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Biomedical subjects

I Tein

Publications and source records attributed to I Tein.

At least 37 records · Page 2Linked to original sources
PubMed1996

An additional mitochondrial tRNA(Ile) point mutation (A-to-G at nucleotide 4295) causing hypertrophic cardiomyopathy.

A third point mutation in the mitochondrial tRNA(Ile) gene associated with hypertrophic cardiomyopathy and respiratory chain dysfunction in heart is reported. An A-to-G transition at nucleotide position 4295 was shown to be highly evolutionarily conserved, never present in control individuals, and to segregate with the disease. A PCR-based diagnostic test and endomyocardial biopsies were used to detect both the biochemical deficiency and the level of heteroplasmy in heart. The implications of this new mitochondrial DNA point mutation are discussed.

Adenine↗
PubMed1996

Metabolic myopathies.

Disorders of glycogen, lipid or mitochondrial metabolism may cause two main clinical syndromes, namely (1) progressive weakness (eg, acid maltase, debrancher enzyme, and brancher enzyme deficiencies among the glycogenoses; long- and very-long-chain acyl-CoA dehydrogenase (LCAD, VLCAD), and trifunctional enzyme deficiencies among the fatty acid oxidation (FAO) defects; and mitochondrial enzyme deficiencies) or (2) acute, recurrent, reversible muscle dysfunction with exercise intolerance and acute muscle breakdown or myoglobinuria (with or without cramps) (eg, phosphorylase (PPL), phosphorylase b kinase (PBK), phosphofructokinase (PFK), phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGAM), and lactate dehydrogenase (LDH) among the glycogenoses and carnitine palmitoyltransferase II (CPT II) deficiency among the disorders of FAO or (3) both (eg, PPL, PBK, PFK among the glycogenoses; LCAD, VLCAD, short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD), and trifunctional enzyme deficiencies among the FAO defects; and multiple mitochondrial DNA (mtDNA) deletions). Myoadenylate deaminase deficiency, a purine nucleotide cycle defect, is somewhat controversial and is characterized by exercise-related cramps leading rarely to myoglobinuria.

Adolescent↗
PubMed1996

Addison's disease presenting with cerebral edema.

BACKGROUND: Increased intracranial pressure with encephalopathy has rarely been reported in Addison's disease. METHOD: Case Study. RESULTS: A 16-year-old female who presented with cerebral edema of unknown etiology was eventually diagnosed as having Addison's disease. She had early morning headaches, fatiguability, diarrhea and deterioration in school performance. She was hyponatremic with a serum sodium of 128 mmol/L and hyperkalemic with a serum potassium of 5.9 mmol/L. She had a low serum osmolality (264 mosm), high urine osmolality (533 mosm) and high urine sodium (87 mosm). She had a postural drop in blood pressure and diffuse hyperpigmentation. An ACTH stimulation test revealed a low baseline cortisol and no response to ACTH. Plasma renin activity was increased. Serum ACTH was elevated. She responded well to intravenous fluids and solu-cortef and was discharged on hydrocortisone and florinef. She remains well 18 months after the acute episode with no neurologic complaints or findings. CONCLUSION: Addison's Disease should be considered in the differential diagnosis of symptomatic cerebral edema and idiopathic intracranial hypertension.

Addison Disease↗
PubMed1995

Heterozygotes for plasmalemmal carnitine transporter defect are at increased risk for valproic acid-associated impairment of carnitine uptake in cultured human skin fibroblasts.

