Inborn Errors of Metabolism PDF

Inborn errors of metabolism Disorders of amino acid metabolism 2nd lecture 2024 Phenylketonuria:  Phenylketonuria is a common autosomal recessive inheritance leads to intellectual disability if untreated.  The estimated incidence of PKU 1 in 10,000 newborns.  Phenylalani...

Inborn errors of metabolism Disorders of amino acid metabolism 2nd lecture 2024 Phenylketonuria:  Phenylketonuria is a common autosomal recessive inheritance leads to intellectual disability if untreated.  The estimated incidence of PKU 1 in 10,000 newborns.  Phenylalanine is an essential AA which means it cannot synthesize in the body and must be taken from the diet. 09/29/2024 2  Cause PKU  The primary cause is deficient of phenylalanine hydroxylase  A secondary (normally little used) involved in decreasing the concentration of phenylalanine in which it converts to phenyl pyruvate which further is reduced or oxidized to form phenyl lactate and phenyl acetate respectively.  Both phenylalanine and phenyl acetate accumulate in tissues and blood which can excrete in urine (phenylketonuria).  The characteristic musty odor of urine is due to phenyl acetate, which raises suspicion during infancy 09/29/2024 3 Clinical symptoms  classic PKU, develop profound and irreversible biochemical abnormalities such as mental retardation and neurological dysfunctions, eczema in the early life of infants.  Few babies may exhibit epilepsy, Parkinson like features and decreased skin and hair pigmentation. 09/29/2024 4 Phenylketonuria 09/29/2024 5  Diagnosis  The estimation of Phe level in the blood (above 600 μmol/L) is primarily used to detect PKU. Increased level of Phenyl alanine and phenyl pyruvate in blood and urine are analyzed to confirm the PKU using Gas chromatography-mass spectrometry Microbiological Guthrie test  A small drop of blood is taken from the heel of a newborn and applied to a card.  In the original form of the test, a punch-out of the dried disc was incubated on a petri dish plated with bacteria (Bacillus subtilis) in the presence of a growth inhibitor(B-2- thienyl-alanine).  High levels of Phe in the blood sample overcome the inhibition, and allow the bacteria to grow. 09/29/2024 6 Phenylketonuria treatment  The aim of treatment is to lower plasma phenylalanine concentrations by giving a low-phenylalanine diet.  Such treatment should be monitored carefully, especially if the patient is planning to conceive or is pregnant.  Remember that the artificial sweetener aspartame is metabolized to phenylalanine. 09/29/2024 7 09/29/2024 8 Tyrosinemia 09/29/2024 9  Tyrosinemia I  Lack of fumaryl acetoacetate hydrolase (FAH) enzyme  Deficiency of this enzyme, fumaryl acetoacetic acid and other intermediate precursors accumulate in the tissue and organ cause liver and renal diseases. Hence, it is also called hepatorenal tyrosinemia. 09/29/2024 10  Tyrosinemia II  This disorder is caused by the deficiency of tyrosine aminotransferase  Accumulation of tyrosine can affect on eyes, skin, and mental development.  This disease begins in early childhood.  Persistent keratitis and hyperkeratosis occur on the fingers, palms of hands and soles of feet, moderate mental retardation. 09/29/2024 11  Neonatal tyrosinemia Type III  This disorder occurs due to the defective enzyme, p-hydroxy phenyl pyruvic hydroxylase  The condition is more common in premature infants.  Estimation of succinyl acetone and tyrosine metabolites in blood and urine establishes the definitive diagnosis of tyrosinemia I and distinguishes from other types of tyrosinemias.  The drug, nitisinone known as NTBC has shown to be effective for the treatment of Tyrosinemia I. (hydroxyphenyl-pyruvate dioxygenase inhibitor) 09/29/2024 12  Alkaptonuria Cause  High level of homogentisic acid in tissues cause a syndrome is called ochronosis.  Alkaptonuria is considered a multi systemic disease starting from the 3rd decade of life and classified as a secondary amyloidosis. On exposure to atmospheric oxygen, urine homogentisic acid is converted into colored compound.  Alkaptonuria incidence is about 2-5 /1000000 live births. 