Diagnosis and management of cerebral folate deficiency. A form of folinic acid-responsive seizures.

Folinic acid-responsive seizures (FARS) are a rare treatable cause of neonatal epilepsy. They have characteristic peaks on CSF monoamine metabolite analysis, and have mutations in the ALDH7A1 gene, characteristically found in pyridoxine-dependent epilepsy. There are case reports of patients presenting with seizures at a later age, and with folate deficiency due to different mechanisms with variable response to folinic acid supplementation. Here, we report 2 siblings who presented with global developmental delay and intractable seizures who responded clinically to folinic acid therapy. Their work-up included metabolic and genetic testing. The DNA sequencing was carried out for the ALDH7A1 gene, and the folate receptor 1 (FOLR1) gene. They had very low 5-methyltetrahydrofolate (5-MTHF) in CSF with no systemic folate deficiency and no characteristic peaks on neurotransmitter metabolite chromatogram. A novel mutation in the FOLR1 gene was found. The mutation in this gene is shown to affect CSF folate transport leading to cerebral folate deficiency. The response to treatment with folinic acid was dramatic with improvement in social interaction, mobility, and complete seizure control. We should consider the possibility of this treatable condition in appropriate clinical circumstances early, as diagnosis with favorable outcome depends on the specialized tests.

Progressive ataxia and myoclonic epilepsy in a patient with a homozygous mutation in the FOLR1 gene.

Several unrelated disorders can lead to 5-methyltetrahydrofolate (5MTHF) depletion in the cerobrospinal fluid (CSF), including primary genetic disorders in folate-related pathways or those causing defective transport across the blood-CSF barrier. We report a case of cerebral folate transport deficiency due to a novel homozygous mutation in the FOLR1 gene, in an effort to clarify phenotype-genotype correlation in this newly identified neurometabolic disorder. A previously healthy infant developed an ataxic syndrome in the second year of life, followed by choreic movements and progressive myoclonic epilepsy. At the age of 26 months, we analyzed CSF 5MTHF by HPLC with fluorescence detection and conducted magnetic resonance (MR) imaging and spectroscopy studies. Finally, we performed mutational screening in the coding region of the FOLR1 gene. MR showed a diffuse abnormal signal of the cerebral white matter, cerebellar atrophy and a reduced peak of choline in spectroscopy. A profound deficiency of CSF 5MTHF (2 nmol/L; NV 48-127) with reduced CSF/plasma folate ratio (0.4; NV 1.5-3.5) was highly suggestive of defective brain folate-specific transport across the blood-CSF/brain barrier. Mutation screening of FOLR1 revealed a new homozygous missense mutation (p.Cys105Arg) that is predicted to abolish a disulfide bond, probably necessary for the correct folding of the protein. Both parents were heterozygous carriers of the same variant. Mutation screening in the FOLR1 gene is advisable in children with profound 5MTHF deficiency and decreased CSF/serum folate ratio. Progressive ataxia and myoclonic epilepsy, together with impaired brain myelination, are clinical hallmarks of the disease.

Diffusion-weighted imaging in preclinical Leigh syndrome.

We report on a preterm Japanese male baby with Leigh syndrome, i.e., intrauterine growth restriction, central apnea, and feeding difficulty. These signs improved at 41 weeks of corrected age. At that time, brain magnetic resonance imaging revealed increased signal in diffusion-weighted imaging in the parietal white matter, bilaterally and symmetrically not respecting vascular territory or boundaries. However, clinical improvement deterred us from further investigation. About 3 months later, he manifested frequent ictal apnea with myoclonic seizures and deterioration of consciousness to semicoma. Subsequent diffusion-weighted imaging revealed increased signal in the bilateral symmetric thalamus, internal segments of the globus pallidus, substantia nigra, and pontine tegmentum. Laboratory investigation indicated remarkable elevation of lactate levels in cerebrospinal fluid. The diagnosis was of Leigh syndrome. We think this is the first reported case of Leigh encephalopathy with transient abnormality of diffusion-weighted imaging of the white matter before apparent clinical onset. Leigh syndrome should be included in the differential diagnosis of abnormality of diffusion-weighted imaging in white matter without apparent clinical signs.

