Keith Hyland

The Clinical Potential of Ademetionine (S-Adenosylmethionine) in Neurological Disorders

SummaryThis review focuses on the biochemical and clinical aspects of methylation in neuropsychiatrie disorders and the clinical potential of their treatment with ademetionine (S-adenosylmethionine; SAMe). SAMe is required in numerous transmethylation reactions involving nucleic acids, proteins, phospholipids, amines and other neurotransmitters. The synthesis of SAMe is intimately linked with folate and vitamin B12 (cyanocobalamin) metabolism, and deficiencies of both these vitamins have been found to reduce CNS SAMe concentrations. Both folate and vitamin B12 deficiency may cause similar neurological and psychiatric disturbances including depression, dementia, myelopathy and peripheral neuropathy. SAMe has a variety of pharmacological effects in the CNS, especially on monoamine neurotransmitter metabolism and receptor systems. SAMe has antidepressant properties, and preliminary studies indicate that it may improve cognitive function in patients with dementia. Treatment with methyl donors (betaine, methionine and SAMe) is associated with remyelination in patients with inborn errors of folate and C-l (one-carbon) metabolism. These studies support a current theory that impaired methylation may occur by different mechanisms in several neurological and psychiatric disorders.

Folinic acid–responsive seizures are identical to pyridoxine-dependent epilepsy†

Folinic acid–responsive seizures and pyridoxine‐dependent epilepsy are two treatable causes of neonatal epileptic encephalopathy. The former is diagnosed by characteristic peaks on cerebrospinal fluid (CSF) monoamine metabolite analysis; its genetic basis has remained elusive. The latter is due to α‐aminoadipic semialdehyde (α‐AASA) dehydrogenase deficiency, associated with pathogenic mutations in the ALDH7A1 (antiquitin) gene. We report two patients whose CSF showed the marker of folinic acid–responsive seizures, but who responded clinically to pyridoxine. We performed genetic and biochemical testing of samples from these patients, and seven others, to determine the relation between these two disorders.

Cerebral folate deficiency with developmental delay, autism, and response to folinic acid

The authors describe a 6-year-old girl with developmental delay, psychomotor regression, seizures, mental retardation, and autistic features associated with low CSF levels of 5-methyltetrahydrofolate, the biologically active form of folates in CSF and blood. Folate and B12 levels were normal in peripheral tissues, suggesting cerebral folate deficiency. Treatment with folinic acid corrected CSF abnormalities and improved motor skills.

Aromatic l-amino acid decarboxylase deficiency Clinical features, treatment, and prognosis

Background: Deficiency of aromatic l-amino acid decarboxylase (AADC) is associated with severe developmental delay, oculogyric crises (OGC), and autonomic dysfunction. Treatment with dopamine agonists and MAO inhibitors is beneficial, yet long-term prognosis is unclear. Objective: To delineate the clinical and molecular spectrum of AADC deficiency, its management, and long-term follow-up. Results: The authors present six patients with AADC deficiency and review seven cases from the literature. All patients showed reduced catecholamine metabolites and elevation of 3-O-methyldopa in CSF. Residual plasma AADC activity ranged from undetectable to 8% of normal. Mutational spectrum was heterogeneous. All patients presented with hypotonia, hypokinesia, OGC, and signs of autonomic dysfunction since early life. Diurnal fluctuation or improvement of symptoms after sleep were noted in half of the patients. Treatment response was variable. Two groups of patients were detected: Group I (five males) responded to treatment and made developmental progress. Group II (one male, five females) responded poorly to treatment, and often developed drug-induced dyskinesias. Conclusions: The molecular and clinical spectrum of AADC deficiency is heterogeneous. Two groups, one with predominant male sex and favorable response to treatment, and the other with predominant female sex and poor response to treatment, can be discerned.

S‐adenosylmethionine levels in psychiatric and neurological disorders: a review

Introduction ‐ S‐adenosylmethionine (SAMe) is an important methyl donor in over 35 methylation reactions involving DNA, proteins, phosphalipids and catechol‐ and indole‐ amines. Material and Methods ‐ This article reviews the studies that have examined brain and blood levels of SAMe in several psychological, neurological and metabolic disorders. Results ‐ Although studies have found no consistent changes in whole blood SAMe levels in psychiatric patients, other investigators have found low cerebrospinal fluid (CSF) SAMe levels in patients with neurological disorders such as Alzheimers dementia, subacute combined degeneration of the spinal cord (SACD), and HIV‐related neuropathies, as well as in patients with metabolic disorders such as 5, 10‐CH2‐H4 folate reductase deficiency. Conclusion ‐ Intravenous or oral administration of SAMe thus represents a possible treatment for these neurological and metabolic disorders.

