Inborn Error of Metabolism[IEM-Rupendra Shrestha


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Rupendra Shrestha B.Sc.MLT Nobel Medical College and Research Hospital Inborn error of metabolism

Inborn error of metabolism : 

Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn error of metabolism

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Also called congenital metabolic diseases or inherited metabolic diseases. The term inborn error of metabolism was coined by a British physician, Archibald Garrod (1857-1936), in the early 20th century (1908). Often treatable if diagnosed early.

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Most difficult task for clinician is to know when to consider IEM and which tests to order for evaluation. Clues to presence of IEM may often be found in Fetal Life

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In IEM,every child with unexplained . . . Neurological deterioration Metabolic acidosis Hypoglycemia Inappropriate ketosis Cardiomyopathy Hepatocellular dysfunction Failure to thrive (Healthy) . . . should be suspected of having a metabolic disorder

When to suspect an IEM : 

Infants have only a limited repertoire of symptoms--sxs non-specific: Vomiting, lethargy, sz’s, resp (tachypnea, hyperpnea, apnea), coma, cardiomyopathy, abnormal hair, dysmorphology Labs: metabolic-acidosis, hypoglycemia, hyperammonemia, reducing substances in urine, ketonuria, pancytopenia Not all infants with life threatening IEM have either acidosis or hyperammonemia (i.e. non-ketotic hyperglycinemia, mild lactate elevation). When to suspect an IEM

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defective enzyme Substrate (increased) Product (decreased) action Metabolites (increased) Co-factor A Co-factor B other enzymes Metabolites (decreased) EFFECT ON OTHER METABOLIC ACTIVITY e.g., activation, inhibition, competition Theoretical consequences of an enzyme deficiency.

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Types of Inborn Error of Metabolism Disorders of carbohydrate metabolism E.g., glycogen storage disease Disorders of amino acid metabolism E.g. phenylketonuria , maple syrup urine disease, Disorders of organic acid metabolism (organic acidurias) E.g., alcaptonuria Disorders of fatty acid oxidation and mitochondrial metabolism E.g. medium chain acyl dehydrogenase deficiency (glutaric acidemia type 2) Disorders of porphyrin metabolism E.g., acute intermittent porphyria

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6. Disorders of steroid metabolism E.g., congenital adrenal hyperplasia 7. Disorders of mitochondrial function E.g., Kearns-Sayre syndrome 8. Disorders of peroxisomal function E.g., Zellweger syndrome 9. Lysosomal storage disorders E.g., Gaucher's disease , Niemann Pick disease Types………………

Manifestations and presentations : 

Manifestations and presentations Growth failure, failure to thrive, weight loss Ambiguous genitalia, delayed puberty, precocious puberty Developmental delay, seizures, dementia, encephalopathy, stroke Deafness, blindness, Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps and bumps Dental abnormalities Immunodeficiency, thrombocytopenia, anemia, enlarged spleen, enlarged lymph nodes Many forms of cancer Recurrent vomiting, diarrhea, abdominal pain Excessive urination, renal failure, dehydration, edema ,Hypotension, heart failure, enlarged heart, hypertension, myocardial infarction Hepatomegaly, jaundice, liver failure Unusual facial features, congenital malformations Excessive-breathing (hyperventilation), respiratory failure Abnormal behavior, depression, psychosis Joint pain, muscle weakness, cramps Hypothyroidism,adrenal insufficiency, hypogonadism, diabetes mellitus

Glycogen Storage Disease : 

Glycogen Storage Disease Glycogen storage disease (GSD) is the result of defects in the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types. Genetic GSD is caused by any inborn error of metabolism (genetically defective enzymes) involved in these processes.

