1. Demographic and Clinical Findings in Pediatric Patients Affected By inherited metabolic disease in Isfahan province 1386-1393

2. M. Hashemipour Isfahan University of Medical Sciences R.Najafi Ilam University of Medical Sciences

3.  Metabolic disorders, which are ascribable to enzyme deficiency lead to either excessive or lack of special metabolic components  Mostly present themselves during infancy or neonatal ages or even adulthood  They lead to accumulation of abnormal biochemical substrates, which may have potential toxic roles

4.  Metabolic disorders have a wide range of clinical symptoms  Twenty percent of full-term infants who are suspected of infectious diseases may be affected by metabolic diseases  Different organs may be involved in metabolic disorders and simultaneously show pathological dysfunctions  Onset of disease may vary due to environmental factors and nature of the disease

5.  Categorized as autosomal recessive  History of infants’ sudden death,parental consanguinity can be exploited as a clinical clue for metabolic disorders.  Damages in vital organs, especially in brain, unless early proper treatment is performed  Screening methods help early diagnosis

6. Sign& symptom  During infancy, lethargy, poor feeding and vomiting may be developed due to these disorders  More importantly regression and mental retardation can affect unless early diagnosis and appropriate treatment are established

7. Paraclinical findings Metabolic acidosis, hyperammonemia, ketosis, sepsis-like conditions, bone marrow suppression,hypoglycemia, hepatic failure can also help the diagnosis process

8. Diagnosis  Measurement of plasma amino acids as well as the analysis of enzymes and organic acids existing in urine  Metabolic screening is not implemented in most of Middle East countries  Some of the studies demonstrated that these diseases are more prevalent in this region  This study aimed to evaluate some of the demographical and clinical findings in pediatric patients affected by IEM in Isfahan province

9. Material and Methods  This cross-sectional study was conducted on metabolic disorder patients within the seven years period of 1386-1393 in Isfahan province  Covered a wide range of cases from new born infants to seventeen years old children  Evaluated demographic information as well as disease history, educational, general, developmental and clinical status of the patients

10. Material and Methods  Information was gathered through telephonic and face to face interviews  Inclusion criteria were clinical and paraclinical signs of IEM  Enzymatic and metabolic evaluation was conducted on patients’ blood in the Wagner Stibbe laboratory in Hanover, Germany.

11. Results  5100 patients were screened  392 patients were affected by one of the metabolic disorders  Girl 45.2%  Boy 54.8%  167/392 patients were diagnosed with organic acidemia

12. Type of diseasenumberpercentIncidence rate Methylmalonic/propionic acidemia 58151:10379 Free fatty acid oxidation disorder 3181:19419 Urea cycle disorder3181:19419 Tyrosinemia287.31:21500 Holocarboxylase/biotinidase246.21:25083 Galactosemia2361:26173 Maple syrupe urine disorder184.71:33444 Isovaleric acidemia184.71:33444 Glutaric aciduria194.81:31684 Mucopolysaccharidosis164.11:37625 Glycogen storage disorder153.91:40133 Frequency of different types of Inherited metabolic diseases

13. Type of diseasenumberpercentIncidence rate Lipid storage disorder123.11:50166 Homocystinuria92.11:66888 Gauchers disease71.81:86000 Mitochondrial disorder51.31:120400 Fructose intolerance51.31:120400 Cystinosis51.31:120400 Peroxisomal disorder3.81:200666 Lisinuric protein intolerance 1.31:602000 Frequency of different types of Inherited metabolic diseases(continued)

14. incidence rate of metabolic disease 1:1536 65:100000 live birth

15. Frequency of different subtypes of organic acidemia PercentNumberSubtypes of organic acidemia 14.858Methylmalonic/propionic acidemia 12.248Other organic acidemia 6.124Holocarboxylase/biotinidase 4.819Glutaric aciduria 4.618Isovaleric acidemia 42.5167Total

16. Frequency of parental consanguinity in patients with IEM  Consanguineous marriage ;82.6% Third degree marriage ;63.5% Marriage in other familiar categories ;19.1%

17.  Mucopolysaccharidosis 86.7%  Gauchers disease 85.5%  Tyrosinemia 78.6%  Methylmalonic /propionic 60 % Frequency of parental consanguinity in different types of IEM