09/29/2024 13 Alkaptonuria Clinical symptoms  Affected person show an abnormal level of homogentisic acid in cartilage tissue caused inflammation and arthritis in older people. Diagnosis  The urine level of homogentisic acid is primarily measured to the diagnosis of alkaptonuria. The excretion level of HGA is usually about 1-8 g/ day in alkaptonuria’s patients. Treatment  Vitamin C and low proteins diet are recommended to control of the ochronosis by reducing the level of homogentisic acid in tissues.  Newborn screening and oral nitisinone therapy may also helpful for the treatment of this disease 09/29/2024 14  Alkaptonuria  The deposition of alkapton in cartilages, with consequent darkening, is called ochronosis and results in visible darkening of the cartilages of the ears and often arthritis in later life.  The conversion of homogentisic acid to alkapton is accelerated in alkaline conditions, and sometimes the most obvious abnormality in alkaptonuria is darkening of the urine as it becomes more alkaline on standing. 09/29/2024 15  Albinism  Albinism is another congenital hereditary disorder in which biosynthesis of melanin is defective.  Melanin is a color pigment absent in certain parts of the body such as eyes, patches of skin and areas of hair.  melanin is polymers tyrosine which gives color to skin, hair and eyes.  The pale skin, pinkish eyes and visual abnormalities are primary symptoms of this disease oculocutaneous albinism ;Albino people require visual rehabilitation such as wear prescription lenses for correction of refractive errors, use hats with brims and dark glasses or transition lenses to reduce discomfort from bright light and wear protective clothing to protect skin from sun exposure 09/29/2024 16  Albinism  A deficiency of tyrosinase in melanocytes causes one form of albinism; it is inherited as an autosomal recessive disorder.   Pigmentation of the skin, hair and iris is reduced and the eyes may appear pink.  Reduced pigmentation of the iris causes photosensitivity, and decreased skin pigmentation is associated with an increased incidence of certain skin cancers.  The tyrosinase involved in catecholamine synthesis is a different isoenzyme, controlled by a different gene; consequently, adrenaline (epinephrine) metabolism is normal. 09/29/2024 17  Homocystinuria  Homocystinuria is a rare inherited disorder of metabolism of the methionine. Cause  This disorder results due to the deficit activity or absence of cystathionine β- synthase involved in methionine degradation.  This defect leads to accumulation of homocysteine in tissues  09/29/2024 18  Homocystinuria Clinical symptoms  High level of homocysteine in cells causing lipid peroxidation, fibrosis, and atherogenesis and affecting muscles, cardiovascular and nervous system, eye disease: cataracts. Diagnosis  Estimation of the level of homocysteine, total homocysteine, homocysteine-cysteine mixed disulfide, and methionine in plasma. Treatment  Vitamin B6 (Pyridoxine) therapy, betaine, folate and vitamin B12 supplementation are used to control the biochemical abnormalities, especially to management the plasma homocysteine and homocysteine concentrations and prevent thrombosis. 09/29/2024 19  Maple syrup urine disease (MSUD)  MSUD is an inherited disorder of branched chain amino acids (BCAAs). Cause  The metabolic deficiency of branched-chain enzyme, α-keto acid dehydrogenase causes MSUD in which the body is unable to breakdown the (BCAAs): Leu, Ile & Val.  This leads to buildup keto-acids in tissues and blood resulting metabolic problem.  MSUD is also called branched-chain ketoaciduria 09/29/2024 20 Maple syrup urine disease 09/29/2024 21  Maple syrup urine disease Clinical symptoms  MSUD is characterized by the sweet-smelling urine. The biochemical features include neurological disorder, poor feeding, vomiting, dehydration, lethargy, hypotonia, ketoacidosis, hyper ammonemia, pancreatitis, and coma. Diagnosis  Biochemical estimation of plasma levels of BCAAs and the urine levels of branched-chain hydroxy acids and keto- acids (BCKAs). Treatment 09/29/2024 22  Dietary restriction.  Histidinemia  Histidinemia is associated with deficiency of histidinase, an enzyme needed for normal histidine metabolism, and is probably inherited as an autosomal recessive trait.  