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
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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. BIOCHIMICA ET BIOPHYSICA ACTA 1361 (1997) 1361: 185-197
•
EWBANK C, KERRIGAN JF, ALECK K. FUMARATE HYDRATASE DEFICIENCY. 2006 JUL 5 [UPDATED 2013 APR 4]. IN: PAGON RA, ADAM MP, ARDINGER HH, ET
AL., EDITORS. GENEREVIEWS® [INTERNET]. SEATTLE (WA): UNIVERSITY OF WASHINGTON, SEATTLE; 1993-2014. AVAILABLE FROM:
HTTP://WWW.NCBI.NLM.NIH.GOV/BOOKS/NBK1506/
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KIMONIS, V.E., J. STELLER, I. SAHAI, D.K. GRANGE, J. SHOEMAKER, B.M. ZELAYA, R. MANDELL, K. SHIH, AND V. SHIH. "MILD FUMARASE DEFICIENCY AND A
TRIAL OF LOW PROTEIN DIET." MOLECULAR GENETICS AND METABOLISM 107.1-2 (2012): 241-42. WEB.
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BAŞTUĞ O., KARDAŞ F., ÖZTÜRK M.A., HALIS H., MEMUR S., KORKMAZ L., TAĞ Z., GÜNEŞ T. “A RARE CAUSE OF OPISTOTONUS; FUMARIC ACIDURIA: THE
FIRST CASE PRESENTATION IN TURKEY” TURKISH ARCHIVES OF PEDIATRICS 2014; 49:74-6
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"FUMARASE DEFICIENCY." GENETICS HOME REFERENCE. N.P., N.D. WEB. 27 SEPT. 2014.
•
"MICROCEPHALY: MEDLINEPLUS MEDICAL ENCYCLOPEDIA IMAGE." U.S NATIONAL LIBRARY OF MEDICINE. U.S. NATIONAL LIBRARY OF MEDICINE, N.D. WEB.
29 SEPT. 2014.
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"HYPOTONIA." IS A CONDITION OF ABNORMALLY LOW MUSCLE TONE. N.P., N.D. WEB. 29 SEPT. 2014. <HTTP://WWW.LIVINGWITHCEREBRALPALSY.COM/HYPOTONIA-CEREBRAL.PHP>.