Diseases due to Errors in Protein Metabolism

The following points highlight the fourteen major diseases caused due to errors in protein metabolism. The diseases are: 1. Albinism 2. Tyrosinosis 3. Tyrosinernia 4. Phenylketonuria 5. Alkaptonuria 6. Maple Syrup Urine Disease 7. Hartnup’s Disease 8. Glycinuria 9. Primary Hyperoxaluria 10. Cystinuria 11. Cystinosis  12. Homocystinuria 13. Histidinemia 14. Hypervalinemia.

Errors in Protein Metabolism: Disease # 1. Albinism:

a. This condition appears in the total absence of tyrosinase inside the melanocytes in the skin.

b. The black pigment melanin is not formed in the skin, eyes and hair.

c. This inherited condition occurs to a greater or less extent in all types of organism.

d. The diagnostic advice is for the preven­tion of exposure of sunlight and protec­tion of the eyes by wearing dark glasses.

Errors in Protein Metabolism: Disease # 2. Tyrosinosis:

a. This syndrome is due to the absence ei­ther of hepatic p-hydroxyphenylpyruvate hydroxylase or of tyrosine transaminase activities.

b. The patient excretes large quantities of ty­rosine in the urine.

c. Diet rich in tyrosine causes the excretion of other p-hydroxyphenyl acids includ­ing 3, 4-dihydroxyphenylalanine (dopa) and p-hydroxyphenyl lactic acid.

Errors in Protein Metabolism: Disease # 3. Tyrosinernia:

A. Neonatal tyrosinernia:

a. Neonatal tyrosinernia occurs in the new born.

b. Tyrosine, p-hydroxphenylpyruvic acid, p-hydroxyphenyl lactic acid and p-hydroxyphenyl acetic acid appear in the urine.

c. A transient deficiency of p-hydro-xyphenyl-pyruvic acid oxidase causes this condition and the condition lasts for a few weeks.

d. Administration of ascorbic acid and reduc­tion of protein intake brings about the normal condition.

B. Hereditary tyrosinernia:

a. This disorder is similar to neo-nataltyrosinernia, but the amount of p- hydroxyphenyl lactic acid in the urine is greater.

b. This disorder is not controlled by the ad­ministration of ascorbic acid.

c. It is due to the inherited deficiency of p-hydroxyphenyl pyruvic acid oxidase.

d. Liver failure and death can occur six months after birth and the infant has a char­acteristic odour.

e. Other patients develop the clinical find­ings including hepatosplenomegaly, a nodular cirrhosis of the liver, abnormali­ties of tyrosine and methionine metabo­lism, multiple defects in renal tubular reabsorption, rickets, hyperphosphaturia, pro­teinuria and amino aciduria.

f. Diet containing low in tyrosine and phe­nylalanine improves renal function and also retards degenerative liver changes.

Errors in Protein Metabolism: Disease # 4. Phenylketonuria:

a. This inherited disorder appears in the absence of phenylalanine hydroxylase which is responsible for the conversion of phenylalanine to tyrosine. As a result, al­ternative catabolizes of phenylalanine are produced; these include phenyl pyruvic acid, deamination product of phenyla­lanine; phenyl acetic acid, the decarboxy­lation and oxidation product of phenyl pyruvic acid.

Much of the phenyl-acetyl-glutamine is excreted in the urine.

b. Mental retardation develops among in­fants and children.

c. Patients with phenylketonuria tend to have a deficiency of serotonin. This may be connected with the defect of myelin synthesis.

d. The accumulation of phenylalanine also impairs melanin synthesis and children with this defect tend to have fair skin and fair hair.

e. Excess of phenylalanine in the blood leads to excretion of the amino acid into the intestine. Here, it competes with the tryptophan for absorption and tryptophan is subjected to the action of intestinal bac­teria.

f. Early diagnosis (shortly after birth) and extreme restriction of phenylalanine in­take is effective in preventing this disor­der.

Errors in Protein Metabolism: Disease # 5. Alkaptonuria:

a. This condition is characterized by the ex­cretion of homogentisic acid (di-hydroxyphenyl acetic acid) in the urine owing to the lack of homogentisic acid oxidase.

b. This abnormal condition is often found in infancy. Over 600 cases have been re­ported. The incidence of alkaptonuria is 2-5 per million live births.

c. The most clinical manifestation is the dark urine due to the oxidation of homogenti­sic acid in air.

d. In this disorder, several grams of homoge­ntisic acid are excreted daily.

e. This condition is present at birth and per­sists throughout life.

f. In later life, accumulation of dark pigment in cartilages and tendons gives rise to the condition known as ochronosis, which is accompanied by arthritic changes.

Errors in Protein Metabolism: Disease # 6. Maple Syrup Urine Disease:

a. This syndrome is characterized by the ab­sence of the enzymes required for the oxidative decarboxylation of the keto ac­ids derived from the branched chain amino acids-valine, leucine and isoleucine. As a result, these keto acids are accu­mulated in the blood and excreted in urine. The urinary excretion of these keto acids produce an odour like that of maple syrup or of burnt sugar.

b. This familial disorder is recognized by central nervous system manifestations of convulsions and attacks of flaccidity and apnea.

c. The patients may be well treated with amino acid mixtures low in the above three amino acids.

d. The infant is difficult to feed and may vomit. The patient suffers from a signifi­cant degree of lethargy.

e. Death may occur by the end of the first year of life without treatment.

