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Biomedical subjects

V T Ramaekers

Publications and source records attributed to V T Ramaekers.

At least 19 recordsLinked to original sources
PubMed2005

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.

Adaptation, Physiological↗
PubMed2005

White-matter disease in 18q deletion (18q-) syndrome: magnetic resonance spectroscopy indicates demyelination or increased myelin turnover rather than dysmyelination.

Proton magnetic resonance spectroscopic data ((1)H-MR spectroscopy) of patients with 18q deletion syndrome have not yet been reported. (1)H-MR spectroscopy, performed in an affected 2-year-old girl with markedly delayed neuromotor development and typical supratentorial white-matter disease (WMD), showed an increase of choline and alpha-glutamate concentrations. Eight months later, simultaneously with clinical improvement, alpha-glutamate had normalised whereas choline remained slightly increased. Active demyelination or increased myelin turnover might contribute to the hitherto unexplained WMD of this rare disorder.

Aspartic Acid↗
PubMed2003

Reduced folate transport to the CNS in female Rett patients.

BACKGROUND: Previous CSF studies in Rett syndrome suggest reduced turnover of the biogenic monoamines serotonin and dopamine. Because diminished turnover may result from CNS folate depletion, the authors studied transport of folate across the blood-brain barrier. METHODS: In four patients with Rett syndrome, the authors measured CSF values of 5-methyltetrahydrofolate (5MTHF), biogenic monoamine end-metabolites, and pterins together with serum and red blood cell folate. In CSF, the overall folate binding capacity by the two soluble folate-binding proteins FBP1 and FBP2 (sFBP) was measured using a radioligand binding method for H3-labeled folate. A specific immunoreactive test (ELISA) detected sFBP1, which normally contributes to 30 to 35% of the total folate binding capacity. Genetic analysis included DNA sequencing of the MECP2, FBP1, and FBP2 genes. Empirical treatment with oral folinic acid was evaluated. RESULTS: Two patients without and two with mutations of the MECP2 gene had normal values for red blood cell folate, serum folate, homocysteine, and methionine. In CSF, all patients had low values for 5MTHF, neopterin, and the serotonin end-metabolite 5-hydroxyindoleacetic acid (5-HIAA). Genetic analysis of FBP1 and FBP2 genes had normal results. Compared to controls, patients with Rett syndrome had normal immunoreactive sFBP1 in CSF, whereas the total folate binding capacity was disproportionately lowered. Empirical treatment with oral folinic acid normalized 5-MHTF and 5-HIAA levels in CSF, and led to partial clinical improvement. CONCLUSION: Irrespective of the MECP2 genotype, 5MTHF transfer to the CNS is reduced in Rett syndrome. Folinic acid supplementation restores 5MTHF levels and serotoninergic turnover. The lowered folate binding capacity of FBP is not explained by a defect of the FBP1 or FBP2 gene, but most likely occurs as a secondary phenomenon in Rett syndrome.

Biogenic Monoamines↗
PubMed2002

Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution.

INTRODUCTION: Normal brain development and function depend on the active transport of folates across the blood-brain barrier. The folate receptor-1 (FR 1) protein is localized at the basolateral surface of the choroid plexus, which is characterized by a high binding affinity for circulating 5-methyltetrahydrofolate (5-MTHF). PATIENTS AND METHODS: We report on the clinical and metabolic findings among five children with normal neurodevelopmental progress during the first four to six months followed by the acquisition of a neurological condition which includes marked irritability, decelerating head growth, psychomotor retardation, cerebellar ataxia, dyskinesias (choreoathetosis, ballism), pyramidal signs in the lower limbs and occasional seizures. After the age of six years the two oldest patients also manifested a central visual disorder. Known disorders have been ruled out by extensive investigations. Cerebrospinal fluid (CSF) analysis included determination of biogenic monoamines, pterins and 5-MTHF. RESULTS: Despite normal folate levels in serum and red blood cells with normal homocysteine, analysis of CSF revealed a decline towards very low values for 5-methyltetrahydrofolate (5-MTHF), which suggested disturbed transport of folates across the blood-brain barrier. Genetic analysis of the FR 1 gene revealed normal coding sequences. Oral treatment with doses of the stable compound folinic acid (0.5-1 mg/kg/day Leucovorin(R)) resulted in clinical amelioration and normalization of 5-MTHF values in CSF. CONCLUSION: Our findings identified a new condition manifesting after the age of 6 months which was accompanied by low 5-MTHF in cerebrospinal fluid and responded to oral supplements with folinic acid. However, the cause of disturbed folate transfer across the blood-brain barrier remains unknown.

