Selective screening of 650 high risk Iranian patients for detection of inborn error of metabolism

Document Type : Original Article


1 Neonatalogy Research center, Department of Pediatrics, Namazee Hospital, School of Medicine, Shiraz University of Medical Sciences ,Shiraz, Iran

2 Neonatlaogy Research center, Department of Pediatrics, Namazee Hospital, School of Medicine, Shiraz University of Medical Sciences ,Shiraz, Iran

3 Department of Pediatrics, Namazee Hospital, School of Medicine, Shiraz University of Medical Sciences ,Shiraz, Iran

4 Neonatalogy Research Center, Department of Pediatrics, Namazee Hospital, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran


Objective: Although metabolic diseases individually are rare ,but overall have an incidence of 1/2000 and can cause devastating and irreversible effect if not diagnosed early and treated promptly. selective screening is an acceptable method for detection of these multi presentation diseases.
Method: using panel neonatal screening for detection of metabolic diseases in 650 high risk Iranian patients in Fars province.
The following clinical features were used as inclusion criteria for investigation of the patients.
Lethargy, poor feeding ,persistent vomiting, cholestasis, intractable seizure ,decreased level of consciousness ,persistent hypoglycemia, unexplained acid base disturbance and unexplained neonatal death.
Result: Organic acidemia with 40 cases (42%) was the most frequent disorder diagnosed in our high risk populations, followed by disorder of galactose metabolism(30%), 15 patient had classic galactosemia(GALT



Inborn error of metabolism (IME) with an overall incidence of 1/2000 population represent a common cause of diseases in newborn period. Most infant with IEM are normal at birth, and the signs often develop in hours to days after birth (1,3).

IEM are part of the differential diagnosis of many infants admitted in PICU (2). Most of them are transmitted as autosomal ressesive genetic traits. A history of parental consanguinity, unexplained neonatal death or sever illness in family should alert the clinician to the possibility of an IEM (3).

Acute symptoms that are particularly associated with IEM include encephalopathy, intractable seizures, hepatic failure, cardiomyopathy, metabolic acidosis and hypoglycemia (2).

Many IEM are amenable to treatment with early diagnoses, for others that are not amenable to treatment, establishing the diagnosis in the index case is important for prenatal diagnosis in subsequent pregnancy. Therefore, selective

screening for inherited metabolic disease represents a major challenge to modern preventive medicine (3).Today the development of new modalities for diagnosis of these disease offers the potential substantially changing the natural history of these disease by reducing the mortality and morbidity. We used the panel newborn screening for diagnosis of aminoacidemias, organic acidemiase, fattyacid oxidation defect and galactosemia .Our purpose was to establish the prevalence of IEM in high risk population, as well as to raise the awareness of these disorders as an important group of genetic disease for medical community.


Material and methods

Over a period of four years (2007-2011) 650 patients with clinical features of IEM were admitted at the hospitals affiliated to Shiraz University of Medical sciences, these children were from Fars province and other provinces in south of Iran.

Table 1. Inborn error of metabolism detected in the populations from south of Iran 


Number of patients (%)

Number of patient analysed


Number of patient diagnosed




MMA, PPA, Cobalamin deficiency


Isovaleric  academia


Glutaric  academia type I














The following clinical features were used as inclusion criteria for investigation of the patients.

Lethargy, poor feeding, persistent vomiting, cholestasis, intractable seizure, decreased level of consciousness, persistent hypoglycemia, unexplained acid base disturbance and unexplained neonatal death.


Sample collection

Blood samples were collected on filter paper and dried for 3-4 hours at room temperature and shipped frozen with dry ice to Wagner laboratory in Germany and lab test was done by neonatal screening panel.



From the 650 symptomatic children screened over a period of 4 years 92 were diagnosed as IEM. The mean age was 15 months, from 15 days to 6 years.Sixty four were male and twenty eight were female (Table 1).


Disorder of metabolism of galactose

Of 27 patient with high galactose 15 had classical galactosemia (GALT<5%), 4 patients had
Table 2.
Clinical finding in patients with IEM


Clinical feature


Lethargy, poor feeding, vomitong, coma, respiratory distress, metabolic acidosis, death


Hyperbili, poor feeding, lethargy, hepatic failure

Isovaleric acidemia

Poor  feeding, lethargy, coma

Glutaric acidemia type I

Macrocephaly developmental regression, dystonia


Lethargy, poor feeding, convulsion, coma, metabolic acidosis


Seizures, microcephaly, light colored skin and hair


Poor feeding, lethargy, vomiting, coma

Carnitin Transcarbomilase deficiency

Hepatic disease, cardiomyopathy, coma


high galactose and galactose -1-posphate, 9 patients had high galactose (one was diagnosed as Fanconi–Bickel syndrome). The most clinical finding were prolonged hyperbilirubinemia, followed by lethargy, poor feeding and liver failure.


Disorder of organic acid metabolism

Methyl malonic acidemia or propionic acidemia were the most common organic acidemia followed by Glutaric -acidemia type I and the isovaleric acidemia other organic acid disorders were relatively rare .patients with MMA or PPA were presented with lethargy, poor feeding, metabolic acidosis pancytopenia, coma and respiratory arrest.


