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K Hyland

Publications and source records attributed to K Hyland.

At least 37 records · Page 2Linked to original sources
PubMed1999

Presentation, diagnosis, and treatment of the disorders of monoamine neurotransmitter metabolism.

For many years, all of the described cases of monoamine neurotransmitter deficiency were associated with hyperphenylalaninemia that was generally detected at neonatal screening. It is now clear that inherited deficiency of monoamines often occurs in the absence of hyperphenylalaninemia and that the normal battery of screening tests used to investigate individuals with suspected metabolic disease will not detect these cases. Diagnosis in this situation must rely heavily on clinical suspicion. This article, therefore, describes the presentation and clinical symptoms that result from defective monoamine neurotransmission; outlines therapeutic approaches; and explains how cerebrospinal fluid profiles of monoamine metabolites, their precursors, and the cofactor required for monoamine synthesis can be used to pinpoint the exact site of the metabolic lesion.

Biogenic Monoamines↗
PubMed1999

Neurochemistry and defects of biogenic amine neurotransmitter metabolism.

The purpose of the current review is to present a brief background examining the mechanisms controlling synthesis, storage, release and action of the biogenic amine neurotransmitters and to provide examples of newly defined conditions that expand our awareness of the diversity and complexity of the inherited diseases that affect these important regulators of central and peripheral homeostasis.

Biogenic Amines↗
PubMed1999

GTP cyclohydrolase I gene expression in the brains of male and female hph-1 mice.

The hph-1 mouse is characterized by low levels of GTP cyclohydrolase I (GTPCH) and tetrahydrobiopterin. A quantitative double-label in situ hybridization technique was used to examine CNS GTPCH mRNA expression within serotonin, dopamine, and norepinephrine neurons of male and female wild-type and hph-1 mice. In wild-type male and female animals the highest levels of GTPCH mRNA expression were observed within serotonin neurons, followed by norepinephrine and then dopamine neurons. Wild-type female animals were found to express lower levels of GTPCH mRNA in each cell type when compared with levels seen in wild-type males. GTPCH mRNA abundance in all three cell types was lower in hph-1 male than in wild-type male mice, with the greatest reduction in serotonin neurons. GTPCH mRNA levels were also lower in hph-1 female than in wild-type female mice, again with the greatest reduction occurring in serotonin neurons. Comparison of hph-1 male and hph-1 female mice revealed that the sex-linked difference in GTPCH mRNA expression observed in wild-type neurons was only present within female dopamine neurons. Overall, these results indicate that not only are basal levels of GTPCH mRNA expression heterogeneous across wild-type murine monoamine cell types but that gene expression is also modified in a sex-linked and cell-specific fashion by the hph-1 gene locus. The hph-1 mutation does not lie within the GTPCH mRNA coding region. The 5' flanking region of the GTPCH gene was cloned and sequenced and shown to be identical for both wild-type and hph-1 genomic DNA. Transient transfection assays performed in PC12 cells demonstrated that this 5' flanking region was sufficient to initiate transcription of a luciferase reporter gene. Although the hph-1 mutation does not lie within the 5' flanking region of the GTPCH gene, this region of the gene can function as a core promoter and is thus crucial to the control of GTPCH gene expression.

Animals↗
PubMed1999

An evaluation of the use of the natural helping network model to enhance the well-being of nursing home residents.

This article describes and evaluates the Buddy Program, which uses a natural helping network model to enhance the well-being of persons in nursing homes. Thirty-six nondemented patients ("buddies") and 33 persons with dementia completed the 6-month study that involved an educational program for the buddies and regular meetings between buddy-dementia patient pairs. Over the 6 months, compared to a matched control group, the dementia patients showed no advantage on any of the seven outcome measures and actually had significantly more depressive symptoms and greater nursing home dissatisfaction. The nondementia buddies showed no differences from the controls on any of the outcome measures. The results suggest that natural helping network models may not be easily imported into nursing home settings.

Aged↗
PubMed1999

Value of lumbar puncture in the diagnosis of genetic metabolic encephalopathies.

Diagnostic testing for genetically determined metabolic disease has for many years relied heavily on the use of generalized screening tests that analyze groups of related compounds in easily accessible peripheral fluids such as plasma and urine. Organic acid profiles in urine and amino acid analysis in plasma are two of the most commonly requested tests; these, together with other protocols that examine peripheral fluids, have been and continue to be invaluable tools. There is, however, an emerging realization that many metabolic encephalopathies do not arise secondary to peripheral metabolic changes but rather have their origins within the central nervous system. In these cases, testing of peripheral fluids might be uninformative. This review is designed to examine the role of cerebrospinal fluid analyses in the investigation of infants and children with undefined encephalopathies. The aims are to review the conditions in which measurement of metabolites in cerebrospinal fluid is critical if a diagnosis is to be made, and to emphasize that considerable forethought is often required to ensure correct collection and handling of cerebrospinal fluid. Thus, fidelity of the diagnostic analytic procedures is maintained. This review will help the pediatric neurologist establish practical diagnostic guidelines that in turn will help in the recognition of recently described conditions. Those conditions can, in general, be identified only after specialized cerebrospinal fluid testing.

