Inherited metabolic diseases Lec 14 Inherited diseeases are

Inherited metabolic diseases Lec. 14

Inherited diseeases are due to: n Genetically determined absence or Modification of specific proteins e. g. sickel cell anamia. Majority of disease, protein is an enzyme which causes metabolic disorder n Defective of receptor synthesis (hypercholesterolaemia) n Many inherited metabolic diseases are due to a mutation of single gene affecting the synthesis of enzymes.

Effects of enzyme defects Metabolism is the sum of the chemical processes and interconversions that take place in the cells and the fluids of the body. n Almost every chemical step of metabolism is catalyzed by an enzyme. Disorders of these enzymes that result from abnormalities in their genes are known as natural errors of metabolism n

Decreased formation of the product It is due to a lack of enzyme c in the previous fig. n If the enzyme c is defective the product D cannot be synthesized n Due to the lack of the formation of D many clinical features will appear n

Accumulation of the substrate C of the missing enzyme. n Accordingly clinical manifestation will result. n Earlier substrates may accumulate if the reactions prior to the one blocked are reversible. A→B↔C↔D→E -ve feedback n

Increased formation of other metabolites Increased formation of E (product of minor pathway may occur if the conc. of C is increased due to enzyme deficiency. n Accordingly clinical syndrome will result. n

Glucose 6 -phosphate deficiency It is due to the lack of formation of the product of the enzyme catalyzed reaction. n Glucose synthesis from glycogen or gluconeogenisis is blocked. n In children → fasting hypoglycaemia n Glucose 6 -phosphate deficiency lead to accumulation of other immediate substrate n Glycogen accumulates in the liver causes hepatomegaly. n

block in gluconeogenesis results in the accumulation of lactate →lactic acidosis n Hyperlipidaemia due to increased fat synthesis n Accumulation of glycogen in platelets→ disordered in platelets function. n Glucagon nor adrinaline increase blood glucoe in case of G 6 Phosphatase deficiency. n

Galactosemia Another common disorder of carbohydrate metabolism is galactosemia, which is due to the inability to form glucose from galactose n The classic form of galactosemia is due to a deficiency of the enzyme galactose-1 phosphate uridyl transferase. n This enzyme is required for the conversion of galactose to glucose 1 -P and galactose cannot convert into glycogen n

As a result galactose 1 - P will accumulated. n The plasma conc. of galactose is increased and the galactose will excreted in the urine. n It presents in the infants with fatal liver failure. n

Phenylketonuria (PKU) is a genetic disorder n characterized by an inability of the body to utilize the essential amino acid (phenylalanine) n The enzyme that breaks down phenylalanine (phenylalanine hydroxylase) PAH, is completely or nearly completely deficient. n

This enzyme normally converts phenylalanine to another amino acid, tyrosine. n Without this enzyme, phenylalanine accumulate in the blood and body tissues. n Chronically high levels of phenylalanine and some of its breakdown products can cause significant brain problems. n

n Children with PKU appear normal at birth. n Many have blue eyes and fairer hair and skin than other family members n Defect in melanin synthesis due to the block of tyrosine formation which responsible for the formation of this pigment.

n Excessive phenylalanine in the blood saturates the large neutral amino acid transporter (LNAAT). Thus, excessive levels of phenylalanine significantly decrease the levels of other LNAAs in the brain. These amino acids are required for protein and neurotransmitter synthesis. Reduced protein and neurotransmitter synthesis disrupts brain development in children, leading to mental retardation.

Women with PKU are advised to lower their blood phenylalanine levels before they become pregnant and carefully control their phenylalanine levels throughout the pregnancy. n Treatment of PKU is the elimination of phenylalanine from the diet. n Phenylalanine found in protein containing foods such as meat, dairy products, fish, grains and legumes. n

Steroid 21 -hydroxylase deficiency Known as congenital adrenal hyperplasia. n It is an inherited disorder that affects the adrenal glands which produce a variety of hormones such as cortisol and aldosterone. n Cortisol maintaining blood sugar levels, protecting the body from stress n People with 21 -hydroxylase deficiency affect the conversion of cholesterol to cortisol and aldosteron which stimulat the synthesis of adrenal androgen. n

DNA analysis n DNA analysis is a standard technique for the investigation of many inherited disorders.

variants A rarer form of the disease occurs when PAH is normal but there is a defect in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH 4) by the patient. This cofactor is necessary for proper activity of the enzyme. n This deficiency of this enzyme is caused by mutation in the PAH gene (on chromosome 12 n