Cerebrospinal fluid pterins and neurotransmitters in early severe epileptic encephalopathies.

Early-onset epileptic encephalopathies are devastating conditions. Little is known about pathophysiology and biological markers. We aimed to identify a relationship between the type and prognosis of epileptic encephalopathies starting in infancy and the cerebrospinal fluid profile of pterins and neurotransmitters. Cerebrospinal fluid samples of 23 infants with epileptic encephalopathies were analysed for biogenic amine metabolites (homovanillic and 5-hydroxyindoleacetic acids), and pterins (neopterin and biopterin). West syndrome, early-infantile epileptic encephalopathy with suppression-bursts or Ohtahara syndrome, severe epilepsy with multiple independent spike foci and partial epilepsy with multiple independent spike foci were the four types of epileptic encephalopathy studied. We report clinical, electroencephalographic, neuroimaging and follow-up data. Among the 23 patients studied, 7 had high neopterin levels. Four of them had partial epilepsy with multiple independent spike foci. High neopterin values were associated with mortality (chi square = 7.304, p = 0.007). 5-Hydroxyindoleacetic acid levels were above reference values in three patients, two with partial epilepsy with multiple independent spike foci and one with West syndrome. Homovanillic acid was normal in almost all infants studied. In conclusion, high neopterin levels suggest a cellular immune activation in the central nervous system of these infants, with apparent prognosis implications.

Cerebrospinal fluid free choline in movement disorders of paediatric onset.

We measured free choline in cerebrospinal fluid (CSF) of 78 patients with movement disorders of paediatric onset and various controls as a putative index of central phospholipid metabolism. Most of the disorders studied were myoclonic disorders, such as progressive myoclonus epilepsy, the opsoclonus-myoclonus syndrome, and essential myoclonus, but other movement disorders, interictal seizure disorders, and different neurological and nonneurological disorders were also included. There were no significant differences in CSF choline concentrations in myoclonic disorders or other movement disorders compared with controls. The CSF choline levels were lowest in children with seizure disorders including progressive myoclonus epilepsy. In progressive myoclonus epilepsy, the CSF choline values resembled other epileptic disorders rather than other myoclonic disorders. When all the data were analysed collectively, no significant relation of CSF choline was found to patient age, gender, aliquot of CSF measured, or the length of time the sample was stored at -70 degrees C. Separate analyses of data from children and adults showed a trend toward a biphasic relation between patient age and CSF choline which could be pursued in developmental studies of normal subjects. Reduced CSF choline may indicate increased choline incorporation into brain phospholipids, disturbances of choline metabolism, decreased choline release, or non-neural factors.

Neuropharmacology of progressive myoclonus epilepsy: response to 5-hydroxy-L-tryptophan.

Low concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) of patients with progressive myoclonus epilepsy (PME) suggest hypofunctional serotonergic neurotransmission. To study this hypothesis, we enrolled 6 patients with PME [Unverricht-Lündborg disease (U-L), mitochondrial encephalomyopathy, or Lafora disease] in a controlled, double-blinded, dose-ranging, cross-over add-on pilot clinical trial of 5-hydroxy-L-tryptophan (L-5-HTP) plus carbidopa after 2 other patients had received open-label L-5-HTP for compassionate use. Prestudy CSF 5-HIAA concentrations were low (< 20 ng/ml) in 6 patients regardless of the etiology of PME. One patient with U-L disease showed clinical improvement and a fivefold increase in CSF 5-HIAA, and 1 with Lafora disease showed a twofold increase in CSF 5-HIAA without improvement. A patient with Lafora disease reported enough improvement in myoclonus-evoked convulsions to continue chronic use of the drug. One patient with mitochondrial encephalomyopathy developed status epilepticus during treatment with L-5-HTP. As a group, patients had no statistically significant changes in myoclonus evaluation scale scores, subjective and objective measures of ataxia, seizure frequency, antiepileptic drug (AED) levels, or routine blood tests. These data suggest a serotonergic abnormality regardless of the underlying etiology of PME, but one that seldom responds to acute treatment with L-5-HTP.

