PREPL deficiency causes neonatal hypotonia, ptosis, neonatal feeding difficulties, childhood obesity, xerostomia, and growth hormone deficiency. Different recessive contiguous gene deletion syndromes ...involving PREPL and a variable combination of SLC3A1 (hypotonia–cystinuria syndrome), CAMKMT (atypical hypotonia–cystinuria syndrome), and PPM1B (2p21 deletion syndrome) have been described. In isolated PREPL deficiency, previously described only once, the absence of cystinuria complicates the diagnosis. Therefore, we developed a PREPL blood assay and further delineated the phenotype.
Clinical features of new subjects with PREPL deficiency were recorded. The presence of PREPL in lymphocytes and its reactivity with an activity-based probe were evaluated by western blot.
Five subjects with isolated PREPL deficiency, three with hypotonia-cystinuria syndrome, and two with atypical hypotonia-cystinuria syndrome had nine novel alleles. Their IQs ranged from 64 to 112. Adult neuromuscular signs included ptosis, nasal dysarthria, facial weakness, and variable proximal and neck flexor weakness. Autonomic features are prevalent. PREPL protein and reactivity were absent in lymphocytes from subjects with PREPL deficiency, but normal in the clinically similar Prader–Willi syndrome.
PREPL deficiency causes neuromuscular, autonomic, cognitive, endocrine, and dysmorphic clinical features. PREPL is not deficient in Prader–Willi syndrome. The novel blood test should facilitate the confirmation of PREPL deficiency.
Sickle cell disease (SCD) is an inherited autosomal recessive hemoglobin disorder caused by the presence of hemoglobin S, a mutant abnormal hemoglobin caused by a nucleotide change in codon 6 of the ...β-globin chain gene. SCD involves a chronic inflammatory state, exacerbated during vaso-occlusive crises, which leads to end-organ damage that occurs throughout the lifespan. SCD is associated with premature mortality in the first years of life. The process of sickling provokes asplenia in the first years of life with an increased risk of infection by encapsulated germs. These complications can be life-threatening and require early diagnosis and management. The most important interventions recommend an early diagnosis of SCD to ensure that affected newborns receive immediate care to reduce mortality and morbidity. The newborn screening program in the region of Murcia for SCD began in March 2016. We aimed to determine the incidence of sickle cell anemia and other structural hemoglobinopathies in the neonatal population of the region of Murcia, an area of high migratory stress, and to systematically assess the benefit of newborn screening for SCD, leading to earlier treatment, as well as to offer genetic counseling to all carriers. The prevalence of SCD in our region is similar to others in Spain, except for Catalonia and Madrid. The newborns with confirmed diagnoses of SCD received early attention, and all the carriers received genetic counseling.
Background
Cystinuria is an inherited metabolic disease involving the defective transport of cystine and the dibasic amino acids in the renal proximal tubules that causes the formation of stones in ...the urinary system. In our regional child health program, cystinuria is included in newborn metabolic screening. Our objectives are the phenotypic characterization of our cystinuric pediatric cohort and to present our experience in neonatal cystinuria screening.
Methods
The study of clinical cases of pediatric patients diagnosed with cystinuria over a period of 32 years. All patients were studied at demographic, clinical, laboratory, radiological, and therapeutic levels.
Results
We diagnosed 86 pediatric patients with cystinuria; 36% of them had the homozygous biochemical phenotype. 95.3% of the patients were detected by neonatal metabolic screening. We performed urine biochemical analyses of parents with additional diagnoses of 63 adult patients. The mean follow-up time was 16.8 ± 8.5 years. 11.6% of patients developed one or more episodes of urinary tract infection during that period. Chronic kidney disease, proteinuria, and hypertension were uncommon (1.2%). 10.5% developed kidney stones at the mean age of presentation of 7.78 ± 7.6 years; 33% were recurrent. The risk of developing lithiasis was higher for homozygous biochemical-phenotype patients. Hypercalciuria was a significant risk factor in the development of lithiasis.
Conclusions
Our clinical data suggest that diagnosing cystinuria through neonatal screening could be a useful strategy for the detection of presymptomatic cases, in order to establish preventive measures, as well as for the detection of relatives at risk.
Graphical abstract
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Supplementary information
The early detection of inborn errors of metabolism by mass spectrometry allows expanding the traditional neonatal screening of phenylketonuria and congenital hypothyroidism to test for ...aminoacidopathies, fatty acid oxidation disorders and organic acid metabolic disorders. Cystic fibrosis and biotinidase deficiency screening is implemented in the Region of Murcia. The aim of the study is to describe our experience in the expanded neonatal screening and to define the prevalence of each of the metabolic disorders early detected.
Since March 2007 until October 2010, a total of 71,595 neonates were screened with this expanded program by mass spectrometry, fluoroimmunoassay or colorimetric methods.
Thirty-eight patients (prevalence 1:1,884) were diagnosed of inborn errors of metabolism by mass spectrometry, 13 patients of cystic fibrosis (prevalence 1:5,507), 38 of congenital hypothyroidism (prevalence 1:1,884) and one of biotinidase deficiency. To date, the global frequency of inborn errors of metabolism is estimated to be 1:804. The positive predictive value for the results obtained by mass spectrometry was 20.25%. Two false negative patients were not identified (cystic fibrosis and methylmalonic aciduria patients) and 6 non neonatal patients were detected through expanded neonatal screening.
