Mild fumarase deficiency and a trial of low protein diet.

We report clinical findings in a 12-year-old girl with a mild case of fumarase deficiency who continues to make progress. She has two novel mutations of the fumarase gene [c.521C>G (p.P174R) and c.908T>C (p.L303S)]. A trial of low protein diet did not reduce fumaric aciduria.

Mindfulness-Based Cognitive Therapy for Late-Life Depression: a Randomised Controlled Trial.

BACKGROUND: Rumination and overgeneral autobiographical memory are dysfunctional cognitions commonly found in older adults with depression. The theoretical underpinnings of mindfulness-based cognitive therapy (MBCT) address the ruminative tendencies and the non-specific retrieval of autobiographical memories. This study aims to examine the efficacy and cognitive mechanisms of MBCT in older adults with active depressive symptoms. METHODS: 57 older adults (mean age, 70 years) with normal cognition and mild to moderate depressive symptoms were randomly allocated to either the MBCT group or the active control group for 8 weeks. The MBCT group consisted of eight 2-hour weekly sessions and a 7-hour full-day retreat, with different themes for each class, guided mindfulness exercises, feedback and discussion, homework review, and psychoeducation. The active control group comprised a 1-hour physical exercise and a standardised health education of the specific theme with group discussion (eg fall prevention, chronic pain). Participants were assessed before and after the 8-week intervention for four outcome measures: the Hamilton Depression Rating Scale (HAMD), the Ruminative Response Scale (RRS), the Autobiographical Memory Test (AMT), and the Mindful Attention Awareness Scale (MAAS). RESULTS: There was a significant reduction in severity of depressive symptoms (HAMD score) in both the MBCT group (F(1, 27) = 35.9, p < 0.001, η2 = 0.57) and the active control group (F(1, 28) = 9.29, p < 0.01, η2 = 0.24), but only the MBCT group showed substantial improvements in autobiographical memory specificity (AMT score), rumination (RRS score), and mindfulness (MAAS score). CONCLUSION: Although both MBCT and active control programme decrease the severity of depressive symptoms in older adults, only MBCT improves AMS, rumination, and mindfulness. Our findings provide empirical support for the theoretical underpinnings of MBCT. Older adults with more severe depression and more severe dysfunctional cognition may benefit more from the specific therapeutic effects of MBCT.

Complementary and alternative medicine (CAM) usage in Singaporean adult cancer patients.

BACKGROUND: In multiracial and multicultural Singapore, patients are exposed to complementary and alternative medicine (CAM) from both eastern and western cultures. Although studies have shown that CAM usage is highly prevalent among cancer patients, no study on the prevalence of CAM in Singaporean adult cancer patients had been published. PATIENTS AND METHODS: 403 adult cancer patients treated at the Ambulatory Treatment Unit of National Cancer Centre Singapore completed an interviewer-administered questionnaire. RESULTS: Median age of patients was 56 years old (range 22-84). Fifty-six percent of patients reported CAM usage and the most commonly used CAM include Traditional Chinese Medicine, bird's nest and special diet. CAM use was found to be associated with race, education level and prior CAM use before cancer diagnosis. Fifty-four percent of respondents informed their oncologists regarding CAM usage and 66.4% of oncologists were agreeable for CAM usage. However, most patients (63%) did not verify information on CAM before usage and a majority of patients taking CAM felt it was effective. CONCLUSION: Majority of adult cancer patients used CAM and it is important for health-care professionals to keep abreast of research on CAM, to actively illicit information regarding usage and to provide appropriate advice and counseling.

Argininosuccinate lyase deficiency: longterm outcome of 13 patients detected by newborn screening.

Argininosuccinate lyase deficiency is a urea cycle disorder which can present in the neonatal period with hyperammonemic encephalopathy, or later in childhood with episodic vomiting, growth and developmental delay. Abnormal hair, hepatomegaly, and hepatic fibrosis are unique features of this disorder. Twelve patients with argininosuccinate lyase deficiency were ascertained between 4 and 6 weeks of age by urine amino acid screening. One infant in a previously identified family was diagnosed shortly after birth. Diagnosis was confirmed by enzyme assay in red blood cells and/or skin fibroblasts. At the time of last follow-up, patients had been followed for 13-33 years. All patients were asymptomatic at detection, 7 had slightly increased blood ammonia, and all were initially treated with low-protein diet. Utilization of (14)C-citrulline by intact skin fibroblasts measured by (14)C incorporation into macromolecules was 74-135% of the control mean for 7 of the 8 patients studied. Nine patients had normal development, 4 had learning disability, 6 had EEG abnormalities, 3 had seizure disorder. None had any episodes of hyperammonemic coma. None had hepatomegaly. Patients detected by screening had higher enzyme activity measured by the (14)C-citrulline incorporation assay than comparison groups of patients with neonatal-onset and with late-onset detected by clinical disease. The ability to utilize (14)C-citrulline by intact fibroblasts seems to correlate with clinical outcome and may have prognostic value. It is likely that early diagnosis and treatment contributed to the relatively mild clinical course of the study group.