Amino acid disorders

Among the disorders of amino acid metabolism, Maple syrup urine disease was the most common



Table 3. Abnormal parameter of disorder of amino acid metabolism

Aminoacidemias (n=15)

Abnormal parameter

Concentration mean range( µmol/L)

Reference range

Phenylketonuria       4


Phenylalanin/Tyrosine  ratio

1113(412-1951)                                          18(11-39)



Citrllinemia                2




Tyrosinemia type I   1




Markedly elevated


Hmocystinuria          1




MSUD                          7


The ratio (Leucine-Isolucine)/Phe









Table 4. Level of abnormal parameters for different organic acidemias

Organic acidemias


Abnormal parameter


Reference range (µmol/L)









Lsovaleric acidemia


Isovaleryl carnitin

Isovaleryl carnitin/acetylcarnitin





Glutartic academia type I


Glutaryl carnitin



Biotidinase deficiency


3-hydroy isovaleryl carnitin



Multiple carboxylase deficiency


3-hydroxy isovaleryl carnitin

Propionyl carnitin






Table 5. Abnormal parameter of galactose metabolism

High galactose




High Galactose-1-phosphate



Fanconi Bickel


followed by phenylketonuria and Citrullinemia. Tyrosinemia type I and homocystinuria were relatively rare. In MSUD the characteristic finding were lethargy poor feeding, convulsion, coma, spasticity and metabolic acidosis. All of the patients had brain edema in CT scan.


Fatty acid oxidation defect

 625 patients investigated, four children had fatty acid oxidation disorder. Two with carnitin transcarbamilase deficiency, one had Medium-Chain-A CO-dehydrogenase deficiency and one had mitochondrial fatty acid oxidation defect.

The clinical findings and abnormal parameters that detected are shown in Table 2-5.



Although early diagnosis of metabolic diseases is very effective in the treatment of these disorders, neonate are screened for few diseases even in the developed world so selective screening is important for diagnosis of specific IEM.

Specific protocol for selective screening of IEM in high risk patient has been introduced since 1950 in several country. A constant improvement of analytical equipment and techniques for assaying has allowed the diagnosis an increasing number of disorder. We used the panel newborn screening for diagnosis.

A total of 92 (14%) of 520 symptomatic patients abnormal result were found in of our patients, which was lower than detection in Egyptian study, they diagnosed IEM in 22.73% of their patients (6), in another study in Karachi the detection rate was 16 out of 62 (25.8%)(9). However several other studies, two in Brazillian (7,8) and one Indian (4) reported lower detection rate 6.5%, 3.17% and 3.2% respectively .Different detection rate in different studies can be due to different criteria for selection of high risk patients and availability of local facility for diagnosis of IEM.

Of these 22 patient had high propionyl carnitin (methy malonic acidemia. Propionic acidemia and cobalamin deficiency), 27 had disorder of galactose metabolism, 8 had Glutaric acidemia typ 1, 7 had MSUD,7 had Isovaleric acidemia, 4 had phenylketonuria, 3 had citrullinemia, 2 had Argininosuccynyl acidemia, 2 had biotidinase deficiency, 1 had multiple carboxylase deficiency, 2 had carnitin transcarbomilase deficiency, 1 had either MC-ACO-dehydrogenase deficiency, Tyrosinmia type 1, Mitochondrial fatty acid oxidation defect, Aryelsulfatase deficiency, Canavan disease, GM2 gangliosidosis, Homocystinuria and Hexo Aminidase deficiency.

Organic acidemias with 40 cases (42%) was the most frequent disorder diagnosed in our high risk populations, followed by disorder of galactose metabolism (30%), 15 patient had classic galactosemia (GALT<5%).

Methyl Malonic acidemia and propionic acidemia were the most common, they become symptomatic from three days to several months after birth. The most common symptoms in these patients were repeated vomiting, respiratory distress and lethargy. Most patient had repeated hospitalization even on special formula. Disorder of amino acid metabolism also is not uncommon (17%) in this high risk population, MSUD was the most common.

MSUD was fairly common in other reports from Asian populations (10,11). MSUD patients become symptomatic at 3-7 days after birth, neurological symptoms were the most common (lethargy, poorfeeding, convulsion, dystonia and coma).

CT scan showed generalized brain edema in all of our patients. Death occurred in 4 out of 7 patients and the other three patients showed mental and motor developmental delays on special amino acid formula and low protein diet. Msud had the poorest outcome among the aminoacidemias.

Of 15 patients with classical galactosemia (GALT activity below 5%) all except one presented with cholestasis. The most common symptoms were jaundice, lethargy and poor feeding. Cataract was also common in our patients (41%).

In a selective study in Karachi organic acidemias were also the most common and represented 62% of their patients (6). In another study in India PKU was the most common disorder (4). PKU is not rare in this country, in study by J. Golbahar et al the incidence of PKU was 27/100000 population (5), lower rate of PKU in this study is due to early detection by screening test. Screening test also take place for galactosemia but in another our study 100% of patient with galactosemia were symptomatic before screening results.

In a selected screening of 231 cases in Egypt organic acidemia was the most common (6), in another study in Brazilian patients, PKU and GM1 gangliosidosis were the diseases with the highest incidence (7).

Fatty acid oxidation defect was relatively rare in this study this is comparable with other study by Moacir Wajner et al (8) and another study in India (4).

We need more sensitive method like MS/MS for separation of organic acidemias.

 Fortunately one local facility with this modality already has started its work in this town.



Although metabolic diseases individually are rare but overall are a common causes of neonatal disease, early diagnosis and treatment can prevent death in many of them but cure doesn`t occur, they survive with mental and motor developmental delay, they need rehabilitation, repeated hospitalization, special formula and associated cost might represent a heavy burden for families with low and middle social economic incomes. Detection of specific mutation is necessary for familial counseling in this country with high rate of consanguineous marriage (12). The government should increasing insurance coverage to patients with IEM.



We thanks Dr Baziary laboratory for all their help.

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