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G F Hoffmann

Publications and source records attributed to G F Hoffmann.

At least 145 records · Page 8Linked to original sources
PubMed1997

Regulatory adaptation of isoprenoid biosynthesis and the LDL receptor pathway in fibroblasts from patients with mevalonate kinase deficiency.

In a search for the pathophysiologic mechanisms, we estimated isoprenoid synthesis and concentration, cellular growth, and the activity of the LDL receptor pathway in fibroblasts from patients with mevalonate kinase deficiency (MKD), a severe multisystemic disorder of cholesterol and non-sterol isoprenoid biosynthesis. In response to different concentrations of LDL and non-lipoprotein-bound cholesterol, MKD cells partially counteracted their enzyme defect by increased activities of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (results from earlier studies) and the LDL receptor pathway, responses similar to the pharmacologic effects seen upon administration of HMG-CoA reductase inhibitors. Rates of N-linked protein glycosylation, estimated as the amount of [14C]galactose-labeled macromolecules secreted into cell culture medium, were significantly decreased in MKD fibroblasts in comparison with control cells which may indicate alterations in the dolichol or dolichol phosphate pool. In response to exogenous cholesterol, the major feedback inhibitor of isoprenoid biosynthesis, growth velocities of MKD fibroblasts declined in comparison with control cells, further suggesting an impairment of non-sterol isoprenoid biosynthesis in MKD. Our results suggest an imbalance in the multilevel regulation of the biosynthesis of cholesterol and non-sterol isoprenoids in MKD, representing an additional causative factor responsible for the pre- and postnatal pathology of MKD.

Adaptation, Physiological↗
PubMed1996

Molecular cloning of human phosphomevalonate kinase and identification of a consensus peroxisomal targeting sequence.

Two overlapping cDNAs which encode human liver phosphomevalonate kinase (PMKase) were isolated. The human PMKase cDNAs predict a 191-amino acid protein with a molecular weight of 21,862, consistent with previous reports for mammalian PMKase (Mr = 21,000-22,500). Further verification of the clones was obtained by expression of PMKase activity in bacteria using a composite 1024-base pair cDNA clone. Northern blot analysis of several human tissues revealed a doublet of transcripts at approximately 1 kilobase (kb) in heart, liver, skeletal muscle, kidney, and pancreas and lower but detectable transcript levels in brain, placenta, and lung. Analysis of transcripts from human lymphoblasts subcultured in lipid-depleted sera (LDS) and LDS supplemented with lovastatin indicated that PMKase gene expression is subject to regulation by sterol at the level of transcription. Southern blotting indicated that PMKase is a single copy gene covering less than 15 kb in the human genome. The human PMKase amino acid sequence contains a consensus peroxisomal targeting sequence (PTS-1), Ser-Arg-Leu, at the C terminus of the protein. This is the first report of a cholesterol biosynthetic protein which contains a consensus PTS-1, providing further evidence for the concept that early cholesterol and nonsterol isoprenoid biosynthesis may occur in the peroxisome.

Amino Acid Sequence↗
PubMed1996

Atypical vitamin B12-unresponsive methylmalonic aciduria in sibship with severe progressive encephalomyelopathy: a new genetic disease?

UNLABELLED: We report on two siblings, a girl of 7 years and a boy of 2 years, who presented in infancy with hypotonia, athetoid movements, myopathy and severe developmental delay. The progressive clinical course was characterized by ophthalmoplegia, pyramidal tract signs, loss of visual contact and failure to thrive. The older sister died at the age of 7 years. The younger brother followed an almost identical clinical course. MRI of the brain revealed bilateral hypodensities and atrophy of the putamen. Neurophysiological investigations were consistent with peripheral neuropathy. Investigations for neurometabolic disorders in urine, plasma and CSF of both patients revealed a consistent increase of methylmalonic acid in urine, plasma and CSF as well as borderline low free GABA in CSF. Except for an inconstant elevation of lactate in the boy, metabolic acidosis, hypoglycaemia, episodic ketoacidosis, or hyperammonaemia, the usual concomitants of organoacidopathies, were absent in both children. Homocystinuria was excluded. Methylmalonic aciduria did not respond to antibiotic treatment, vitamin B12 therapy nor dietary protein restriction. Incorporation of [14C]propionate into protein in cultured fibroblasts was pathologically but inconsistently decreased. Both patients' cell lines showed only minimal response to hydroxocobalamin and normal methylmalonyl-CoA mutase activity. CONCLUSION: Even though the definitive underlying enzymatic defect in this sibship remains obscure our results suggest a new genetic disorder. This report illustrates that hitherto undescribed metabolic disorders remain to be elucidated even in long investigated areas of intermediary metabolism such as methylmalonic aciduria.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Severe hyperchloriduria-hyperkaliuria: a new congenital renal tubular abnormality?

