First missense mutation (W679R) in exon 10 of the adrenoleukodystrophy gene in siblings with adrenomyeloneuropathy.
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ATP Binding Cassette Transporter, Subfamily D, Mem↗
Biomedical subjects
F Hanefeld
Publications and source records attributed to F Hanefeld.
Creatine protects the central respiratory network of mammals under anoxic conditions.
The effect of creatine (Cr) on the response of the respiratory center to anoxia was analyzed at different postnatal stages in a brainstem slice preparation of mice. Spontaneous rhythmic activity was recorded from hypoglossal rootlets (XII) and from identified neurons within the preBötzinger complex using the whole cell patch clamp technique. The hypoxic response was evaluated in slices from animals (n = 46), which received normal nutrition (controls, n = 16), from litters of animals fed with Cr (2 g/kg/day; nutrition group, n = 8), or after incubating slices for 3 h in Cr (200 microM) (incubation group, n = 22). ATP was measured in slices from controls and Cr-incubated slices which underwent 30-min anoxia. In neonatal animals (P0-5), amplitudes of hypoglossal bursts increased initially during anoxia by 14% in controls and by 41% in Cr-supplemented animals when compared with preanoxic values. Hypoglossal burst duration increased by 3% in controls, but by 18% in the Cr-nutrition group. In brainstem slices, the initial increase of amplitudes changed from 14% (controls) to 59% (Cr incubation) and prolongation of bursts from 3% (controls) to 37% (Cr incubation) compared with preanoxic values. In juvenile controls (P6-13), burst amplitude and duration increased by 12 and 14% during early anoxia when referred to preanoxic values. In slices from Cr-pretreated animals, increases of 48% (amplitude) and 21% (burst duration) occurred. The ATP levels remained constant during a 30-min anoxic period in the Cr-pretreated group compared with a decrease of 44% in slices from controls. Our data suggest that Cr can ameliorate hypoxic energy failure. Further studies will examine the neuroprotective potential in humans.
Animals↗
S1 nuclease hybrid analysis of mitochondrial DNA amplified by long-distance PCR: rapid screening for small-scale rearrangements.
We report on a method suitable for screening large regions (>3 kb) of mtDNA for structural changes of <500 bp and their localization. Heteroduplexes consisting of a wild-type and a mutant strand are cleaved by S1nuclease when single-stranded loops are present due to deletions or duplications/insertions. This strategy was successfully applied to screen the muscle mtDNA of 20 patients with mitochondrial encephalomyopathies. In three of them, an altered cleavage pattern was observed caused by a homoplasmic 9 bp deletion as shown by subsequent mapping and sequencing studies.
Base Sequence↗
Guanidinoacetate methyltransferase deficiency: a newly recognized inborn error of creatine biosynthesis.
In an infant with progressive, severe extrapyramidal movement disorder and extremely. low urinary creatinine excretion, in vivo proton magnetic resonance spectroscopy of the brain showed a depletion of creatine and an accumulation of guanidinoacetate, the immediate precursor of creatine. The suggested defect in creatine biosynthesis at the level of guanidinoacetate methyltransferase was confirmed by the demonstration of defective activity of this enzyme in liver tissue and by identification of the underlying genetic defect. Creatine substitution by means of oral creatine monohydrate at high dosage (4-8 g per day) resulted in a striking improvement of the extrapyramidal movement disorder, normalisation of abnormal slow background activity in the EEG, and disappearance of bilateral abnormal signal intensities in the globus pallidus. The low urinary creatine excretion normalized and brain creatine and creatine phosphate, as measured by in vivo magnetic resonance spectroscopy, increased significantly. Guanidinoacetate methyltransferase deficiency is a new, treatable inborn error of metabolism. Screening methods and non-invasive diagnosis of the enzyme defect are needed for the early detection and treatment of patients with this effect.
Amino Acid Metabolism, Inborn Errors↗
Treatment of apneustic respiratory disturbance with a serotonin-receptor agonist.