Biogenic Amines↗
PubMed1999

Folinic acid-responsive neonatal seizures.

We report three cases of folinic acid-responsive intractable neonatal seizures. All patients were born at term following normal gestation and delivery. In the first infant, seizures began on the 5th day of life and were unresponsive to phenobarbital, pyridoxine, and valproate, but stopped within 24 hours of initiation of folinic acid treatment at the age of 6 months. Her sibling had died at age 6 months with intractable seizures. In the second infant, seizures began in the 2nd hour of life. These were initially controlled with phenobarbital; however, at 3 months of age she developed status epilepticus refractory to anticonvulsants, steroids, and pyridoxine and she required repeated induction of pentobarbital coma. Seizures stopped within 24 hours of starting folinic acid. Seizures and encephalopathy were noted in the third infant on the 2nd day of life. These were controlled with phenobarbital, but at 8 weeks of age seizures recurred and were difficult to control despite the addition of phenytoin. Immediately after folinic acid was initiated the seizures stopped. Breakthrough seizures in all patients have responded to increases in folinic acid; two of the three remain on standard anticonvulsants. All patients have global developmental delay. Cranial magnetic resonance imaging in the second patient shows diffuse atrophy, and in the third patient shows increased signal on T2 images in the white matter of the frontal and parietal lobes. Analysis of cerebrospinal fluid from these patients using high-performance liquid chromatography with electrochemical detection has consistently revealed an as-yet unidentified compound, which can be used as a marker for this condition. We suggest that cerebrospinal fluid be analyzed for the presence of this compound and a trial of folinic acid be considered in neonates with unexplained early onset intractable seizures.

Anticonvulsants↗
PubMed1998

Cerebrospinal fluid homovanillic acid levels in rapid-onset dystonia-parkinsonism.

Rapid-onset dystonia-parkinsonism (RDP) is characterized by sudden onset over hours to days of dystonia, dysphagia, dysarthria, and parkinsonism. RDP has been reported by our group in two apparently unrelated families. We now report analysis of cerebrospinal fluid metabolites of dopamine, norepinephrine, and serotonin for mild and severely affected individuals, known asymptomatic gene carriers, and at-risk individuals from both families with RDP. Levels of the dopamine metabolite homovanillic acid (HVA) were decreased in severely affected patients and in some asymptomatic gene carriers. HVA levels increased with treatment in some affected individuals, but this increase did not predict clinical response to carbidopa/levodopa. We suggest that a low HVA level is a biological marker with modest association to the diagnosis of RDP.

Adult↗
PubMed1998

Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations.

Mutations in the GTP-cyclohydrolase I (GCH) gene have been identified as a cause of two disorders: autosomal dominant hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and autosomal recessive GCH-deficient hyperphenylalaninemia (HPA). Detailed clinical descriptions and genetic analysis of patients with phenotypes intermediate between HPD/DRD (mild) and GCH-deficient HPA (severe) have not been reported. We conducted genomic DNA sequencing of the GCH gene in two patients (Cases 1 and 2) manifesting generalized dystonia responsive to levodopa and severe developmental motor delay. In the pedigree of Patient 1, there were HPD/DRD patients in three generations preceding the index case. Patients 1 and 2 were compound heterozygotes with maternally and paternally transmitted mutations in the coding region of the GCH gene. In both compound heterozygotes, tetrahydrobiopterin (BH4) levels in cerebrospinal fluid were lower than those in HPD/DRD. Administration of BH4, in addition to levodopa, further improved the symptomatology of Patient 1. Our data demonstrate a new phenotype of GCH deficiency associated with compound heterozygosity for GCH gene mutations and suggest the usefulness of combined BH4 and levodopa therapy for this disorder.

Adolescent↗
PubMed1998

Chronic exposure to MPTP as a primate model of progressive parkinsonism: a pilot study with a free radical scavenger.

The development of a validated primate model of progressive parkinsonism is a critical step in the evaluation of drugs that might halt or slow progression of Parkinson's disease. In this pilot study, we gradually exposed 14 cynomolgus monkeys to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), at a weekly dose of 0.5 mg/kg s.c. for 10 weeks, to determine their probability of not reaching a predetermined endpoint on a disability scale by Kaplan-Meier analysis. Four other MPTP-exposed animals were coadministered the potent free radical scavenger 7-hydroxy-1-[4-(3-methoxyphenyl)-1-piperazinyl]acetylamino-2,2,4,6- tetramethylindan (OPC-14117) as a single oral daily dose of 0.6 g/kg, starting 2 weeks before MPTP initiation. The risk of reaching endpoint by week 10 was 79% and mean time before reaching endpoint was 6 weeks. Global motor activity, recorded in a subset of animals using a portable activity monitor, declined following the first MPTP dose and never recovered. Several cerebrospinal fluid indices of central monoamine metabolism collected by suboccipital puncture at 0, 5, and 10 weeks, including HVA, DOPAC, and tetrahydrobiopterin but not MHPG, were found to be "trait" markers for MPTP exposure, whereas CSF DOPAC and tetrahydrobiopterin constituted potential "state" markers for reaching endpoint. The antioxidant OPC-14117 did not protect against MPTP-induced parkinsonism. Further attempts to validate this incremental model of neurotoxin-induced parkinsonism as a predictor of patient responses to putative neuroprotective agents appear warranted.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

A common point mutation in the tyrosine hydroxylase gene in autosomal recessive L-DOPA-responsive dystonia in the Dutch population.

