Novel OCTN2 mutations: No genotype–phenotype correlations: Early carnitine therapy prevents cardiomyopathy

Primary systemic carnitine deficiency or carnitine uptake defect (OMIM 212140) is a potentially lethal, autosomal recessive disorder characterized by progressive infantile‐onset cardiomyopathy, weakness, and recurrent hypoglycemic hypoketotic encephalopathy, which is highly responsive to L ‐carnitine therapy. Molecular analysis of the SLC22A5 (OCTN2) gene, encoding the high‐affinity carnitine transporter, was done in 11 affected individuals by direct nucleotide sequencing of polymerase chain reaction products from all 10 exons. Carnitine uptake (at Km of 5 μM) in cultured skin fibroblasts ranged from 1% to 20% of normal controls. Eleven mutations (delF23, N32S, and one 11‐bp duplication in exon 1; R169W in exon 3; a donor splice mutation [IVS3+1 G > A] in intron 3; frameshift mutations in exons 5 and 6; Y401X in exon 7; T440M, T468R and S470F in exon 8) are described. There was no correlation between residual uptake and severity of clinical presentation, suggesting that the wide phenotypic variability is likely related to exogenous stressors exacerbating carnitine deficiency. Most importantly, strict compliance with carnitine from birth appears to prevent the phenotype. © 2002 Wiley‐Liss, Inc.     

Predictors of Caregiver Participation in an Engagement Strategy to Increase Initiation into a Family-Based Preventive Intervention

Previous studies have shown that engagement strategies can help increase enrollment and initiation of families in evidence-based preventive programs under natural service delivery settings. However, little is known about factors that predict completion of these engagement strategies. This study aimed to examine predictors (i.e., perceived need, perceived barriers, and sociocultural context) of caregiver participation in an evidence-based engagement call strategy. This call was expected to increase initiation into a school-based, family-focused prevention program. In addition, this study examined engagement call completion as a predictor of program initiation among already enrolled families. Participants included ethnically diverse families recruited from three Title I schools (n = 413) who were randomized to receive the prevention program. Results showed that interparental conflict—an indicator of perceived need—was associated with an increased likelihood of completing the engagement call. Furthermore, caregivers from low-socioeconomic status (SES), foreign-born, Spanish-speaking, Hispanic families were more likely to complete the call relative to those from low- and mid-SES, US born, English-speaking, ethnically diverse families. Importantly, engagement call completion was associated with an increased likelihood of program initiation. These findings provide limited support that families with higher perceived needs are more likely to participate in an evidence-based engagement call strategy. Results suggested that the call strategy provides a promising way to reduce attrition from family prevention programs, which is commonly observed between enrollment and initiation. Project Number: R01 DA035855; Date of Registration: 06/15/2014.

     

Nebulizer and Spacer Device Maintenance in Children with Asthma

Objective. To evaluate inhalation device cleaning practices of children with asthma and its effect on their asthma morbidity. Methods. A survey of patients aged 4 to 18 years admitted to an urban pediatric emergency department (ED) with an acute asthma exacerbation. Questions included demographics, asthma history, preference of delivery devices, and frequency of device cleaning. Patients were followed until their disposition from the ED, or until the end of their hospitalization, if admitted. Results. 220 subjects completed the survey. Mean age was 9.2 (± 3.9) years-old. One hundred and four (47.3%) patients used both nebulizers and spacer devices, while 18 (8.1%) used spacers only and 98 (44.5%) used nebulizers alone. Seventy-seven (38.1%; 95%CI: 31.7%–45.0%) patients cleaned their nebulizers and 57 (46.7%; 95%CI: 38.1%–55.4%) cleaned their spacer devices after each use as recommended by the Centers for Disease Control. There were no detectable differences in visit admission rate, total number of previous admissions, number of asthma exacerbations per year, and number of ED visits in one year between users who cleaned their devices after every, or every other use, compared to those who cleaned their devices less frequently. Conclusion. Although the majority of patients did not follow accepted guidelines for inhalation device cleaning, further studies are necessary to correlate cleaning practices to patients' clinical outcome.     

Role of carnitine and fatty acid oxidation and its defects in infantile epilepsy

Defects in fatty acid oxidation are a source of major morbidity and are potentially rapidly fatal. Fatty acid oxidation defects encompass a spectrum of clinical disorders, including recurrent hypoglycemic, hypoketotic encephalopathy or Reye-like syndrome in infancy with secondary seizures and potential developmental delay, progressive lipid storage myopathy, recurrent myoglobinuria, neuropathy, and progressive cardiomyopathy. As all of the known conditions are inherited as autosomal recessive diseases, there is often a family history of sudden infant death syndrome in siblings. Early recognition and prompt initiation of therapy and the institution of preventive measures may be life saving and significantly decrease long-term morbidity, particularly with respect to central nervous system sequelae. Seizures may be the result of cerebral bioenergetic failure associated with acute episodes of hypoglycemic, hypoketotic encephalopathy, or hypoxic-ischemic encephalopathy in the context of cardiac arrhythmias and/or cardiomyopathy. This review provides an overview of the fatty acid oxidation pathway and the central role of carnitine, as well as a discussion of normal fasting adaptation and the critical metabolic adaptations that occur at birth. The increased vulnerability of infants and young children to fasting and defective fatty acid oxidation is discussed in the context of the heightened bioenergetic demands of the developing brain. Clinical and laboratory features of specific genetic defects in fatty acid oxidation, approaches to diagnosis, and current treatment methodologies are described. Indications for carnitine supplementation in childhood epilepsy are also discussed.     