Glycogen Storage Disease : 

Glycogen Storage Disease

Disorders of amino acid metabolism : 

Inborn errors of amino acid metabolism are metabolic disorders which impair the synthesis and degradation of amino acids. e.g. Alkaptonuria, Phenylketonuria , Maple syrup urine disease Homocystinuria ,Tyrosenemia, Disorders of amino acid metabolism

Alkaptonuria : 

Alkaptonuria (black urine disease or alcaptonuria) is a rare inherited genetic disorder of phenylalanine and tyrosine metabolism. This is an autosomal recessive condition that is due to a defect in the enzyme homogentisate 1,2-dioxygenase (EC, which participates in the degradation of tyrosine. Alkaptonuria

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Alkaptonuria As a result, a toxic tyrosine byproduct called homogentisic acid (or alkapton) accumulates in the blood and is excreted in urine in large amounts(hence -uria). The homogentisate in the urine is ten oxidized by the oxygen in air to a brownish-black pigment

Alkaptonuria : 

Black urine disease Autosomal recessive condition due to defect in enzyme homogentisate 1,2-dioxygenase,participtates in degradation of tyrosine As a result toxic tyrosine by product called homogentisic acid (or, alkapton) accumulates in blood and excreted in urine Excessive homogentisic acid causes damage to cartilage( onchronosis leading to osteoarthritis) and heart valve. Treatment with nistionone, which supress homogentisic acid prodution Alkaptonuria

Sign and symptoms : 

Asymptotic but sclera of eyes may be pigmented and skin may be darkened on sun exposed area Sweat brown colored Urine may turn brown when exposed to air Ochronosis Renal and prostate stones Ear wax exposed to air turns red or black (depending on diet) due to accumulation of homogentisic acid after several hour: distinctive characteristic Sign and symptoms

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Signs and symptoms Alkaptonuria is often asymptomatic, but the sclera of the eyes may be pigmented (often only at a later age), and the skin may be darkened in sun-exposed areas . Around sweat glands; sweat may be coloured brown . Urine may turn brown if collected and left exposed to open air, especially when left standing for a period of time.

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Ochronosis: a buildup of dark pigment in connective tissues such as cartilage and skin, is also characteristic of the disorder. This blue-black pigmentation usually appears after age 30. People with alkaptonuria typically develop arthritis, particularly in the spine and large joints, beginning in early adulthood . Kidney stones and stone formation in the prostate (in men) are common and may occur in more than a quarter of cases . The main symptoms of alkaptonuria are due to the accumulation of homogentisic acid in tissues. In the joints this leads to cartilage damage, specifically in the spine, leading to low back pain at a young age in most cases . A distinctive characteristic of alkaptonuria is that ear wax exposed to air turns red or black (depending on diet) after several hours because of the accumulation of homogentisic acid

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Homogentisic acid is a natural intermediary of the metabolism of tyrosine, an amino acid. Hepatic homogentisate 1,2-dioxygenase (coded by the HGD gene) metabolises homogentisic acid into 4-maleylacetoacetate. Alkaptonuria arises in people who have inherited two abnormal HGD genes: one from each parent. Numerous different HGD mutations have been identified

Diagnosis Treatment : 

The diagnosis of alkaptonuria can be done by paper chromatography and thin layer chromatography. Both blood plasma and urine can be used for diagnosis. In healthy subjects, homogentisic acid is absent in both blood plasma and urine. In alkaptonuria, plasma levels of homogentisic acid are 6.6 micrograms/ml on average, and urine levels are on average 3.12 mmol/mmol of creatinine Diagnosis Treatment

Treatment : 

Commonly recommended treatments include dietary restriction of phenylalanine and tyrosine and large doses of ascorbic acid (vitamin C). The insecticide nitisinone inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme that generates homogentisic acid from 4-hydroxyphenylpyruvic acid. This reduces homogentisic acid. The main side-effect is irritation of the cornea Treatment

Phenylketonuria : 

Phenylketonuria (PKU), caused by a deficiency of phenylalanine hydroxylase is the most common clinically encountered inborn error of amino acid metabolism Phenylketonuria

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Hyperphenylalaninemias arise from defects in phenylalanine hydroxylase itself (type I, classic phenylketonuria or PKU), in dihydrobiopterin reductase (types II and III), or in dihydrobiopterin biosynthesis (types IV and V). Alternative catabolites are excreted .

