Search PubMed⌕ Search

Biomedical subjects

F Hanefeld

Publications and source records attributed to F Hanefeld.

At least 55 records · Page 3Linked to original sources
PubMed2000

Two brothers with Hennekam syndrome and cerebral abnormalities.

We report two brothers with mental retardation, lymphoedema of the limbs and facial anomalies. Hennekam et al. (Am J Med Genet 34:593-600; 1989) described four patients with identical signs and intestinal lymphangiectasia. To confirm the diagnosis of Hennekam syndrome we undertook a duodenal biopsy from the older brother which revealed intestinal lymphangiectasia. So far only one patient with Hennekam syndrome and cerebral abnormalities has been described. This patient presented with pachygyria in the parietal area. Cerebral MRI in our two cases revealed small subcortical hyperintensities in both patients and a large cystic lesion in the younger patient probably representing an old media infarction.

Abnormalities, Multiple↗
PubMed2000

Primarily chronic and cerebrovascular course of Lyme neuroborreliosis: case reports and literature review.

As part of an ongoing study aiming to define the clinical spectrum of neuroborreliosis in childhood, we have identified four patients with unusual clinical manifestations. Two patients suffered from a primarily chronic form of neuroborreliosis and displayed only non-specific symptoms. An 11 year old boy presented with long standing symptoms of severe weight loss and chronic headache, while the other patient had pre-existing mental and motor retardation and developed seizures and failure to thrive. Two further children who presented with acute hemiparesis as a result of cerebral ischaemic infarction had a cerebrovascular course of neuroborreliosis. One was a 15 year old girl; the other, a 5 year old boy, is to our knowledge the youngest patient described with this course of illness. Following adequate antibiotic treatment, all patients showed substantial improvement of their respective symptoms. Laboratory and magnetic resonance imaging findings as well as clinical course are discussed and the relevant literature is reviewed.

Adolescent↗
PubMed2000

Anoxic ATP depletion in neonatal mice brainstem is prevented by creatine supplementation.

BACKGROUND: Sufficient ATP concentrations maintain physiological processes and protect tissue from hypoxic damage. With decreasing oxygen concentration, ATP synthesis relies increasingly on the presence of phosphocreatine. AIM: The effect of exogenously applied creatine on phosphocreatine and ATP concentrations was studied under control and anoxic conditions. METHODS: Pregnant mice were fed orally with creatine monohydrate (2 g/kg body weight/day). Brainstem slices from these mice pups were compared with those from pups of non-creatine supplemented pregnant mice. Measurements were performed under normoxic and anoxic conditions. In addition, brainstem slices from non-creatine treated mice pups were incubated for 3 hours in control artificial cerebrospinal fluid (CSF) (n = 10) or in artificial CSF containing 200 microM creatine (n = 10). ATP and phosphocreatine contents were determined enzymatically in single brainstem slices. RESULTS: ATP concentrations were in the same range in all preparations. However, there was a significant increase of phosphocreatine in the brainstems from pups of creatine fed mice when compared with the brainstems of pups from non-creatine treated mice or in non-incubated brainstems of control animals. After 30 minutes anoxia, ATP as well as phosphocreatine concentrations remained significantly higher in creatine pretreated slices compared with controls. CONCLUSION: The data indicate that exogenous application of creatine is effective in neuroprotection.

Adenosine Triphosphate↗
PubMed2000

Aminophylline modulation of the mouse respiratory network changes during postnatal maturation.

