الفهرس 
Propionic AcidemiaOnly 14 pages are availabe for public view
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Abstract
Propionic acidemia (PA) and Methylmalonic aciduria (MMA) are two of the most encountered organic acidemias. These two disorders are due to complete or partial deficiency of Propionyl Co A carboxylase and Methylmalonyl Co A mutase enzyme, respectively. The common clinical presentations include toxic encephalopathy with vomiting, poor feeding, neurologic symptoms such as seizures; hypotonia; abnormal movements; lethargy; and coma, which commonly happen in the newborn period. In the older children, the presentation can be intellectual deterioration, ataxia or other neurologic signs, Reye syndrome, recurrent episodes of ketoacidosis, or psychiatric symptoms occurring during stress, i.e. infection. The goal of therapy is to regain biochemical and physiologic homeostasis, and it includes dietary restriction of the “offending” amino acids and use of adjunctive medications to enhance the urinary excretion of these toxic metabolites. Although cyclic metronidazole has been used for a long time to treat propionic and methylmalonic acidemia, there have been no studies that addressed the clinical benefit from using this medication. The aim of this work was to study the benefit of the use of metronidazole by evaluating its clinical efficacy in improving the clinical outcome, reducing/preventing long term complications, increasing natural protein tolerance and decreasing the frequency of acute metabolic decompensation episodes, in addition to biochemical improvement in pediatric patients with propionic acidemia and methylmalonic aciduria. This was observational retrospective cohort study from July 2018- July 2020.The study included 20 pediatric patients, propionic acidemia (n= 10) and methylmalonic acidemia (n = 10). All children of the study were subjected to the following: I. Complete history taking: - Personal data: sex, date of birth. - Present history: food aversion, nasogastric tube usage, and detailed dietetic history; protein intake (total, complete and incomplete). - Past history: Age of disease onset, age of diagnosis, symptoms at diagnosis, PICU admission, number of hospital admissions, number of decompensation episodes per year, and number of decompensation episodes in the first year of life, along with review of the length of hospital stay in the first episode and in the following decompensation episodes. - Retrospective review of medical records: Assessment of patients’ compliance to the treatment, the metronidazole monthly regimen. - Developmental History. - Family history: similar condition, sudden infant death in the family, consanguinity. - Obstetric history: Gestational age, mode of delivery. II. Thorough clinical examination: - Full examination with special emphasis on assessment of growth by taking the anthropometric measures, i.e. head circumference, height/length, weight and ophthalmological examination. - Neurological examination. III. Investigations: • Assessment of metabolic control: - Tandem mass spectrometry (aminogram and acylcarnitine profile), urine organic acid: C3, C3/C2, Glycine level - Lactate level. - Ammonia level: at presentation, and peak ammonia level when not decompensating. - Venous blood gas: pH, and bicarbonate level. • Assessment of nutritional state: - Albumin level. Plasma amino acids. CBC. Calcium level. Urea & BUN, ferritin, Vitamin D level. • EEG, and Brain MRI. • Liver function tests: Mainly ALT and AST, total bilirubin level, direct bilirubin level, albumin, PT. • Left wrist X-ray to evaluate bone age. • IQ: Those between 2 and 7 years had their IQ tested by using the Wechsler Preschool and Primary Scale of Intelligence. DQ for those ≤ 2 years. • Echocardiography follow up for cardiomyopathy. • ECG and 24- hour Holter monitoring for prolonged QTc and other conduction defects. Metronidazole Regimen: Metronidazole was prescribed for 10 days each month in a dose of 10 mg/kg/ day, orally in two divided doses. The cohort was divided into two groups: In the first group, patients were on cyclic metronidazole, and in the second group, patients were not on metronidazole. The decision to assign a patient to the “off-metronidazole” group was considered if the patient had missed at least 75% of the yearly dose or has declined the usage of the medication when offered. Patients were considered in the “on-metronidazole” group when it was evident form the patient follow up and monitoring that they were compliant to the treatment regimen or