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DNA probes facilitate prenatal diagnosis of defects in phenylalanine hydroxylase or dihydrobiopterin reductase. A diet low in phenylalanine can prevent themental retardation of PKU

Characteristics of PKU: : 

Elevated phenylalanine: Phenylalanine is present in elevated concentrations in tissues, plasma, and urine. Phenyllactate ,phenylacetate, and phenylpyruvate, which are not normally produced in significant amounts in the presence of functional phenylalanine hydroxylase, are also elevated in PKU .These metabolites give urine a characteristic musty("mousey") odor. The disease acquired its name before the phenylketone present in the urine was identified to be phenylpyruvate.] Characteristics of PKU:

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b. CNS symptoms: Mental retardation, failure to walk or talk, seizures, hyperactivity, tremor, microcephaly, and failure to grow are characteristic findings in PKU. The patient with untreated PKU typically shows symptoms of mental retardation by the age of one year. Virtually all untreated patients show an IQ below fifty

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c. Hypopigmentation: Patients with phenylketonuria often show a deficiency of pigmentation (fair hair, light skin color, and blue eyes). The hydroxylation of tyrosine by tyrosinase, which is the first step in the formation of the pigment melanin, is competitively inhibited by the high levels of phenylalanine present in PKU.

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Neonatal diagnosis of PKU: Early diagnosis of phenylketonuria is important because the disease is treatable by dietary means .Because of the lack of neonatal symptoms, laboratory testing for elevated blood levels of phenylalanine is mandatory for detection. However, the infant with PKU frequently has normal blood levels of phenylalanine at birth because the mother clears increased blood phenylalanine in her affected fetus through the placenta. Thus, tests performed at birth may show false negative results.

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Normal levels of phenylalanine may persist until the newborn is exposed to at least 24 hours of protein feeding. Blood levels of phenylalanine should be determined on a second blood sample obtained after the infant has ingested protein. Normally, feeding breast milk or formula for 48 hours is sufficient to raise the baby's blood phenylalanine to levels that can be used for diagnosis.

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Antenatal diagnosis of PKU: Classic PKU is a family of diseases caused by any of forty or more different mutations in the gene that codes for phenylalanine hydroxylase {PAH). The frequency of any given mutation varies among populations, and the disease is often doubly heterozygous, that is, the PAH gene has a different mutation in each allele. Despite this complexity, the majority of PKU cases in most populations are caused by a small number of mutations (six to ten). A fetus can be tested in vitro to determine if it carries a PKU mutation

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A less reliable screening test employs FeCl3 to detect urinary phenylpyruvate. FeCl3 screening for PKU of the urine: fecl3 reacts with the -OH group which gives the purple color .

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Treatment of PKU: Most natural protein contains phenylalanine, and it is impossible to satisfy the body's protein requirement when ingesting a normal diet without exceeding the phenylalanine limit. Therefore, in PKU, blood phenylalanine is maintained in the normal range by feeding synthetic amino acid preparations low in phenylalanine, supplemented with some natural foods (such as fruits, vegetables, and certain cereals) selected for their low phenylalanine content.

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The amount is adjusted according to the tolerance of the individual as measured by blood phenylalanine levels. The earlier treatment is started, the more completely neurologic damage can be prevented. Because phenylalanine is an essential amino acid, overzealous treatment that results in blood phenylalanine levels below normal should be avoided because this can lead to poor growth and neurologic symptoms.

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In patients with PKU, tyrosine cannot be synthesized from phenylalanine and, therefore, it becomes an essential amino acid that must be supplied in the diet. Discontinuance of the phenyalanine-restricted diet before eight years of age is associated with poor performance on IQ tests. Adult PKU patients show deterioration of IQ scores after discontinuation of the diet .Life-long restriction of dietary phenylalanine is, therefore, recommended.

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Maternal PKU: When women with PKU who are not on a low phenylalanine diet become pregnant, the offspring are affected with "maternal PKU syndrome." High blood phenylalanine levels in the mother cause microcephaly, mental retardation, and congenital heart abnormalities in the fetus. Some of these developmental responses to high phenylalanine occur during the first months of pregnancy. Thus, dietary control of blood phenylalanine must begin prior to conception, and must be maintained throughout the pregnancy. Children borne to mothers with PKU in metabolic control often show some residual developmental or behavioral effects, such as hyperactivity.