Blood-Brain Barrier↗
PubMed2001

Phenotypic variation of a novel nonsense mutation in the P0 intracellular domain.

Mutations in the gene for the peripheral myelin protein zero (P0, MPZ) cause type 1B of Charcot-Marie-Tooth sensorimotor neuropathy (CMT1B). Here we report a German family with a novel heterozygous P0 nonsense mutation (G206X) that supposedly removes four-fifths of the amino acid residues constituting the P0 intracellular domain. The 12-year-old propositus had childhood-onset CMT1B associated with bilateral pes cavus, moderate lower limb weakness, and mildly reduced sensory qualities in the distal legs. The electrophysiology was consistent with a demyelinating neuropathy. He inherited the mutation from his mother who had no complaints but slight pes cavus deformity and slow nerve conduction velocities (NCV). Conclusively, truncating mutations within the P0 intracellular domain do not necessarily cause a severe phenotype such as Dejerine-Sottas syndrome (DSS) or congenital hypomyelinating neuropathy (CHN), but can result in mild or moderate CMT1B with intrafamilial clinical variability.

Adult↗
PubMed2001

A novel neurodevelopmental syndrome responsive to 5-hydroxytryptophan and carbidopa.

Tryptophan hydroxylase (TPH; EC 1.14.16.4) catalyzes the first rate-limiting step of serotonin biosynthesis by converting l-tryptophan to 5-hydroxytryptophan. Serotonin controls multiple vegetative functions and modulates sensory and alpha-motor neurons at the spinal level. We report on five boys with floppiness in infancy followed by motor delay, development of a hypotonic-ataxic syndrome, learning disability, and short attention span. Cerebrospinal fluid (CSF) analysis showed a 51 to 65% reduction of the serotonin end-metabolite 5-hydroxyindoleacetic acid (5HIAA) compared to age-matched median values. In one out of five patients a low CSF 5-methyltetrahydrofolate (MTHF) was present probably due to the common C677T heterozygous mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. Baseline 24-h urinary excretion showed diminished 5HIAA values, not changing after a single oral load with l-tryptophan (50-70 mg/kg), but normalizing after 5-hydroxytryptophan administration (1 mg/kg). Treatment with 5-hydroxytryptophan (4-6 mg/kg) and carbidopa (0.5-1.0 mg/kg) resulted in clinical amelioration and normalization of 5HIAA levels in CSF and urine. In the patient with additional MTHFR heterozygosity, a heterozygous missense mutation within exon 6 (G529A) of the TPH gene caused an exchange of valine by isoleucine at codon 177 (V177I). This has been interpreted as a rare DNA variant because the pedigree analysis did not provide any genotype-phenotype correlation. In the other four patients the TPH gene analysis was normal. In conclusion, this new neurodevelopmental syndrome responsive to treatment with 5-hydroxytryptophan and carbidopa might result from an overall reduced capacity of serotonin production due to a TPH gene regulatory defect, unknown factors inactivating the TPH enzyme, or selective loss of serotonergic neurons.

5-Hydroxytryptophan↗
PubMed2001

Phenotypic heterogeneity and adverse effects of serine treatment in 3-phosphoglycerate dehydrogenase deficiency: report on two siblings.

Clinical experience with the treatment of 3-phosphoglycerate dehydrogenase deficiency, a rare inherited disorder of serine synthesis, is scarce. We report on two sisters with phenotypic heterogeneity and a favourable response to combined serine and glycine supplementation. The elder sibling was found to be normocephalic at birth and showed moderate delay of white matter myelinisation, while her seizures arrested spontaneously even without treatment. In the younger sister with the classical phenotype, feeding difficulties with recurrent gastro-oesophageal reflux prompted us to treat her temporarily with high-dose serine (1400 mg/kg/day). An arrest of head growth then occurred but could be reversed by reducing the serine supply. In both children serine therapy was associated with decreased concentrations of methionine, isoleucine, and ornithine in the cerebrospinal fluid, attributed to competitive inhibition of neutral amino acid transport across the blood-brain barrier. In contrast to reports in the literature, these findings demonstrate that congenital microcephaly, intractable seizures, and dysmyelinisation are not invariably present in patients with 3-phosphoglycerate dehydrogenase deficiency. An adverse effect of high-dose serine therapy on head growth and on the transport of neutral amino acids across the blood-brain barrier should be considered and requires adjustment of treatment.