Apneusis is a disturbance of respiratory rhythm characterized by severely prolonged inspiratory effort. It may occur after damage to the respiratory network within the lower brain stem and pons from an overdose of central nervous system depressants, blockade of glutamate receptors, asphyxia, hypoxia, or ischemia. Experimental studies conducted on laboratory mammals, such as anesthetized cats and rats, suggest that apneusis results mostly from depression of glutamatergic synaptic processes that are necessary for activation of inhibitory mechanisms that terminate inspiration. The impairment of synaptic transmission leads to prolonged inspiratory efforts and apneustic discharges of brainstem respiratory neurons. Apneustic patterns can be consistently converted to normal by administration of serotonin type 1A (5-HT1A) receptor agonists. This observation encouraged a treatment of severe apneusis with buspirone, an agonist for 5-HT1A receptors, in a child after neurosurgery for an astrocytoma in the pons and medulla oblongata. Oral administration of buspirone produced a prompt and highly effective remission of apneusis without side effects. Treatment with 5-HT1A agonists, therefore, might offer a novel and effective pharmacotherapy against apneustic disturbances of breathing.
Animals↗
Guanidino compounds in guanidinoacetate methyltransferase deficiency, a new inborn error of creatine synthesis.
The first inborn error of creatine metabolism (guanidinoacetate methyltransferase [GAMT] deficiency) has recently been recognized in an infant with progressive extrapyramidal movement disorder. The diagnosis was established by creatine deficiency in the brain as detected by in vivo magnetic resonance spectroscopy and by defective GAMT activity and two mutant GAMT alleles in a liver biopsy. Here, we describe characteristic guanidino-compound patterns in body fluids of this index patient with GAMT deficiency. Concentrations of guanidino compounds (creatine and guanidinoacetate) and creatinine were determined by cation-exchange chromatography and by color reaction with picric acid, respectively, in urine, plasma, and cerebrospinal fluid (CSF). Creatine concentrations were low in plasma, CSF, and urine while guanidinoacetate concentrations were markedly elevated. Daily urinary creatinine excretion was low, whereas creatinine concentrations in random urine samples were not always discriminative. Guanidino compound to creatinine ratios were not informative, as low creatinine concentrations resulted in high values for all determined compounds. During a 22-month period of oral treatment with creatine-monohydrate, plasma and urinary creatine concentrations increased to levels high above the normal range, and daily urinary creatinine excretion-proportional to total body creatine-became normalized. Guanidinoacetate concentrations remained elevated even during additional substitution of ornithine, which inhibits guanidinoacetate synthesis in vitro. The results indicate that GAMT deficiency can be recognized noninvasively by determination of guanidino compounds (creatine and guanidinoacetate) in body fluids. A deficiency of creatine, but not an accumulation of guanidinoacetate, can be corrected by treatment with oral creatine substitution.
Administration, Oral↗
Intracellular signal pathways controlling respiratory neurons.
Medullary respiratory neurons are influenced by a variety of neuromodulators, but there is a lack of information about the specific intracellular signal pathways involved. In this report we describe the modulatory effects of the cyclic adenosine-triphosphate (cAMP)-dependent protein kinase and of protein kinase C pathways on voltage- and ligand-controlled ionic conductances and demonstrate their functional significance in regulating the excitability of medullary respiratory neurons of the vivo cat. Evidence is presented that PKA and PKC pathways are persistently activated. PKA regulates current flow through persistently activated and GABAB receptor-controlled potassium channels as well as GABAA receptor-controlled chloride channels. PKC also depresses persistent potassium currents but it potentiates excitatory and inhibitory synaptic currents. The clinical significance of these intracellular signal pathways is demonstrated in a case of a child suffering from apneustic breathing, who was successfully treated with a 5HT-1A receptor agonist.
Animals↗
Decreased platelet membrane anisotropy in patients with adrenoleukodystrophy treated with erucic acid (22:1)-rich triglycerides.
Low platelet count and bleeding diathesis have been observed in patients with adrenoleukodystrophy (ALD) treated with erucic acid (22:1)-rich triglycerides ("Lorenzo's oil'). To investigate possible alterations of biophysical membrane properties, we measured platelet membrane anisotropy, which is inversely related to membrane fluidity, in 16 patients with and in 3 patients without treatment. In patients on treatment, platelet membrane anisotropy was significantly decreased. Additionally, we found increased platelet concentrations of 22:1 and compromised in vitro platelet aggregation response. The decrease of platelet membrane anisotropy is probably a main cause of bleeding diathesis. Long-term haematological side-effects must be considered in ALD patients treated with Lorenzo's oil.
