الفهرس 
Introduction
Aim of the workOnly 14 pages are availabe for public view
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Abstract
Inborn errors of metabolism (IEM) are a group of genetic diseases leading to severe complications in newborns, infants, children, adolescents, or adults. Inborn errors of metabolism are caused by the defect of an enzyme, its cofactor or a transporter resulting in the accumulation of a substrate and/or the deficiency of its downstream products. Inborn errors of metabolism constitute an important cause of neurological disease in the neonatal period and can present clinically as encephalopathy, although it is relatively rare, but it is important to have a high index of suspicion for diagnosing these disorders. These disorders are biochemically characterized by accumulation of specific metabolites or their by-products in tissues and biological fluids of the affected individuals that may cause toxic effects in the organism leading to severe metabolic crises that can result in permanent neurological damage, physical disability and even fatality. The detection of IEM relies on a high index of clinical suspicion and coordinated access to specialized laboratory services, biochemical analysis forms the basis of the final confirmed diagnosis in several types of these disorders.
Appropriate investigations and a step-wise approach to diagnosis allow for early institution of treatment and can prevent significant morbidity and mortality. Since 1961, newborn screening for inborn errors of metabolism (IEM) has improved the diagnosis, treatment and outcome of newborns with an IEM. Recently, advances in laboratory technology with tandem mass spectrometry (MS/MS) have increased the identification of newborns with an IEM with a single dried filter paper blood spot.
The present study included 200 newborn of age range from 1 to 28 days admitted to NICU of children’s Hospital of Assiut University during the period from the first of January 2015 to the end of June 2018 with suspected metabolic disorders. Among them we found totally 93 cases as mostly suspected to have inborn errors of metabolic disorders, 85 cases of them were diagnosed and confirmed as IEM and 8 cases suspected to have IEM but confirmatory test was not completed.
Studied cases were subjected to:
Meticulous history taking: Assessment of the following factors as: Sex, birth weight, gestational age, consanguinity, complaint by their parents and clinical manifestation.
Full clinical examination: (general, abdominal, cardiac, chest and neurological examination).
Investigations that include:
o Routine investigations
Complete blood picture.
Liver function tests.
Serum electrolytes level and ionized serum calcium level.
o Specific metabolic investigations:
Arterial blood gas (ABG).
Blood glucose.
Blood ammonia.
Blood lactate.
C-reactive protein (CRP).
Metabolic screen in blood.
Organic acid in urine.
from our 93 neonates, 86 % (n=80) were full-terms, and 13.9 % (n=13) were pre-terms; 60% were males (n=56) and 40% were females (n=37).
Positive consanguinity was detected among 69(74%) of them with significante difference (P. Value = 0.012). In our study the mean age of presentation was 7.57±1.6 day after birth and the mean weight of neonates at presentation was 2.70±0.5 kg.
The most common presenting manifestations among the diagnosed cases with IEM from all suspected cases was poor suckling present in 65.5 % (n=61) with significante difference between groups (AAD, FAOD and galactosemia) (P. Value = 0.014), followed by respiratory distress in 61 % (n=57) case, then convulsions 58 % (n=54), and vomiting was present in 55% (n=52) case.
Routine investigation for screening had done and revealed metabolic acidosis with high anion gap detected in 37.6 % (n=35) of cases with positive significante difference between the diagnosed groups (P.value =.001), all cases diagnosed with organic acidemia had metabolic acidosis (100%) with serum bicarbonate level mean ±SD (14.44±5.4) mmol/l. Elevated serum Ammonia was detected in 83% (n=78) of neonates with mean ±SD 66.06 ±11.7µmol/l and significance difference between three groups (P. Value =0.015), this high serum level of ammonia was detected in all cases with UCD, hyperphenylalanemia, organic acidemia cases and all of cases with suspected tyrosinemia. Serum level of lactate increased in 83.8% (n=78) of cases with mean ±SD level (21.21±5.9 mg/dl) and significante difference between the diagnosed groups was (P. Value =0.004), increase serum level of ammonia in 100% of cases diagnosed to have UCD and organic acidemia. Low glucose level was present in 37% (n=53) of cases with serum level (55.99±8.7 mg/dl) and P. Value <0.001.