Isovaleric and -methylbutyric acidemias induced by hypoglycin A: mechanism of Jamaican vomiting sickness.

Hypoglycin A, the causative agent of the Jamaican vomiting sickness, produced a marked increase in concentration of isovaleric acid in the plasma of rats, when administered in a single dose. alpha-Methylbutyric acid, a position isomer, also accumulated. The use of hypoglycin A reproduced some features of human isovaleric acidemia. Accumulation of these branched pentanoic acids may be another factor contributing to the pathogenesis of the Jamaican vomiting sickness.

Metabolism of [1-(14)C] and [2-(14)C] leucine in cultured skin fibroblasts from patients with isovaleric acidemia. Characterization of metabolic defects.

Leucine metabolism in cultured skin fibroblasts from patients with isovaleric acidemia was compared with that in normal fibroblasts and in cells from patients with maple syrup urine disease using [1-(14)C] and [2-(14)C] leucine as substrates. Inhibitory effects of methylenecyclopropylacetic acid on leucine metabolism in normal cells were also investigated. Production of 14CO2 from [2-(14)C] leucine was very reduced (96-99%) in both types of mutant cells. Radioactive isovaleric acid accumulated in assay media with isovaleric acidemia cells but not in those with maple syrup urine disease cells. Unexpectedly, 14CO2 production from [1-(14)C] leucine was partially depressed (80%) in isovaleric acidemia cells whereas in maple syrup urine disease cells it was strongly depressed (99%) as expected. These two mutant cells were clearly distinguished by detection of 14C-isovaleric acid accumulation after incubation with [2-(14)C] leucine. A pattern of inhibition of leucine oxidation similar to that seen in isovaleric acidemia cells was induced in normal cells by the addition of 0.7 mM methylenecyclopropylacetic acid to the assay medium. The partial inhibition of [1-(14)C] leucine oxidation seen in isovaleric acidemia cells and also in normal cells in the presence of the inhibitor appears to be, at least in part, due to an accumulation of isovalerate in the cells. Isovaleric acid (5-10) mM) inhibited [1-(14)C] leucine oxidation 32-68% when added to the assay medium with normal cells. Addition of flavin adenine dinucleoside to culture medium or assay medium or both did not restore oxidation of either leucine substrate in isovaleric acidemia cells.

Molybdenum cofactor biosynthesis in humans. Identification of two complementation groups of cofactor-deficient patients and preliminary characterization of a diffusible molybdopterin precursor.

Molybdenum cofactor deficiency is a devastating disease with affected patients displaying the symptoms of a combined deficiency of sulfite oxidase and xanthine dehydrogenase. Because of the extreme lability of the isolated, functional molybdenum cofactor, direct cofactor replacement therapy is not feasible, and a search for stable biosynthetic intermediates was undertaken. From studies of cocultured fibroblasts from affected individuals, two complementation groups were identified. Coculture of group A and group B cells, without heterokaryon formation, led to the appearance of active sulfite oxidase. Use of conditioned media indicated that a relatively stable, diffusible precursor produced by group B cells could be used to repair sulfite oxidase in group A recipient cells. Although the extremely low levels of precursor produced by group B cells preclude its direct characterization, studies with a heterologous, in vitro reconstitution system suggest that the precursor that accumulates in group B cells is the same as a molybdopterin precursor identified in the Neurospora crassa molybdopterin mutant nit-1, and that a converting enzyme is present in group A cells which catalyzes an activation reaction analogous to that of a converting enzyme identified in the Escherichia coli molybdopterin mutant ChlA1.

Short-chain acyl-coenzyme A dehydrogenase deficiency. Clinical and biochemical studies in two patients.