did not fulfill the criteria of the “offmetronidazole” group. The data were collected retrospectively from patients’ charts and by reviewing patients during out-patient clinic regular follow up visits. Forty (40%) of the patients were “off-metronidazole”, while 60% were receiving metronidazole for 10 days each month with a dose of 10 mg/kg/day. We compared both groups as regards growth percentiles, protein intake, DQ/IQ, PICU admissions, length of hospital stay, frequency of decompensation episodes, developmental delay, and ammonia levels. The Results of the study revealed that: • Majority of the patients (70%) were delivered normally, at term with no tendency to prematurity. The birth weight was 3.9 ± 1.2 kg. • The age of onset of symptoms was 5.38 ± 1.38 months, 60 % presenting in the first 3 months of life with only 3 (15%) patients in the neonatal period and 40% after 3 months of age. • The most frequent presenting symptoms were vomiting (85%) followed by refusal of feeding (70%), dehydration (60%), encephalopathy (55%), hypotonia (55%), shock (45%), hepatomegaly (45%), seizures (20%), dystonia (10%), and ataxia (5%). There was no significant statistical difference between PA and MMA in the frequency of the presenting symptoms, (p > 0.05) except for hypotonia which was more frequent in PA,(p = 0.038). • The triggering factors were fever and GI illness in 45% of the patients, upper respiratory infection in 40%, and no trigger factor could be identified in 15%. • Severe metabolic acidosis with bicarbonate < 10 mmol/l was found in 35% (7/20), 45% (9/20) had bicarbonate 10 -16 mmol/l and 20% (4/20) had bicarbonate > 16 mmol/l. • The anion gap was 22.5 ± 8.38, and MMA patients tended to have higher anion gap, p = 0.005. The glycine level was 386 ± 167.1 μmol/l, and it tended to be significantly higher in PA, p = 0.003. • The ammonia level had significant negative correlation with both pH and bicarbonate level, and significant positive correlation with lactate and anion gap (p < 0.05). • There was significant positive correlation between glycine and both pH (p = 0.01) and HCO3 (p = 0.026). • All patients, in all age groups (0-6 months, 1-3 years, 4-8 years) had total protein intake (gm/kg/day) that exceeded the recommended DRI for age. • The growth indices (height/length, weight, head circumference) had significant positive correlation with both natural protein intake and natural/synthetic protein ratio. • There was no statistically significant correlation between ferritin level and both total, and natural dietary protein intak. • There was no significant correlation between the protein intake (total, and natural) and the level of calcium and vitamin D, p > 0.05. • There was significant positive correlation between the amount of natural protein intake and the albumin level, p < 0.001, and there was significant negative correlation between the synthetic protein intake and the albumin level, p = 0.031. • Global developmental delay was found in 40%, speech delay in 15%, and motor delay in 15%. The second most encountered complication was hypotonia in 55% (11/20), being significantly more frequent in PA, p = 0.038. • In terms of IQ/DQ, 55% of the patients had an IQ of ≤ 90. MMA patients tended to have a higher IQ when compared to PA patients, p < 0.001. • Patients who did not require PICU admission had a higher IQ/DQ (95.44 ± 10.08) when compared to those who did (73.81 ± 23.85, p = 0.016). In addition, patients with mode ammonia level of 60 μmol/l had significantly lower IQ/DQ when compared to patients whose mode ammonia was < 60 μmol/l, p = 0.03. • Eight (40%) patients were not on cyclic metronidazole treatment and 12 (60%) patients were receiving metronidazole for 10 days each month with a dose of 10 mg/kg/ day, orally in two divided doses. • The average total daily protein intake was 2.15 ± 0.35 gm/kg/day, the natural protein intake was 0.69 ± 0.07 gm/kg/day, and the medical formula intake was 1.48 ± 0.31 gm/kg/day with a natural protein to medical formula ratio of 0.48 ± 0.122 in the group not receiving metronidazole which was statistically not significant when compared with the other group. • There was no significant difference in the growth percentiles between the two groups. • As regards the clinical course of our patients, the patients receiving metronidazole did not show any significant improvement in their clinical course, i.e. frequency of decompensations, ICU admissions, length of hospital stay, and IQ/DQ when they were compared to the patients not receiving metronidazole (p > 0.05).