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.

Diagnosis, genetic characterization and clinical follow up of mitochondrial fatty acid oxidation disorders in the new era of expanded newborn screening: A single centre experience.

INTRODUCTION: Mitochondrial fatty acid oxidation disorders (FAODs) are a heterogeneous group of hereditary autosomal recessive diseases included in newborn screening (NBS) program in Italy. The aim of this study was to analyse FAODs cases, identified either clinically or by NBS,for clinical and genetic characterization and to evaluate a five years' experience of NBS, in the attempt to figure out the complexity of genotype-phenotype correlation and to confirm the clinical impact of NBS in our centre experience. MATERIALS AND METHODS: We analysed FAODs patients diagnosed either by NBS or clinically, followed since February 2014 to April 2019 at the Regional Screening Centre and Inherited Metabolic Diseases Unit of Verona. Diagnosis was confirmed by plasma acylcarnitines, urinary organic acids, enzymatic and genetic testing. For not clear genotypes due to the presence of variants of uncertain significance, in silico predictive tools have been used as well as enzymatic activity assays. Patients underwent clinical, nutritional and biochemical follow up. RESULTS: We diagnosed 30 patients with FAODs. 20 by NBS: 3 CUD, 6 SCADD, 5 MCADD, 4 VLCADD, 2 MADD. Overall incidence of FAODs diagnosed by NBS was 1:4316 newborns. No one reported complications during the follow up period. 10 patients were diagnosed clinically: 2 CUD, 2 CPT2D, 1 VLCADD, 5 MADD. Mean age at diagnosis was 29.3 years. Within this group, complications or symptoms were reported at diagnosis, but not during follow-up. 12 mutations not previously reported in literature were found, all predicted as pathogenic or likely pathogenic. DISCUSSION AND CONCLUSIONS: Our study highlighted the great phenotypic variability and molecular heterogeneity of FAODs and confirmed the importance of a tailored follow up and treatment. Despite the short duration of follow up, early identification by NBS prevented diseases related complications and resulted in normal growth and psycho-motor development as well.

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.

Wernicke-like encephalopathy during classic maple syrup urine disease decompensation.

We describe a new neuroradiologic picture observed during metabolic decompensation in two maple syrup urine disease (MSUD) patients that resembles Wernicke encephalopathy (WE). Clinical observations and the review of the literature regarding WE and MSUD pathophysiology prompted us to hypothesize a pathogenic link between these two disorders. Based on these findings, clinicians and neuroradiologists should be aware of MSUD as a possible predisposing factor of WE in children.

Kidney length and scarring in children with urinary tract infection: importance of ultrasound scans.

BACKGROUND: Many studies have demonstrated that dimercaptosuccinic acid (DMSA) scintigraphy is the most sensitive diagnostic method in the identification of irreversible renal lesions (scars) in children with previous episodes of acute pyelonephritis (APN). This study assessed the reliability of ultrasound in identifying reflux nephropathy in children with acute pyelonephritis with or without vesicoureteric reflux (VUR). METHODS: Eighty children (45 female and 35 male, age range 5 months to 10 years, average age 2 years 1 month) with a positive history for at least one episode of APN participated in this study. All children underwent voiding cystourethrography, DMSA scintigraphy 4 to 8 months after the most recent episode of APN, and an ultrasound test evaluation less than 2 months after DMSA scintigraphy. RESULTS: Voiding cystourethrograms showed VUR in 52 children (68%); 13 of these were bilateral, for a total of 65 refluxing kidney units of the 154 (42%) evaluated; DMSA scintigram was normal for 108 of 154 kidneys (70%). Of the 65 kidneys with VUR, DMSA scintigram displayed normal findings in 29 cases (45%) and pathologic findings in 36 (55%). In the 79 nonrefluxing kidneys, DMSA scintigram was normal in 69 cases (87%). The relative risk of scarring in VUR kidneys is 2.6. The ultrasound study recorded a maximum longitudinal diameter between the 5th and 95th percentiles in 80 of 89 (81%) kidneys without VUR and in 21 of 65 (32%) with VUR. A significant correlation was found between maximum longitudinal diameters and DMSA scintigraphic findings in kidneys with VUR and those without VUR, respectively. CONCLUSION: This study establishes that ultrasound scans, by means of a simple and reproducible measurement technique, maximum longitudinal diameter, have a predictive value with regard to the presence of scars, with few exceptions. This finding, in our opinion, could lead to a decrease in the number of invasive procedures, in particular DMSA scan, in patients with APN.