Our data support the necessity of unifying the set of metabolic diseases to be screened in all Regions of Spain for early detection of a defined panel of inborn errors of metabolism and to provide every newborn the same opportunities to be early diagnosed.
Diazepam inhibits phosphodiesterase type 4 and enhances the effect of some 3',5'-cyclic adenosine monophosphate (cAMP)-dependent positive inotropic drugs. We sought to determine whether diazepam and ...the selective phosphodiesterase type 4 inhibitor rolipram enhances the contractile response and cAMP levels induced by dopamine in rat myocardium. Dopamine (3-100 microM) produced concentration-dependent positive inotropic effects (-log EC50 = 5.21 +/- 0.2, n = 5), which were augmented in the presence of 10 microM diazepam (-log EC50 = 5.40 +/- 0.08, n = 6, P < 0.05) or 1 microM rolipram (-log EC50 = 5.41 +/- 0.1, n = 6, P < 0.05). The effect of diazepam was not mimicked by 100 microM gamma-aminobutyric acid nor it was antagonized by a 5 microM concentration of the blockers of central and peripheral type benzodiazepine receptors, flumazenil and PK 11195. cAMP levels (pmol/g) produced by dopamine (744.4 +/- 111.8, n = 5) in this tissue were enhanced by the presence of diazepam (1073 +/- 97.7, n = 6, P < 0.05) or rolipram (1034.0 +/- 245.2, n = 5, P < 0.05). Therefore, diazepam, like rolipram, augments the inotropic and biochemical effects of dopamine in rat myocardium. This effect is not mediated by benzodiazepine receptors but is probably the consequence of the phosphodiesterase type 4 inhibitory activity of diazepam.
The effects of phosphodiesterase (PDE) inhibitors (1–3) on tissue cAMP concentrations and the inotropic responses to dobutamine and glucagon were investigated in electrically driven right ventricular ...strips of the rat heart.
Dobutamine (0.3–100 μM) produced a concentration-dependent positive inotropic effect which was not affected by 50 nM (±)-1-(2,3-(dihydro-7-methyl-1
H-inden-4-yl)oxy)-3-((1-methylethyl)amino)-2-butanol hydrochloride (ICI 118551), a β
2-receptor antagonist, but was virtually abolished by 0.3 μM (±)-2-hydroxy-5-(2-((2-hydroxy-3-(4-(1-methyl-4-(trifluoromethyl)-1
H-imidazol-2-l)phenoxy)propyl)amino)ethoxy)-benzamide methanesulfonate (CGP 20712A), a β
1-receptor antagonist. Glucagon (0.01–1 μM) also enhanced the contractility of the preparation in a concentration-dependent way. Selective inhibitors of PDE 1 8-methoxymethyl-3-isobutyl-1-methylxantine (MIMX, 1 μM), PDE 2 erythro-9-2-hydroxy-3-nonyladenine (EHNA, 1 μM) and PDE 3 cilostamide (0.1 μM) did not affect basal contractility. Cilostamide increased the positive inotropic effects of glucagon but not those of dobutamine. MIMX and EHNA did not alter the effects of either dobutamine or glucagon. Dobutamine (3 μM), but not glucagon (0.1 μM), increased tissue levels of cAMP. 1 μM of MIMX or EHNA were devoid of effects and failed to alter the effects of dobutamine and glucagon on cAMP. Cilostamide (0.1 μM) did not increase the effects of dobutamine but caused glucagon to enhance cAMP.
The pharmacological and biochemical data presented in this study can be explained quantitatively by a cell compartment model in which PDE 3 appears to be colocalized with the contractile machinery responsible for the effects of glucagon but not those of dobutamine. Neither PDE 1 nor PDE 2 appears to regulate the inotropic effects of dobutamine and glucagon in rat ventricular myocardium.
Glucagon increases cardiac contractility through G(s) protein-coupled glucagon receptors, but the inotropic responses fade. The fade could be due to receptor desensitisation or to the action of ...phosphodiesterases (PDE), or to both mechanisms. We investigated the effects of the PDE4 inhibitor rolipram (1 microM) on the inotropic and cAMP-responses to glucagon in paced right ventricular strips of the rat heart. Responses to the partial agonist dobutamine, mediated through beta(1)-adrenoceptors, were studied for comparison. Glucagon increased contractility (-logEC(50)M=7.3 for maximum responses with E(max)=32% of the response to 9 mM Ca(2+)), but the responses tended to fade (-logEC(50)M=7.1 for faded responses with E(max)=11.5%). Dobutamine (-logEC(50)M=5.8, E(max)=56%) produced positive inotropic effects that did not fade. Rolipram did not affect basal contractility and cAMP levels. Rolipram enhanced the contractile responses to glucagon and reduced fade (-logEC(50)M=7.5 and 7.3 with E(max)=74% and 45% for maximum and faded responses respectively). The response to glucagon (0.1 microM) completely faded in the absence of rolipram, but only partially faded and then remained stable in the presence of rolipram (1 microM). Rolipram enhanced contractile responses to dobutamine (-logEC(50)M=6.0, E(max)=75%). Dobutamine (3 microM), but not glucagon (0.1 microM), increased tissue levels of cAMP. Consistent with the inotropic data, rolipram caused glucagon to augment cAMP and enhanced the effects of dobutamine. Thus, PDE4 activity limits the responses mediated through both glucagon receptors and beta(1)-adrenoceptors. PDE4-catalysed hydrolysis of cAMP contributes to the inotropic tachyphylaxis of glucagon.
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