Aminophylline is a respiratory stimulant commonly used for the treatment of central apnea. Experiences from clinical practice, however, revealed that aminophylline is not reliably effective in preterm infants, whereas it is normally effective in infants and mature patients. In an established animal model for postnatal development of respiratory control mechanisms, we therefore examined the hypothesis that the clinical observations reflect a developmental change in the sensitivity of the central respiratory network to methylxanthines. The medullary respiratory network was isolated at different postnatal ages (postnatal days 1-13; P1-P13) in a transverse mouse brain stem slice preparation. This preparation contains the pre-Bötzinger complex (PBC), a region that is critical for generation of respiratory rhythm. Spontaneous rhythmic respiratory activity was recorded from the hypoglossal (XII) rootlets and from neurons in the PBC by using the whole cell patch clamp technique. Bath-applied aminophylline [20 microM] increased the frequency (+41%) in neonatal animals (P1-P6) without affecting the amplitude of respiratory burst activity in XII rootlets. The same concentration of aminophylline did not have any significant effect on the frequency of respiratory XII bursts but increased the amplitude (+31%) in juvenile animals (P7-P13). In the same age group, aminophylline also augmented the amplitude and the duration of respiratory synaptic drive currents in respiratory PBC neurons. The data demonstrate that augmentation of the respiratory output is due to direct enhancement of central respiratory network activity and increase of synaptic drive of hypoglossal motoneurons in juvenile, but not neonatal, animals. This indicates a developmental change in the efficacy of aminophylline to reinforce central respiratory network activity. Therefore, we believe that the variable success in treating respiratory disturbances in premature infants reflects maturational changes in the expression of receptors and/or intracellular signal pathways in the central respiratory network.

Age Factors↗
PubMed1999

Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy.

The congenital nemaline myopathies are rare hereditary muscle disorders characterized by the presence in the muscle fibers of nemaline bodies consisting of proteins derived from the Z disc and thin filament. In a single large Australian family with an autosomal dominant form of nemaline myopathy, the disease is caused by a mutation in the alpha-tropomyosin gene TPM3. The typical form of nemaline myopathy is inherited as an autosomal recessive trait, the locus of which we previously assigned to chromosome 2q21.2-q22. We show here that mutations in the nebulin gene located within this region are associated with the disease. The nebulin protein is a giant protein found in the thin filaments of striated muscle. A variety of nebulin isoforms are thought to contribute to the molecular diversity of Z discs. We have studied the 3' end of the 20. 8-kb cDNA encoding the Z disc part of the 800-kDa protein and describe six disease-associated mutations in patients from five families of different ethnic origins. In two families with consanguineous parents, the patients were homozygous for point mutations. In one family with nonconsanguineous parents, the affected siblings were compound heterozygotes for two different mutations, and in two further families with one detected mutation each, haplotypes are compatible with compound heterozygosity. Immunofluorescence studies with antibodies specific to the C-terminal region of nebulin indicate that the mutations may cause protein truncation possibly associated with loss of fiber-type diversity, which may be relevant to disease pathogenesis.

Australia↗
PubMed1999

Novel GLRA1 missense mutation (P250T) in dominant hyperekplexia defines an intracellular determinant of glycine receptor channel gating.

Missense mutations as well as a null allele of the human glycine receptor alpha1 subunit gene GLRA1 result in the neurological disorder hyperekplexia [startle disease, stiff baby syndrome, Mendelian Inheritance in Man (MIM) #149400]. In a pedigree showing dominant transmission of hyperekplexia, we identified a novel point mutation C1128A of GLRA1. This mutation encodes an amino acid substitution (P250T) in the cytoplasmic loop linking transmembrane regions M1 and M2 of the mature alpha1 polypeptide. After recombinant expression, homomeric alpha1(P250T) subunit channels showed a strong reduction of maximum whole-cell chloride currents and an altered desensitization, consistent with a prolonged recovery from desensitization. Apparent glycine binding was less affected, yielding an approximately fivefold increase in Ki values. Topological analysis predicts that the substitution of proline 250 leads to the loss of an angular polypeptide structure, thereby destabilizing open channel conformations. Thus, the novel GLRA1 mutant allele P250T defines an intracellular determinant of glycine receptor channel gating.

Amino Acid Sequence↗
PubMed1999

Quantitative proton magnetic resonance spectroscopy of cerebral metabolic disturbances in patients with MELAS.