NADPH oxidase activity and chemotaxis by neutrophils in two patients with glycogen storage disease type Ib treated with recombinant human granulocyte-monocyte colony-stimulating factor.

Polymorphonuclear neutrophils play an important role against pathogens through the production of toxic oxygen metabolites by the NADPH oxidase enzyme, which reduces oxygen to superoxide anion in the respiratory burst. Neutropenia, infectious complications and impaired neutrophil function are often reported in glycogen storage disease type Ib (GSDIb), a metabolic disorder characterized by increased glycogen and decreased glucose-6-phosphatase (G-6-P) activity in the liver. Two children with GSDIb and associated neutropenia with recurrent bacterial infections were treated daily with different doses of rHu-GM-CSF. NADPH oxidase activity and chemotaxis in patients were assessed before and during therapy in stimulated and unstimulated neutrophils. During rHu-GM-CSF treatment, any increase found in the NADPH oxidase activity of patients was not significant with respect to that in controls. In one patient chemotaxis was greater than of controls. This finding suggests that in patients with GSDIb both neutropenia and PMN abnormalities may be responsible for infections, and PMN dysfunction probably depends on the degree of inherited functional G-6-P deficit.

Enzymes of lysosomal origin in plasma of twin neonates.

The levels of some enzymes of lysosomal origin were assayed during days 2 and 5 of life in plasma from 11 sets of twin neonates and from 25 neonates from single pregnancies (13 of weight appropriate for gestational age and 12 small for their gestational age) as controls. The plasma enzyme levels were also determined in the correspondent twin and control mothers 2 days after delivery. N-Acetyl-beta-D-glucosaminidase isoenzymes were assayed after chromatofocusing separation. All the plasma enzyme levels were higher in the group of twin neonates and of their mothers than in the respective control groups with differences highly statistically significant for two enzymes, beta-D-galactosidase and alpha-D-glucosidase. In neonate plasma lysosomal enzymes are increased at the fifth day of life with respect to the second day. Full term control neonates showed the same enzyme trend. For the N-acetyl-beta-D-glucosaminidase the more significant differences concerned the isoenzyme I2-P (pregnancy). The pattern of the lysosomal enzymes in the twins resembled that of neonates of diabetic mothers who had had no insulin therapy. Since lysosomal enzymes are considered to be particularly sensitive indicators of carbohydrate metabolism abnormalities, we conclude that twin pregnancies are more at risk for these abnormalities than single ones.

Allopurinol challenge test in children.

The allopurinol challenge test was performed on 44 healthy subjects (28 children and 16 adolescents) in order to establish normal values of urinary orotic acid excretion following allopurinol ingestion in the paediatric population. The subjects were divided into three groups according to their age: 6 months to 6 years; 6 years to 10 years; and 10 years to 17 years. They were given 100 mg, 200 mg, or 300 mg of allopurinol, respectively (based on age) in a single oral dose. Maximum peak urinary orotic acid levels following ingestion of allopurinol were 13.0 (n = 14), 9.3 (n = 14), and 10.2 (n = 16) mumol/mmol creatinine in the three groups, respectively. In all children tested the peak orotic acid level was 3.1 +/- 2.7 mumol/mmol creatinine (mean +/- SD, n = 44). This allopurinol challenge test was also performed in six children with urea-cycle disorders, including five females with ornithine transcarbamylase (OTC) deficiency, all of whom demonstrated abnormally elevated levels of urinary orotic acid (peak levels of 26-134 mumol/mmol creatinine) following allopurinol ingestion.