18. Type of diseaseGirls (%)Boys(%) Lipid storage disorder58.341.7 Homocystinuria50 Gauchers disease14.385.7 Mitochondrial disorder6040 Fructose intolerance8020 Cystinosis50 Peroxisomal disorder0100 Lisinuric protein intolerance1000 Methylmalonic/propionic acidemia56.943.1 Free fatty acid oxidation disorder41.958.1 Sex distribution in patients with different types off IEM

19. Type of diseaseGirls(%)Boys (%) Urea cycle disorder45.254.8 Tyrosinemia53.646.4 Holocarboxylase/biotinidase29.270.8 Galactosemia26.173.9 Maple syrupe urine disorder66.733.3 Isovaleric acidemia50 Glutaric aciduria55.644.4 Mucopolysaccharidosis31.368.8 Glycogen storage disorder6040 Sex distribution in patients with different types of IEM

20. Number of Hospitalization(days) in patients with IEM

21. The median age of disease onset in patients with IEM

22. Frequency of IEM diagnosis in different age group of patients

23. Frequency of different biochemical findings in patients with IEM  Acidosis %42  Hyperammonemia 21%  Hypoglycemia 11.1%

24. Frequency of different signs and symptoms in patients withIEM  Developmental delay 37.8%  Seizure 28.2%  Hepatomegaly 13%

25. Mortality rate in family with IEM Methylmalonic/propionic acidemia Free fatty acid oxidation disorder Glycogen storage disease The rate of mortality was higher in families of patients with metabolic disorders 38%

26. Frequency of death in IEM with higher rate of mortality Mitochonderial disorder 80% Maple syrupe urine disorder 44.4% Tyrosinemia 42.8%

27. The trend of IEM diagnosis from1386 to1393

28. Educational status of patients with IMD

29. Discussion

30. Trend of IEM diagnosis  During the study time,from 1386 to 1393,diagnosis of IEM had increasing trend, it may be due to;  Availability of sensitive diagnostic techniques  Increased knowledge of families about IMD  Increased clinical suspicion of physicians

31. Prevalence of IEM Reported incidence rate of IEM have great variability in different populations  England 40/100000  Saudi Arabia 150/100000  Australia 1/ 2855  Isfahan 1/1536

32. Prevalence of different types of IEM Reported prevalence rate of different types of IMD are not similar in different studies worldwide  In the study of Christiano et al. in Brazil, the most common types of IEM were PKU and MPS  In another study in Brazil lysosomal storage disease (59.8%) and aminoacidopathy (21.2%) were the most common types of IEM  In a study in India,the most frequent IEM was PKU with a prevalence rate of 27/100000 live birth

33. Prevalence of different types of IEM  In a study in Saudi Arabia, Moammar et al. have reported lysosomal storage disease as the most common IEM  Aminoacidopathy was reported as the most prevalent type of IEM in Bahrein,Lybia and Australia *During this study we did not include PKU cases

34. Prevalence of organic acidemia  Previous studies indicated that organic acidemia is more prevalent in the Middle East countries  1/8000 in Bahrain  150/100000 in Saudi Arabia Reported prevalence rate was lower in  Canada  Australia  Italy(1/21422 in Italy

35. Incidence rate of organic academia  In current study, incidence rate of organic acidemia was 27/100,000 live birth (1:3604)  PA/MAA with incidence rate of 1/10379 live births was the most common type of organic acidemia  (29% of organic acidemia cases)  Our findings regarding the higher prevalence rate of PA/MMA was in accordance with analogous studies conducted in China and Saudi Arabia, Pakistan and Egypt

36. Parental consanguinity and IMD  Parental consanguinity is considered as a risk factor for IEM  According to the report of WHO, prevalence of parental consanguinity is higher in Middle East countries,including Iran  Prevalence of consanguineous marriage was reported to be 30-40% in Iran  In this study, the rate of parental consanguinity was 82.6%in patients with IEM.

37. Parental consanguinity and IEM  In a study in Turkey, Stike et al. have indicated that consanguinity is one the main risk factors for higher rate of IEM  In another study in Saudi Arabia, Dammam and colleagues, have reported that parents of 57.7% of patients with IEM had consanguineous marriage.