One of the mechanisms by which chronic valproic acid (VPA) therapy induces serum and tissue depletion of carnitine in normal controls is through inhibition of plasmalemmal carnitine uptake (Tein et al 1993). To determine the effect of VPA on proven heterozygotes for the plasmalemmal carnitine transporter defect, we studied this system in cultured human skin fibroblasts with reduced Vmax for the carnitine transporter using L-[3H]carnitine. There was en exponential dose-dependent decrease in carnitine uptake with increasing VPA concentrations and the relative inhibitory effect was the same for all three carnitine concentrations for a given cell line. Importantly, the lower the maximal velocity of carnitine uptake of the heterozygote, the lower the number of carnitine transporters and the lower the carnitine uptake per given concentration of VPA. The degree of inhibition was also directly proportional to the time of VPA preincubation up to a specific maximal saturation time. The maximal effect of VPA exposure time was reached by 10 days in the control cell line and by 3 days in the two heterozygote lines, probably reflecting earlier saturation. We conclude that patients who are heterozygous for the plasmalemmal carnitine transporter defect are at increased risk for VPA-associated serum and tissue depletion of carnitine through inhibition of plasmalemmal carnitine uptake.

Carnitine↗
PubMed1995

Fatty acid oxidation abnormalities in childhood-onset spinal muscular atrophy: primary or secondary defect(s)?

The purpose of this study was to further identify and quantify the fatty acid oxidation abnormalities in spinal muscular atrophy, correlate these with disease severity, and identify specific underlying defect(s). Fifteen children with spinal muscular atrophy (3 type I, 8 type II, 4 type III) were studied. Serum carnitine total/free ratios demonstrated a tendency toward an increased esterified fraction ranging 35-58% of total carnitine (normal: 25-30% of total) in younger children with types I and II. The remaining type II and III patients, older than 23 months of age at sampling, had normal esterified carnitine levels. Urinary organic acid analysis demonstrated mild to moderate medium-chain dicarboxylic aciduria in type I patients and normal, mild, or moderate increases in short-chain and medium-chain organic acids in type II patients. In the type III group, the organic acids were normal except for one patient with mild medium-chain dicarboxylic aciduria. Muscle intramitochondrial beta-oxidation was measured in 5 children (2 type I, 2 type II, and 1 type III) and a significant reduction in the activities of short-chain L-3-hydroxyacyl-CoA dehydrogenase, long-chain L-3-hydroxyacyl-CoA dehydrogenase, acetoacetyl-CoA thiolase, and 3-ketoacyl-CoA thiolase were found; however, normal crotonase activity was documented. Most strikingly, there was a marked increase (3- to 5-fold) in the activity ratios of crotonase to L-3-hydroxyacyl-CoA dehydrogenase and thiolase activities with both short- and long-chain substrates. The combined abnormalities suggest a defect in a mitochondrial multifunctional enzyme complex, distinct from the trifunctional enzyme. These abnormalities may be either primary or secondary and may respond to dietary measures to reduce the dependence on fatty acid oxidation.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1995

Clinical and neurophysiologic response of myopathy and neuropathy in long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency to oral prednisone.

The purpose of this study was to evaluate the clinical and neurophysiologic responses to oral prednisone therapy in a boy with enzymatically confirmed long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency in biopsied muscle and cultured skin fibroblasts. This boy presented with progressive limb girdle myopathy, recurrent myoglobinuria, peripheral sensorimotor axonopathy, and intraventricular conduction delays. Prior to prednisone therapy, at age 8 years, he exhibited marked distal weakness greater than proximal weakness with a waddling and high-steppage gait, Gowers' maneuver (10 s to rise from the floor), fatigue after 3-20 yards of walking and the ability to climb only 2 stairs. Serum levels of creatine kinase rose from 34 to 4,124 U/L following mild exertion. Nerve conduction studies revealed progressive axonopathy with secondary demyelination. Four weeks after initiation of oral prednisone (0.75 mg/kg/day) therapy, there was approximately a 100% increase in power and endurance. He was able to walk at least 100 yards before tiring, could rise from sitting on the floor in 3-4 s, and was able to climb 20 steps in 30 s. There was concurrent improvement in nerve conduction studies. Prednisone was gradually withdrawn over the next 4 months to 0.19 mg/kg/day; lower doses of 0.08 mg/kg/day resulted in a marked deterioration in power to the prior state. Although 0.19 mg/kg/day did not maintain the peak power achieved at 0.75 mg/kg/day, it provided adequate baseline power and endurance. It is concluded that there was a significant clinical and neurophysiologic response to prednisone at a dosage > or = 0.16 mg/kg/day. Prednisone may stabilize muscle and neuronal plasma membranes, as well as the fatty acid oxidation enzyme complex in the mitochondrial membrane.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1994

Reversal of valproic acid-associated impairment of carnitine uptake in cultured human skin fibroblasts.

