In-born Errors of Metabolism PDF

# In-born Errors of Metabolism ## Introduction - Inborn errors of metabolism occur when some enzyme involved in metabolism is abnormal. - The abnormality occurs due to a mutation in gene encoding the enzyme. The affected enzyme may be absent or deficient. - Inborn errors may occur in the metabolis...

# In-born Errors of Metabolism ## Introduction - Inborn errors of metabolism occur when some enzyme involved in metabolism is abnormal. - The abnormality occurs due to a mutation in gene encoding the enzyme. The affected enzyme may be absent or deficient. - Inborn errors may occur in the metabolism of all nutrients, including amino acids. When an enzyme is absent or deficient, metabolism of the concerned amino acid becomes abnormal. ## Disorders of Amino Acid Metabolism - Over 50 inborn errors of metabolism of amino acids have been discovered due to decreased synthesis of products, accumulation of intermediates, formation of alternate metabolites. - Many disorders result in neurological abnormalities and mental retardation. - Early diagnosis and treatment can prevent neurological abnormalities. - Generally, the treatment comprises restricted intake or exclusion of the affected amino acid from the diet. - Some relatively common inborn errors are: - Maple syrup urine disease (MSUD) - Cystinuria - Phenylketonuria (PKU) - Alkaptonuria - Albinism ## 1) Phenylketonuria - Phenylketonuria is the commonest inborn error of amino acid metabolism. - It has an incidence of about 1 in 10,000 live births. - It was the first inborn error of amino acid metabolism to be treated successfully by diet manipulation. - There is a block in the conversion of phenylalanine into tyrosine in PKU, and it is converted to phenyl pyruvate and excreted in urine. ## Phenylketonuria (PKU) A diagram shows the difference between normal metabolism of Phenylalanine and what happens in PKU. - Protein from food and protein from muscle go through the same metabolic pathways in a normal person and a person with PKU. - In a normal person, phenylalanine is converted to tyrosine using phenylalanine hydroxylase. - In a person with PKU, phenylalanine hydroxylase is inactive. There is a build up of phenylalanine, leading to health problems. ## Causes - Autosomal recessive disorder caused by mutation in PAH gene - Located on the 12th chromosome. - A carrier does not have symptoms of the disease, but can pass on the defective gene to his or her children ## PKU Symptoms - Mental retardation - Behavioural or social problems - Seizures, tremors, jerking movements in the arms and legs - Hyperactivity - Stunted growth - Skin rashes (eczema), musty odor in children's breath, skin or urine - Microcephaly - Fair skin and blue eyes (phenylalanine cannot transform into melanin) ## Treatment - Phenylketonuria (PKU) can be successfully treated with a low-protein diet and dietary supplements. - The diet must be strictly followed. - Those who continue the diet into adulthood have better physical and mental health. - Administration of tetrahydrobiopterin is recommended ## 2) Cystinuria - Cystinuria is an inherited disease that causes stones made of the amino acid cystine to form in the kidneys, bladder, and ureters. - Inherited diseases are passed down from parents to children through a defect in their genes. - To get cystinuria, a person much inherit the defect from both parents. - Defects, also called mutation, in the genes SLC3A1 and SLC7A9 cause cystinuria. - The defect in the gene causes cystine to accumulate inside the kidney, which are the organs that help regulate what goes in and out of your bloodstream. ## Symptoms - Osteoporosis - Dislocation of lenses in the eyes - Mental retardation - Ischaemic vascular disease - Blood in the urine - Severe pain in the side or the back, almost always on one side - Nausea and vomiting - Pain near the groin, pelvis, or abdomen ## Treatment - Changes to your diet, medication, and surgery are options for treating the stones that form due to cystinuria. - The treatment consists of a low-methionine, high-cysteine diet. Pyridoxine supplements may be given to activate the residual cystathionine synthetase. - Reducing salt intake to less than 2 grams per day has also been shown to be helpful in preventing stone formation. ## 3) Alkaptonuria - Alkaptonuria is an inborn error of tyrosine metabolism. - It is due to an absence of homogentisate oxidase. - Alkaptonuria is caused by a mutation on your homogentisate 1,2-dioxygenase (HGD) gene. - Homogentisate, an intermediate in