38. Parental consanguinity and IEM  Karimzadeh et al. have reported parental consanguinity among 50% of patients with MMA  Rate of parental consanguinity was 84% (21/25) in the study of Golbahar  The rate was 86.9% in a study in Libya  In a study in Saudi Arabia by Hissa et al.,prevalence of parental consanguinity was 40-60% in different regions of the country.

39. Parental consanguinity and IEM  In the study of Chirstiano et al. in Brazil, prevalence of parental consanguinity was 25%  Al Ageel and colleagues have reported that the rate of parental consanguinity ranged between 60-70% in Middle east which result in occurrence of higher rate of specific genetic disorders in these regions.  Whereas prevalence of mentioned disorders are low or rare in Western countries with lower rate of parental consanguinity

40. Parental consanguinity and IEM  Genotypes of these diseases generally are autosomal recessive  Hamad waleed et al. found that consanguinity marriages rate were as high as 60 % in some societies which provided a risk factors of these metabolic diseases  Our study showed a higher frequency of parental consanguinity in PA/MAA patients

41. Signs and symptoms of IEM  It is suggested that signs and symptoms of the IMD is different in different studies regarding the methods of study and the type of IMD which is more common in the studied regions  In this study the most common clinical presentations of IMD were developmental delay and seizure  The most prevalent biochemical characteristics of the patients with IEM in our study were acidosis and hyperamonemia  In this study, most of the patients with PA/MMA presented by acidosis and more than 50% of them presented by developmental delay,seizure and hyperamonemia

42. Signs and symptoms of IEM  In a study in Pakistan,Shehla et al have reported that the two most common presentation of IEM in their studied patients were seizure and coma  In a study in Libya, hepatomegaly and jaundice were the more prevalent clinical presentations of IEM  Karimzadeh et al. have reported that the rate of developmental delay, seizure and acidosis among their studied patients with IEM, were 85%,60% and 25%,respectively

43. Signs and symptoms of IEM  Acidosis was found in half of the cases  One third of these patients had some degrees of developmental disorders and convulsion  One third of patients with IEM in the study of Kimberly in Canada and in a study in China had developmental delay  In another study, which was conducted by Wajner et al, organic acidemia cases dominantly showed neurologic abnormalities as well as metabolic acidosis, and growth retardation, in 65 %, 42 %, and 14 % of the cases respectively

44. Age of onset in IEM  In this study, more than 50% of clinical presentations of IEM were initiated during neonatal period, whereas 1/6 of the cases of IEM diagnosed during this period.  In the study of Shehla et al. in Pakistan,60% of patients with IEM diagnosed during neonatal period.  In the study which conducted in Libya, in 50% of cases, the presentations of IEM were initiated during 1-6 months after birth

45. Rate of mortality in IEM  In a study in Libya, the rate of mortality was 50%  In our study, the rate of mortality was 25%

46. Rate of mortality in IEM  Our study, as well as the previous one conducted by Wajner et al, documented a low frequency of mortality rate (25%).  On the contrary, mortality rates in France, Thailand and China were higher (29 %, 36 %, and 50 % respectively

47. Limitations  Lack of patient availability and cooperation, especially when they could not afford to pay for the paraclinical examinations, were assumed as our limitation

48. Conclusion  Although IEM is considered a rare disease, but totally it seems to be a common problem in our population  Early diagnosis and treatment would reduce the rate of mortality  Delay in diagnosis and treament would result in permanent development and motor impairment  Most of the patients with IEM need rehabilation  Most of the patients with IEM frequently require hospitalization

49. Conclusion  Almost all of the patients with IEM need special formula and diet as well as special care  The disorders has a high cost for both families and community  It is necessary to determine genetic mutations of the patients specially in populations with higher rate of parental consanguinity  Insurance should have better coverage for these patients

50. Conclusion  In general, early diagnosis of organic acidemia is obviously essential and can potentially prevent irremediable disorders.  Neonatal screening is crucial since the disease’s outcomes are improved when the age of the disease diagnosis is closer to onset of the disease.