Much attention has focussed on the role of valproic acid induced secondary carnitine deficiency in predisposing children to life-threatening hepatotoxicity and a Reye-like syndrome. One mechanism by which valproic acid therapy induces serum and tissue depletion of carnitine is through inhibition of plasmalemmal carnitine uptake. In cultured control human skin fibroblasts, this effect is directly proportional to the duration of exposure and concentration of valproic acid; the maximal effect of valproic acid exposure time is achieved by 14 days, beyond which there appears to be no additional significant effect (1). To determine whether this effect is reversible, we preincubated control fibroblasts with varying concentrations (0-1700 mumol/L) of valproic acid for 14 days, washed the fibroblasts free of valproic acid, and then continued the fibroblast growth in valproic acid-free medium for periods of 4 hours to 14 days. The fibroblasts were subsequently incubated with fixed carnitine concentrations of 50 mumol/L (normal physiological concentration), 20 mumol/L (as seen in secondary carnitine deficiency disorders), or 5 mumol/L (as seen in the homozygous plasma membrane carnitine transporter defect) and the carnitine uptake was determined. The inhibitory effect of valproic acid on carnitine uptake was completely reversed, for all 3 carnitine concentration conditions, following > or = 5 days of growth in valproic acid-free medium.

Carnitine↗
PubMed1994

Carnitine palmitoyltransferase II deficiency: a new cause of recurrent pancreatitis.

An 18-year-old female patient had a history of recurrent pancreatitis after prolonged periods of exercise coupled with a high-fat diet at the ages of 12 and 15 years. After the onset of recurrent myoglobinuria when she was 16 years old, deficiency of carnitine palmitoyltransferase type II (32% residual activity) was diagnosed on the basis of cultured skin fibroblasts. We conclude that deficiency of carnitine palmitoyltransferase type II may be a cause of pancreatitis and should be considered in the differential diagnosis, even in the absence of overt myoglobinuria.

Acute Disease↗
PubMed1994

Maternally inherited hypertrophic cardiomyopathy due to a novel T-to-C transition at nucleotide 9997 in the mitochondrial tRNA(glycine) gene.

We report a unique heteroplasmic T-to-C transition at nucleotide 9997 in the mitochondrial tRNA(glycine) gene in a multiplex family who manifested nonobstructive cardiomyopathy. The degree of mtDNA heteroplasmy generally correlated with the severity of the symptoms. This T-to-C transition disrupts hydrogen bonding in the region adjacent to the acceptor stem of the tRNA molecule. The thymine residue at position 9997 is highly conserved in mammals, as well as in various vertebrates and invertebrates. A PCR diagnostic test for the presence of the 9997 T-to-C transition revealed that the base change was always present in high proportion in affected family members, not present in unaffected family members, and never present in control subjects from various ethnic groups (25 groups sampled, 42 individuals), thus ruling out the possibility that this change represents a polymorphic variant in the general population. The degree of heteroplasmy in lymphoblast cultures also correlated with the level of enzyme activity present for cytochrome c oxidase (complex IV) and succinate cytochrome c oxidoreductase (complexes II and III). The absence of previously reported mtDNA mutations associated with hypertrophic cardiomyopathy was verified by both PCR diagnostic procedures and sequence analysis. All mitochondrial tRNA genes, as well as genes encoding ATPase subunits 6 and 8, were sequenced and found not to possess base changes consistent with the clinical profile. More detailed biochemical and molecular biological investigations are discussed.

Adenosine Triphosphatases↗
PubMed1993

Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS): clinical, radiological, pathological, and genetic observations.