A female infant, aged 5 weeks, had metabolic alkalosis associated with severe electrolyte disturbances. In addition to findings typically seen in patients with Bartter syndrome or hyperprostaglandin E syndrome, she had massive urinary excretion of prostaglandins E2 and E-M, normal calcium metabolism, hyperphosphaturia, and severe hyperchloriduria and hyperkaliuria with limited response to indomethacin. These findings may represent a new congenital renal tubular abnormality.

Bartter Syndrome↗
PubMed1996

Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency.

BACKGROUND: Glutaryl-CoA dehydrogenase deficiency (GDD) is a recessively inherited neurometabolic disorder associated with encephalopathic crises and severe extrapyramidal symptoms. Treatment regimens including glucose and electrolyte infusions during acute illnesses, oral carnitine supplementation and/or a low-protein or lysine-restricted diet have been recommended, but their efficacy has been documented only on an anecdotal basis. SUBJECTS AND METHODS: We conducted a retrospective analysis of 57 patients with proven GDD-relating appearance and severity of neurological disease to age and clinical status at diagnosis, glutaric acid levels in body fluids, and different treatment regimens. RESULTS: Thirty-six patients were diagnosed after the onset of neurological disease (symptomatic group), twenty-one before (presymptomatic group). Carnitine levels were found to be reduced in all patients at diagnosis. In the symptomatic group, macrocephaly had been present around birth and was followed by rapid postnatal head growth in 70% of the children. The patients often showed symptoms such as hypotonia, irritability, and jitteriness followed by an acute encephalopathic crisis occurring on average at 12 months of age. Common neuroimaging findings included frontotemporal atrophy, subependymal pseudocysts, delayed myelination, basal ganglia atrophy, chronic subdural effusions and hematomas. In four patients the latter two findings were initially misinterpreted as resulting from child abuse. Other important misdiagnoses in older siblings who were affected and went undiagnosed include postencephalitic cerebral palsy, dystonic cerebral palsy and sudden infant death syndrome. Metabolic treatment did not convincingly improve the neurological disease, although it may have prevented further deterioration. Symptomatic treatment with baclofen or benzodiazepines was effective in reducing muscle spasms. Children in the presymptomatic group were diagnosed because of familiarity for the disease (n = 13), macrocephaly and/or additional minor neurological signs in infancy (n = 6), or acute encephalopathy, which was fully reversible after prompt treatment (n = 2). After diagnosis, all children were treated with oral carnitine, fluid infusion during intercurrent illnesses and, in addition, a diet was started in 13 of the 21 children. All 21 children except one (born prematurely at 31 weeks) have continued to develop normally up to now. Mean age at report is 6.3 years with a range from 6 months to 14.8 years. In older patients, the neuroradiological changes, present in infancy as in the symptomatic patients, became less prominent and in one girl disappeared. CONCLUSIONS: In presymptomatic children with GDD, the onset of neurological disease can be prevented by vigorous treatment of catabolic crises during illnesses together with carnitine supplementation. The importance of dietary therapy remains unclear and needs further evaluation. The potential treatability of GDD calls for increased attention to early presenting signs in order to recognize the disorder and to initiate treatment before the onset of irreversible neurological disease.

Adolescent↗
PubMed1994

Selective screening for inborn errors of metabolism--past, present and future.

