ABSTRACT
CSF purines were grossly elevated compared with controls only in adenylosuccinate lyase (ADSL) deficiency and TB meningitis. The former representing low permeability, the latter severe damage to the normal blood/brain barrier. By contrast, the similarity to controls, with no difference between Lesch-Nyhan disease (LND) or LND variants, would exclude hypoxia as a factor in the severe neurological deficits in LND. Similar findings in purine nucleoside phosphorylase (PNP) deficiency (although nucleosides replace the normal bases) likewise exclude hypoxia in the aetiology of the albeit milder neurological deficits.
Subject(s)
Adenylosuccinate Lyase/deficiency , Nucleotides/cerebrospinal fluid , Adenylosuccinate Lyase/genetics , Adolescent , Adult , Aged , Blood-Brain Barrier , Case-Control Studies , Child , Child, Preschool , Female , Humans , Hypoxia , Infant, Newborn , Lesch-Nyhan Syndrome/cerebrospinal fluid , Male , Purine-Nucleoside Phosphorylase/deficiency , Purines/chemistry , Time Factors , Tuberculosis, Meningeal/cerebrospinal fluid , Uric Acid/blood , Uric Acid/metabolismSubject(s)
Amino Acids/cerebrospinal fluid , Brain/metabolism , Hypoxanthine Phosphoribosyltransferase/cerebrospinal fluid , Lesch-Nyhan Syndrome/metabolism , Cystathionine/cerebrospinal fluid , Humans , Hypoxanthine Phosphoribosyltransferase/deficiency , Lesch-Nyhan Syndrome/cerebrospinal fluid , gamma-Aminobutyric Acid/cerebrospinal fluidABSTRACT
We studied 5 boys, 2 to 10 years old, with marked or complete deficiency of hypoxanthine-guanine phosphoribosyltransferase and Lesch-Nyhan syndrome with varying degrees of mental retardation, dysarthria, chorea, dystonia, spasticity, and ataxia. Four patients had marked reduction of homovanillic acid in the cerebrospinal fluid (CSF) and all showed low CSF 3-methoxy-4-hydroxy phenylethylene glycol, indicating reduced dopamine and norepinephrine turnover. Three patients showed high CSF 5-hydroxyindoleacetic acid, suggesting increased serotonin turnover. Some patients improved with carbidopa-levodopa, but others benefited from tetrabenazine, a monoamine-depleting agent. This study provides support for the theory of abnormal central monoamine metabolism in Lesch-Nyhan syndrome.
Subject(s)
Glycols/cerebrospinal fluid , Homovanillic Acid/cerebrospinal fluid , Hydroxyindoleacetic Acid/cerebrospinal fluid , Lesch-Nyhan Syndrome/cerebrospinal fluid , Methoxyhydroxyphenylglycol/cerebrospinal fluid , Movement Disorders/etiology , Self Mutilation/etiology , Carbidopa/therapeutic use , Catecholamines/metabolism , Child , Child, Preschool , Fluphenazine/therapeutic use , Humans , Lesch-Nyhan Syndrome/complications , Lesch-Nyhan Syndrome/drug therapy , Levodopa/therapeutic use , Male , Movement Disorders/cerebrospinal fluid , Movement Disorders/drug therapy , Self Mutilation/cerebrospinal fluid , Self Mutilation/drug therapy , Tetrabenazine/therapeutic useABSTRACT
Serial determinations of spinal fluid homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were made in four patients with the Lesch-Nyhan syndrome over a 5-year period. Control spinal fluids for age-matched comparison were obtained from 194 neurologic and nonneurologic pediatric patients. A rapid decline in control spinal fluid HVA and 5-HIAA occurs over the first 3 years of life (50 and 60%, respectively), and a more gradual decline persists throughout adolescence. The Lesch-Nyhan subjects have similar age-related changes in their spinal fluid neurotransmitter levels. Sequential 5-HIAA determinations from the four Lesch-Nyhan boys fall within the control range. The Lesch-Nyhan HVA levels are lower than the mean value for the age-matched control group in 18 of 19 samples. Ten of 19 determinations fell below the control range. Our findings provide evidence for altered CNS dopamine metabolism in the Lesch-Nyhan syndrome.
Subject(s)
Homovanillic Acid/cerebrospinal fluid , Hydroxyindoleacetic Acid/cerebrospinal fluid , Lesch-Nyhan Syndrome/cerebrospinal fluid , Phenylacetates/cerebrospinal fluid , Adolescent , Child , Child, Preschool , Chromatography, High Pressure Liquid , Dopamine/metabolism , Humans , Infant , Male , Serotonin/metabolism , Spinal PunctureABSTRACT
In a patient with the Lesch-Nyhan syndrome we found decreased spinal fluid 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of serotonin, and decreased homovanillic acid (HVA), the major metabolite of dopamine, indicating a decrease in monoamine metabolism. Administration of 5-hydroxytryptophan and carbidopa produced an increase in spinal fluid 5-HIAA, indicating that it might be possible to correct the serotonin deficiency in this syndrome, but there were no changes in the marked mental retardation and neurological deficits. Self-mutilation appeared to be suppressed by therapy but the effectiveness of the drugs decreased with time. There were also changes in the spinal fluid concentration of amino acids that might affect brain protein synthesis. These changes were corrected during administration of 5-hydroxytryptophan and carbidopa.
Subject(s)
5-Hydroxytryptophan/pharmacology , Amino Acids/metabolism , Dopamine/metabolism , Lesch-Nyhan Syndrome/metabolism , Serotonin/metabolism , 5-Hydroxytryptophan/therapeutic use , Amino Acids/cerebrospinal fluid , Carbidopa/therapeutic use , Homovanillic Acid/cerebrospinal fluid , Humans , Hydroxyindoleacetic Acid/cerebrospinal fluid , Infant , Infant, Newborn , Intellectual Disability/drug therapy , Lesch-Nyhan Syndrome/cerebrospinal fluid , Male , Self Mutilation/drug therapyABSTRACT
The effects of 5-hydroxytryptophan (5-HTP), a serotonin precursor, were studied in a boy with the Lesch-Nyhan syndrome. During the course of drug treatment, self-mutilation, crying, sleep state architecture, serum dopamine B-hydroxylase (DBH), and cerebrospinal fluid levels of 5-hydroxyindolylacetic acid and homovanillic acid were studied. Treatment with 5-HTP failed to affect this child's biting behavior. However, the drug significantly reduced irritability as measured by crying time. Moreover, 5-HTP may have affected sleep state architecture, making it more normal in character. Serum DBH levels were normal throughout the study. Neither the patient's mother nor his maternal grandmother showed a hypertensive response on the cold pressor test.