Four patients with clinically and genetically defined MELAS were examined using quantitative localized proton magnetic resonance spectroscopy of the brain. Acute and chronic lesions were located in the occipital lobe and mostly characterized by strongly elevated concentrations of lactate (Lac) and glucose (GIc) as well as severely reduced concentrations of total N-acetylaspartyl compounds (tNAA, neuroaxonal markers), glutamate (Glu), and total creatine. These findings indicate a high degree of nonoxidative glycolysis reflecting either impaired oxidative energy metabolism or the use of anaerobic metabolism by infiltrating macrophages as well as damage or loss of viable neuroaxonal tissue. In contrast, glial cell populations, in particular astrocytes, seem to remain unaffected as evidenced by unchanged concentrations of myo-inositol (glial marker). In addition, all patients including one who never experienced a stroke-like episode showed elevated Lac and Glc as well as reduced tNAA and Glu in tissues appearing normal on MRI. These disturbances were stronger in cortical gray matter and cerebellum than in white matter and indicate that neuroaxonal damage is not restricted to structural lesions. The steady presence of Lac is consistent with a reduced capacity of the mitochondrial oxidative energy metabolism resulting from impaired respiratory chain function.

Adolescent↗
PubMed1999

Increase of total creatine in human brain after oral supplementation of creatine-monohydrate.

The effect of oral creatine supplementation on brain metabolite concentrations was investigated in gray matter, white matter, cerebellum, and thalamus of healthy young volunteers by means of quantitative localized proton magnetic resonance spectroscopy in vivo (2.0 T, stimulated echo acquisition mode sequence; repetition time = 6,000 ms, echo time = 20 ms, middle interval = 10 ms, automated spectral evaluation). Oral consumption of 4 x 5 g creatine-monohydrate/day for 4 wk yielded a statistically significant increase (8.7% corresponding to 0.6 mM, P < 0.001) of the mean concentration of total creatine (tCr) when averaged across brain regions and subjects (n = 6). The data revealed considerable intersubject variability (3.5-13.3%), with the smallest increases observed for the two male volunteers with the largest body weights. A regional analysis resulted in significant increases of tCr in gray matter (4.7%), white matter (11.5%), and cerebellum (5.4%) and was most pronounced in thalamus (14.6% corresponding to 1.0 mM). Other findings were significant decreases of N-acetyl-containing compounds in cerebellum and thalamus as well as of choline-containing compounds in thalamus. All cerebral metabolic alterations caused by oral Cr were reversible, as evidenced by control measurements at least 3 mo after the diet. This work demonstrates that excess consumption of Cr yields regionally dependent increases of the tCr concentration in human brain over periods of several weeks.

Administration, Oral↗
PubMed1999

Regional age dependence of human brain metabolites from infancy to adulthood as detected by quantitative localized proton MRS.

Regional changes of metabolite concentrations during human brain development were assessed by quantitative localized proton magnetic resonance spectroscopy in vivo. Apart from measurements in young healthy adults, the study was based on regional spectra from 97 children who were either healthy or suffered from mental retardation, movement disorders, epilepsies, neoplasm, or vascular malformation. Metabolite quantitation focused on cortical gray and white matter, cerebellum, thalamus, and basal ganglia in six age groups from infancy to adulthood. During infancy and childhood, the concentration of the neuroaxonally located N-acetylasparate increased in gray matter, cerebellum, and thalamus, whereas a constant level was detected in white matter. These findings are in line with regional differences in the formation of synaptic connections during early development and suggest a role of N-acetylaspartate as a marker of functioning neuroaxonal tissue rather than of the mere presence of nerve cells. This view is further supported by high concentrations of taurine in gray matter and cerebellum during infancy, because taurine is also believed to be involved in the process of synapse formation. Remarkably, in basal ganglia both N-acetylaspartate and taurine remain constant at relatively high concentrations. Other metabolite changes during maturation include increases of N-acetylaspartylglutamate, especially in thalamus and white matter, and a decrease of glutamine in white matter. Despite regional differences and some small changes during the first year of life, the concentrations of creatine, phosphocreatine, choline-containing compounds, myoinositol, and glutamate remain constant afterward. The creatine to phosphocreatine concentration ratio yields 2:1 throughout the human brain irrespective of region or age. The observed increase of the proton resonance line-width with age is most pronounced in basal ganglia and corresponds to the age-related and tissue-dependent increase of brain iron.

