Long-term use of carglumic acid in methylmalonic aciduria, propionic aciduria and isovaleric aciduria in Italy: a qualitative survey.

OBJECTIVE: Organic acidurias (OAs) are a group of rare metabolic disorders that disrupt the regular amino acid metabolism. OAs are characterized by recurrent episodes of acidemia, ketonuria and hyperammonemia which can result in brain/liver damage and renal failure, and despite the life-long protein-restricted diet, impaired growth and long-term complications can occur. Consequently, a long-term management of OAs patients is required, aimed principally at reducing the frequency and duration of metabolic decompensation/hyperammonemia episodes. Nevertheless, unlike the acute phase, evidence on the chronic management of OAs patients is less consolidated. SUBJECTS AND METHODS: To expand the knowledge on this field, 13 Italian referral centers for the management of OAs were involved in a survey focused on the long-term use of carglumic acid (Carbaglu®, Recordati Rare Diseases). RESULTS: Participating centers reported a reduction between 69% and 81% in the annual number of metabolic decompensations with the chronic use of carglumic acid and an improvement in protein intake. Most centers reported no difficulty using carglumic acid as a long-term therapy, along with a great compliance. CONCLUSIONS: Taken together, obtained data align with the available literature and support a positive clinical experience with the long-term carglumic acid administration. Additional studies aimed at better defining a proper dosage for the chronic administration of carglumic acid and the clinical and biochemical characteristics of patients treated chronically are needed. In addition, the potential impact of this treatment regimen on the neurological development and growth of patients should be elucidated.

Formulation and Clinical Evaluation of Sodium Benzoate Oral Solution for the Treatment of Urea Cycle Disorders in Pediatric Patients.

BACKGROUND: Sodium benzoate, a common food preservative, is used in the treatment of patients with urea cycle disorders (UCDs) as it stimulates ammonia removal by a non-urea cycle-based pathway. Despite its use in the clinical routine, no commercially available oral formulations currently exist. Liquid formulation is normally well accepted in pediatric age and allows precise dosage according to the children's needs. AIMS: (1) To prepare an oral sodium benzoate solution in different tastes and determine its stability, palatability, and tolerability and (2) to describe the long-term follow-up of two pediatric patients with UCDs treated with our formulation. METHODS: We prepared five oral solutions of sodium benzoate (200 mg/ml) by adding different flavoring agents. We measured drug concentration in the samples by high-performance liquid chromatography (HPLC). We evaluated palatability and tolerability with adult volunteers. Long-term drug compliance and metabolic control were appraised in two pediatric patients. RESULTS: All the oral solutions remained stable at room temperature along the 96-day test period, and they were well tolerated. The mint-flavored solution resulted the most palatable and preferred by adult volunteers. We report good drug compliance and good metabolic outcomes for both pediatric patients during the entire follow-up. CONCLUSIONS: Our study highlighted the stability and tolerability of flavored sodium benzoate oral solutions. These solutions were well accepted during a long-term follow-up and guaranteed a good metabolic control. Since taste attributes are critical to ensure acceptable medication adherence in the pediatric age, flavored liquid formulations of sodium benzoate may be an efficient strategy to achieve therapeutic outcomes in UCD pediatric patients.

Vitamin B12 Administration by Subcutaneous Catheter Device in a Cobalamin A (cblA) Patient.

Cobalamin A deficiency (cblA) is an inherited disorder of intracellular cobalamin metabolism, caused by impaired 5'-deoxy-adenosylcobalamin (AdoCbl) synthesis. Hydroxocobalamin (OHCbl) is the cornerstone of cblA treatment because vitamin B12 may completely restore AdoCbl deficiency. Parenteral administration, intravenous, subcutaneous or intramuscular, is generally required to achieve effect. Daily injections represent a problem for the parents and the caregivers, and this may lead to poor compliance and scarce adherence to the long-term treatment.Our report describes the case of a patient with cblA deficiency, diagnosed by newborn screening, positively treated with daily OHCbl administration by a subcutaneous injection port (i-port advanceTM). After the insertion of the device, we checked methylmalonic acid (MMA) levels weekly for the first month and then monthly. MMA level remained always in the normal range.To date, placement of a subcutaneous catheter to minimize the pain related to parenteral vitamin B12 punctures has been described only in a patient with deficiency of the enzyme methylmalonyl-CoA mutase (MUT). No other experiences are described in the literature.Our case shows that OHCbl administration using a subcutaneous catheter is safe and effective even in patients with cblA deficiency. The use of subcutaneous devices may reduce difficulties in providing parenteral daily injections which is the main reason discouraging physicians and families to use such an invasive treatment. Moreover, our experience may be translated to other inherited metabolic disorders, such as cobalamin C (cblC) disease, which may require daily parenteral drug administration.

Significant association among growing pains, vitamin D supplementation, and bone mineral status: results from a pilot cohort study.