Adolescent↗
Progression of X-linked adrenoleukodystrophy under interferon-beta therapy.
The cerebral phenotype of X-linked adrenoleukodystrophy (ALD) is a rapidly progressive neurodegenerative disorder characterized by a cerebral inflammatory response and elevated very long-chain fatty acids (VLCFA). Interferon-beta (INFB) is known to suppress the synthesis of tumour necrosis factor alpha and interferon-gamma, which have been reported to be elevated in the margin of the areas of demyelination in ALD brains. We report on treatment with interferon-beta in 8 patients with cerebral ALD, who additionally received glycerol trioleate/glycerol trierucate. INFB-1 a (Rebif, Serono, Switzerland) was given subcutaneously once a week, 3 million units for the first 3 months and 6 million units for the next 9 months. All patients showed an unimpeded progression of neurological symptoms during INFB therapy. Therapy was stopped within 6 months in 4 patients because of the fast neurological deterioration with loss of walking. In all patients the MRI demonstrated a progression of demyelination with a qualitatively unchanged gadolinium enhancement. Further studies are needed to elucidate the pathomechanism of demyelination in ALD in order to find an effective therapy for cerebral ALD patients.
Adolescent↗
GC-MS determination of guanidinoacetate in urine and plasma.
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Child↗
Intrathecal IgA synthesis in X-linked cerebral adrenoleukodystrophy.
Cerebrospinal fluid data on 25 patients suffering from various phenotypes of X-linked adrenoleukodystrophy have been evaluated neurochemically including cerebrospinal fluid/serum quotient diagrams. Intrathecal IgA production in 13 of 14 patients with cerebral adrenoleukodystrophy was the most sensitive parameter in cerebrospinal fluid and was not seen in any of the neurologically asymptomatic patients or in the patients with adrenomyeloneuropathy. A blood-cerebrospinal fluid barrier dysfunction was found in 9 of these 14 patients. Additional intrathecal IgG or IgM synthesis was observed in 3 patients each. In 1 patient with lumbar punctures before and after onset of neurologic symptoms intrathecal IgA synthesis was seen only after the appearance of neurologic symptoms. Repetition of lumbar punctures in 5 neurologically symptomatic patients with cerebral adrenoleukodystrophy revealed a similar pattern of intrathecal IgA synthesis with a tendency of decreasing IgA concentration. The pathophysiologic aspects of intrathecal IgA synthesis are discussed in relation to other demyelinating and inflammatory neurologic diseases.
Adolescent↗
Hypoparathyroidism and deafness associated with pleioplasmic large scale rearrangements of the mitochondrial DNA: a clinical and molecular genetic study of four children with Kearns-Sayre syndrome.
In four children with hypoparathyroidism and deafness as initial major manifestations of Kearns-Sayre syndrome, a unique pattern of mitochondrial DNA rearrangements was observed. Hypocalcemic tetany caused by PTH deficiency started between age of 6-13 y and was well controlled by small amounts of 1.25-(OH)2-cholecalciferol. Rearranged mitochondrial genomes were present in blood cells of all patients and consisted of partially duplicated and deleted molecules, created by the loss of 7813, 8348, 8587, and 9485 bp, respectively. The deletions were localized between the origins of replication of heavy and light strands and encompassed at least eight polypeptide-encoding genes and six tRNA genes. Sequence analysis revealed imperfect direct repeats present in all rearrangements flanking the break-points. The duplicated population accounted for 25-53% of the mitochondrial genome and was predominant to the deleted DNA (5-30%) in all cases. The proportions of the mutant populations (30-75%) correlated with the age at onset of the disease. We conclude that, unlike heteroplasmic deletions, pleioplasmic rearrangements may escape selection in rapid-dividing cells, distribute widely over many tissues, and thus cause multisystem involvement. Hypoparathyroidism and deafness might be the result of altered signaling pathway caused by selective ATP deficiency.
Child↗
Variability of endocrinological dysfunction in 55 patients with X-linked adrenoleucodystrophy: clinical, laboratory and genetic findings.