We reviewed 10 patients (5 males, 5 females) with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The age of symptom onset ranged from 3 months to 12 years. All had lactic acidosis, multiple stroke-like events with secondary neurological deficits, radiological changes of progressive brain infarction, and muscle biopsy showing ragged-red fibers. In patients with earlier onset of symptoms (< 2 yr), involvement tended to be more diffuse, with failure to thrive and early onset of delayed development. Patients whose symptoms appeared later tended to have focal neurological deficits with migraine-like headache, and a rate of cognitive regression reflecting the rapidity of disease progression. Radiological changes included multiple areas of infarction with initial predilection for parietal occipital areas, progressing to generalized atrophy. Pathological findings in muscle biopsies included type 1 fiber predominance, ragged-red fibers, increased intermyofibrillar lipid deposition, and abnormal mitochondria. Four patients showed mitochondrial DNA tRNA mutation at position 3,243. No difference was noted in clinical, radiological, or pathological findings in patients with and without this mutation, suggesting that multiple sites of point mutation may give rise to mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.

Base Sequence↗
PubMed1993

Skin fibroblast carnitine uptake in secondary carnitine deficiency disorders.

Skin fibroblast carnitine uptake studies may identify and differentiate primary and secondary carnitine deficiency disorders. To confirm the specificity of these studies in differentiating primary from secondary carnitine deficiency disorders, we have studied carnitine uptake in the cultured skin fibroblasts from 5 children who have various enzymatic defects in intramitochondrial beta-oxidation including short-chain, medium-chain and long-chain acyl-CoA dehydrogenase and short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiencies, and in 4 children with cytochrome oxidase deficiency. Carnitine uptake was normal in the intramitochondrial beta-oxidation cases, suggesting other mechanisms for their carnitine deficiency. Therefore, intramitochondrial beta-oxidation defects associated with carnitine deficiency can be differentiated from primary carnitine deficiency not only by the presence of an abnormal dicarboxylic aciduria but by normal skin fibroblast carnitine uptake. In contrast to these findings, carnitine uptake in the cultured skin fibroblasts of four children with secondary carnitine deficiency due to cytochrome oxidase deficiency demonstrated a partial decrease in the maximal velocity of uptake (20-47% control Vmax), similar to that observed in the primary carnitine deficiency heterozygotes. We propose that this observation may be due to a generalized decrease in intracellular ATP, thus decreasing the efficiency of the energy- and sodium-dependent carnitine transporter. We conclude that carnitine uptake studies in cultured skin fibroblasts will contribute to an understanding of the mechanisms of carnitine depletion in the primary and secondary carnitine deficiency disorders.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1993

Valproic acid impairs carnitine uptake in cultured human skin fibroblasts. An in vitro model for the pathogenesis of valproic acid-associated carnitine deficiency.

The mechanisms of valproate-associated carnitine deficiency are controversial. The urinary excretion of valproylcarnitine is insufficient to account for tissue carnitine depletion. To explore this mechanism, we studied the effects of valproic acid (VPA) on carnitine uptake in cultured human skin fibroblasts by the method of Tein et al. (Pediatr Res 28:247-255, 1990). Fibroblasts were preincubated with varying concentrations (0-2000 microM) of VPA for 1, 3, 5, 7, 10, 14, 21, and 28 d and then incubated with fixed carnitine concentrations of 50 microM (normal physiologic concentration), 20 microM (as seen in secondary carnitine deficiency disorders), or 5 microM (as seen in the plasma membrane carnitine transport defect). There was an exponential dose-dependent decrease in carnitine uptake with increasing VPA concentrations, and the relative inhibitory effect was the same for all three carnitine concentrations. The mean percentages +/- SD (n-1) of residual carnitine uptake for all combined preincubation periods (1-28 d) and combined carnitine concentrations (5, 20, and 50 mumol/L) with increasing concentrations of VPA varied from 83.4 +/- 2.6% (10 microM VPA) to 56.7 +/- 0.1% (500 microM) to 19.8 +/- 1.3% (2000 microM). The degree of inhibition was directly proportional to the time of VPA preincubation and parallel for all three carnitine concentrations; the longer the preincubation period, the lower the toxic dose of VPA (to a minimum of 450 microM), resulting in a 50% suppression of carnitine uptake (TD50).(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport↗
PubMed1991

Short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency in muscle: a new cause for recurrent myoglobinuria and encephalopathy.

