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Metabolic Disorders Noushin Rostampour Assistant professor of pediatric endocrinology and metabolism

Metabolic Disease Many childhood conditions are caused by single gene mutations These mutations can result in the alteration of primary protein structure or the amount of protein synthesized. These hereditary biochemical disorders are also termed inborn errors of metabolism or inherited metabolic disorders

Metabolic disorder Congenital metabolic disorders result from the absence or abnormality of an enzyme or its cofactor, leading to either accumulation or deficiency of a specific metabolite

COMMON CHARACTERISTICS OF GENETIC DISORDERS OF METABOLISM The affected infant is normal at birth and becomes symptomatic later on in life.

COMMON CHARACTERISTICS OF GENETIC DISORDERS OF METABOLISM In general, the earlier the appearance of clinical symptoms the more severe is the disease. The majority of conditions are inherited as autosomal recessive

COMMON CHARACTERISTICS OF GENETIC DISORDERS OF METABOLISM A history of consanguinity in the parents Unexplained death in the neonatal period Question of an inherited metabolic disease in the sick infant?

COMMON CHARACTERISTICS OF GENETIC DISORDERS OF METABOLISM Most of the genetic metabolic conditions can be controlled successfully by some form of therapy These patients can have a normal life if diagnosed and treated early, before irreversible damage to organs

COMMON CHARACTERISTICS OF GENETIC DISORDERS OF METABOLISM This underlines the importance of early diagnosis, which can be achieved through screening of all newborn infants

CLINICAL MANIFESTATIONS In the newborn period, the clinical findings are usually nonspecific and similar to those seen in infants with sepsis.

CLINICAL MANIFESTATIONS Lethargy Poor feeding Convulsions Vomiting

CLINICAL MANIFESTATIONS Children : Mental retardation Motor deficits Developmental regression Convulsions Myopathy Recurrent emesis Cardiomyopathy

CLINICAL MANIFESTATIONS Developmental delay Unusual odor Acidosis Coma Hepatomegaly Renal stones

Laboratory studies Measurements of ammonia, bicarbonate, and pH are often very helpful initially

INITIAL EVALUATION Testing should be performed: At the time of presentation When symptoms are most pronounced Laboratory values may be normal when the patient is well.

INITIAL EVALUATION CBC diff Arterial blood gas Blood glucose Serum ammonia Electrolytes BUN/ Cr

INITIAL EVALUATION Urine (color, odor, dipstick, ketones)

Treatment Special diets Peritoneal dialysis or hemodialysis Administration of the deficient metabolite Administration of the deficient enzyme Administration of the cofactor Bone marrow transplantation Liver transplantation

CLASSIFICATION Amino acid disorders Organic acidemias Urea cycle defects Disorders of carbohydrate metabolism Fatty acid oxidation defects Mitochondrial disorders Peroxisomal disorders Lysosomal storage diseases

Organic acidemia

Organic acidemia Organic acidemias are a group of disorders characterized by increased excretion of organic acids in urine. They result from deficiencies of specific enzymes in the breakdown pathways of amino acids.

Classification Branched-chain organic acidemias MMA PA IVA Multiple carboxylase deficiency Glutaric acidemia type 1

Clinical presentation Newborns typically present during the first one to two weeks after birth Poor feeding Vomiting Floppiness Muscular hypotonia Lethargy Coma

Clinical presentation Pregnancy and perinatal history frequently are uncomplicated. Family history may reveal consanguinity and/or siblings who died during the neonatal period

Clinical presentation The initial presentation in older infants, children: Lethargy Vomiting FTT Seizures Acute decompensation Pancytopenia

Management Intravenous hydration Correction of metabolic acidosis Hyperammonemia TX Hypoglycemia TX Correction of electrolyte abnormalities Treatment of infections

Urea cycle disorders

Urea cycle disorders The urea cycle is the metabolic pathway that transforms nitrogen to urea Deficiency of any of the enzymes in the pathway causes a UCD. Examples of UCDs include ornithine transcarbamylase deficiency and citrullinemia.

Urea cycle disorders UCDs often present in newborns who are initially well and become hyperammonemic after a period of protein feeding However, patients with partial enzyme activity may present later

CLINICAL FEATURES Initial signs: Somnolence Poor feeding Vomiting Lethargy Coma

Lab Data Hyperammonemia Respiratory alkalosis

Ammonia Newborn: mean plasma ammonia :45 ± 9 micromol/L Upper limit of normal : 80 to 90 micromol/L

Ammonia Children older than one month : 50 micromol/L Plasma ammonia greater than 100 to 150 micromol/L: further testing

Treatment Treatment should be initiated as soon as UCD is suspected

Phenylketonuria

PKU Deficiency of phenylalanine hydroxylase or its cofactor tetrahydrobiopterin : accumulation of phenylalanine in body fluids and the CNS

PHENYLALANINE HYDROXYLASE The normal metabolism of phenylalanine (pathways a and b) BREAKDOWN Dietry sources, particularly plant proteins PHENYLALANINE HYDROXYLASE PHENYLALANINE TYROSINE (b) (a) BODY PROTEINS © 2008 Paul Billiet ODWS