Analysis of glial fibrillary acidic protein in the cerebrospinal fluid of children investigated for encephalopathy.

The clinical application of a newly developed highly sensitive ELISA method (20) to assay glial fibrillary acidic protein (GFAP) in the cerebrospinal fluid (CSF) was investigated in children and adolescents with neurological disorders. GFAP analysis was explored as a tool to differentiate disorders with ongoing astrocytosis. A consecutive series of 34 subjects, 17 boys and 17 girls, with nonprogressive and progressive neurological encephalopathies was compared to 10 healthy controls. The mean CSF GFAP concentration of the controls was 60.6 +/- 54 ng/l (SD). The group of 24 subjects (12 boys and 12 girls) with progressive neurologic disorders had higher mean CSF GFAP levels than the group of 10 subjects (5 boys and 5 girls) with non-progressive disorders, 222.6 +/- 186 and 127.5 +/- 86 ng/l, respectively. The progressive encephalopathies differed significantly from controls (p < 0.01) while the non-progressive did not. The mean GFAP concentration of the epilepsy cases (n = 18) and non-epilepsy cases (n = 16) was 212.9 +/- 196 and 174.0 +/- 132 ng/l, respectively. The epilepsy cases differed significantly from controls which could be explained by the dominance of progressive cases (15 out of 18).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino acid levels in cerebrospinal fluid of rats after administration of pentylenetetrazol.

1. We studied the effect of pentylenetetrazol (PTZ)-induced myoclonic jerks and generalized clonic-tonic convulsions (GC) on the levels of neurotransmitter amino acids in the cisternal CSF of rats. 2. The levels of aspartate, glutamate, glycine, and taurine were elevated in the CSF during myoclonic jerks and more distinctly immediately after GC. 3. During the recovery period of postictal depression seen in EEG (5 min after GC), the CSF levels of transmitter amino acids were lower than in the control group. 4. PTZ-induced irritative activity in the EEG disappeared in 24 hr but the levels of amino acids remained abnormal. 5. Amino acid changes in the CSF following PTZ-induced convulsions might indicate that the release of amino acids into the extracellular space is increased before and during the propagation of PTZ-induced seizure and decreased during postictal depression.

Myoclonic encephalopathy due to bismuth salts: treatment with dimercaprol and analysis of CSF transmitters.

Two cases of myoclonic encephalopathy due to bismuth salts intoxication are reported. In both, treatment with dimercaprol led to clinical recovery. This therapy was shown to enhance bismuth clearance. We also present data on the CSF metabolites dopamine, norepinephrine and serotonin of one patient.

Indole levels in human lumbar and ventricular cerebrospinal fluid and the effect of L-tryptophan administration.

Levels of tryptophan (TRP), 5-hydroxytryptophan (5-HTP), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in human lumbar and ventricular cerebrospinal fluid (CSF) were measured by reversed phase liquid chromatography (HPLC) with electrochemical detection. The levels of TRP ranged from 1593 to 4865 nmol/l in ventricular (VF) and from 1257 to 2557 nmol/l in lumbar CSF. The level of 5-HTP varied from 1.1 to 68.9 nmol/l in VF and from 5.3 to 10.8 nmol/l in lumbar CSF; no previous reports of 5-HTP levels in CSF exist. The serotonin level was 1.9-27.3 nmol/l in VF and 5.7-12.0 nmol/l in lumbar CSF. The levels of 5-HIAA were considerably higher in VF than in lumbar fluid with respective means of 498 +/- 52.4 nmol/l and 112 +/- 15.6 nmol/l (P less than 0.001). An oral dose of 2 g L-tryptophan significantly increased all indole levels except that of 5-HT, both in patients with progressive myoclonus epilepsy and in controls.