The aim of our study was to analyze the possible relationship between growing pains, vitamin D levels, and bone mineral status. We enrolled 33 children affected by growing pains. Their pain intensity was evaluated through a questionnaire using the Wong-Baker Faces Pain Rating Scale for pain assessment. Serum 25-hydroxyvitamin D (25-OH-D), parathyroid hormone (PTH), and alkaline phosphatase levels were measured as well. A quantitative ultrasound assessment (QUS) was also done, measuring both the amplitude-dependent speed of sound (AD-SOS) and the bone transmission time (BTT), correlating, respectively, with bone density and with cortical thickness. After 3 and 24 months of vitamin D supplementation, we re-evaluated pain intensity and laboratory results. After 24 months we re-assessed QUS parameters. At the beginning of the study the children reported a mean growing pain intensity of 7.5 ± 1.6 SD. The mean values of 25-OH-D and PTH levels were 15.7 ± 6.9 ng/ml and 57.3 ± 27.3 pg/ml, respectively. The AD-SOS Z score was -0.53 ± 1.19 SD, and the mean value of the BTT Z score was -0.72 ± 0.96 SD. After the first 3 months of vitamin D supplementation we observed an increase in 25-OH-D levels (34.1 ± 17.8, p < 0.001) and a reduction in both PTH levels (47.3 ± 30.6, p = 0.135) and pain intensity (2.7 ± 2.2, p < 0.001). After 24 months we observed a further significant reduction in the pain intensity (3.9 ± 3.4, p < 0.001) and in PTH levels (43.7 ± 28.5, p = 0.004) and an improvement in the QUS parameters, in particular in BTT Z scores (p = 0.014). Our study suggests an interesting relationship between growing pains, vitamin D levels and bone mineral status.

Hypovitaminosis D and nocturnal hypertension in obese children: an interesting link.

In adults, low levels of vitamin D are associated with hypertension. The aim of this study was to evaluate the relationship between 24-h blood pressure (BP) patterns and vitamin D levels in obese children. We recorded anthropometric parameters, took blood samples for 25-hydroxivitamin D measurements and monitored ambulatory BP (ABP) in 32 obese children (male/female: 21/11, age 7-16 years). Subjects in the lower tertiles had higher homeostasis model assessment of insulin resistance, nighttime systolic and diastolic ABP, nighttime systolic and diastolic ABP load, 24-h ABP index and nighttime systolic and diastolic ABP index than those in the higher tertile. Vitamin D correlated negatively with 24-h and nighttime systolic ABP, 24-h systolic ABP load, nighttime systolic and diastolic ABP load, 24-h systolic ABP index and nighttime systolic ABP index. The percentage of subjects with pathological 24-h systolic BP (SBP) load, nighttime SBP load, nighttime diastolic BP (DBP) load, nighttime SBP index and nighttime DBP index increased progressively as the vitamin deficiency categories increased (χ(2)=10.26, P<0.05; χ(2)=16.34, P<0.01; χ(2)=10.23, P<0.05; χ(2)=10.38 and χ(2)=10.06, P <0.01). Low levels of vitamin D in obese children were associated with a higher BP burden, especially at night.

Genotype in the diagnosis of 21-hydroxylase deficiency: who should undergo CYP21A2 analysis?

AIMS: to confirm the diagnosis of 21-hydroxylase deficiency (21-OHD) by the analysis of CYP21A2 gene in infants with clinical and/or biochemical features of 21-OHD in order to clarify which patients to submit to genetic analysis; to analyze the genotype-phenotype concordance in these infants. SUBJECTS AND METHODS: We studied 25 children with clinical and/or biochemical features of 21-OHD. All of them and their parents were submitted to genetic analysis of CYP21A2. Patients were classified in 3 groups according to mutations' severity: severe (group A), moderate (group B) or mild (group C). RESULTS: CYP21A2 gene mutations were found in 17 children. Whereas all infants of groups A and B presented a classical form of 21- OHD, children of group C had a non-classical form of 21-OHD. Four infants resulted heterozygotes and 4 children were wildtype. A girl clinically presenting a non-classical form of 21-OHD resulted compound heterozygote with one of the mutations not described in literature (R25W) and whose residual enzymatic activity is not already known. All affected children presented a 17-OHP level after ACTH stimulation greater than 100 nmol/l. We found an optimal concordance between 17-OHP levels after ACTH test and genotype. CONCLUSIONS: CYP21A2 analysis permitted to confirm the diagnosis of 21-OHD in 68% of our children. To improve this percentage we suggest to perform the CYP21A2 analysis only when 17-OHP after ACTH test is greater than 100 nmol/l. Moreover, we found an optimal genotype-phenotype concordance in the 21-OHD patients.

Serum inhibin B levels before and after varicocelectomy in early adolescence.

BACKGROUND: Whereas no clear relationship has been observed between varicocelectomy and serum inhibin B levels in men, in adolescents comparison between inhibin B levels before and after varicocelectomy is lacking. AIM: To evaluate the effect of varicocele surgical treatment on inhibin B levels in adolescents at the beginning of puberty compared to a group of healthy adolescents. SUBJECTS AND METHODS: We studied 28 adolescents in Tanner 2 pubertal stage with a grade III left-sided varicocele (patients) compared to 13 age and pubertal stage-matched healthy adolescents (controls). All patients underwent blood tests to determine serum inhibin B levels before and 6 months after varicocelectomy by Palomo procedure. For comparison we investigated inhibin B levels in controls and repeated this test 6 months later. Testicular ultrasound was performed for patients only. RESULTS: Baseline inhibin B concentrations of patients and controls were 109.90 ± 40.26 and 109.33 ± 38.34 pg/ml, respectively. No significant changes were observed in patients' inhibin B concentrations after varicocelectomy (116.00 ± 42.65 pg/ml), or in controls during the 6 months' follow-up (99.12 ± 30.09 pg/ml). Doppler examination after treatment shows a complete resolution of varicocele in all the patients without alterations in testicular parenchyma. CONCLUSIONS: Varicocelectomy performed on adolescents at T2 pubertal stage might be useful to avoid alteration in inhibin B production and consequently in testicular function. Further studies are necessary to confirm the prognostic value of inhibin B levels and the benefit of early varicocelectomy in preserving the fertility of these adolescents.