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Objective: Cystinosis causes renal and other organ failure. Treatment with 6-hourly cysteamine bitartrate (Cystagon, Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A recent study showed that an enteric-release cysteamine required less frequent daily dosing. This report describes the long-term use of enteric-coated (EC) cysteamine bitartrate (Cystagon) in children with cystinosis. Study design: After a pharmacokinetic and pharmacodynamic study of EC-cysteamine in children with cystinosis, 5 patients remained on twice-daily treatment. White blood cell cystine levels were measured 12 hours after ingestion every 4 to 8 weeks. These levels were then compared with the patient''s previous 6-h post-dose levels taken while on regular cysteamine bitartrate before entering the study. Blood chemistry was also measured. Results: Five children with cystinosis (mean age, 9 years; range, 8 to 17 years) who previously took cysteamine bitartrate (mean dose, 47 mg/kg body wt), received EC-cysteamine for 10 to 27 months (mean dose, 25 mg/kg body wt) and had mean white blood cell cystine levels of 0.77 and 0.71 nmol half-cystine/mg protein, respectively. During the study period, patients maintained adequate growth and there was no significant deterioration in renal or thyroid function. Two children were required to restart acid suppression after 6 months on EC-cysteamine therapy. Conclusions: Long-term, twice-daily EC-cysteamine, given at approximately 60% of the previous daily dose of cysteamine bitartrate, was effective at maintaining white blood cell cystine levels within a satisfactory range. There was no significant deterioration in renal or thyroid function. [Copyright &y& Elsevier]

Objectives: To test the hypothesis that a controlled-release preparation of cysteamine, with fewer daily administrations, would improve the quality of life for patients with cystinosis. Study design: A specifically designed nasoenteric tube was used to administer cysteamine directly into the stomach, small intestine (SI) and colon and serial plasma cysteamine, serum gastrin and leukocyte cystine levels were measured. Results: Eight control subjects (mean age 23.2 years) and 6 subjects with cystinosis (mean age 15.2 years) were studied. Cysteamine absorption (maximum concentration and area under the curve of the concentration-time gradient) was greater from the SI than stomach or cecum (P < .01). Leukocyte cystine depletion was greater after delivery of cysteamine into the SI than stomach or cecum; this effect was associated with the plasma cysteamine maximum concentration and area under the curve (P < .001 and < .02, respectively). Gastrin levels were not affected by site of drug delivery and were elevated only in patients with cystinosis with gastrointestinal symptoms. Conclusions: The absorption of cysteamine and the effect of this agent on leukocyte cystine depletion are more profound after SI administration. Enteric-coated cysteamine, targeted for SI release, may require fewer daily dosages. Not all patients with cystinosis require acid-suppression therapy. [Copyright &y& Elsevier]

Abstract: In order to examine correlations which might be useful in ascertaining or confirming the diagnosis of mitochondrial disease, a retrospective analysis of urine organic acids was performed. Among 3646 analyses from randomly selected samples referred to our laboratory, there were 258 specimens from 67 patients with various known disorders of mitochondrial oxidative function, most of whom were known to have chronic and persistent elevations of blood lactic acid, and 176 samples from 21 patients with diagnosed organic acidemia. Urine lactate was not a useful discriminator; only 7.6% of results from infants with mitochondrial disease fell the 95th percentile for patients without mitochondrial disease. Most of the Krebs cycle intermediates were also not useful in discriminating patients with mitochondrial disorders. Interestingly, there was strikingly poor correlation among most of those analytes in all patient groups, but fumarate and malate were uniquely well correlated (r2=0.840). Fumarate and malate were also the most useful in distinguishing patients with mitochondrial disease and organic acidemia from the pool of unselected or undiagnosed patients, although the utility was somewhat limited. Using a cutoff value of approximately 90 mmol/mol creatinine for fumarate or malate at age <1 year, or a cutoff of approximately 25 for older patients, 25ndash;30% of mitochondrial disease patients can be distinguished with a 5% false positive rate. Further refinements to this approach may better characterize the metabolomic profile and may improve the diagnostic utility of quantitative organic acid analysis in mitochondrial disease. [Copyright &y& Elsevier]