catabolism of tyrosine, cannot be metabolised further. - Homogentisate is excreted in urine. - Freshly voided urine is normal in colour. Urine becomes dark on exposure to air due to oxidation of homogentisate by oxygen. - It is also called black urine disease. - This condition is rare, affecting 1 in 250,000 to 1 million people worldwide. ## Diagnosis - A urine test (urinalysis) is done to test for alkaptonuria. - If ferric chloride is added to the urine, it will turn the urine a black colour in patients with this condition. ## Treatment - There's no specific treatment for alkaptonuria. - A low-protein diet is recommended. Large doses of ascorbic acid, or vitamin C, is given to slow down the accumulation of homogentisic acid in your cartilage - Some patients benefit from high-dose vitamin C ## Clinical symptoms of alkaptonuria - Dark spots in the sclera (white) of your eyes - Thickened and darkened cartilage in your ears - Blue discoloration of your skin, particularly around sweat glands - Dark-coloured sweat or sweat stains - Black earwax - Kidney stones and prostate stones - Arthritis (especially hip and knee joints) ## 4) Albinism - Albinism (from Latin *albus*, "white" also called achromia, achromasia, or achromatosis) is a congenital disorder characterized by the complete or partial absence of pigment in the skin, hair and eyes. - This is due to absence or defect of tyrosinase, a copper-containing enzyme involved in the production of melanin. - Albinism results from inheritance of recessive gene alleles and is known to affect all vertebrates, including humans. ## Causes - A person inherits one or more defective genes that cause them to be unable to produce the normal amounts of a pigment called melanin. - The genes are located on "autosomal" chromosomes. Autosomes are the chromosomes that contain genes for general body characteristics. - Both parents must carry a defective gene to have a child with albinism. - When neither parent has albinism but both carry the defective gene, there is a one in four chance that the baby will be born with albinism. ## Characteristics - Little to no melanin (important pigment) in eyes, skin, and hair - Vision problems are a result of the low amounts of melanin in albinos - Eyes are usually blue or light brown, but can sometimes appear red - Skin and hair is very pale in color - More likely to sunburn - Sensitivity to bright light ## Types of Albinism - **Ocular Albinism (OA)** affects only the eyes, not the skin or hair. It results from an X-linked chromosomal inheritance and so occurs mostly in boys. - **Oculocutaneous Albinism (OCA)** affects the eyes, hair and skin and includes several different forms. The first form, OCA1 involves the tyrosinase enzyme, which converts tyrosine (an amino acid) into melanin. Melanin is a chemical that colours our skin, eyes and hair. ## Treatment - There is no real cure for albinism, but the goal of treatment is to relieve symptoms. - Treatment involves protecting the skin and eyes from the sun: Reduce sunburn risk by avoiding the sun, using sunscreen, and covering up completely with clothing when exposed to the sun. - Sunscreen should have a high SPF. - Sunglasses may relieve light sensitivity. - Glasses are often prescribed to correct vision problems and eye position. - Eye muscle surgery is sometimes recommended to correct abnormal eye movements ## 5) Maple Syrup Disease - Rare metabolic disorder - Produces urine that has maple syrup odor. - Incidence is approximately 1 in 185,000 infants worldwide. - MSUD occurs at the same rate in males and females. ## Inheritance - Autosomal recessive - Develops from inheriting a mutated gene from each parent. - Caused by mutations, or changes in the genes that are related to the BCKDC enzymes. - When those genes are defective, the BCKDC enzymes aren't produced or don't work properly. - These gene mutations are inherited on the chromosomes you receive from your parents. ## Symptoms - Lethargy - Poor appetite - Weight loss - Weak sucking ability - Irritability - High-pitched cry - Irregular sleep patterns - Maple sugar odor in sweat and urine - Seizures - Neurological deficiencies - Developmental delays - Feeding problems - Poor growth ## Treatment - It must be started as soon as possible. - Involves a complex approach to maintain metabolic control. - A special, carefully controlled diet is the focus of daily treatment. - Careful monitoring of protein intake. - Infant will be given an MSUD formula such as Enfamil or Similac. - A liver transplant is an optional treatment.