We report on a 16-year-old girl with short-chain L-3-hydroxyacyl-coenzyme A (CoA) dehydrogenase deficiency resulting in juvenile-onset recurrent myoglobinuria, hypoketotic hypoglycemic encephalopathy, and hypertrophic/dilatative cardiomyopathy. Urinary organic acids showed traces of 3-hydroxy-dodecanedioic acids and small amounts of suberic, sebacic, and adipic acids. There was a marked decrease in L-3-hydroxyacyl-CoA dehydrogenase activity in muscle with acetoacetyl-CoA as substrate (2.48 mumol/min/gm; normal = 6.90 +/- 1.80 mumol/min/gm of tissue; n = 11), contrasting with normal L-3-hydroxyacyl-CoA dehydrogenase activity with 3-ketooctanoyl-CoA and 3-ketopalmitoyl-CoA as substrates. Short-chain L-3-hydroxyacyl-CoA dehydrogenase activity was normal in fibroblasts, suggesting a tissue-specific defect.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1990

Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy.

Evidence is emerging that primary systemic carnitine deficiency, a potentially lethal but eminently treatable inborn error of fatty acid oxidation, involves a cellular defect in the uptake of carnitine. We present four unrelated children with primary carnitine-responsive cardiomyopathy, weakness (with or without hypoketotic hypoglycemic encephalopathy), low serum and/or tissue carnitine concentrations, and severe renal carnitine leak. Dicarboxylic acids were absent in the urine of three children who were tested, and all four had a rapid and dramatic improvement in cardiac function, strength, and somatic growth after carnitine therapy. We studied carnitine uptake in cultured skin fibroblasts from all four children and seven of the eight healthy nonconsanguinous parents. [3H]L-carnitine uptake was evaluated in vitro under linear time kinetics. Substrate concentrations were varied from 0.1 to 1000 microM. Physiologic uptake was determined at carnitine concentrations between 0.1 and 50 microM. Nonspecific uptake was determined at a concentration of 10 mM. The four patients had negligible uptake throughout the physiologic range, implying a marked deficiency in the specific high-affinity, low-concentration, carrier-mediated uptake mechanism. At a concentration of 5 mumol/L, the mean velocity of uptake in the four patients was 2% of control values. Their parents showed intermediate maximal rates of carnitine uptake ranging from 13 to 44% of control Vmax values, but normal Km values, suggesting that the heterozygotes had a reduced number of normal functioning carnitine transporters. The observed reduction in Vmax values for the parents supports an autosomal recessive inheritance pattern and may be a more sensitive indicator of heterozygosity than serum carnitine concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport, Active↗
PubMed1990

Recurrent childhood myoglobinuria.

Recurrent heritable childhood myoglobinuria is a potentially fatal entity (mortality up to 35%) in which prompt diagnosis and treatment are critical. Sixty childhood cases have been reported between 1910 to 1988, most with undiagnosed etiologies. We have studied an additional 40 cases referred to CPMC (1980-1988), suggesting that this condition is largely underdiagnosed or unreported. We have found important differences between the childhood and adult-onset cases. Of 77 cases of adult-onset recurrent myoglobinuria, 45% have been diagnosed biochemically. In contrast, only 30% of the 60 childhood cases from the literature have been diagnosed; 11 with CPT deficiency and 7 with various glycolytic defects, and only 5 of our 40 childhood cases have been diagnosed, all with CPT deficiency. The 100 combined childhood cases can be divided into an exertional group (type I) with exertion as the leading precipitating factor (46 literature and 10 CPMC cases), a toxic group (type II) with infection and/or fever as the primary precipitant (14 literature and 23 CPMC cases), and 7 undefined cases. The type I group resembles the adult-onset group in which exercise is also the leading precipitating factor. There is a slight female predominance (male/female = 1:1.3) in the toxic group vs. a marked male predominance in the exertional and adult groups (4:1). Only 4 of 37 cases (11%) of the toxic group are diagnosed (all with CPT deficiency) vs. 19 of 56 cases (34%) of the exertional group (12 CPT, 7 glycolytic) and 45% of the adult group. The toxic group is also differentiated by a higher mortality rate and by the presence of additional clinical features, including ictal bulbar signs (8 of 18), encephalopathy (4 of 19), and seizures (2 of 7), as well as persistent cardiac abnormalities, developmental delay (4 of 17), and dysmorphic features (2 of 9). These clinical characteristics clearly differentiate the childhood from the adult cases and suggest the presence of more generalized disease processes and different biochemical etiologies. A study of the heritable causes of myoglobinuria is important because identification of the biochemical defect may elucidate the pathogenetic mechanism of the myoglobinuria and facilitate the development of rational treatment strategies aimed at circumventing or correcting the metabolic block.