Hereditary fructose intolerance (HFI) caused by fructose aldolase B deficiency results in hepatic dysfunction unless managed with severely restricted dietary intake of fructose and sucrose. The potential of FOS to provide a fructose load in compromised individuals has not been determined. The purpose of this study was to evaluate the safety and tolerance of FOS among subjects with established diagnoses of HFI. Five subjects with HFI (ages 14-52 yrs; 4 male, 1 female) participated in a prospective, non-randomized open challenge with FOS at 6 g/m2/d for 2 days. A female infant (5 mos) with resolved neonatal hepatitis was also studied. Diet records were maintained for the 48-hr period and analyzed for dietary fructose. Tolerance was assessed through evaluation of serum AST, ALT, GGT, glucose, bilirubin, uric acid, phosphorus, and electrolytes, upon initiation and at 12-hr intervals during the challenge. Blood chemistry values were within normal ranges and did not change appreciably during the study period, except for two patients with slight elevations of uric acid. One subject reported gastric discomfort on day 2 of the FOS challenge. These data suggest that FOS providing approximately 4.7 mg fructose/kg bw/d for 2 days is safe and well tolerated among individuals with diagnosed HFI. [Copyright &y& Elsevier]

: ObjectiveTo investigate the effects of estrogen (E) and psychological stress on plasma total homocysteine levels in relation to menopausal status.: DesignDouble-blind, randomized, placebo-controlled study.: SettingThe General Clinical Research Center of a university hospital.: Patient(s)Thirty-six postmenopausal women and 26 premenopausal women. Both samples were healthy nonsmokers.: Intervention(s)Both premenopausal and postmenopausal women were subjected to a 6-minute psychological stressor. Postmenopausal women were randomized to one of three treatment arms: 2 mg of E2 or 2 mg of E2 + 5 mg of medroxyprogesterone acetate (MPA), or a placebo, all of which were given orally for 3 months. The psychological stressor was readministered after the 3-month regimen.: Main outcome measure(s)Plasma total homocysteine levels were measured before and after the psychological stressor on one occasion for premenopausal women and before and after hormone replacement or placebo for postmenopausal women.: Result(s)There were no significant differences in homocysteine levels between premenopausal (7.2 ± 1.7 μmol/L; mean ± SD) and postmenopausal women (7.9 ± 2.06; mean ± SD). There was no effect of stress or hormone replacement on homocysteine levels.: Conclusion(s)Psychological stress, menopausal status, and oral hormone replacement therapy (HRT) do not affect plasma total homocysteine levels in women with normal basal homocysteine levels. [Copyright &y& Elsevier]

Objective: Cystinosis causes renal and other organ failure. Regular 6-hourly cysteamine bitartrate (Cystagon; Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A formulation of cysteamine requiring less frequent dosing may improve compliance and possibly patient outcome. Methods: Enteric-release cysteamine was prepared. For a period of 1 month, patients received their regular cysteamine dose every 6 hours (stage I). The patients then underwent pharmacokinetic and pharmacodynamic studies following washout periods using single-doses of cysteamine and enteric-release cysteamine (stage II). Finally, the patients commenced regular enteric-release cysteamine therapy (stage III). Weekly trough white blood cell (WBC) cystine levels were recorded. Results: Seven children with cystinosis (mean age, 11.8 years; range, 8-17 years) who received cysteamine and enteric-release cysteamine (mean dose, 45 and 28.8 mg/kg body weight/day, respectively) had mean WBC cystine levels of 0.7±0.3 and 0.41±0.22 nmol half-cystine/mg protein in study stages I and III, respectively. Study stage II showed that the mean time (Tmax) to reach the maximum plasma cysteamine level (Cmax) was longer for enteric-release cysteamine than for cysteamine (176 minutes vs 60 minutes; P =.001), but the mean Cmax at the same dose was similar. Mean serum gastrin levels were similar after ingestion of cysteamine and enteric-release cysteamine. Conclusions: Twelve-hour enteric-release cysteamine, given at approximately 60% of the previous daily dose of cysteamine, was effective in maintaining trough WBC cystine levels within a satisfactory range. [Copyright &y& Elsevier]

Abstract: The major coenzyme Q species in humans is the decaprenyl quinoid derivative coenzyme Q10 (CoQ10), and its measurement is somewhat challenging owing to its hydrophobicity and tendency to be oxidized. There are three major methods which are suited for analysis of CoQ10: HPLC-coupled UV or electrochemical detection, and tandem mass spectrometry. The techniques are discussed, and results of these applications to determine CoQ10 concentrations in various human fluids and tissues are summarized. [Copyright &y& Elsevier]