Demyelination and decreased S‐adenosylmethionine in 5.10‐methylenetetrahydrofolate reductase deficiency

We previously described demyelination in the brain and subacute combined degeneration of the spinal cord in a patient with 5,10-methylenetetrahydrofolate reductase deficiency. To assess the role of methionine, S-adenosylmethionine, folate, and neurotransmitter amine metabolism in the demyelination process, we measured these metabolites in CSF from this patient; the findings are compared with those obtained from three patients in whom neurologic deterioration had been halted by the administration of betaine. Folate concentrations were low, and amine and biopterin metabolism were abnormal in all patients. Methionine and S-adenosylmethionine concentrations were undetectable in the first patient. In those receiving betaine, methionine concentrations were proportional to the dose administered and S-adenosylmethionine concentrations were near normal. The results provide the first evidence for an association between defective S-adenosylmethionine metabolism and demyelination in humans.

Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study

Summary Background Dopamine transporter deficiency syndrome is the first identified parkinsonian disorder caused by genetic alterations of the dopamine transporter. We describe a cohort of children with mutations in the gene encoding the dopamine transporter (SLC6A3) with the aim to improve clinical and molecular characterisation, reduce diagnostic delay and misdiagnosis, and provide insights into the pathophysiological mechanisms. Methods 11 children with a biochemical profile suggestive of dopamine transporter deficiency syndrome were enrolled from seven paediatric neurology centres in the UK, Germany, and the USA from February, 2009, and studied until June, 2010. The syndrome was characterised by detailed clinical phenotyping, biochemical and neuroradiological studies, and SLC6A3 mutation analysis. Mutant constructs of human dopamine transporter were used for in-vitro functional analysis of dopamine uptake and cocaine-analogue binding. Findings Children presented in infancy (median age 2·5 months, range 0·5–7) with either hyperkinesia (n=5), parkinsonism (n=4), or a mixed hyperkinetic and hypokinetic movement disorder (n=2). Seven children had been initially misdiagnosed with cerebral palsy. During childhood, patients developed severe parkinsonism-dystonia associated with an eye movement disorder and pyramidal tract features. All children had raised ratios of homovanillic acid to 5-hydroxyindoleacetic acid in cerebrospinal fluid, of range 5·0–13·2 (normal range 1·3–4·0). Homozygous or compound heterozygous SLC6A3 mutations were detected in all cases. Loss of function in all missense variants was recorded from in-vitro functional studies, and was supported by the findings of single photon emission CT DaTSCAN imaging in one patient, which showed complete loss of dopamine transporter activity in the basal nuclei. Interpretation Dopamine transporter deficiency syndrome is a newly recognised, autosomal recessive disorder related to impaired dopamine transporter function. Careful characterisation of patients with this disorder should provide novel insights into the complex role of dopamine homoeostasis in human disease, and understanding of the pathophysiology could help to drive drug development. Funding Birmingham Childrens Hospital Research Foundation, Birth Defects Foundation Newlife, Action Medical Research, US National Institutes of Health, Wellchild, and the Wellcome Trust.

Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population.

ABSTRACT: Accurate diagnosis and management of inborn errors of monoamine neurotransmitter and tetrahydrobiopterin metabolism depend on reliable reference ranges of key metabolites. Cerebrospinal fluid (CSF) was collected in a standardized way from 73 children and young adults with neurologic disease, with strict exclusions. In each specimen, concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (HIAA), total neopterin, 7,8-dihydrobiopterin, and tetrahydrobiopterin (BH4) were measured using HPLC. There was a continuous decrement in CSF HVA, HIAA, and BH4 during the first few years of life; this was independent of height (or length). Age-related reference ranges for each metabolite are given. Extensive correlations between HVA, HIAA, 7,8-dihydrobiopterin, and BH4 were further analyzed by multiple regression. Age and CSF BH4 were significant explanatory variables for CSF HIAA, but CSF HVA had only HIAA as a significant explanatory variable.

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

Abstract 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.

Aromatic L-amino acid decarboxylase deficiency: overview of clinical features and outcomes.

In this paper, we provide a brief update of diagnostic considerations and biochemical phenotype in L‐amino acid decarboxylase deficiency. We review clinical features and outcome data in 11 affected patients, including 7 previously unreported cases. All had onset of the characteristic movement disorder by 6 months of age. The phenomenology of the movement disorder is identical to that previously reported, and includes intermittent oculogyric crises and limb dystonia, generalized athetosis, and impaired voluntary movement in all patients. Autonomic dysfunction is characterized by a significant impairment of sympathetic regulation of heart rate and blood pressure, as documented via detailed studies with spectral analysis techniques in two patients. Functional clinical outcomes as a group remain poor, in spite of a variety of attempted treatment interventions, with marked impairment in motor abilities as well as in speech and communication; however, outcome was quite variable from patient to patient and covered a broad spectrum of neurological disability. Much further work remains to identify and refine the best treatment options for patients with L‐amino acid decarboxylase deficiency. Ann Neurol 2003;54 (suppl 6):S49–S55