Amino Acids↗
PubMed2000

Hereditary motor and sensory neuropathy with absence of large myelinated fibers due to absence of large neurons in dorsal root ganglia and anterior horns, clinically associated with deafness, mental retardation, and epilepsy (HMSN-ADM).

Hereditary motor and sensory neuropathy (HMSN) with autosomal recessive inheritance represents a genetically heterogeneous group of disorders with variable clinical, pathologic and electrophysiologic manifestations. A new variant of autosomal recessive HMSN, clinically defined by sensorimotor polyneuropathy associated with deafness and mental retardation, has recently been described. We report on the first autopsy case with this type of HMSN: a girl of non-consanguineous parents with a presumably autosomal recessive type of motor and sensory neuropathy clinically associated with deafness, mental retardation, and epilepsy. The autopsy showed complete absence of large myelinated fibers in peripheral motor and sensory nerves corresponding to a lack of large neurons in dorsal root ganglia and anterior horns of the spinal cord, moderate neurogenic muscle atrophy, and nearly complete absence of neurons in the dentate nucleus of the cerebellum. Molecular genetic analyses in our case revealed neither genetic alterations in the survival motor neuron gene nor in the PMP-22 gene.

Anterior Horn Cells↗
PubMed1999

X-linked dominant Charcot-Marie-Tooth neuropathy: clinical, electrophysiological, and morphological phenotype in four families with different connexin32 mutations(1).

The sensorimotor neuropathy of the Charcot-Marie-Tooth type (CMT) is the most common hereditary disorder of the peripheral nervous system. The X-linked dominant form of CMT (CMTX) is associated with mutations in the gene for the gap junction protein connexin32. We examined four CMTX pedigrees two of which had potentially novel mutations in the only coding exon of connexin32. One previously unreported missense mutation, Ala39Val, was found in a family displaying a CMT phenotype with additional upper limb postural tremor reminiscent of a Roussy-Lévy syndrome. A novel single base insertion, 679insT, is among the first mutations found in the fourth transmembrane domain of connexin32. Frameshift and premature stop of translation are supposed to result in a non-functional carboxy-terminus. Two further families had the known missense mutations Arg15Trp and Arg22Gln. Several female carriers were found normal on clinical presentation, however, the genotype was paralleled by decreased nerve conduction velocities (NCV) and slowed central conduction of brain stem auditory evoked responses (BAER). Median motor NCVs showed mild (in women) to intermediate (in males) reduction, indicating a peripheral neuropathy with a predominating axonal component. Nerve biopsy findings were consistent with the electrophysiological data showing a marked loss of large myelinated fibres and clusters of regenerating axons. Electron microscopy revealed various alterations of the axoglial attachment zone. This suggests defective axon-Schwann cell interactions which may induce the axonopathy in CMTX.

Adolescent↗
PubMed1998

X-linked dominant Charcot-Marie-Tooth disease: nerve biopsies allow morphological evaluation and detection of connexin32 mutations (Arg15Trp, Arg22Gln).

X-linked Charcot-Marie-Tooth neuropathy (CMTX) is caused by mutations in the connexin32 gene on Xq13. Because of overlapping morphological and clinical data, CMTX patients often meet the criteria of autosomal-dominant CMT2, the neuronal type of CMT. Hence, it might be useful to analyse the connexin32 gene in suspected CMT2 patients when there is no male-to-male transmission. We selected a cohort of 30 patients who were considered having CMT2 on the basis of previous clinical and histopathological evaluation. DNA was extracted from paraffin-embedded sural nerve biopsy samples and screened for connexin32 mutations to verify the possible diagnosis of CMTX. In 2 patients mutations were found corresponding to amino acid substitutions of arginine for tryptophan in codon 15 and arginine for glutamine in codon 22 of connexin32. This study illustrates that archival material allows genetic classification of suspected CMT cases. Furthermore, there is additional proof that connexin32 mutations represent the underlying genetic defect in some cases of predominantly neuronal CMT.