X-linked adrenoleucodystrophy (ALD) has been shown to be one of the most frequent causes of Addison's disease in men. It is characterized by an impaired peroxisomal beta-oxidation of very long chain fatty acids and is associated with mutations of the ALD gene resulting in a defective peroxisomal membrane transport protein. There is a striking variability of endocrinological and neurological symptoms in patients with ALD, with no clearly evident correlation between mutations of the ALD gene and the different neurological phenotypes. No data on endocrinological symptoms and the ALD genotype have been published so far. We report endocrinological, clinical, laboratory and molecular genetic data from 55 patients with ALD from 34 families. Endocrinological symptoms of adrenal insufficiency were observed in 33 patients, 20 of whom showed additional neurological symptoms of cerebral ALD or adrenomyeloneuropathy. Isolated neurological symptoms were seen in 12 patients; in nine patients there were neither endocrinological nor neurological symptoms. Mutations of the ALD gene (n = 28) were detected in 50 patients (including nine sets of brothers) from 32 families. No correlation was found between the ALD gene mutation and endocrinological dysfunction. However, we found that all sets of brothers were concordant for the endocrinological phenotype (cortisol synthesis was reduced in two sets and normal in seven sets), whereas four sets showed a discordant neurological phenotype. As yet unknown hereditary factors other than mutations within the ALD gene may interfere with the endocrinological phenotype more strongly than with the neurological phenotype of ALD.
Addison Disease↗
Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism.
BACKGROUND: The creatine/creatine-phosphate system is essential for the storage and transmission of phosphate-bound energy in muscle and brain. In infants, inefficiency or failure of this metabolic pathway can impair the development of motor control and mentation. METHODS: We studied and treated an infant with extrapyramidal signs who was shown--by assay for urinary creatinine and by analysis of brain metabolites with use of nuclear magnetic resonance spectra--to have depletion of body and brain creatine, due to inborn deficiency of guanidinoacetate methyltransferase (GAMT). FINDINGS: Long-term oral administration of creatine-monohydrate (4-8 g per day) to this index patient resulted in substantial clinical improvement, disappearance of magnetic resonance (MRI) signal abnormalities in the globus pallidus, and normalisation of slow background activity on the electroencephalogram (EEG). During the 25-month treatment period, both brain and total body creatine concentrations became normal. INTERPRETATION: Oral creatine replacement has proved to be effective in one child with an inborn error of GAMT. It may well be effective in the treatment of other disorders of creatine synthesis.
Basal Ganglia Diseases↗
Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype.
We report on monozygotic twins with different clinical phenotypes of X-linked adrenoleukodystrophy. At the age of 10 years both boys were neurologically asymptomatic. The first cranial magnetic resonance examination showed normal findings in the first twin and parietooccipital demyelination in the second. The latter developed behavioral problems 9 months later, followed by visual impairment and gait ataxia. His cranial magnetic resonance image at the age of 11 years showed progressive demyelination. In contrast, neurological status and magnetic resonance images remained normal in the first twin. The same point mutation in exon 8 of the adrenoleukodystrophy gene (C2203T) was detected in both boys. All genotype examinations were consistent with the diagnosis of monozygotic twins, suggesting that some nongenetic factors may be important for different adrenoleukodystrophy phenotypes.
Adrenoleukodystrophy↗
Localized proton magnetic resonance spectroscopy of a cerebellar tumor in a two-year-old child.
Noninvasive localized proton magnetic resonance spectroscopy (MRS) was used for differential diagnosis of a focal brain lesion in a 2.5-year-old girl. The clinical signs were a mild head tilt and neck pain. Magnetic resonance imaging (MRI) revealed a lesion in the right hemisphere of the cerebellum, but its nature remained obscure. In this lesion quantitative determinations of cerebral metabolites by fully relaxed, short-echo-time proton MRS revealed markedly lowered N-acetylaspartate (NAA) and pronounced elevations of choline-containing compounds (Cho) and myo-inositol (Ins), whereas metabolite concentrations in cortical gray matter and white matter were within normal ranges. The metabolite pattern of the lesion indicated loss of vital neuroaxonal tissue (low NAA) and enhanced glial proliferation (high Cho and Ins), which, together with the MRI morphology, suggested a brain tumor. The diagnosis was established by neurosurgical exploration and total extirpation of the tumor. Histology confirmed an astrocytoma (WHO II). After 2 weeks' recovery the child was discharged with no neurological signs.
Astrocytoma↗
Failure of beta interferon therapy in X-linked adrenoleukodystrophy.
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Adjuvants, Immunologic↗