Oddvar Stokke

Methylmalonic acidemia. A new inborn error of metabolism which may cause fatal acidosis in the neonatal period.

A new inborn error of metabolism characterized by severe metabolic acidosis, polyuria, dehydration, emaciation and the urinary excretion of large amounts of methylmalonic acid is described. Two siblings of the patient have died in the neonatal period with clinical symptoms strongly resembling those of our patient. Our studies indicate that the metabolic block is located in the degradation of methylmalonic acid to succinic acid.Valine was shown to be a precursor of methylmalonic acid in accordance with the known metabolic formation of this acid. Small amounts of valine were metabolized to CO2, suggesting that the metabolic defect is incomplete. The blood concentration, body burden, distribution volume, serum half life and renal clearance of methylmalonic acid were determined.Treatment with cyanocobalamin and with cobamide coenzyme did not appear to influence the course of the disease.A diet low in isoleucine, valine, threonine and methionine significantly reduced the urinary excretion of methylmalonic acid...

Pyroglutamic Aciduria — a New Inborn Error of Metabolism

A new metabolic disorder of the urea cycle is described. The patient is a 19-year-old mentally retarded male, who also has other neurological signs of cerebral damage, and suffers from episodic vomitings. Laboratory analyses revealed urinary excretion of about 30 g of pyroglutamic acid per day, a reduced urea production, and a chronic metabolic acidosis. The findings indicate a defect in one of the early steps in the urea cycle.

Screening for Metabolic Disorders Using Gas-Liquid Chromatography, Mass Spectrometry, and Computer Technique

A system for multicomponent analyses of biological materials, using gas-liquid chromatography (GLC) for separation purpose, mass spectrometry for identification and structure studies, and computer technique for data handling, is described. Various extraction steps, hydrolysis and methods of derivative formation have been assembled into 8 different GLC-systems. Identification of the GLC-peaks is done by computer matching of unknown mass spectra against a library file of reference spectra. This file presently comprises 7600 compounds. The screening system has proved to be a valuable tool in the diagnosis of known metabolic errors; about 40 of them can be detected. The system has resulted in the discovery of 3 new inborn errors of metabolism: Methylmalonic acidemia, β-hydroxyisovaleric aciduria &β-methylcrotonylglycinuria, and pyroglutamic aciduria.

Plasma C-reactive protein as a marker of cardiac allograft vasculopathy in heart transplant recipients.

OBJECTIVES This study was initiated to determine whether heart transplant recipients (HTRs) with cardiac allograft vasculopathy (CAV) have increased levels of high-sensitivity C-reactive protein (hsCRP) and to examine whether an increase in hsCRP after heart transplantation predicts the development of CAV. Furthermore, the effect of pravastatin on plasma levels of hsCRP in HTRs was investigated. BACKGROUND The relationship between CAV and hsCRP, as well as the effect of statins on hsCRP in HTRs, has not been well established. METHODS On referral for their annual angiographic control study, 150 consecutive HTRs (mean 6.5 years since transplantation) were included. Plasma levels of hsCRP were measured before angiography and compared with patients with (n = 52) and without (n = 98) CAV. In 49 of these patients, we additionally analyzed hsCRP in blood samples stored from their six-month visit after the transplantation procedure. Furthermore, in a randomized, crossover study, hsCRP was analyzed in 17 male HTRs before and after six weeks of treatment with 20 mg pravastatin. RESULTS Median levels of CRP were elevated among patients with CAV compared with those with normal angiograms [3.86 (1.78 to 7.00) vs. 1.08 (0.72 to 2.13) mg/l, p < 0.001]. Prospectively evaluated hsCRP levels from six months to follow-up were significantly higher among those who developed CAV compared with those with normal angiograms [+2.76 (1.56 to 5.00) vs. +0.07 (-0.57 to 0.41) mg/l, p < 0.001]. On multivariate analysis, the increase in hsCRP was the only significant predictor of CAV. Six weeks of treatment with pravastatin significantly reduced hsCRP levels by 25%, without any relation to changes in lipid values. CONCLUSIONS Elevated plasma levels of CRP are associated with angiographic evidence of CAV, and the increase in hsCRP is a strong predictor of development of CAV. Statin treatment reduces levels of hsCRP and should be used in HTRs, regardless of their lipid levels.