Adolescent↗
PubMed1998

Delayed-onset profound biotinidase deficiency.

Children with biotinidase deficiency usually exhibit symptoms at several months to years of age. We describe four children who had symptoms later in childhood or during adolescence; they had motor limb weakness, spastic paresis, and eye problems, such as loss of visual acuity and scotomata, rather than the more characteristic symptoms observed in young untreated children with the disorder. These older children each have different mutations, but they are the same as those of children who have exhibited symptoms at an early age. Biotinidase deficiency should be considered in older children who suddenly experience limb weakness and/or spastic paresis and eye symptoms.

Acyltransferases↗
PubMed1998

Early and late onset manifestations of cerebral vasculitis related to varicella zoster.

Varicella-zoster associated cerebral vasculitis (VZCV) as a cause of cerebral infarction has hitherto been considered a rare condition. Ischemic stroke in previously healthy children has occurred during recovery from chickenpox or has been attributed to virus reactivation among immunosuppressed patients. The clinical, radiologic and immunologic findings in four children with VZCV will be reported. Clinical manifestations included sudden onset of hemiparesis, motor aphasia and disturbed consciousness in previously healthy children. Only one child had a history of chickenpox six weeks prior to the onset of stroke, whereas a latency period of up to four years between chickenpox and the onset of stroke was found in the other three children. Diagnosis of VZCV was confirmed repeatedly by demonstrating intrathecal production of varicella-zoster IgG antibodies in three children or a four-fold increase of varicella-zoster serum IgA-antibodies in one child. Intrathecal production of antibodies against other latent viruses and borreliosis could be excluded. PCR for varicella on CSF, performed in two patients, remained negative. No intrathecal production of varicella-zoster antibodies has been found in a control group of twenty clinically healthy children (age range from 2-18 years) with a previous varicella infection. During follow-up two children recovered completely whereas two children still suffer from serious neurological deficits. Immunological investigations, performed in three children, showed circulating immune-complexes with slightly lowered complement concentrations in two patients. In addition a lowered T-helper/T-suppressor cell ratio of unknown origin was found in three children. These immunological findings will be discussed in the light of the pathophysiology of VZCV.

Adolescent↗
PubMed1997

Central pontine myelinolysis associated with acquired folate depletion.

After long-standing malnutrition a 15-month-old boy with signs of kwashiorkor was admitted in a moribund state with serious hyponatraemic dehydration, hypothermia, somnolence, and signs of a pontine disconnection syndrome. Folic acid levels were below the detection level in the presence of normal cobalamin levels. MRI of the brain showed global volume loss and signal abnormalities on the T2-weighted images suggestive for central pontine myelinolysis (CPM). Brainstem acoustic evoked responses have remained normal. The serious metabolic and nutritional derangements required substitution of folic acid, vitamins and trace elements as well as slow correction of hyponatraemic dehydration with return of the sodium level over a period of four days. This therapeutic regimen resulted in complete neurological recovery. Follow-up MRI documented normalisation of the initial pathologic findings. The hypothesis was put forward linking the pathogenesis of CPM with the combination of folate depletion and superimposed hyponatraemic dehydration. The previously acquired folate depletion could affect normal appositional function of myelin basic protein molecules due to insufficient methylation of arginine in position 107. The subsequent development of intramyelinic edema and CPM will then be triggered by the superimposed hyponatraemic dehydration. The verification of this hypothesis requires further investigations.

Dehydration↗
PubMed1997

Genetic disorders and cerebellar structural abnormalities in childhood.

Amongst 78 patients with either unilateral or bilateral (ponto-) cerebellar hypoplasia, atrophy or lesions on neuro-imaging (CT and/or MRI), 16 showed unilateral hypoplasia or lesions, 15 vermis defects, nine pontocerebellar hypoplasia, 10 non-progressive conditions with bilateral cerebellar hemisphere hypoplasia or lesions and 28 progressive cerebellar atrophy. Known genetic conditions did not occur with unilateral cerebellar involvement, whereas a high incidence of mostly autosomal recessively inherited diseases could be diagnosed in more than half of the patients with either pontocerebellar hypoplasia or progressive bilateral cerebellar atrophy. A minority of patients with vermis defects or non-progressive cerebellar hypoplasia suffered from genetic conditions. An overview of the literature is presented describing genetic and non-genetic syndromes, or metabolic disorders associated with cerebellar structural abnormalities. From these data, new proposals for improved diagnostic investigations will be presented.

