Crigler-Najjar Syndrome Doloroso, Quevedo, Lalluces, Banarias

Introduction

TWO of the five diseases associated with defects in Crigler-Najjar Syndrome _______________________________________________________________________ Two distinct types of Congenital Unconjugated Hyperbilirubenia TWO of the five diseases associated with defects in BILIRUBIN metabolism

BILIRUBIN * Yellow breakdown product of heme catabolism * Tetrapyrrole in structure * Can be conjugated or unconjugated * Produced in the breakdown of RBCs of the body Released as urobilin (urine) and stercobilin (feces)

TYPE 1 TYPE 2 Impaired activity Deficiency in the enzyme activity of URIDINE DIPHOSPHATE GLUCURONYSYLTRANSFERASE Inability to conjugate bilirubin Virtually absent activity TYPE 1 TYPE 2 Impaired activity

Medical Presentation

TYPE 1 TYPE 2 Autosomal recessive inheritance Neonatal Jaundice and Kernicterus Death within 24 months 340 – 770 umol/L of serum bilirubin No bilirubin glucuronisides in blood Arias Syndrome Autosomal recessive inheritance Predominant Mild jaundice, no brain damage 104 – 342 umol/L of serum bilirubin bilirubin glucuronisides in blood

SYMPTOMS Kernicterus NEONATAL JAUNDICE Yellow coloration of skin And sclera of the eyes Due to accumulation of: Unconjugated bilirubin Kernicterus Lethargy, Fever MORO reflex Muscle Spasms Ophistotonus Spasticity,hypotonia Build up of bilirubin in The CNS Jaundice is the most common condition that requires medical attention in newborns. The yellow coloration of the skin and sclera in newborns with jaundice is the result of accumulation of unconjugated bilirubin. In most infants, unconjugated hyperbilirubinemia reflects a normal transitional phenomenon. However, in some infants, serum bilirubin levels may rise excessively, which can be cause for concern because unconjugated bilirubin is neurotoxic and can cause death in newborns and lifelong neurologic sequelae in infants who survive (kernicterus). For these reasons, the presence of neonatal jaundice frequently results in diagnostic evaluation. Infants with Crigler-Najjar syndrome type I are at risk for developing kernicterus, also known as bilirubin encephalopathy, within the first month of life. Kernicterus is a potentially life-threatening neurological condition in which toxic levels of bilirubin accumulate in the brain, causing damage to the central nervous system. Early signs of kernicterus may include lack of energy (lethargy), vomiting, fever, and/or unsatisfactory feedings. Other symptoms that may follow include absence of certain reflexes (Moro reflex); mild to severe muscle spasms, including spasms in which the head and heels are bent or arched backward and the body bows forward (opisthotonus); and/or uncontrolled involuntary muscle movements (spasticity). In addition, affected infants may suck or nurse weakly, develop a high-pitched cry, and/or exhibit diminished muscle tone (hypotonia), resulting in abnormal "floppiness."  Kernicterus can result in milder symptoms such as clumsiness, difficulty with fine motor skills and underdevelopment of the enamel of teeth, or it can result in severe complications such as hearing loss, problems with sensory perception, convulsions, and slow, continuous, involuntary, writhing movements (athetosis) of the arms and legs or the entire body. An episode of kernicterus can ultimately result in life-threatening brain damage.  Although kernicterus usually develops early during infancy, in some cases, individuals with Crigler-Najjar syndrome type I may not develop kernicterus until later during childhood or in early adulthood.  Crigler-Najjar syndrome type II is a milder disorder than type I. Affected infants develop jaundice although in some cases, jaundice may not be apparent except during times when an infant is sick (concurrent illness), has not eaten for an extended period of time (prolonged fasting) or is under general anesthesia. Some cases of Crigler-Najjar syndrome type II have not been detected until affect individuals are adults. Kernicterus is rarely associated with Crigler-Najjar syndrome type II, but can occur especially when an affected individual is sick, not eating or under anesthesia.

DIAGNOSIS Venipuncture Test for serum bilirubin Blood tests[edit] Bilirubin is degraded by light. Blood collection tubes containing blood or (especially) serum to be used in bilirubin assays should be protected from illumination. For adults, blood is typically collected by needle from a vein in the arm. In newborns, blood is often collected from a heelstick, a technique that uses a small, sharp blade to cut the skin on the infant's heel and collect a few drops of blood into a small tube. Non-invasive technology is available in some health care facilities that will measure bilirubin by using an instrument placed on the skin (transcutaneous bilirubin meter) Bilirubin (in blood) is in one of two forms: Abb.Name(s)Water-solubleReaction"BC""Conjugated" or "direct bilirubin"Yes (bound to glucuronic acid)Reacts quickly when dyes (diazo reagent) are added to the blood specimen to produce azobilirubin "Direct bilirubin""BU""Unconjugated" or "indirect bilirubin"NoReacts more slowly, still produces azobilirubin, Ethanol makes all bilirubin react promptly, then: indirect bilirubin = total bilirubin – direct bilirubinTotal bilirubin (TBIL) measures both BU and BC. Total and direct bilirubin levels can be measured from the blood, but indirect bilirubin is calculated from the total and direct bilirubin. Indirect bilirubin is fat-soluble and direct bilirubin is water-soluble.

EPIDEMIOLOGY ________________________________________________________________ 1 in 750,000 – 1,000,000 Often misdiagnosed or undiagnosed _ Describe misdiagnosis on differential diagnostics

Biochemical Pathway

Heme Catabolism Pathway Heme  biliverdin through heme oxygenase ( o2  CO2) Biliverdin  bilirubin through biliverdin reductase Liver  functional unit  hepatocyte  liver canaliculi through the multidrug resistant protein 2 to be secreted aling with bile to the common bile duct to the intestines Urobilin  oxidized form to be released in urine Heme Catabolism Pathway

Step 4: Conjugation of Bilirubin This increased its water solubility, decreases its lipid solubility and eases its excretion. Conjugation is accomplished by attaching two molecules of glucuronic acid to it in a two step process. The substrates are bilirubin (or bilirubin monoglucuronide) UDP-glucuronic acid. The reaction is a transfer of two glucuronic acid groups sequentially to the propionic acid groups of the bilirubin. The major product is bilirubin diglucuronide (pronounce). Bilirubin diglucuronide is excreted in the bile. It is subject to subsequent transformations to other species by the intestinal flora. Unconjugated bilirubin not water soluble because of intramolecular hydrogen bonding Step 4: Conjugation of Bilirubin Mediated by uridine diphosphate glucuronysyltransferase

Unconjugated Bilirubin In Crigler-Najjar ________________________________________________________________ Deficiency or absence of UDT Unconjugated Bilirubin Water insoluble substance Cannot be excreted Bilirubin Build up in the blood

Treatment and Support

TYPE 1 TRANSPLANTATION Liver Hepatocyte PHOTOTHERAPY EXCHANGE TRANSFUSION LIVER DIRECTED GENE THERAPY

TYPE 2 PHENOBARBITALS ANTICONVULSANTS LIPID LOWERING AGENTS GALLSTONE SOLUBILIZING DRUGS CALCIUM SALTS PHENOTHIAZINE

sources http://www.rarediseases.org/rare-disease-information/rare- diseases/byID/1084/printFullReport http://ghr.nlm.nih.gov/condition/crigler-najjar-syndrome http://www.patient.co.uk/doctor/crigler-najjar-syndrome