Pediatrics 5th year, 15th lecture/part one (Dr. Jamal)
Inborn Errors of Metabolism(IEM)This is a group of genetically determined diseases, most of which areinherited by A.R. mean. Several hundred diseases have so far beenidentified and the number is increasing.Nearly all forms of IEM are caused by absence of a single enzyme leadingto disturbance of a particular metabolic pathway. Accumulation ofcompounds proximal to the enzymatic block in the metabolic pathway ordue to deficiency of products distal to it is the underlying causative factorin the majority of cases.A large proportion of IEM present soon after birth while others presentlater with various manifestations.Clinical situations and finding which should make IEM highly suspiciousinclude:In neonate: lethargy, prolonged jaundice, convulsion, acidosis.In infants and older children: delayed intellectual and motor mile stones,unexplained odors during acute illness, corneal opacity, cataract or lensdislocation, unexplained renal stones and unexplained episodes of vomiting,acidosis and coma.Classifications of IEM: 1. Errors in protein metabolism:
a. Errors in plasma protein synthesis: e.g. Afibrinogenemia, hemophilia, agamaglobulinemia…etc b. Errors in Hb synthesis as hemoglobinopathies. c. Errors in amino acid metabolism or transport defects as PKU, Alkaptunurea, Homocystinurea, maple syrup urine disease, Hartnup disease, Fanconi syndrome, Cystinurea and cystinosis. 2. Errors in carbohydrate metabolism; Congenital lactose intolerance, Galactosemia, Glycogen storage diseases, D.M.& Mucopolysaccharidosis. 3. Errors in lipid metabolism; Lipidosis ( Gauchers, Neimann-pick and Tay-Sachs disease), Abetalipoproteinemia& hyperlipidemia. 4. Errors in pigment metabolism; Albinism, porphyria, Meth- hemoglobinemia, primary hemochromatosis, Dubin-johnson and Gilbert disease. 5. Unknown biochemical errors as ontogenesis imperfect, Marfan syndrome, Achondroplasia and Ehlers-Danlos syndrome. Examples of IEM: Phenylketonurea
An A.R. disorder which occurs at a rate of 1 in 10.000, caused by a defect in the enzyme phenyl alanine hydroxylase which is responsible for converting phenylalanine to tyrosine Phenyl alanine hydroxylase Phenyle alanine Tyrosine Melanin Affected children look normal at birth, then they become blonde and have blue eyes due to melanin deficiency .they also suffer progressive deterioration becoming intellectually retarded, hyperactive, have convulsion and may show skin eczema. They also suffer anorexia vomiting, excessive sweating with a peculiar odor of sweat and urine. Diagnosis is made by urine ferric chloride test and then by serum phenyl- alanine level. Treatment is by special formula which is low in phenylalanine, this should be started from neonatal period and continued for several years. Homozygous affected females should go back to this treatment during every pregnancy to avoid prenatal affection of the fetus. Galactosemia:
An A.R. disorder caused by absence of the enzyme Galactose-1-phosphate–uridyl- transferase which is responsible for converting galactose toglucose, as a result of this galactose accumulates in the blood & differentbody tissues causing permanent damage in some of them.Clinically affected children show symptoms as soon as galactose (from milklactose) is consumed, they will show feeding difficulty, vomiting, prolongedjaundice, hepatomegaly, hypoglycemia and convulsion.Mental retardation, cataract, and renal manifestations (albuminurea andaminoaciduria) may occur after neonatal period in untreated patients.Diagnosis can easily be made at the bedside of the patient by having +veclinitest (indicate presence of a reducing substance) and –ve clinistix(specific for glucose), further confirmation requires estimation of theinvolved enzyme in RBC.Treatment consists of absolute withdrawal of milk and its products forseveral years. Glycogenstorage diseases “GSD”:A group of A.R. disorders, caused by deficiency of various enzymes andhave various clinical manifestations. Type 1 GSD (Von-Geirkes disease): the commonest form of the group, caused by glucose-6-phoshpatase deficiency. Clinically this type is characterized by frequent attacks of hypoglycemia, doll-face,
short stature, massive hepatomegaly, hyperurecemia, ketonurea and bleeding tendency. Diagnosis is confirmed by liver biopsy which shows increased fat and glycogen while absence of the involved enzyme. Treatment is by frequent feeding during infancy. Type IIa (pompes disease) characterized by progressive cardiomegaly and congestive H.F. Type IIb characterized by skeletal muscle dystrophy without heart affection. Type III (cori) characterized by involvement of liver, skeletal muscle and RBC. Mucopolysaccharidosis (MPS)A group of hereditary conditions, characterized by storage of acid-mucopolysaccharides in different body tissues.The known types of MPS are:1- Hurler syndrome.2- Hunter syndrome.3- Sanfillipo disease.4- Morquio disease.5- Sly syndrome.
6- Maroteaux-Lamy. The main characteristics of MPS in general include: • Specific enzyme deficiency in each type e.g.: a-L-iduronidase in Hurler and iduronosulfate sulfatase in Hunter type. • Skeletal deformity (dysostosis multiplex) occurs in all type. • Affection of multiple organs and body systems in most. • All are A.R. except type II (hunter) which is XLR. • Intellectual sub normality (in all except in Morquio and Maroteaux Lamy). • Diagnosis depends on : 1. Clinical manifestations. 2. Urinary excretion of mucopolysaccharides. 3. Finding of the specific enzyme deficiency. • No treatment is yet available for any of them. B.M. or cord blood transplant or specific enzyme replacement may in future be a successful treatment for them. Lipidosis (lipid storage diseases): A rare group of inherited (A.R.) diseases, characterized by, deposition oflipid in various tissues & body organs.
The 3 main types of which are: 1. Gauchers disease: caused by deficiency of the enzyme Beta- glucosidase. • Infantile type is characteristically rapidly progressive, hepatosplenomegaly and mental retardation. • Juvenile type spares the brain while only causes hepatosplenomegaly. • The adult type is less severe and causes anemia, thrombocytopenia and involvement of long bones. Diagnosis is by finding Gauchers cell in the bone marrow. Treatment is symptomatic. Death is nearly always the rule in all forms. 2. Neimann-Pick disease (NPD): caused by deficiency of sphingomylinase enzyme, which results in accumulation of sphingomylin in various tissues and organs. Affected patients have mental retardation, anemia, hepatosplenomegaly, lymphadenopathy and a cherry-red spot is seen in the region of macula in 1/3 of cases. Diagnosis is made by finding NP cells in the bone marrow or blood. Miliary T.B. –like picture can be seen on chest X-ray. No treatment is available and the condition is almost fatal. 3. Tay-sachs disease (Amaurotic family idiocy) caused by hexosaminidase deficiency and is far more common in Jewish.
There is cerebral but no-visceral involvement. Macula cherry-red spot isseen in some.