Adolescent↗
PubMed1997

Increased plasma malondialdehyde associated with cerebellar structural defects.

BACKGROUND: Malondialdehyde (MDA) in plasma is regarded as an indicator for increased lipid peroxidation. METHOD: Measurements of MDA concentrations in plasma were compared among healthy children (n = 31), patients with neurological disorders or epileptic syndromes (n = 15), and children with pontocerebellar structural defects (n = 31), where the cause or genetic defect remained unknown. RESULTS: In healthy children the median MDA value was 5.86 nmol/ml (mean (SD) value: 6.25 (1.97), range: 3.76-11.19). For the group with various neurological disorders or epilepsy, the values were similar with the median value at 5.66 nmol/ml (range 0.22-10.86). Compared with healthy controls and the neurological/ epileptic group, the 31 children with pontocerebellar structural defects had significantly increased MDA values with a median value at 11.29 nmol/ml (mean (SD) value: 11.62 (3.27), range 3.65-19.22). IMPLICATION: These findings of increased plasma MDA in the majority of children with pontocerebellar structural defects of unknown origin raised the question whether increased lipid peroxidation leads to prenatal and postnatal pontocerebellar maldevelopment or degeneration.

Adolescent↗
PubMed1995

Biotinidase Km-variants: detection and detailed biochemical investigations.

We describe a simple method for the detection of biotinidase Km-variants and detailed biochemical investigations in 5 such patient. They were detected among 103 patients with plasma biotinidase activity which ranged from undetectable to 30% of the mean normal value. Two different types of biotinidase Km-variants were found. (1) In 3 infants biotinidase had a single 105-430-fold elevated Km for biocytin. Biotinidase showed very low activities (0.2-4% of the mean normal value) in the routine colorimetric assay and was not functional in vivo. Accordingly, these patients presented with classical clinical illness. (2) In two patients biotinidase showed biphasic kinetics indicating the presence of one component with a normal Km and reduced Vmax (1.7% and 12%), and another with 330- and 59-fold elevated Km, respectively. In these two patients, biotinidase proved to be at least partially functional in vivo. However, the first patient developed severe symptoms and biotin deficiency late, at the age of 10-15 years, and the second had marginal biotin deficiency at the age of 2 years but no clinical symptoms. Comparative studies revealed that both patients had more severe biotin deficiency than age-matched patients with similar levels of residual biotinidase activity and a single normal Km. Therefore, all patients with residual biotinidase activity should be evaluated for the presence of a Km-mutation, since such patients should be treated with biotin. These can easily be detected by including a second substrate concentration (1.5 mmol/L) in the routine colorimetric biotinidase assay which is performed with 0.15 mmol/L biotin. Increased activity with the higher substrate concentration indicates the presence of a Km-mutation. Detailed kinetic studies are needed to evaluate the distinct forms of Km-variants.

Amidohydrolases↗
PubMed1994

Selenium deficiency triggering intractable seizures.

Two children with severe neurodevelopmental retardation and elevated liver function tests developed intractable seizures during the first year of life. Detectable neurometabolic conditions have been ruled out. At the time of seizures evidence for systemic selenium deficiency could be documented. The youngest patient, who manifested intractable fits from the fourth day of life, died at the age of ten months. Neuropathologic examination was consistent with Progressive Neuronal Degeneration of Childhood (PNDC) with liver disease or formerly known as Alpers disease. In the oldest child, whose diet was normally balanced, fits started from the age of 11 months and features of long-standing selenium deficiency became apparent from the age of 1 1/2 years and consisted of liver function disturbances, depigmented hair and osteoarthropathy. Oral substitution with selenium supplements in both children (3-5 micrograms/kg body weight) resulted in reduction of seizures and improvement of the EEG recordings after two weeks while liver function became normal. Two of the seleno-dependent enzymes Glutathione Peroxidase (GPX) and Phospholipid Hydroperoxide Glutathione Peroxidase (PHGPX) are speculated to play a key-role in the defence of neuronal cells against oxygen radical formation and peroxidative processes. Our findings support the hypothesis that the presence of selenium depletion in the brain amongst patients with epilepsy constitutes an important triggering factor for the origin of intractable seizures and subsequent neuronal damage.

Atrophy↗