Adolescent↗
PubMed1998

Carbohydrate-deficient glycoprotein syndrome type V: deficiency of dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl glucosyltransferase.

Deficiency of dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl glucosyltransferase is the cause of an additional type of carbohydrate-deficient glycoprotein syndrome (CDGS type V). Clinically this type resembles the classical type Ia of CDGS caused by the deficiency of phosphomannomutase. As a result of the glucosyltransferase deficiency in CDGS type V nonglucosylated lipid-linked oligosaccharides accumulate. The defect is leaky and glucosylated oligosaccharides are found on nascent glycoproteins. The limited availability of glucosylated lipid-linked oligosaccharides explains the incomplete usage of N-glycosylation sites in glycoproteins. This finding is reflected in the presence of transferrin forms in serum that lack one or both of the two N-linked oligosaccharides and the reduction of mannose incorporation to about one-third of control in glycoproteins of fibroblasts.

Cells, Cultured↗
PubMed1998

Pyruvate dehydrogenase complex deficiency and altered respiratory chain function in a patient with Kearns-Sayre/MELAS overlap syndrome and A3243G mtDNA mutation.

Combined alteration of the pyruvate dehydrogenase complex and respiratory chain function is described in a 21 year-old male patient with overlapping MELAS (mitochondrial encephalomyopathy, lactic acidosis, and 'stroke-like' episodes) and Kearns-Sayre syndrome. Progressive external ophthalmoplegia, pigmentary retinopathy and right bundle branch block were present when he experienced the first 'stroke-like' episode at 18 years old. The A>G tRNALeu(UUR) point mutation at nucleotide 3243 of the mitochondrial DNA was predominant in muscle tissue (79%) and present, but at lower levels in fibroblasts (49%) and blood cells (37%). Biochemical analysis revealed diminished activities of pyruvate dehydrogenase (23%) and respiratory chain complexes I and IV (57%, respectively) in muscle, but normal activities in the fibroblasts. Immunochemical studies of the muscular pyruvate dehydrogenase components showed normal content of E1alpha, E1beta and E2 protein. Molecular screening of the E1alpha gene did not indicate a nuclear mutation. These observations suggest that mitochondrial DNA defects may be associated with altered nuclear encoded enzymes which are actively imported into mitochondria and constitute components of the mitochondrial matrix. Biochemical workup of mitochondrial disorders should not be restricted to the respiratory chain even if mitochondrial DNA mutations are present.

Adult↗
PubMed1998

Molecular characterization of two deletion events involving Alu-sequences, one novel base substitution and two tentative hotspot mutations in the hypoxanthine phosphoribosyltransferase (HPRT) gene in five patients with Lesch-Nyhan syndrome.

Mutations identified in the hypoxanthine phosphoribosyltransferase (HPRT) gene of patients with Lesch-Nyhan (LN) syndrome are dominated by simple base substitutions. Few hotspot positions have been identified, and only three large genomic rearrangements have been characterized at the molecular level. We have identified one novel mutation, two tentative hot spot mutations, and two deletions by direct sequencing of HPRT cDNA or genomic DNA from fibroblasts or T-lymphocytes from LN patients in five unrelated families. One is a missense mutation caused by a 610C-->T transition of the first base of HPRT exon 9. This mutation has not been described previously in an LN patient. A nonsense mutation caused by a 508C-->T transition at a CpG site in HPRT exon 7 in the second patient and his younger brother is the fifth mutation of this kind among LN patients. Another tentative hotspot mutation in the third patient, a frame shift caused by a G nucleotide insertion in a monotonous repeat of six Gs in HPRT exon 3, has been reported previously in three other LN patients. The fourth patient had a tandem deletion: a 57-bp deletion in an internally repeated Alu-sequence of intron 1 was separated by 14 bp from a 627-bp deletion that included HPRT exon 2 and was flanked by a 4-bp repeat. This complex mutation is probably caused by a combination of homologous recombination and replication slippage. Another large genomic deletion of 2969 bp in the fifth patient extended from one Alu-sequence in the promoter region to another Alu-sequence of intron 1, deleting the whole of HPRT exon 1. The breakpoints were located within two 39-bp homologous sequences, one of which overlapped with a well-conserved 26-bp Alu-core sequence previously suggested as promoting recombination. These results contribute to the establishment of a molecular spectrum of LN mutations, support previous data indicating possible mutational hotspots, and provide evidence for the involvement of Alu-mediated recombination in HPRT deletion mutagenesis.