Maple Syrup Urine Disease : 

Maple Syrup Urine Disease Maple syrup urine disease (MSUD) is a recessive disorder in which there is a partial or complete deficiency in branched chain α-ketoacid dehydrogenase, an enzyme that decarboxylates leucine, isoleucine, and valine. These amino acids and their corresponding α-keto acids accumulate in the blood, causing a toxic effect that interferes with brain functions. The disease is characterized by feeding problems, vomiting, dehydration, severe metabolic acidosis, and a characteristic maple syrup odor to the urine. If untreated, the disease leads to mental retardation, physical disabilities, and death .

Classification : 

Classification The term maple syrup urine disease includes a classic type and several variant forms of the disorder. a. Classic type: This is the most common type of MSUD. Leukocytes or cultured skin fibroblasts from these patients show little or no branched-chain α-ketoacid dehydrogenase activity. Infants with classic MSUD show symptoms within the first several days of life. b. Intermediate and intermittent forms: These patients have ahigher level of enzyme activity (approximately three to fifteenpercent of normal). The symptoms are milder and show an onset from infancy to adulthood. c. Thiamin-responsive form: Large doses of thiamin can helppatients with this rare variant of MSUD achieve increased branched-chain α-ketoacid dehydrogenase activity.

Treatment : 

Treatment Treated with synthetic formula that contains limited amounts of leucine, isoleucine, and valine—sufficient to provide the branched-chain amino acids necessary for normal growth and development without producing toxic levels. Infants suspected of having any form of MSUD should be tested within 24 hours of birth. Early diagnosis and treatment is essential if the child with MSUD is to develop normally.

Albinism : 

Albinism Group of conditions in which a defect in tyrosine metabolism results in a deficiency in the production of melanin. These defects result in the partial or full absence of pigment from the skin, hair, and eyes.

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Albinism appears in different forms, and it may be inherited by one of several modes: autosomal recessive, autosomal dominant or X-linked. Complete albinism (also called tyrosine negative oculocutaneous albinism) results from a deficiency of tyrosinase activity, causing a total absence of pigment from the hair, eyes, and skin

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Affected people may appear to have white hair, skin, and iris color, and they may have vision defects. They also have photophobia (sunlight is painful to their eyes), they sunburn easily, and do not tan.

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In the inherited disorder cystinuria, the carrier system responsible for reabsorption of the amino acids cysteine , ornithine , arginine , and lysine in the proximal convoluted tubule of the kidney is defective. The inability to reabsorb cystine leads to kidney stones. one transport system is responsible for reabsorption of the amino acids cystine, ornithine, arginine, and lysine in kidney tubules. The inherited disorder cystinuria, the carrier system is defective, resulting in the appearance of all four amino acids cystine ,ornithine ,arginine and lysine in the urine Cystinuria

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The disease expresses itself clinically by the precipitation of cystine to form kidney stones (calculi), which can block the urinary tract. Oral hydration is an important part of treatment for this disorder. Cystinuria occurs at a frequency of 1 in 7000 individuals, making it one of the most common inherited diseases, and the most common genetic error of amino acid transport.

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Catabolism of histidine proceeds via urocanate,4-imidazolone-5-propionate,andN-formiminoglutamate(Figlu). Formimino group transfer to tetrahydrofolate forms glutamate, then α-ketoglutarate . In folic acid deficiency, group transfer is impaired and Figlu is excreted. Excretion of Figlu following a dose of histidine thus has been used to detect folic acid deficiency. Benign disorders of histidine catabolism include histidinemia and urocanic aciduria associated with impaired histidase. Histidinemia

Wilson’s disease : 

Wilson’s disease Mutations in the gene encoding a copper-dependent ATPase Wilson disease (hepatolenticular degeneration), a disease due to abnormal metabolism of copper Ceruloplasmin Binds Copper and Low Levels of This Plasma Protein Are Associated With Wilson Disease. Copper is an essential trace element. It is required in the diet because it is the metal cofactor for a variety of enzymes Some important enzymes that contain copper.