Genetic PKU is inherited as an autosomal recessive trait

PKU The prevalence of PKU in the United States :1/14,000 to 1/20,000

Clinical presentation Newborn infants are asymptomatic prior to the initiation of feeds In untreated patients, the hallmark of the disease is intellectual disability

Clinical presentation MR may develop gradually and may not be evident for the 1st few months Vomiting, sometimes severe enough to be misdiagnosed as pyloric stenosis, may be an early symptom

Clinical presentation Older untreated children become hyperactive, with purposeless movements, rhythmic rocking, and athetosis These infants are lighter Some may have a seborrheic or eczematoid rash

Clinical presentation These children have an unpleasant odor of phenylacetic acid(musty or mousey)

Clinical presentation Most infants are hypertonic with hyperactive DTR. About 25% of children have seizures More than 50% have EEG abnormalities

Clinical presentation Microcephaly Prominent maxilla Enamel hypoplasia Growth retardation

Diagnosis Early diagnosis can only be achieved by mass screening of all newborn infants Elevated serum phenylalanine Classic PKU: >20 mg/dL(1200 micromol/L)

Treatment The goal of therapy is to reduce phenylalanine in the body The diet should be started as soon as diagnosis is established.

Treatment Overtreatment may lead to phenylalanine deficiency Lethargy Failure to thrive Anorexia Anemia Rash Diarrhea Death

Treatment Treatment is designed to maintain plasma phenylalanine:2-6 mg/dl using a diet Treatment is lifelong

Galactosemia

Galactose Milk and dairy products contain lactose, the major dietary source of galactose. Lactose  Glucose + Galactose The metabolism of galactose produces fuel for cellular metabolism through its conversion to glucose-1-phosphate.

Galactose Galactose also plays an important role in the formation of galactosides, which include glycoproteins, glycolipids, and glycosaminoglycans.

Galactosemia Denotes the elevated level of galactose in the blood and is found in three distinct disorders of galactose metabolism defective in one of the following enzymes Galactose-1-phosphate uridyl transferase Galactokinase Uridine diphosphate galactose-4-epimerase.

Galactosemia Autosomal recessive disease. It affects the body’s ability to use or metabolize galactose resulting in the accumulation of galactose 1-phosphate in the body.

Galactosemia Galactosemia is a serious disease with early onset of symptoms; the incidence is 1/60,000. The infants is unable to metabolize galactose-1-phosphate: the accumulation of which results in injury to kidney, liver, eyes and brain.

Clinical features Jaundice Hepatomegaly Vomiting Hypoglycemia Convulsions Lethargy Irritability Feeding difficulties

Clinical features Poor weight gain Aminoaciduria Cataracts Vitreous hemorrhage Hepatic cirrhosis Ascites Splenomegaly Mental retardation.

Clinical features Patients with galactosemia are at increased risk for E.coli neonatal sepsis The onset of sepsis often precedes the diagnosis of galactosemia. When the diagnosis is not made at birth, damage to the liver (cirrhosis) and brain (mental retardation) becomes increasingly severe and irreversible.

Clinical features Galactosemia should be considered for the newborn or young infant who is not thriving or who has any of the preceding findings.

Diagnosis Reducing substance in several urine specimens collected while the patient is receiving human milk, cow's milk, or another formula containing lactose. Deficient activity of GALT is demonstrable in hemolysates of erythrocytes, which also exhibit increased concentrations of galactose-1-phosphate.

Treatment The only treatment for galactosemia is eliminating lactose and galactose from the diet There is no definite cure for Galactosemia, the condition is life long and it can only be controlled Calcium supplement

Prognosis Elimination of galactose from diet reverses growth failure and renal and hepatic dysfunction. Cataracts regress, and most patients have no impairment of eyesight Early diagnosis and treatment have improved the prognosis of galactosemia

Prognosis On long-term follow-up, patients still manifest ovarian failure , developmental delay, and learning disabilities that increase in severity with age Most manifest speech disorders, whereas a smaller number demonstrate poor growth and impaired motor function and balance

Tyrosinemia

Tyrosinemia Inborn error in the degradation of the amino acid tyrosine Genetic: Autosomal recessive Three types (type I, type II, type III).

Type I Tyrosinemia Most common type of tyrosinemia Caused by a mutation in the FAH gene that encodes for the FAH enzyme.

Symptoms of Type I Tyrosinemia Failture to gain weight Diarrhea and vomiting Jaundice Cabbage-like odor Increased tendency to bleed PNS involvement kidney and liver failure Liver cirrhosis Hepatocellular carcinoma

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Type II Tyrosinemia Mutation in the TAT gene that encodes for the hepatic TAT enzyme. Autosomally recessive Also known as “Richner-Hanhard syndrome”

Symptoms of Type II Tyrosinemia Elevated plasma tyrosine Lesions of skin and eyes Due to clumping of cellular tyrosine crystals Excessive tearing and photophobia Mental retardation (elevated blood tyrosine levels) Symptoms often begin in early childhood.

Treatments Dietary restriction of tyrosine and phenylalanine. (aim Tyrosine below 500 μmol/L) NTBC (2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione) to block metabolism. Protects patients from fatal, end stages of disease However, increases plasma tyrosine and requires several follow-ups. Liver transplant

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