This report concerns one new mutation in the tyrosine hydroxylase (TH) gene in three patients originating from three unrelated Dutch families with autosomal recessive L-DOPA-responsive dystonia (DRD). In this study, all exons of the TH gene were amplified by the polymerase chain reaction and subjected to analyses by single-strand conformation polymorphism. An aberrant migration pattern was observed for exon 6 of the TH gene in all patients. Direct sequencing of the coding region of exon 6 revealed the presence of one novel missense mutation. An a698g transition resulted in the substitution of the evolutionary conserved arginine 233 by a histidine (R233H). All patients were homozygous for the mutation. This new mutation in the TH gene was confirmed by restriction enzyme analysis with the restriction enzyme HhaI. Thus, a high proportion of defective TH alleles may be R233H in The Netherlands.

Chromosomes, Human, Pair 11↗
PubMed1998

Time-dependent effects of levodopa on regional brain dopamine metabolism and lipid peroxidation.

Levodopa treatment in Parkinson's disease has been suggested to contribute to disease progression through free radical generation. We compared the time course of levodopa-induced dopamine metabolism, and the resulting oxidative stress, between rat brain regions with varying dopaminergic innervation. At 1, 4, 8, and 12 h after levodopa administration (100 mg/kg), dopamine, dihydroxyphenylacetic acid, and homovanillic acid were measured in striatum and ventral midbrain, regions containing marked dopaminergic innervation, and in prefrontal cortex and cerebellum, which possess little dopaminergic innervation. Malondialdehyde, a marker of oxidative stress, was measured in additional animals. The return of dopamine and its metabolites to control concentrations tended to be slower (by 3-8 h) in cerebellum and prefrontal cortex than in dopaminergic regions. Malondialdehyde concentrations were decreased (p < 0.05) in ventral midbrain 8 h posttreatment, but increased in cerebellum 12 h posttreatment. We concluded that levodopa increases dopamine metabolism in nondopaminergic as well as dopaminergic regions, with delayed clearance of dopamine and its metabolites in nondopaminergic regions. The slower return of dopamine to control levels in nondopaminergic regions may be relevant to some of the side effects of levodopa. No support was found for the hypothesis that levodopa treatment induces oxidative stress.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

One-methyl group metabolism in non-ketotic hyperglycinaemia: mildly elevated cerebrospinal fluid homocysteine levels.

Non-ketotic hyperglycinaemia (NKH) is a rare, severe brain disease caused by deficient glycine cleavage enzyme complex activity resulting in elevated glycine concentrations. Recent experience suggests that factors in addition to glycine kinetics are involved in its pathogenesis. The glycine cleavage reaction through the formation of methylenetetrahydrofolate is an important one-methyl group donor. A deficiency in one-methyl group metabolites, in particular of choline, has been hypothesized in NKH. We investigated metabolites involved in one-methyl group metabolism in plasma and CSF of 8 patients with NKH, and monitored the effect of treatment with choline in one patient. Plasma and CSF choline and phosphatidylcholine concentrations were normal, except for a low plasma choline in the single neonate studied. Choline treatment did not change brain choline content, and was not associated with clinical or radiological improvement. Methionine concentrations and, in one-patient, S-adenosylmethionine and 5-methyltetrahydrofolate concentrations were normal in CSF. Homocysteine concentrations in CSF, however, were slightly but consistently elevated in all four patients examined, but cysteine, cysteinylglycine and glutathione were normal. Serine is important in the transfer of one-methyl groups from mitochondria to cytosol. Serine concentrations were normal in plasma and CSF, but dropped to below normal in CSF in three patients on benzoate treatment. These observations add to our understanding of the complex metabolic disturbances in NKH.

Amino Acid Metabolism, Inborn Errors↗
PubMed1998

Interracial and intraracial differences in neuropsychiatric symptoms, sociodemography, and treatment among nursing home patients with dementia.

Using an adaptation of George's (1989) social antecedent model of psychopathology, this article examines interracial and intraracial differences in neuropsychiatric symptoms, sociodemography, and treatment among nursing home patients with dementia. The final sample consisted of 164 U.S.-born African Americans, 54 African Caribbeans, and 68 Caucasians. Although there were appreciable interracial differences in sociodemographics, there were minimal clinical differences. This finding may reflect both racial differences in pathways to institutionalization and the homogenization of clinical characteristics created by new governmental standards for nursing homes. There were no substantial differences between African Americans and African Caribbeans. Use of medication to treat neuropsychiatric symptoms was low, and may have reflected difficulties in diagnosis and concerns about the abuse of medications.

Black or African American↗