Alu Elements↗
PubMed1998

Characterization of the mitochondrial genome in childhood multiple sclerosis. I. Optic neuritis and LHON mutations.

The occurrence of optic neuropathy in patients with MS-like disorders who carry one of the pathogenetically significant LHON mutations as well as the higher incidence of maternal transmission in familial cases of MS support the hypothesis that mitochondrial genes may be implicated in susceptibility to MS. We sequenced the entire mtDNA of six children with MS who developed optic neuritis as early and prominent visual involvement. The analysis revealed a high degree of nucleotide variations relative to the standard mtDNA sequence. After excluding various synonymous nucleotide changes and common neutral polymorphisms, eight discrete novel missense mutations within the protein coding, tRNA or rRNA genes were detected. None of the eight polymorphic sites were found in common between the patients with MS. Of particular interest was the observation that five of six children carried a total of nine secondary LHON mutations at nucleotide positions 4216, 4917 or 13708. We conclude that variation in mtDNA is unlikely to contribute to genetic predisposition for MS. However, secondary LHON mutations may be regarded as additional risk factor for developing prominent optic nerve involvement. The association of individual sets of mtDNA variations with phenotypic presentation in certain subgroups of MS patients remains to be clarified.

Child↗
PubMed1998

Characterization of the mitochondrial genome in childhood multiple sclerosis. II. Multiple sclerosis without optic neuritis and LHON-associated genes.

The occurrence of mitochondrial mutations with primary pathogenic significance for Leber's hereditary optic neuropathy in patients with a multiple sclerosis-like phenotype and the preferential maternal transmission points to an involvement of the mitochondrial genome in conferring increased susceptibility to MS. To evaluate the link between MS and mtDNA variations we investigated a total of thirteen children with MS as well as twenty controls by sequencing eight mitochondrial encoded genes which are known to be the loci for LHON-associated mutations. Numerous synonymous nucleotide substitutions and common polymorphisms were excluded from comparative analyses. No primary LHON mutations were found. Secondary LHON mutations were identified more frequently in control subjects than in the children with MS. The remaining eight discrete missense mutations were chosen for further characterization. Only two of them were found in more than one patient. Our results suggest that nucleotide substitutions within the ND1, ND2, ND4, ND5, ND6, COI, COIII or cytochrome b genes of mtDNA do not contribute to the etiology of typical MS. However, the association of LHON mutations with visual impairment in MS as well as the relationship between phenotypic diversity in certain subgroups of patients with individual mtDNA genotypes merits further investigations.

Adolescent↗
PubMed1998

Characterization of the mitochondrial genome in childhood multiple sclerosis. III. Multiple sclerosis without optic neuritis and the non-LHON-associated genes.

The higher maternal transmission of multiple sclerosis in familial cases and the coincidence of a MS-like phenotype with mitochondrial point mutations in patients with Leber's hereditary optic neuropathy has inspired a detailed assessment of the mitochondrial genome as an etiological factor in the pathogenesis of MS. To further elucidate the contribution of maternally transmitted mutations to MS susceptibility, we sequenced five protein- and all RNA-coding genes of the mtDNA from thirteen children with MS and twenty unaffected individuals. After excluding several synonymous mutations and common polymorphisms, a total of ten ambiguous missense or protein synthesis mutations were selected and analysed. By defining minimal criteria for pathogenity--incidence, location and degree of evolutionary conservation--we conclude that sequence variations in COII, ATPase6 and 8, ND3, or ND4L subunits of oxidative phosphorylation as well as in rRNA and tRNA genes are unlikely to increase susceptibility for the development of MS.

Adolescent↗