Errors in Protein Metabolism: Disease # 7. Hartnup’s Disease:

a. It is a hereditary disease characterized by a pellagra-like rash and mental deteriora­tion in the abnormal metabolism of tryp­tophan.

b. The urine of the patients contain signifi­cantly increased amounts of indole acetic acid as well as tryptophan.

c. The urinary excretion comes to normal after administration of broad spectrum an­tibiotics.

Errors in Protein Metabolism: Disease # 8. Glycinuria:

a. This condition is associated with the ex­cess urinary excretion of glycine with a tendency to form oxalate renal stones in spite of the normal amount of excretion of oxalate in the urine.

b. The plasma content of glycine is normal in glycinuric patients while the urinary excretion of glycine ranges form 600-1,000 mg./d.

c. It is supposed that glycinuria is due to a defect in renal tubular transport of gly­cine and the decreased reabsorption of glycine by the renal tubule permits the amino acid to pass into the urine in high concentration.

Errors in Protein Metabolism: Disease # 9. Primary Hyperoxaluria:

a. This is an inherited disorder characterized by increased urinary excretion of oxalate which is not related to dietary intake of oxalate.

b. The deficiency of the enzyme glycine transaminase together with some impair­ment of glycine oxidation to formate is the cause of excess oxalate in the form of glyoxalate formed from glycine.

c. The clinical features exhibit progressive bilateral calcium oxalate urolithiasis, nephrocalcinosis and recurrent infection of the urinary tract which may be due to re­nal failure or hypertension.

d. Death occurs in childhood or early adult life from renal failure or hypertension.

Errors in Protein Metabolism: Disease # 10. Cystinuria:

a. It is an inherited metabolic disease in which lysine, arginine, ornithine and cys­tine are excreted in the urine in large amounts.

b. Cystinuria is due to renal transport defect.

c. Cystinuria is a misnomer, so that cystinelysinuria may be preferred as the descrip­tive term for this disease.

d. Cystine is an insoluble amino acid which may precipitate in the kidney tubules to form cystine calculi in cystinuric patients. This is a major complication of this dis­ease.

e. The mixed disulfide of L-cysteine and L- homocysteine present in the urine of cystinuric patients is more soluble than cysteine and hence reduces formation of cystine crystals and calculi.

Errors in Protein Metabolism: Disease # 11. Cystinosis (Cystine Storage Disease):

a. It is a rare lysosomal disorder characte­rized by defective carrier-mediated trans­port of cystine resulting cystine crystals.

b. These cystine crystals are accumulated in liver, spleen, bone-marrow, peripheral leukocytes, lymph nodes, kidney and cor­nea. These crystals are particularly accu­mulated in reticuloendothelial system.

c. Cystinosis is usually accompanied by aminoaciduria, glycosuria, polyuria, chronic acidosis leading to uremia and death.

d. This disorder may be due to the impaired conversion of cystine to cysteine in the involved tissues as a result of the defi­ciency of the enzyme cystine reductase.

e. The renal functions are seriously impaired for which patients die in the young stage from acute failure.

f. In adults, cystine gets deposited in cor­nea.

g. Cystine crystals can be detected easily in cornea by slit lamp microscopy and con­firmed by chemical determination of cys­tine crystals of peripheral leukocytes or cultured fibroblasts.

Errors in Protein Metabolism: Disease # 12. Homocystinuria:

a. In this abnormal condition, homocystine (300 mg/d) together with S-adenosylmethionine in some cases is excreted in the urine and plasma methionine levels are elevated.

b. The clinical findings of this disease are the occurrence of thrombosis, osteoporo­sis, dislocated lenses in the eyes and fre­quently mental retardation.

c. This condition appears due to the lack of cystathionine synthetase in the liver due to which both homocystine and methio­nine are accumulated in blood and urine.

d. A low methionine and a high cystine diet effectively prevent this condition if treated earlier.

Errors in Protein Metabolism: Disease # 13. Histidinemia:

a. It is an inherited disorder of histidine me­tabolism in which the amounts of histi­dine in the blood and urine are increased. There is also increased excretion of imi­dazole pyruvic acid.

b. The metabolic block of histidine is due to the insufficient activity of liver histidase which impairs the conversion of histidine to urocanic acid.

c. Development of speech in this condition is retarded. Mental development is also retarded.

d. Histidine excretion is also increased dur­ing normal pregnancy but not in the tox­aemia of pregnancy. This increase is not due to metabolic defect.

e. These histidinemic patients are treated well with a diet containing protein hydro- lysate free from histidine instead of intact protein.

Errors in Protein Metabolism: Disease # 14. Hypervalinemia:

a. In this abnormal condition, the infants suf­fer from stunted growth, muscle wasting and vomiting.

b. The valine content of blood and urine is very high.

c. A diet containing protein hydrolysate low in valine prevents this condition effec­tively.