett syndrome (RTT) is characterized by specific motor, cognitive, and behavioral deficits. Because several of these abnormalities occur in other disease states associated with alterations in aminergic neurotransmitters, we investigated the contribution of such alterations to RTT pathogenesis. We found that both individuals with RTT and Mecp2-null mice have lower-than-normal levels of aminergic metabolites and content. Deleting Mecp2 from either TH-positive dopaminergic and noradrenergic neurons or PET1-positive serotonergic neurons in mice decreased corresponding neurotransmitter concentration and specific phenotypes, likely through MeCP2 regulation of rate-limiting enzymes involved in aminergic neurotransmitter production. These data support a cell-autonomous, MeCP2-dependent mechanism for the regulation of aminergic neurotransmitter synthesis contributing to unique behavioral phenotypes.dopamine ͉ norepinephrine ͉ Rett syndrome ͉ serotonin R ett syndrome (RTT, MIM 312750) is an X-linked neurodevelopmental disorder caused, in the vast majority of cases, by mutations in Methyl-CpG Binding Protein 2 (MECP2) (1). RTT primarily affects females, with a milder clinical phenotype correlating with late truncating and some missense mutations (2, 3). It has been suspected that aminergic neurons malfunction in RTT, because the heightened anxiety, aggression, and mood alterations seen in RTT and MECP2 disorders are associated with abnormalities of the serotonergic system in other human disorders (4-6). Rigidity and movement abnormalities are associated with dysfunction of dopaminergic system (7-9). Autonomic dysfunction underlying breathing irregularities could be attributable to decreased norepinephrine (7, 10). Although clinical studies have explored the hypothesis that the aminergic neurotransmitter systems might be altered in RTT, no solid conclusions have been reached. Early work suggested decreased aminergic metabolite levels in the spinal fluid of individuals with RTT (11, 12), but subsequent reports failed to identify such changes (13,14). More recently, one study reported instances of both decreased and increased aminergic metabolite levels in a few individuals with RTT (15). The interpretation of these clinical data are hindered by clinical heterogeneity, small sample sizes, and lack of a sufficient number of controls. To circumvent these problems, we explored the role of the aminergic neurotransmitter system by performing both clinical and animal studies. To determine whether the aminergic neurotransmitter system is altered in RTT, we analyzed the levels of the dopamine metabolite homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in spinal fluid from women who both met the clinical criteria for RTT and had a diseasecausing MECP2 mutation. We also evaluated neurotransmitter changes in a RTT murine model and studied the neurochemical, molecular, and behavioral consequences of deleting Mecp2 from either TH-positive dopaminergic and noradrenergic neurons or PET1-positive serot...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities

Samaco¹,

Mandel‐Brehm²,

Chao

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

227

214

View full text Add to dashboard Cite

show abstract

“…Studies of CSF neurotransmitters in RTT patients without genetic studies have reported contradictory results of dopamine levels [5,21,22], but neuropathological studies found a significant reduction of the metabolites of dopamine and norepinephrine in the Substantia nigra, more prominent in the older RTT females, and the possibility of age-related abnormality was considered [23][24]. The progressive reduction of dopamine with age could explain the decreased intensity of the stereotypies and the appearance of dystonia and Parkinsonian symptoms.…”

Section: Csf Neurotransmitters In Rtt and Rdmentioning

confidence: 99%

“…Nomura et al [3] were among the first to suggest that neurotransmitter anomalies could form the chemical basis for RTT, postulating that its movement disorder and altered sleep structure could be related to a deficiency in brainstem dopamine and serotonin, respectively; nevertheless conflicting reports regarding the levels of biogenic amine metabolites and pterine values in the cerebrospinal fluid (CSF) have appeared from several laboratories [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

“…Folate is involved in the biosynthesis of GTP, a precursor of tetrahydrobiopterine (BH 4 ), and therefore it could modulate phenylalanine catabolism and serotonin and dopamine biosynthesis. They studied 4 RTT patients (2 with and 2 without an identified mutation); all had low CSF levels of the folate metabolite 5-methyltetrahydrofolate (5-MTHF) and normal serum folate levels.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of CSF neurotransmitters and folate in 25 patients with Rett disorder and effects of treatment

Temudo

Ríos

Prior

et al. 2009

Brain and Development

View full text Add to dashboard Cite

Background: Rett disorder (RD) is a progressive neurodevelopmental entity caused by mutations in the MECP2 gene. It has been postulated that there are alterations in the levels of certain neurotransmitters and folate in the pathogenesis of this disease. Here we re-evaluated this hypothesis. Patients and methods: We evaluated CSF folate, biogenic amines and pterines in 25 RD patients. Treatment with oral folinic acid was started in those cases with low folate. Patients were clinically evaluated and videotaped up to 6 months after therapy. Results: CSF folate was below the reference values in 32% of the patients. Six months after treatment no clinical improvement was observed. Three of the four patients with the R294X mutation had increased levels of a dopamine metabolite associated to a particular phenotype. Three patients had low levels of a serotonin metabolite. Two of them were treated with fluoxetine and one showed clinical improvement. No association was observed between CSF folate and these metabolites, after adjusting for the patients age and neopterin levels. Conclusion: Our results support that folinic acid supplementation has no significant effects on the course of the disease. We report discrete and novel neurotransmitter abnormalities that may contribute to the pathogenesis of RD highlighting the need for further studies on CSF neurotransmitters in clinically and genetically well characterized patients.

show abstract

Decreased cerebrospinal fluid levels of ?-phenylethylamine in patients with Rett syndrome

et al. 2000

View full text Add to dashboard Cite

To clarify the mechanism of brain impairment in Rett syndrome, we measured the cerebrospinal fluid levels of β‐phenylethylamine (PEA) in 17 patients with Rett syndrome. Findings were compared with those obtained in age‐matched controls and diseased controls. The cerebrospinal fluid level of PEA was significantly lower in patients with Rett syndrome than in the controls (31% of control values). The alteration in the cerebrospinal fluid level of PEA may reflect dopamine system impairment in Rett syndrome. Ann Neurol 2000;47:801–803

show abstract

Cerebrospinal fluid values for monoamine metabolites, γ-aminobutyric acid, and other amino compounds in Rett syndrome

Cited by 54 publications

References 13 publications

Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities

Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities

Evaluation of CSF neurotransmitters and folate in 25 patients with Rett disorder and effects of treatment

Decreased cerebrospinal fluid levels of ?-phenylethylamine in patients with Rett syndrome

Contact Info

Product

Resources

About