Adolescent↗
PubMed1989

Normal muscle CPT1 and CPT2 activities in hepatic presentation patients with CPT1 deficiency in fibroblasts. Tissue specific isoforms of CPT1?

Human carnitine palmitoyltransferase (CPT) deficiency results in 2 clinical forms: a more common "muscular form" with myoglobinuria with or without delayed or impaired ketogenesis and a rare "hepatic form" with hypoketotic hypoglycemia, encephalopathy and seizures without muscular manifestations. We present 2 patients, a male (patient 1) and a female (patient 2) with infantile "hepatic" CPT deficiency and previously documented CPT1 deficiency in fibroblasts. In patient 2, a deficiency of "total" CPT activity in liver had also been previously documented. We set up an isotope exchange assay system that effectively differentiated CPT1 and CPT2 activities in muscle. We found normal CPT1 and CPT2 activities in our patients under near saturating substrate conditions. The CPT1 and CPT2 activities were suppressed to a strikingly similar degree under different kinetic conditions as compared to control muscle and were found to have similar Km values for carnitine and PCoA. With Km concentrations of carnitine, the mean residual activities of CPT1 for patients 1 and 2 were 49 and 44%, respectively (control range 40-53%); the mean residual activities of CPT2 were 60 and 46%, respectively (control range 49-59%). With Km concentrations of PCoA, the mean residual activities of CPT1 for patients 1 and 2 were 52 and 58%, respectively (control range of 52-59%); mean residual activities of CPT2 were 54% and 56%, respectively (control range of 51-68%). When the Vmax concentration of PCoA was doubled and bovine serum albumin reduced to 0.1%, the mean residual activities of CPT1 for patients 1 and 2 were 69 and 63%, respectively (control range 60-80%). In "muscular" patients, a marked absolute deficiency of CPT2 activity (less than 12% residual) was found with an apparent increased sensitivity to suppression of enzymatic activity when the Km concentration of carnitine was used. We suggest that CPT1 and CPT2 may be separate proteins. Furthermore, CPT1 itself may exist as tissue-specific isoforms being the same protein in liver and fibroblasts and a different protein in muscle. Either could be encoded for by the same or closely related genes.

Acyltransferases↗
PubMed1985

Possible valproate teratogenicity.

The teratogenic risk of maternal valproic acid therapy and the prenatal effects on growth and morphogenesis have been difficult to determine, in part, because of the small number of epileptic women who receive valproic acid as the sole anticonvulsant therapy. An increased incidence of open neural tube defects has been suggested and other isolated case reports have noted the presence of certain dysmorphic features. We present a patient whose defects in morphogenesis appear to be associated with valproic acid exposure only, and suggest a clinical phenotype that our patient shares with other children exposed to prenatal valproic acid therapy. Features described previously include dysmorphic facies with hypertelorism, prominent forehead, low flat nasal bridge, low-set or odd-shaped ears, and micrognathia with growth deficiency of prenatal or postnatal onset. A striking and perhaps unique feature in our patient consists of hypoplasia of the lateral margins of the zygomatic arches. We discuss the pharmacokinetics of valproic acid in pregnancy and in the neonatal period.

Abnormalities, Multiple↗