We describe two patients with short-chain acyl-coenzyme A (CoA) dehydrogenase (SCADH) deficiency. Neonate I excreted large amounts of ethylmalonate and methylsuccinate; ethylmalonate excretion increased after a medium-chain triglyceride load. Neonate II died postnatally and excreted ethylmalonate, butyrate, 3-hydroxybutyrate, adipate, and lactate. Both neonates' fibroblasts catabolized [1-14C]butyrate poorly (29-64% of control). Neonate I had moderately decreased [1-14C]octanoate catabolism (43-60% of control), while neonate II oxidized this substrate normally; both catabolized radiolabeled palmitate, succinate, and/or leucine normally. Cell sonicates from neonates I and II dehydrogenated [2,3-3H]butyryl-CoA poorly (41 and 53% of control) and [2,3-3H]octanoyl-CoA more effectively (59 and 95% of control). Mitochondrial acyl-CoA dehydrogenase (ADH) activities with butyryl- and octanoyl-CoAs were 37 and 56% of control in neonate I, and 47 and 81% of control in neonate II, respectively. Monospecific medium-chain ADH (MCADH) antisera inhibited MCADH activity towards both butyryl- and octanoyl-CoAs, revealing SCADH activities to be 1 and 11% of control for neonates I and II, respectively. Fibroblast SCADH and MCADH activities were normal in an adult female with muscular SCADH deficiency.

Type II hyperprolinemia. Delta1-pyrroline-5-carboxylic acid dehydrogenase deficiency in cultured skin fibroblasts and circulating lymphocytes.

Type II hyperprolinemia is an inherited abnormality in amino acid metabolism characterized by elevated plasma proline concentrations, iminoglycinuria, and the urinary excretion of delta1-pyrroline compounds. To define the enzymologic defect of this biochemical disorder, we developed a specific, sensitive radioisotopic assay for the proline degradative enzyme delta1-pyrroline-5-carboxylic acid dehydrogenase. Using this assay, we have shown an absence of delta1-pyrroline-5-carboxylic acid dehydrogenase activity in the cultured fibroblasts from three patients with type II hyperprolinemia. We confirmed this result on cultured cells by demonstrating a similar absence of delta1-pyrroline-5-carboxylic acid dehydrogenase activity in extracts prepared from the peripheral leukocytes of these patients. Additionally, we found significantly decreased levels of delta1-pyrroline-5-carboxylic acid dehydrogenase activity in the leukocyte extracts from five obligate heterozygotes for type II hyperprolinemia. We also demonstrated a reduction in leukocyte delta1-pyrroline-5-carboxylic acid dehydrogenase activity in three successive generations of a family. These results prove that an absence of delta1-pyrroline-5-carboxylic acid dehydrogenase is the enzymologic defect in type II hyperprolinemia and that this defect is inherited in an autosomal recessive fashion.

Hereditary pancreatitis. Nonspecificity of aminoaciduria and diagnosis of occult disease.

Hereditary pancreatitis appears in many different ways and in a variety of age groups, spanning both pediatric and adult medicine. The variable expression of hereditary pancreatitis is emphasized by the difficulty in diagnosing it in a patient obviously at risk because of a severely affected father and son. The morphine prostigmine test and hypotonic duodenogram were most helpful. Aminoaciduria previously associated with this disorder is coincidental or nonspecifically related to acute pancreatic inflammation. The increased risk for pancreatic carcinoma (about 20%) is emphasized by the concern for that complication in the proband's grandfather.

Inflammation, homocysteine, and vitamin B6 status after ischemic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies have described an association between low vitamin B6 (measured as pyridoxal 5'-phosphate [PLP]) and ischemic stroke, independent of homocysteine (tHcy). We investigated B6 status, tHcy, and inflammation (measured by C-reactive protein [CRP]) in patients with stroke and controls. METHODS: Consecutive cases with new ischemic stroke were compared with matched controls. Fasting tHcy, PLP, and CRP were measured. RESULTS: The adjusted odds ratio of low PLP in the highest compared with the lowest CRP quartile was 16.6 (2, 139.9, P=0.01). Age, CRP, supplemental vitamin use, and albumin were independent predictors of PLP (P<0.05 for all). No relationship was observed between CRP and tHcy. CONCLUSIONS: The relationship between inflammation and low B6 status may partially explain the findings of previous epidemiological studies.

Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.

A 39-year-old man and his 42-year-old sister, both vegetarians, had episodic confusion for many years, but their mental function was normal between those episodes. They were recently diagnosed with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. Hyperammonemia was documented during an episode of confusion in the male sibling but not in his sister. Both had elevated plasma ornithine, glutamine, and alanine levels and persistently low plasma lysine levels. Homocitrulline was present in their urine, and orotic aciduria and orotidinuria developed in the male sibling following ingestion of allopurinol. Studies on their cultured skin fibroblasts showed deficient metabolism of ornithine, indicating a defect in ornithine transport across the mitochondrial membrane. During therapy with citrulline and phenylbutyrate sodium, plasma ornithine levels increased in both patients, while plasma levels of glutamine and alanine decreased to normal. Since therapy started, their clinical conditions have also improved, and no recurrent neurologic dysfunction has occurred during a follow-up period of 20 months.

