result of 19 years collaborative study on metabolic disorders

in 1902, well known archibald garrod applied mendels gene concept to human characters. he opened a new window in understanding the etiology of metabolic disorders. he proposed biochemical changes as the etiology of metabolic disorders in his series of papers inborn errors of metabolism (1906). after establishing prenatal diagnosis facilities for the detection of chromosomal abnormalities in our center in 1990, we came across the demand for prenatal diagnosis for other genetic diseases including hemoglobinopathies and muscular and metabolic disorders. we became aware that the clinical genetic department of erasmus university (cgdeu) is working on diagnosis and prenatal diagnosis of metabolic disorders by identifying the deficient enzyme. we requested collaboration with that center which was duly accepted. our responsibility was to complete the clinical work up, ascertaining families, preparing a clinical history, drawing pedigrees, clinical examination, requesting paraclinical tests and narrowing down the diagnosis. the required sample (blood, urine, skin biopsy) was prepared in our center and sent to cgdeu for enzyme assay for confirmation of diagnosis. once diagnosis was established, we were able to offer prenatal diagnosis to the families and amniotic fluid or chorionic villi was sent for prenatal diagnosis. a large number of families with affected offsprings have been referred for genetic counseling. some probands were clinically diagnosed with a given metabolic disorder upon referral and required confirmation yet, a large number lacked a specific diagnosis and needed to be clinically screened. the clinical work up for families according to suspected clinical diagnosis was performed including: i. clinical history a. pedigree b. fetal development c. perinatal history d. neonatal history e. developmental milestones f. mental development ii. physical examination a. measurements: height, weight, head circumference b. facial features: screening for coarseness, corneal opacities, c. stature: skeletal posture d. limbs and torso: joints iii. neurological examination a. muscular tonicity b. gait c. myoclonus d. hypotonia iv. ophthalmological examination a. orientation and gaze b. retinal examination: pigmentation, degeneration, cherry red spot c. corneal opacities v. cardiovascular examinations when abnormality suspected vi. skeletal survey: when deformity suspected vii. paraclinical tests: a. general tests: a. blood: arterial blood gas, electrolytes, blood glucose, ammonia, complete blood count, lactate, pyruvate b. urine: glucose, ph, ketones, reducing substance b. specialized tests: when required a. liver enzymes b. reducing substances c. amino acids d. organic acids viii. brain ct scan or mri upon necessity. results are summarized in the following tables. results of prenatal screening for metabolic disorders in our lab. from aug. 1990 - nov.01.2009 type of disease lipid storage disease no. of families affected members pnd normal affected fetuses mld 20 21 17 12 4 niemann-pick 16 26 10 8 2 gauchers 12 15 3 2 1 tay-sachs 14 14 10 5 5 canavan 5 10 - - - mucolipidosis 8 9 4 4 - sand hoff 7 9 4 2 2 alexander 3 3 - - - lipidosis 3 5 - - - nclf 3 4 - - - gm1-gangliosis 2 6 3 3 - fabry 2 5 - - - krabbe 3 3 4 3 1 fucosidosis 1 1 1 1 - wolman (lsd) 1 2 - - - sbh 1 2 - - - total 101 135 56 40 15 mps no. of families affected members pnd normal affected fetuses mps i 21 24 20 17 3 mps ii 24 40 19 11 8 mps iii a 17 22 18 12 6 mps b 16 19 14 11 3 mps c 1 2 1 1 0 mps d 2 6 3 2 1 mps iv - - 4 4 - mps v - - - - - mps vi 18 25 13 13 - multiple mps 1 2 0 0 0 total 105 146 92 72 21 miscellaneous no. of families affected members pnd normal affected fetuses ataxia telangictasia 3 6 3 1 2 xeroderma pigmentosa 5 9 10 6 4 cockayne syndrome 6 6 2 2 – tyrosinemia type i 2 2 2 1 1 mma 1 3 – – – 2-hyroxyglutaric acidemia 2 2 – – – msud 9 17 12 10 2 zellweger 1 2 – – – propionic acidemia 1 1 – – – g. s. d iii, ix 1 1 1 1 1 – 1 – – – chondro dysplasia punctata 1 2 – – – lesh-nyhan 1 3 1 – 1 total 34 56 32 21 10 grand total 240 283 180 133 47 we would like to propose our collaborative model as an appropriate beneficial style in spite of the long distance. within this model, it is important to establish close communication among various involved groups: clinicians who care for the patients, those who counsel these families, the practitioners involved in the diagnosis of the cases and finally, the laboratories who run diagnostic tests. the appropriate sample, transport and media are essential for reliable test results these are factors which have to be modeled upon available internal resources. in these cases, as in all situations where a net diagnosis is required, we would like to stress the importance of limiting clinical impressions and possible diagnosis before attempting expensive laboratory testing. in our experience, emphasis on clinical workup prior to testing can cut down unnecessary expenses, time and effort. acknowledgement i extend my best appreciation to the netherlandss group otto van diggelen, w. j. kleijer, and jan huijmans for their valuable collaboration. i also have to thank my colleagues in our center: youssef shafeghati md., fariba afoozan md., bita bozorgmehr md., navid almadani md., valeh hadavi and roxana kariminejad ph.d.