Some individuals may have intellectual disabilities and speech defects, but others may be normal.  The diagnosis is made by demonstrating raised plasma levels of histidine, and by finding histidine and the metabolite imidazole pyruvic acid in the urine  the diagnosis of folic acid def. by histidine load test 09/29/2024 23  Amino acid transport disorders  Groups of chemically similar substances are often transported by shared or inter-related pathways.  Such group-specific mechanisms usually affect transport across all cell membranes, and defects often involve both the renal tubules and intestinal mucosa.  Ex. Hartnup’s disease, familial iminoglycinuria 09/29/2024 24  Aminoaciduria  Specific aminoaciduria is due to increased excretion of either a single amino acid or a group of chemically related amino acids.  Non-specific aminoaciduria, in which there is increased excretion of a number of unrelated amino acids, is almost always due to an acquired disorder.  It may be overflow in type as in severe hepatic disease when impaired deamination of amino acids causes raised plasma concentrations; more commonly, renal aminoaciduria results from non-specific proximal tubular damage, and other substances that are usually almost completely reabsorbed by the proximal tubule are also lost (phosphogluco aminoaciduria; Fanconi’s syndrome). 09/29/2024 25 Amino aciduria Chromatographic pattern of amino aciduria. 09/29/2024 26  Dibasic amino acids Cystine, ornithine, arginine and lysine – (COAL )  Cystinuria is the result of an autosomal recessive inherited abnormality of tubular reabsorption, with excessive urinary excretion, of the dibasic amino acids.  A similar transport defect has been demonstrated in the intestinal mucosa, but, although dibasic amino acid absorption is reduced, deficiencies do not occur because they can be synthesized in the body. 09/29/2024 27  Cystinuria Cystine is relatively insoluble and, because of the high urinary concentrations, may precipitate and form calculi in the renal tract.  The diagnosis of cystinuria is made by demonstrating excessive urinary excretion of the characteristic amino acids.  All these amino acids must be identified to distinguish this from cystinuria occurring as part of a generalized aminoaciduria.  The management of cystinuria aims to prevent calculi formation by reducing urinary concentration. The patient should drink plenty of fluid. Alkalinizing the urine increases the solubility of cystine. If these measures prove inadequate, D-penicillamine may be given; this forms a chelate which is more soluble than cystine alone 09/29/2024 28  Cystinosis  This is a very rare but serious disorder of cystine metabolism, characterized by intracellular accumulation and storage of cystine in many tissues.  It must be distinguished from cystinuria, a relatively harmless condition.  Renal tubular damage by cystine causes Fanconi’s syndrome.  Amino aciduria is non-specific and of renal origin.  Affected individuals may die young 09/29/2024 29  Hartnup’s disease  Hartnup’s disease is a rare autosomal recessive disorder.  Many of the clinical manifestations can be ascribed to reduced intestinal absorption and increased urinary loss of tryptophan.  This amino acid is normally partly converted to nicotinamide, the conversion being especially important if the dietary intake of nicotinamide is low.  The clinical features are intermittent and resemble those of pellagra a red, scaly rash on exposed areas of skin, reversible cerebellar ataxia and mental confusion of variable degree.  Excessive amounts of indol compounds originating from bacterial action on unabsorbed tryptophan are absorbed from the gut and excreted in the urine. 09/29/2024 30  Familial iminoglycinuria  Increased urinary excretion of the imino acids proline and hydroxyproline and glycine; despite normal plasma concentrations, is due to a transport defect for these 3 AAs.   The condition is inherited as an autosomal recessive trait.  It is apparently harmless, but must be differentiated from other more serious causes of iminoglycinuria, such as the defect of proline metabolism, hyperprolinaemia. 09/29/2024 31