Diagnosis of metabolic disorders in the studied cases shows that:
85/200 case (42.5%) had confirmed diagnosis with IEM, and still to have highly suspected metabolic disorders in 8/200 case (4%) as suspected tyrosinemia, galactosemia and multiple carboxylase deficiency diagnosed according to their clinical presentation, routine and metabolic investigations by tandem mass spectrometry but they needs another confirmatory test as enzymatic assay that can’t be done. Undiagnosis of suspected cases present in 44 case out of 200 (22%) were undiagnosed as they died before complet their investigations, and 63 cases out of 200 (31.5%) were diagnosed to have other disorders rather than IEM as hyperinsulinemia, hypoparathyroidism, congenital adrenal hyperplasia, necrotizing entercolitis and hypoxic ischemic encephalopathy.
Amino acid disorders were detected in 69/85 of cases (81%), their family history shown positive consanguinity in 55 cases (79%), the presenting manifestations shown poor suckling in 47 cases (68%), convulsions in 39 cases (56%), vomiting was present among 38 cases (55%), and disturbed conscious level in 19 cases (27%). By investigation both hyperamonemia, and increase serum level of lactate was present in 60 patients (87%), and hypoglycaemia in 37 cases (41.6%).
Among amino acid disorders; 20 cases out of 200 (23.5%) diagnosed as UCD with increased serum level of ornithine, citrullin and arginine in MS test. 18 out of 85 (21%) case diagnosed as MSUD with high serum level of leucine, iso-leucine was (361.9±18.4 µmol/l), and valine level was (377.1±43.5 µmol/l). Hyperphenylalanemia detected in 15 cases out of 85 (17.5%) with serum level of phenylalanine was181.6±18.9 µmol/l.
Organic acidemia was found in 14 cases out of 85 (16%), the most frequent type was methylmalonic acidemia in 7/14 patient (8.5%), followed by propionic acidemia in 5/14(5.8%) patients, one case diagnosed as B-ketothiolase deficiency and one case was diagnosed as 3-hydroxy methylcrotonyl COA carboxylase deficiency.
Solitary cases diagnosed with IEM includes: Non ketotic hyperglycinaemia was present in one case out of 85 newborn (1%). Di–hydropyrmidine deficiency was diagnosed in one case out of 85(1%) , this case was presented with persistent vomiting and acidosis from first day after birth that shown increase uracil and thymine in urine, and Glutaric acidemia also in one case /85 detected cases. Suspected galactosemia was present in 3 cases out of 200 cases (1.5%), suspected tyrosinemia was present in 4/200 (2%) and suspected multiple carboxylase deficiency was found in 1 case (0.5%).
Fatty acid oxidation disorders diagnosed in: 15/85 (17.5%) cases, regarding the presenting manifestation, hypoglycaemia was present in 12 cases of them (80%), metabolic acidosis in 6 cases (40%), convulsion in 8 cases (53%), vomiting in 6 cases (40%) and previous affected neonate with same symptoms in 3 cases (20%) out of them. By metabolic testing showing increase level of:
Acyl-carnitine types Result value Normal value
• C-6 Carnitine 1.08 ± 0.6 µmol/l < 0.16
• C-8 Carnitine 1.30 ± 0.9 µmol/l < 0.18
• C-10 Carnitine 1.98 ± 0.5 µmol/l < 0.26
• C-12 carnitine 1.76±0.6 µmol/l <0.410
• C-18 carnitine 1.64±0.4 µmol/l <0.413
• C5-OH carnitine 1.92±0.3 µmol/l <0.8
• C-16 Carnitine 6.07 ± 0.6 µmol/l < 5.06
• C-18:1 Carnitine 4.75 ± 2.9 µmol/l < 3.50
Increase in serum level of C-8, C-10, and C-12 is consistent with medium chain acyl COA dehydrogenase deficiency and increase in serum level of C-16, C-18, and C-18:1 is coordinated with defect in carnitine cycle mostly carnitine palmitoyl transferase –II deficiency.
The treatment modalities for neonates with inborn error of metabolism and the outcome of studied patient, show that 29/93 (31%) case of diagnosed cases received special milk formula from Ain shams university genetics unit and from Ministry of Health according to the result of metabolic screening. 73/93 (68%) neonates recieved management for hyperamonemia in form of sodium benzoate 250 mg /kg by oral route as IV drug not available in our hospital. Multivitamins supply given in form of vitamin B complex and vitamin D for 57 cases (61%) of the studied patients. Patients with metabolic acidosis in their investigations bicarbonate therapy given by intravenous and oral route to 35/93 (38%) case and follow up arterial blood gas for PH and HCO3 level which shown improvement in PH and bicarbonate serum level, after diagnosis and management given to the studied cases 34/93(36%) discharged from the neonatal intensive care unit and follow up in genetics clinic, and 59/93 (64%) died from complications.