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Ceruloplasmin (about 160 kDa) is an α2-globulin. It has a blue color because of its high copper content and carries 90% of the copper present in plasma. Each molecule of ceruloplasmin binds six atoms of copper very tightly, so that the copper is not readily exchangeable. Albumin carries the other 10% of the plasma copper but binds the metal less tightly than does ceruloplasmin . Albumin thus donates its copper to tissues more readily than ceruloplasmin and appears to be more important than ceruloplasmin in copper transport in the human body. Ceruloplasmin exhibits a copper-dependent oxidase activity, but its physiologic significance has not been clarified. The amount of ceruloplasmin in plasma is decreased in liver disease. In particular, low levels of ceruloplasmin are found in Wilson disease (hepatolenticular degeneration). In order to clarify the description of Wilson disease, we shall first consider the metabolism of copper in the human body and then Menkes disease, another condition involving abnormal copper metabolism.

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Copper accepts and donates electrons and is involved in reactions involving dismutation, hydroxylation, and oxygenation. However, excess copper can cause problems because it can oxidize proteins and lipids, bind to nucleic acids, and enhance the production of free radicals. It is thus important to have mechanisms that will maintain the amount of copper in the body within normal limits. The body of the normal adult contains about 100 mg of copper, located mostly in bone, liver, kidney, and muscle. The daily intake of copper is about 2–4 mg, with about 50% being absorbed in the stomach and upper small intestine and the remainder excreted in the feces. Copper is carried to the liver bound to albumin, taken up by liver cells, and part of it is excreted in the bile. Copper also leaves the liver attached to ceruloplasmin, which is synthesized in that organ.

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Wilson Disease Is Also Due to Mutations in a Gene Encoding a Copper-Binding P-Type ATPase :Wilson disease is a genetic disease in which copper fails to be excreted in the bile and accumulates in liver,brain, kidney, and red blood cells. It can be regarded as an inability to maintain a near-zero copper balance, resulting in copper toxicosis. The increase of copper in liver cells appears to inhibit the coupling of copper to apoceruloplasmin and leads to low levels of ceruloplasmin in plasma. As the amount of copper accumulates, patients may develop a hemolytic anemia, chronic liver disease (cirrhosis, hepatitis), and a neurologic syndrome owing to accumulation of copper in the basal ganglia and other centers. A frequent clinical finding is the Kayser-Fleischer ring. This is a green or golden pigment ring around the cornea due to deposition of copper in Descemet’s membrane.

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Major laboratory tests used in the investigation of diseases of copper metabolism Wilson disease is suspected, a liver biopsy should be performed; a value for liver copper of over 250 μg per gram dry weight along with a plasma level of ceruloplasmin of under 20 mg/dL is diagnostic.

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The cause of Wilson disease was also revealed in 1993, when it was reported that a variety of mutations in a gene encoding a copper-binding P-type ATPase were responsible. The gene is estimated to encode a protein of 1411 amino acids, which is highly homologous to the product of the gene affected in Menkes disease. In a manner not yet fully explained, a nonfunctional ATPase causes defective excretion of copper into the bile, a reduction of incorporation of copper into apoceruloplasmin, and the accumulation of copper in liver and subsequently in other organs such as brain. Treatment for Wilson disease consists of a diet low in copper along with lifelong administration of penicillamine, which chelates copper, is excreted in the urine, and thus depletes the body of the excess of this mineral.

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Menkes Disease Is Due to Mutations in the Gene Encoding a Copper- Binding P-Type ATPase Menkes disease (“kinky” or “steely” hair disease) is a disorder of copper metabolism. It is X-linked, affects only male infants, involves the nervous system, connective tissue, and vasculature, and is usually fatal in infancy. In 1993, it was reported that the basis of Menkes disease was mutations in the gene for a copper-binding P-type ATPase. Interestingly, the enzyme showed structural similarity to certain metal-binding proteins in microorganisms. This ATPase is thought to be responsible for directing the efflux of copper from cells. When altered by mutation, copper is not mobilized normally from the intestine, in which it accumulates, as it does in a variety of other cells and tissues, from which it cannot exit. Despite the accumulation of copper, the activities of many copper-dependent enzymes are decreased, perhaps because of a defect of its incorporation into the apoenzymes. Normal liver expresses very little of the ATPase, which explains the absence of hepatic involvement in Menkes disease.