Selective screening for hereditary metabolic disorders has developed from a highly specialized activity, provided mostly by research oriented scientists, to an important diagnostic tool in the work-up of paediatric patients. A brief overview is given of the present status of selective screening in Europe, the USA and Israel including the distribution of centres and resources for diagnosis, therapy and follow-up. Current status and most pressing problems vary widely between different countries. Most countries still lack an organized network of clinical genetic centres which are capable of competent and comprehensive diagnostic and therapeutic services. For example, it must be assumed that more than 60% of patients with inherited metabolic diseases, which could be diagnosed nowadays, remain un(mis)diagnosed in former Western Germany. Early diagnosis and treatment are important determinants for a successful approach towards inherited metabolic diseases. Therefore, screening and therapy for inborn errors of metabolism has to be organized in clinical genetic centres, each serving a population between 2 and 4 million. The quality of the services provided depends on good pre- and postgraduate training of physicians (paediatricians) in the field of metabolic diseases, good co-operation between the referring physician and the clinical genetic centre and a broad spectrum of highly specialized metabolic investigations in the respective centre. The institutionalization has to include licensing of laboratories, directors and personnel, as well as quality control and proficiency testing. The size of the centres cannot be judged on the basis of the work involved with selective screening for inborn errors of metabolism alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Europe↗
PubMed1994

Screening for defects of branched-chain amino acid metabolism.

Screening for defects of branched-chain amino acid metabolism is a sequential process involving clinical evaluation of the patient, plasma carnitine determination, urinary organic acid analysis, and enzyme studies in cultured or isolated peripheral cells. This report will summarize clinical and metabolite features and enzymological methods available for the diagnosis of the more common defects of branched-chain amino acid metabolism, including isovaleryl-CoA dehydrogenase deficiency, 3-methylcrotonyl-CoA carboxylase deficiency, 3-methylglutaconic aciduria due to 3-methylglutaconyl-CoA hydratase deficiency and other less well characterized defects, 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, and 2-methylacetoacetyl-CoA thiolase deficiency. Newer enzymatic methodologies utilizing NaH14CO3 fixation coupled assays are described which allow for the estimation of six enzyme activities in the catabolic pathways of L-leucine and L-isoleucine catabolism. These coupled assays facilitate the rapid identification of five of the six enzyme abnormalities described above. Their ease of use should allow them to be implemented in any laboratory which screens for inborn errors of metabolism.

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Neurological manifestations of organic acid disorders.

Neurological manifestations are very common and can be the leading and/or presenting feature in organic acid disorders, sometimes in the absence of metabolic derangement. Review of the time course and presentation of neurological disease in organic acid disorders reveals characteristic clinical findings of ataxia, myoclonus, extrapyramidal symptoms, metabolic stroke and megalencephaly. A group of organic acid disorders presents exclusively with neurological symptoms. These include glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I), succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria), mevalonic aciduria, N-acetylaspartic aciduria (Canavan disease) and L-2-hydroxyglutaric aciduria. As a group these "cerebral" organic acid disorders appear to remain often undiagnosed and their true incidence is much less well-known than that of the "classical" organic acid disorders. Unfortunately, stringent guidelines for a clinical preselection of neuropaediatric patients to be investigated for organic acid disorders cannot be provided. Today, screening for neurometabolic disorders should be as comprehensive as possible and include determinations of amino acids, purines and pyrimidines and markers of peroxisomal function in addition to organic acid analysis.

Brain Diseases, Metabolic↗
PubMed1994

Impaired synthesis of lipoxygenase products in glutathione synthetase deficiency.

Glutathione synthetase deficiency (GSD) is an inborn error of glutathione (GSH) metabolism leading to a generalized intracellular GSH deficiency. Because GSH is required for leukotriene C4 (LTC4) synthesis, we studied synthesis and metabolism of several lipoxygenase products in two patients with GSD by radio-HPLC, UV spectrophotometry, and enzyme immunoassays. In both patients, LTC4 synthesis was significantly decreased in calcium ionophore-stimulated neutrophils (up to 0.4 ng/10(6) cells; controls, 5.0 +/- 0.9) and monocytes (up to 3.6 ng/10(6) cells; controls, 30.2 +/- 3.3). LTB4 synthesis was about seven times higher in GSD cells compared with controls, whereas synthesis of other 5-, 12-, and 15-lipoxygenase products and prostaglandin E2 was not affected. Neutrophils and monocytes from both patients showed a marked reduction in capacity to form [3H]LTC4 from [3H]LTA4 (9-14% of control values). Urinary LTE4 was finally found to be 50-fold lower in GSD, reflecting a decreased synthesis of cysteinyl LT in vivo. GSD may serve as a unique model for the linkage between LT synthesis and GSH metabolism in vivo.

Calcimycin↗