Concentrations of gamma-aminobutyric acid and adenosine in the CSF in progressive myoclonus epilepsy without Lafora's bodies.

Progressive myoclonus epilepsy without Lafora's bodies (PME) is a rare inherited disease found predominantly in Finland, where the incidence is one case per 20,000 to 30,000 children. This fatal disease is characterized by normal early development, progressive stimulus-sensitive myoclonus, ataxia, dysarthria, occasional grand mal seizures, and loss of cerebellar Purkinje cells. Concentrations of gamma-aminobutyric acid in the CSF averaged 89 +/- 10 pmole/mL (mean +/- SE) in eight patients with PME, compared with 135 +/- 18 pmole/mL in ten control patients. The concentrations of adenosine (16 pmole/mL v 17 pmole/mL), inosine (560 pmole/mL v 570 pmole/mL) and hypoxanthine (6.2 nmole/mL v 6.1 nmole/mL) were the same in patients with PME and in controls.

Decrease of GABA in the cerebrospinal fluid of patients with progressive myoclonus epilepsy and its correlation with the decrease of 5HIAA and HVA.

The degenerative type of progressive myoclonus epilepsy (PME) is a hereditary disease with grand mal seizures, stimulus sensitive myoclonus, characteristic EEG and mental deterioration in the late stage. GABAergic antiepileptic drugs are the most effective ones in this disease, with an unknown etiology. In this study, the GABA concentration in the CSF of 15 PME patients was measured and compared with values of sex- and age-matched epileptic controls. It was correlated with the concentrations of 5HIAA and HVA in the CSF, which were determined earlier from the same patients. The GABA concentration in the PME patients was statistically significantly decreased, to about 75% of that of the epileptic controls. It correlated with HVA and 5HIAA concentrations in the PME patients, but not in the epileptic controls. It is unknown whether these findings are related to the primary cause of PME or whether they are only secondary, owing to a loss of respective neurons or synapses.

CSF oligoclonal bands, immunoglobulins, and viral antibodies in progressive myoclonus epilepsy.

We studied CSF and serum samples from 16 patients with progressive myoclonus epilepsy (PME). These patients had juvenile-onset PME with evidence of autosomal recessive inheritance and no Lafora bodies. Twelve of the 16 patients with PME had immunologic abnormalities. Oligoclonal gamma bands were seen in six of the eight patients from whom sufficient CSF was available. The CSF albumin and serum/CSF albumin ratios were normal in all 16 patients, indicating the presence of intact blood-brain barriers. Six of the 16 patients showed increased CSF IgG levels and five had an increased CNS IgG synthesis. All patients had normal serum and CSF IgM and IgA levels. Three patients, all with bands, had reduced measles and/or vaccinia serum/CSF antibody ratios. The findings suggest altered immune response of the CNS of some patients with PME apparently caused by nonspecific immunostimulation.

Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with progressive myoclonus epilepsy.

The possibility of disturbed dopamine and serotonin metabolism in the progressive myoclonus epilepsy (PME) occurring in Finland (a type of PME without Lafora bodies) was examined. Both basal concentrations of HVA and 5-HIAA in the CSF and their increase after oral probenecid administration were studied in 19 PME patients and in 19 age- and sex-matched control patients. The control patients had grand mal epilepsy but not myoclonus or ataxia. The basal value of HVA was significantly reduced and that of 5-HIAA was also slightly reduced in the PME patients as compared to the values of the epileptic controls or to those of 26 nonepileptic controls. The concentrations of HVA and 5-HIAA also seemed to correlate with the severity of the PME. The most severely affected patients had generally the lowest values. After oral probenecid this trend was also seen when the increases of HVA and 5-HIAA were expressed per microgram CSF probenecid, i.e. the mildly affected PME group showed higher increases in response to probenecid than the most severely affected PME group. The PME patients had higher probenecid levels in the CSF than the epileptic controls.