FUMARASE DEFICIENCY BING (BECKY) CHENG, BRENDA YEE MEI LI, JOHN NGUYEN, GUIHONG TENG PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson PRESENTATION OVERVIEW • BACKGROUND KNOWLEDGE OF FUMARASE • REVIEW OF KREB’S CYCLE • WHAT IS FUMARASE DEFICIENCY • SYMPTOMS • TREATMENTS AND THERAPIES • SUMMARY • REFERENCES WHAT IS FUMARASE? • ALSO KNOWN AS FUMARATE HYDRATASE • HOMOTETRAMERIC PROTEIN WITH ISOENZYMES LOCATED IN MITOCHONDRIA AND CYTOSOL • BOTH FORMS ARE ENCODED BY SAME GENE ON CHROMOSOME 1Q.42.1 VIA ALTERNATIVE INITIATION OF TRANSLATION • CATALYZES THE REVERSIBLE HYDRATION/CONDENSATION REACTION IN THE KREB’S CYCLE CONVERTING FUMARATE TO L-MALATE • CYTOSOLIC FUMARASE IS INVOLVED IN THE PROCESSING OF FUMERIC ACID FROM THE UREA CYCLE AND PURINE METABOLISM 3D STRUCTURE OF FUMARASE IN HUMANS Source: http://modbase.compbio.ucsf.edu/modbase-cgi-new/search_form.cgi KREB’S CYCLE (CITRIC ACID CYCLE) • EIGHT DIFFERENT REACTIONS INVOLVING THE REMOVAL OF CARBON FROM ACETYL-COA • MAJOR FUNCTION IS TO CONVERT CARBON COMPOUNDS INTO REDUCED COENZYMES NADH AND FADH2 • NADH AND FADH2 CAN UNDERGO OXIDATIVE PHOSPHORYLATION TO CREATE ATP FOR THE BODY • REQUIRES HYDROLYSIS TO PRODUCE OXYGEN AND CO2 FOR OXIDATIVE REACTIONS (EX. FUMERATE TO L-MALATE) KREB’S CYCLE MUTATIONS IN FUMARASE • • • Figure A shows possible missense mutations in fumerase Figure B shows the location of the active site Figure C shows a change in the loop conformation of the active site caused by H-bonds in the helical region WHAT IS FUMARASE DEFICIENCY • 17 DIFFERENT MUTATIONS ON FH GENE ARE CURRENTLY KNOWN TO CAUSE FUMARASE DEFICIENCY • DISRUPTING THE KREBS CYCLE IS HARMFUL TO ALL CELLS, BUT ESPECIALLY HARMFUL TO CELLS IN A DEVELOPING BRAIN • INFANTS USUALLY ONLY SURVIVE FOR A FEW MONTHS, FEW MAY LIVE INTO ADULTHOOD • FUMARASE DEFICIENCY IS INHERITED IN AN AUTOSOMAL RECESSIVE PATTERN • RARE, 100 PEOPLE AFFECTED WORLDWIDE • AFFECTED INDIVIDUALS EXPERIENCE SLOW/DELAYED DEVELOPMENT (GROWTH RATE, WEIGHT GAIN, ETC) SYMPTOMS AND CONSEQUENCES • MICROCEPHALY; ABNORMALLY SMALL HEAD SIZE • SEVERE DEVELOPMENTAL DELAY • METABOLIC CRISIS- BUILD UP OF FUMARATE • PSYCHOMOTOR RETARDATION • HYPOTONIA-POOR MUSCLE TONE • FACIAL DYSMORPHISM, IE. LOW SET EARS, SMALL JAW, PROMINENT FOREHEAD, DEPRESSED NASAL BRIDGE • ENLARGED LIVER AND SPLEEN, POLYCYTHEMIA, OR LEUKOPENIA MAY BE ASSOCIATED WITH FUMARASE DEFICIENCY SYMPTOMS… TREATMENTS AND THERAPIES • CURRENTLY NO CURE • A NUMBER OF SUPPORTIVE THERAPIES CAN CONTROL SYMPTOMS • CONTROL EPILEPTIC SEIZURES • GASTOSTOMY PLACEMENT (OPTIMIZE NUTRITION AND PREVENT ASPIRATION) • PHYSICAL THERAPY AND ORTHOPEDIC MANAGEMENT (MINIMIZE CONTRACTURES AND PREVENT SCOLIOSIS) • SPECIAL NEEDS SERVICES (DEVELOPMENTAL DEFICITS) TREATMENTS AND THERAPIES CTD… • KETOGENIC DIETS SHOULD NOT BE USED FOR TREATING EPILEPSY ASSOCIATED WITH FUMARATE HYDRATASE DEFICIENCY • LOW PROTEIN DIET WAS SUGGESTED INITIALLY • BUT NO SIGNIFICANT DECREASE IN FUMARIC ACID SUMMARY • FUMARASE IS A HYDRATASE THAT CATALYZES THE REACTION OF FUMARATE TO L-MALATE IN KREB’S CYCLE • TWO FORMS ARE FOUND: MITOCHODRIAL AND CYTOSOLIC • FUMARASE DEFICIENCY IS DUE TO MUTATIONS OF FH GENE ON CHROMOSOME 1 • FUMARASE DEFICIENCY IS A RARE AUTOSOMAL RESSESIVE DISORDER • SYMPTOMS INCLUDE PHYSICAL DYSMORPHISM AND PSYCHOMOTOR RETARDATION • CURRENTLY THERE IS NO CURE BUT THERE ARE A NUMBER OF WAYS TO ALLEVIATE THE SYMPTOMS REFERENCES • COOPER, JONATHAN B. "FUMARASE." PESTICIDE BE-GONE: 3-CHLOROACRYLATE DEHALOGENASE AND A PERSISTENT PESTICIDE. DEPARTMENT OF BIOCHEMISTRY, UNIVERSITY OF ARIZONA, N.D. WEB. 19 SEPT. 2014. HTTP://WWW.BIOCHEM.ARIZONA.EDU/CLASSES/BIOC462/462BH2008/462BHONORSPROJECTS/462BHONORS2006/COOPERJ/FUMARASE.HTM • REMES AM, FILPPULA SA, RANTALA H, LEISTI J, RUOKONEN A, SHARMA S, JUFFER A, HILTUNEN JK. A NOVEL MUTATION OF THE FUMARASE GENE IN A FAMILY WITH AUTOSOMAL RECESSIVE FUMARASE DEFICIENCY. J MOL MED (2004) 82:550–554. • SAINI A, SINGHI, P. INFANTILE METABOLIC ENCEPHALOPATHY DUE TO FUMARASE DEFICIENCY. JOURNAL OF CHILD NEUROLOGY (2012) 28(4): 535-537 • DESCHAUTER M, GIZATULLINA Z, SCHULZE A, PRITSCH M, KNOPPEL C, KNAPE M, ZERIZ S, GELLERICH FN. MOLECULAR AND BIOCHEMICAL INVESTIGATIONS IN FUMARASE DEFICIENCY. MOLECULAR GENETICS AND METABOLISM (2006) 88:146–152 • RUSTIN P, BOURGERON T, PARFAIT B, CHRETIEN D, MUNNICH A, ROTIG A. INBORN ERRORS OF THE KREBS CYCLE: A GROUP OF UNUSUAL MITOCHONDRIAL DISEASES IN HUMANS. 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