: PurposeTo evaluate total plasma homocysteine (tHcy) levels in patients diagnosed with primary open-angle glaucoma (POAG) and normal subjects.: DesignCase-control study.: MethodsThis study involved 55 POAG patients, 16 patients with secondary open-angle glaucoma or angle-closure glaucoma (non-POAG group), and 39 control healthy subjects undergoing ocular surgery. All glaucoma patients had characteristic glaucomatous optic disk damage and visual field loss. Fasting tHcy concentrations of all study participants were determined using high-performance liquid chromatography. Analysis of variance was used to compare homocysteine levels among the three diagnostic groups, and multivariate analysis was conducted to assess the associations between tHcy and diagnostic group, age, gender, smoking status, systemic hypertension, hyperlipidemia, and cardiovascular or cerebrovascular disease.: ResultsMean ± standard deviation of tHcy levels in POAG individuals, non-POAG patients and control subjects was 14.90 ± 6.45 μmol/l, 14.30 ± 4.35 μmol/l, and 14.81 ± 4.56 μmol/l, respectively (P = .93; ANOVA). No statistically significant difference was found in the proportion of patients with abnormal tHcy levels among the three diagnostic groups. In multivariate analysis, only age and positive smoking status were significantly correlated with total plasma homocysteine levels.: ConclusionNo significant difference was found in plasma homocysteine levels among POAG patients and normal control individuals. [Copyright &y& Elsevier]

We report that recessive inheritance of a post-GPI attachment to proteins 2 (PGAP2) gene variant results in the hyperphosphatasia with neurologic deficit (HPMRS) phenotype described by Mabry et al., in 1970. HPMRS, or Mabry syndrome, is now known to be one of 21 inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs), or GPI biosynthesis defects (GPIBDs). Bi-allelic mutations in at least six genes result in HPMRS phenotypes. Disruption of four phosphatidylinositol glycan (PIG) biosynthesis genes, PIGV , PIGO , PIGW and PIGY , expressed in the endoplasmic reticulum, result in HPMRS 1, 2, 5 and 6; disruption of the PGAP2 and PGAP3 genes, necessary for stabilizing the association of GPI anchored proteins (AP) with the Golgi membrane, result in HPMRS 3 and 4. We used exome sequencing to identify a novel homozygous missense PGAP2 variant NM_014489.3:c.881C > T, p.Thr294Met in two index patients and targeted sequencing to identify this variant in an unrelated patient. Rescue assays were conducted in two PGAP2 deficient cell lines, PGAP2 KO cells generated by CRISPR/Cas9 and PGAP2 deficient CHO cells, in order to examine the pathogenicity of the PGAP2 variant. First, we used the CHO rescue assay to establish that the wild type PGAP2 isoform 1, translated from transcript 1, is less active than the wild type PGAP2 isoform 8, translated from transcript 12 (alternatively spliced to omit exon 3). As a result, in our variant rescue assays, we used the more active NM_001256240.2:c.698C > T, p.Thr233Met isoform 8 instead of NM_014489.3:c.881C > T, p.Thr294Met isoform 1. Flow cytometric analysis showed that restoration of cell surface CD59 and CD55 with variant PGAP2 isoform 8, driven by the weak (pTA FLAG) promoter, was less efficient than wild type isoform 8. Therefore, we conclude that recessive inheritance of c.881C > T PGAP2 , expressed as the hypomorphic PGAP2 c.698C > T, p.Thr233Met isoform 8, results in prototypical Mabry phenotype, HPMRS3 (GPIBD 8 [MIM: 614207]). This study highlights the need for long-term follow up of individuals with rare diseases in order to ensure that they benefit from innovations in diagnosis and treatment. [ABSTRACT FROM AUTHOR]

The ‘classical’ organic anion secretory pathway of the renal proximal tubule is critical for the renal excretion of the prototypic organic anion, para-aminohippurate, as well as of a large number of commonly prescribed drugs among other significant substrates. Organic anion transporter 1 (OAT1), originally identified as NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J. G., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471–6478), has physiological properties consistent with a role in this pathway. However, several other transporters (e.g. OAT2, OAT3, and MRP1) have also been proposed as important PAH transporters on the basis of in vitro studies; therefore, the relative contribution of OAT1 has remained unclear. We have now generated a colony of OAT1 knockout mice, permitting elucidation of the role of OAT1 in the context of these other potentially functionally redundant transporters. We find that the knock-out mice manifest a profound loss of organic anion transport (e.g. para-aminohippurate) both ex vivo (in isolated renal slices) as well as in vivo (as indicated by loss of renal secretion). In the case of the organic anion, furosemide, loss of renal secretion in the knock-out results in impaired diuretic responsiveness to this drug. These results indicate a critical role for OAT1 in the functioning of the classical pathway. In addition, we have determined the levels of ∼60 endogenous organic anions in the plasma and urine of wild-type and knock-out mice. This has led to identification of several compounds with significantly higher plasma concentrations and/or lower urinary concentrations in knock-out mice, suggesting the involvement of OAT1 in their renal secretion. We have also demonstrated in xenopus oocytes that some of these compounds interact with OAT1 in vitro. Thus, these latter compounds might represent physiological substrates of OAT1. [ABSTRACT FROM AUTHOR]