An antispasticity effect of threonine in multiple sclerosis.

To determine whether the naturally occurring amino acid threonine, a potential precursor for glycine biosynthesis in the spinal cord, has an effect on spasticity in multiple sclerosis, 26 ambulatory patients were entered into a randomized crossover trial. Threonine administered at a total daily dose of 7.5 g reduced signs of spasticity on clinical examination, although no symptomatic improvement could be detected by the examining physician or the patient. In contrast to the side effects of sedation and increased motor weakness associated with antispasticity drugs commonly used for the treatment of multiple sclerosis, no side effects or toxic effects of threonine were identified. Levels of threonine were elevated in serum and cerebrospinal fluid during treatment, but glycine levels did not change. Enhancement by threonine of glycinergic postsynaptic inhibition of the motor reflex arc in the spinal cord may represent a non-sedating, nontoxic approach to the management of spasticity in multiple sclerosis.

Glutaric acidemia: a metabolic disorder causing progressive choreoathetosis.

A boy with glutaric acidemia had psychomotor retardation first noted at age 6 months, recurrent metabolic acidosis, and a progressive quadriparesis with choreoathetosis. He died at age 3 1/2 years. Cultured skin fibroblasts lacked glutaryl-CoA dehydrogenase activity. There was a biochemical, but not a clinical, response to dietary restriction of lysine and tryptophan. The caudate and putamen of the brain showed severe loss of nerve cells and fibers with proliferation of astrocytes, as well as markedly reduced gamma-aminobutyric acid and glutamate decarboxylase activity.

Homocysteine, MTHFR 677C-->T polymorphism, and risk of ischemic stroke: results of a meta-analysis.

BACKGROUND: Data are conflicting concerning risk for ischemic stroke associated with hyperhomocyst(e)inemia (hyper-Hcy) and a common polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR 677C-->T), which predisposes to hyper-Hcy in vivo. METHODS: Search of MEDLINE, Science Citation Index, and abstracts of conference proceedings revealed relevant articles. Exposure was defined as follows: 1) prevalence of hyper-Hcy; 2) absolute difference in the mean Hcy concentration between subjects with and without ischemic stroke; and 3) the MTHFR TT genotype frequency. Outcome was defined as ischemic stroke with or without neuroimaging. Inclusion criteria were retrospective and prospective studies with reported odds ratios (OR) or hazard ratios (HR) or arithmetic mean Hcy levels. Exclusion criteria were absence of OR or HR, outcome defined as carotid atherosclerosis or intima-media thickening, stroke in patients younger than 18 years old, and studies in languages other than English. Statistical analyses for between-study heterogeneity and pooled risk estimates were performed using Stata software (Stata Corporation, College Station, TX). RESULTS: Among 16 studies (1,487 stroke and 2,554 nonstroke cases), the pooled mean Hcy level in patients with ischemic stoke was 2.32 micromol/L (95% CI, 1.6 to 3.04; p < 0.001) greater than that in those without ischemic stroke. Among 14 included studies (1,769 stroke and 7,400 nonstroke cases), the pooled OR estimate of ischemic stroke associated with hyper-Hcy was 1.79 (95% CI, 1.61 to 2.0; p < 0.001). Among 19 included studies (2,788 stroke and 3,962 nonstroke cases), the OR associated with the TT genotype was 1.23 (95% CI, 0.96 to 1.58; p = 0.1). CONCLUSION: These data support an association between mild-to-moderate hyper-Hcy and ischemic stoke. The MTHFR TT genotype may have a small influence in determining susceptibility to ischemic stoke.

Vascular endothelial function in cyclosporine and tacrolimus treated renal transplant recipients.

BACKGROUND: Endothelial dysfunction is an early key event in the development of arteriosclerotic cardiovascular disease (ASCVD), thus an early marker of subclinical ASCVD. Endothelial function is impaired in renal transplant recipients (RTR) treated with cyclosporine (CyA). Tacrolimus is associated with less hyperlipidemia and hypertension than CyA, however, there are no data on endothelial function in tacrolimus-treated RTR. METHODS: High-resolution brachial ultrasonography was used to assess endothelium-dependent dilatation (EDD), and endothelium-independent dilatation (EID) in 20 stable RTR and a control group of 10 healthy subjects without clinical evidence of ASCVD. The RTR group included patients receiving CyA (n=10) and tacrolimus (n=10). EDD and EID were measured as percent increase in brachial artery diameter in response to reactive hyperemia and nitroglycerin, respectively. RESULTS AND CONCLUSIONS: EDD was significantly lower in RTR versus controls (1.7+/-0.7 vs. 7.3+/-0.7%, P<0.0001), whereas EID was similar in the two groups. No significant differences were found in EDD or in EID between CyA- and tacrolimus-treated RTR. Glomerular filtration rate, plasma homocysteine, blood pressure, and lipid profiles were similar in CyA- and tacrolimus-treated RTR.