N-Acetylaspartic aciduria in a child with a progressive cerebral atrophy

Excessive excretion of N-acetylaspartic acid in urine is reported in a 6-yr-old child with extensive and progressive cerebral atrophy. The concentration in urine was 947-1,433 mumol/mmol creatinine (controls, n = 10, 5-21 mumol/mmol creatinine) and the daily excretion approximately 3-4 mmol. In cerebrospinal fluid from the patient the concentration was 611 mumol/l (controls, n = 10, not detectable, detection limit 2.3 mumol/l). The concentration of N-acetylaspartic acid in serum was 7 mumol/l. The low level in serum compared to the high urinary excretion of NAA suggests the possibility that NAA is synthesized in the kidneys in addition to the brain. This patient may cast new light on the functional role of N-acetylaspartic acid in humans.

Studies on the Metabolic Error in Refsum's Disease*

Studies utilizing mevalonic acid-2-(14)C and D(2)O as precursors failed to provide evidence for an appreciable rate of endogenous biosynthesis of phytanic acid in a patient with Refsums disease. Orally administered tracer doses of phytol-U-(14)C were well absorbed both by seven normal control subjects (61 to 94%) and by two patients with Refsums disease (74 and 80%). The fraction of the absorbed dose converted to (14)CO(2) in 12 hours was 3.5 and 5.8% in Refsums disease patients and averaged 20.9% in seven control subjects. Labeled phytanic acid was demonstrated in the plasma of both control subjects and patients given phytol-U-(14)C, establishing phytol in the diet as a potential precursor of phytanic acid. This labeled phytanic acid had disappeared almost completely from the plasma of the seven control subjects by 24 to 48 hours, whereas it persisted at high concentrations in the plasma of the two patients for many days. We conclude that the phytanic acid accumulating in Refsums disease is primarily of exogenous origin and that patients with Refsums disease have a relative block in the degradation of phytanic acid and possibly other similar branched-chain compounds. This may relate to a deficiency in mechanisms for release of phytanic acid from stored ester forms or, more probably, to reactions essential to oxidative degradation of the carbon skeleton.

Monitored high-dose azathioprine treatment reduces acute rejection episodes after renal transplantation

BACKGROUND Azathioprine (AZA) is widely used in organ transplantation. Common practice is to adjust dose according to body weight only, despite documented pharmacokinetic variability. The purpose of this study was to investigate whether high-dose AZA treatment monitored by 6-thioguanine nucleotides (6-TGN) levels reduces the incidence of rejection episodes in renal transplantation without a corresponding increase in myelotoxicity. METHODS Patients receiving cyclosporine, steroids, and AZA were randomized into either the low-dose AZA group (3 mg/kg on day 0, then 2 mg/kg/day the first week and 1 mg/kg/day thereafter) or the high-dose AZA group. In the latter, AZA was started at 5 mg/kg/day and then adjusted to keep 6-TGN concentrations (measured twice weekly) between 100 and 200 pmol/8 x 10(8) RBCs. RESULTS A total of 360 transplant recipients were included in the final analysis. The cumulative incidence of first rejection episodes was reduced by 21%, from 62.8% in the low-dose group to 49.4% in the high-dose group (difference: 13.3%; 95% confidence interval: 3.2-23.5). Similar results were found in subgroups according to HLA-DR match. The 6-TGN concentration was significantly higher in the high-dose AZA group during the first month, and the reduction in rejection episodes was achieved in the same period. A larger proportion of patients in the high-dose group had nadir white blood cell count below 2.0 x 10(9) leukocytes/L (13.3% vs. 4.4%; difference: 8.9%; confidence interval: 3.1-14.7). CONCLUSIONS High-dose AZA therapy in a triple-drug regimen, monitored by 6-TGN, will keep myelotoxicity within acceptable limits with the benefit of a reduction in acute rejection episodes.