Neonatal blood carnitine concentrations: normative data by electrospray tandem mass spectometry

Despite a number of published reports, there is limited information about carnitine metabolism in the newborn. To establish normative data, we analyzed whole-blood carnitine concentrations in 24,644 newborns at age 1.85 +/- 0.95 d and umbilical cord whole blood and plasma carnitine concentrations in 50 full-term newborns. Total carnitine (TC), free carnitine (FC), and acylcarnitine (AC) were measured by electrospray tandem mass spectrometry. AC/FC ratios were derived from these measurements. The entire cohort was stratified according to TC values into a middle TC group representing 90% of the population and lower and upper TC groups representing 5% of the population, respectively. Normative data were derived from the middle TC group of full-term infants (N = 19,595). TC was 72.42 +/- 20.75 microM, FC was 44.94 +/- 14.99 microM, AC was 27.48 +/- 8.05 microM, and AC/FC ratio was 0.64 +/- 0.19 (+/-SD). These values differed significantly from umbilical cord whole blood TC values of 31.27 +/- 10.54 microM determined in 50 samples. No meaningful correlation was found between TC and gestational age or birth weight in any group. In controlled analyses, prematurity was not associated with TC levels, whereas low birth weight (<2500 g) and male sex were significantly associated with higher TC levels. The association of low birth weight with higher TC values may be related to decreased tissue carnitine uptake. The sex effect may be related to hormonal influences on carnitine metabolism. Our study provides normative data of carnitine values measured by the highly precise method of electrospray tandem mass spectrometry in a large cohort of newborns and provides the basis for future studies of carnitine metabolism in health and disease states during the neonatal period.     

Organic cation/carnitine transporter family expression patterns in adult murine heart

Organic cation/carnitine transporters transport carnitine, drugs, and xenobiotics (e.g. choline, acetylcarnitine, quinidine, and verapamil), and are expressed in muscle, heart, blood vessels, etc. To characterize expression patterns of mOctn1, -2, and -3 in adult murine heart, we applied our transporter-specific antibodies to mOctn1, -2, and -3, followed by secondary antibody and DAB peroxidase detection to adult murine heart sections counterstained with hematoxylin. All three transporters showed strong expression in cardiomyocytes, lamina fibrosa of cardiac valves, great arteries and intermuscular arterioles, and a striking differential expression in the vagal innervated sinoatrial and atrioventricular nodes. The hOCTN2 deficiency presents with carnitine-responsive cardiomyopathy. Octn1, -2, and -3 are expressed in many regions of murine heart with a pattern suggestive of potential roles in modulating myocardial bioenergetics, valvular function, and acetylcholine generation for parasympathetic vagal innervation of the cardiac conduction system. This distribution may play a role in the hypertrophic cardiomyopathy seen in hOCTN2 deficiency, and may also affect the absorption/elimination of organic cationic cardiac drugs.     

Spinal 2-chloroprocaine: effective dose for ambulatory surgery

Background: There is an interest in finding a safe, short-acting spinal anaesthetic, suitable for ambulatory surgery. In this prospective study, we evaluated the effective dose of plain 2-chloroprocaine (2-CP) for lower limb surgery, including knee arthroscopy and saphenectomy.
Methods: Sixty-four ASA physical status I–III patients undergoing elective lower limb surgery were randomly allocated to one of the four local anaesthetic groups for spinal anaesthesia in a double-blind manner. The patients ( n =16 patients in each group) received 35, 40, 45 or 50 mg of 10 mg/ml isobaric 2-CP.
Results: In all patients, anaesthesia was sufficient for the planned surgery. The median peak block height (T9) was similar in all four groups ( P =0.66). Time to complete sensory block regression was faster in the 35 mg group (111 min, mean) and in the 40 mg group (108 min) than in the 50 mg group (134 min, P =0.005). No differences in time to complete motor block regression were observed ( P =0.3). Home discharge time was faster in the 35 mg group (123 min) and in the 40 mg group (122 min) than in the 50 mg group (165 min, P =0.001). No complications related to spinal anaesthesia were observed and no transient neurologic symptoms (TNS) were reported at the 3-day follow-up.
Conclusion: Spinal 2-CP, 10 mg/ml 35, 40, 45 and 50 mg provide reliable sensory and motor block for ambulatory surgery, while reducing the dose of 2-CP to 35 and 40 mg resulted in a spinal block of faster ambulation.