Massachusetts Metabolic Disorders Screening Program. II. Methylmalonic aciduria.

Screening neonates for methylmalonic aciduria is part of routine screening for metabolic disorders in Massachusetts. The process of urine collection by the parent and transmitted to the central screening laboratory was described in a previous publication (Pediatrics 49: 825, 1972). The primary objective of screening for methylmalonic aciduria is to detect methylmalonic acidemia, an inherited organic acid disorder. During the most recent 5 1/2-year period when the sensitive fast blue B stain was used in the analysis, four infants with methylmalonic acidemia were detected among 293,535 screened. Additional infants and children who came to attention because of clinical illness or family study also could be readily detected. Prior to this period, 325,634 neonates had been screened with the aniline-xylose method, which proved to be not sensitive enough for the identification of methylmalonic aciduria. Some affected infants have responded well to therapy and are clinically normal while two have shown poor biochemical response and are developmentally delayed. Four children in two families appear to have a benign variant of methylmalonic acidemia. Based on these studies the observed incidence of methylmalonic acidemia in Massachusetts is 1:48,000. Screening for methylmalonic aciduria may be an appropriate addition to newborn screening programs.

Dietary management reverses grooving and abnormal polarization of hair shafts in argininosuccinase deficiency.

We have observed that the fragile hair of two untreated patients with argininosuccinic aciduria showed abnormal alternating zones of bright and dark banding by polarizing microscopy. Scanning electron microscopy documented discontinuous grooves with a 50 to 100 microns periodicity. Results of amino acid analysis of the hair were essentially normal. After the patients were treated with a low-protein, arginine-supplemented diet, the hair assumed a normal appearance. Five patients already treated with diet showed no hair abnormalities. The pathogenesis of the hair changes in unknown, but our findings suggest that products generated in the disease can adversely affect metabolically active tissue such as hair.

Defective lysosomal release of vitamin B12 (cb1F): a hereditary cobalamin metabolic disorder associated with sudden death.

Here we report on a girl who presented with failure to thrive, developmental delay, minor facial anomalies, stomatitis, skin rashes, macrocytosis, mild homocystinemia(uria), and methylmalonic acidemia(uria). Fibroblast studies showed abnormal intracellular cobalamin (vitamin B12) metabolism. Reduced incorporation of 14C from [14C] propionate and [14C] methyltetrahydrofolate into TCA-precipitable macromolecules reflected decreased synthesis of adenosylcobalamin and methylcobalamin respectively. The diagnosis of cb1F mutation was established by demonstrating the accumulation of unmetabolized free cyanocobalamin in fibroblasts and by lack of genetic complementation with fibroblasts from the only other known cb1F patient. The defect is in the lysosomal release of endocytosed cobalamin. Administration of hydroxocobalamin resulted in clinical and biochemical improvement but sudden death occurred at age 5 months. The absence of brain pathological changes suggests that early treatment may prevent the neurological complications in cobalamin cofactor deficiency.

Central respiratory effects of glutamine synthesis inhibition in dogs.

Glutamic acid is an excitatory neurotransmitter that may have a significant role in the central chemical drive of ventilation. Therefore cardiorespiratory function was measured in pentobarbital sodium-anesthetized dogs before and after central inhibition of glutamate metabolism by means of methionine sulfoximine (MSO), a specific inhibitor of glutamine synthase (GS) catalyzing amidation of glutamate to glutamine. GS was inhibited centrally by perfusing the ventriculocisternal space with artificial cerebrospinal fluid (CSF) containing 92.5 mmol MSO per liter at a fixed pH, perfusion rate, and pressure. After GS inhibition, CSF transfer rate of [13N]glutamine synthesized from 13NH4+ amidation of glutamate was reduced five-fold, and minute ventilation increased from 2.90 +/- 0.41 (SE) l/min (0.164 +/- 0.020 l.min-1.kg body wt-1) to 4.46 +/- 0.52 l/min (0.254 +/- 0.029 l.min-1.kg body wt-1). This increase in ventilation with endogenous glutamate and the increase in ventilation previously observed during ventriculocisternal perfusion of exogenous glutamate are compared quantitatively via a model of central neurotransmitter glutamate chemoreception. The results support the hypothesis that the endogenous brain glutamate is important in the central chemical drive of ventilation.