Clinical and biochemical heterogeneity in conditions with phytanic acid accumulation

Phytanic acid accumulation has for more than 20 years been used as a diagnostic criterion of Refsums disease. Recently, however, phytanic acid has also been found in peroxisomal disorders (Zellwegers syndrome, neonatal adrenoleukodystrophy, infantile Refsums syndrome, rhizomelic chondrodysplasia punctata). The 17 patients with Refsums disease in the present study had serum phytanic acid values differing from 73 to less than 0.5 mg/dl (normal). alpha-Oxidation of phytanic acid in skin fibroblast cultures showed a defective capacity in all, with only small differences in residual activity. Phytanic acid determinations in serum from 3 of the 7 patients with peroxisomal disorders showed slightly elevated levels in 2. The alpha-oxidation capacity in the fibroblasts was defective in all, with a residual activity similar to that of Refsums disease. An assay of the alpha-oxidation capacity may be useful in the diagnosis of both Refsums disease and the peroxisomal disorders. The distinction between Refsums disease and the peroxisomal disorders can easily be done on a clinical basis.

Pyroglutamic aciduria: studies on the enzymic block and on the metabolic origin of pyroglutamic acid

Abstract A 20-year-old mentally retarded male with pyroglutamic aciduria has recently been described. The laboratory findings in this disorder are a high pyroglutamic acid (pyrrolidone-2-carboxylic acid) excretion (25–35 g/24 h), low excretion of urea (5–10 g/24 h) and metabolic acidosis. The serum and the cerebrospinal fluid contain 5 and 30 mg/100 ml, respectively, of pyroglutamic acid. The serum level of proline is 3 times the normal. Biochemical studies of the disorder show that (a) the patient converts ammonia to urea in a normal manner and responds normally to a high-calorie, low-protein diet. (b) A correlation exists between urinary ammonia and pyroglutamic acid, the excretion of both being independent of urinary pH. (c) Neither glutamine nor glutamic acid are direct precursors of pyroglutamic acid. (d) The patient, in contrast to normals, is unable to hydrolyze pyroglutamic acid to glutamic acid, (e) That i.v. infusion of amino acids to the patient is the only condition found which significantly increases the excretion of pyroglutamic acid. These studies indicate that pyroglutamate is involved in the renal handling of amino acids, and that the patient has a block in one of the steps (pyroglutamic acid to glutamic acid) of the γ-glutamyl cycle proposed by Orlowski and Meister.

Infantile Refsum's disease: A generalized peroxisomal disorder: Case report with postmortem examination

Infantile Refsums disease (IRD) is a peroxisomal deficiency disease which is closely related to neonatal adrenoleukodystrophy (NALD) and the Zellweger syndrome (ZS). Recent observations suggest that NALD and ZS are separate genetic disorders but the delimitation towards IRD remains uncertain. We present here the first autopsy report of a patient who was clinically and biochemically diagnosed as having IRD, and we compare the findings with those from NALD and ZS. The main gross and microscopic findings comprised micronodular liver cirrhosis, small hypoplastic adrenals without degenerative changes, and large groups of lipid macrophages in liver, lymph nodes and certain areas of the cerebral white matter. The brain showed no malformations except for a severe hypoplasia of the cerebellar granule layer and ectopic location of the Purkinje cells in the molecular layer. A mild and diffuse reduction of axons and myelin was found in the corpus callosum and periventricular white matter, the corticospinal tracts, and the optic nerves. Large numbers of perivascular macrophages were present in the same areas but there was no active demyelination. The retina and cochlea showed severe degenerative changes. Peripheral nerves, skeletal system and kidneys were normal. Electron microscopy showed characteristic cytoplasmic inclusions with bilamellar profiles in macrophages in the liver, lymph nodes and brain but not in the adrenals. Similar inclusions were found in liver cells and astrocytes. The findings differ from ZS which shows cortical renal cysts, skeletal changes, liver changes, cerebral micropolygyria, neuronal heterotopias, and demyelination of the white matter. Cases with NALD show mild cerebral malformations, active demyelination, degenerative changes of the adrenals, liver changes, and bilamellar electromicroscopic inclusions in macrophages. Our cases thus resembled NALD but lacked active demyelination, cerebral cortical malformations and adrenal degenerative changes. Further autopsy studies will be necessary to determine whether these changes are consistent findings in IRD.