Garrod's Croonian Lectures 1908

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Garrod's Croonian Lectures (1908) and the charter
"Inborn Errors of Metabolism" Albinism,
Alkaptonuria, Cystinuria and Pentosuria at age
100 in 2008 By Charles R. Scriver SSIEM-Lisbon,
September 5th, 2008
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EPIGRAPH The fox knows many things but the
hedgehog knows one big thing
Archilochus (680-645 B.C.)
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The fox is alert to particularities
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The hedgehog has a unifying view of reality
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Garrod was a hybrid a hedgefox
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The Croonian Lectures to the Royal College of
Physicians were established in 1749
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Garrods enduring reputation is imbedded in his
Croonian Lectures of 1908
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Garrods Croonian Lectures have become landmarks
in the history of Biochemistry Human
Genetics Medicine
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The Lectures were delivered June 18th,23rd,25th
and 30th, 1908

• They were published in Lancet
• a month later on the topics
• Albinism
• Alkaptonuria
• Cystinuria
• Pentosuria

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The Lectures were republished in Book form (1909)
with its famous title
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• Garrods message was subtle and simple
• The inborn errors revealed that metabolism was
  dynamic.
• The inborn errors revealed Mendelian
  inheritance.
• The inborn errors highlighted normal functions
  gone wrong.

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There was novelty in Garrods interpretation of
Inborn Errors of Metabolism
He derived physiological conclusions from
pathological conditions. In this way he
pre-figured the path taken half a century later
by Beadle and Tatum.
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• Reception of Garrods Lectures
• Biochemists understood his evidence that
  metabolism was dynamic.
• Geneticists of the day were largely
  biometricians and were sceptical about
  discontinuous Mendelian traits.
• Physicians were generally disinterested in rare
  congenital hereditary conditions that offered
  little help to the practice of medicine.

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Bearns biography of Garrod is a recommended
source of information about Garrod, his career
and his thoughts
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Barton Childs article (1970) in NEJM anchors the
relevance of Garrods ideas in medical thinking
Childs B., Sir Archibald Garrods conception of
chemical individuality a modern appreciation.
New Engl J Med. 28271-77, 1970.
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In 1923 Garrod added two new Inborn Errors and
updated information about the 4 original
disorders. The second edition of Inborn Errors
did not recruit much new interest.
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In 1935, Penrose told Garrod about Asbjørn
Føllings discovery of the Mendelian disorder now
known as Phenylketonuria
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Garrod was ahead of his time in his thinking
about Inborn FACTORS in disease The new
essay was about complex traits and diathesis (ie.
susceptibility) - and evolution
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ALKAPTONURIA Garrod A.E. The incidence of
Alkaptonuria. A study in chemical
individuality. Lancet 2 1616-1620,
1902. -------------------- Online Mendelian
Inheritance in Man 203500 607474. OMMBID
Chapter 92, 92S.
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Garrod Sees Homogentisic Acid, as a normal
metabolite in a normal pathway with normal
enzymes at each step

• The pathway is dynamic and supports a flux of
  chemical reactants.
• The variant enzyme is explained by Mendelian
  inheritance.

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The clinical significance of Alkaptonuria is
not of much moment Osler 1904

• Garrod called Alkaptonuria an inherited metabolic
  SPORT.
• A SPORT has
• outlier chemical individuality
• sibling involvement
• likely to have first cousin parents
• essentially benign in its effect on health

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The View that Alkaptonuira is a benign sport is
open to revision, following careful analysis of
its natural history OBrien et al. Am J Med
34 813-838, 1963. Phornphutkul et al. N. Engl.
J. Med. 347 2111-2121, 2002.
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Life table analyses of manifestations in
Alkaptonuria

• Joint replacement, 55 years.
• Renal stones, 64 years.
• Cardiac valve damage, 54 years.
• Coronary Artery Calcification, 59 years.
• Males more affected than females.
• Symptoms accelerate after age 30.

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The enzyme deficiency in Alkaptonuria is the loss
of homogentisate 1,2-dioxygenaseLa Du et al. J.
Biol. Chem. 230 251-260, 1958.

• The enzyme deficiency in Alkaptonuria is
  demonstrated in liver biopsy material from
  patients.
• Activities of all other enzymes in tyrosine
  oxidation are intact.

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The genomic locus (AKU) is mapped to chromosome
3q21-23 by various means in 1993 and 1994.

• The candidate gene (HGD) is isolated and cloned
  in 1996.
• Fernandez-Canon et al. Nat. Genet. 14 19-24,
  1996.
• Gehrig et al. Cytogenet. Cell Genet. 761 4-16,
  1997.
• Mutations in HGD gene tend to cluster in a
  CCC/GGG motif.

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From Garrod to Gene Such a long journey
Scriver C.R. Nature Genetics, 145-6, 1996.
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The crystal structure of human homgentisate
dioxygenase is known.Titus et al. Nat. Struct.
Biol. 7542-546, 2000.The enzyme functions as a
dimer of trimers.
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Possible treatment of Alkaptonuria with NTBC
(Nitisinone)Kayser et al. OMBID, Chapter 92S,
2008.
Animal Model AvailableSuzuki et al. J. Hum.
Genet. 44, 79-84, 1999.
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CYSTINURIA - 1 It will be clear from all that
has gone before that we are still far from being
in a position to formulate a satisfactory theory
of Cystinuria It will be necessary to
accumulate many more data above all
quantitative data. Garrod, Inborn Errors of
Metabolism 2E, 1923.
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CYSTINURIA - 2 The fox did not know enough
things. The hedgehog could not know the new big
thing. C.R. Scriver, JIMD, 2008.
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CYSTINURIA - 3 Cystinuria is not an inborn
error affecting an enzyme in a pathway. Cystinuri
a is an inborn error of a membrane transport
system a here to there ase (W.E. Knox,
1958).
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CYSTINURIA - HISTORICAL

• Wollaston 1810
• Nieman 1860s - Cystinuria is
• congenital
• affects sibs
• does not affect longevity
• It behaves as a sport

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CYSTINURIA - ANALYTICAL

• 1908 (Wolf and Shaffer)
• Undetermined nitrogen fraction in urine.
• 1947 (Yeh)
• Microbiological assay discovers excess amino
  acids.
• 1951 (Stein)
• Column chromatography reveals excess of cys,
  lys, arg, orn.
• 1951 (Dent and Rose)
• Selective increase of amino acid renal clearance
  rates.
• 1960s(Rosenberg)
• First in vitro evidence for deficient transport
  function in kidney and intestine.

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CYSTINURIA - HEREDITY

• Mendelian trait MIM 220100
• Two phenotypes (Harris)
• Completely recessive (type 1)
• Incompletely recessive (type 2)
• Three phenotypes? (Rosenberg)
• Phenotype uncertainty resolved into type 1 and
  non-type 1 phenotypes (Palacin).

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CYSTINURIA MOLECULAR BASISHeteromeric amino
acid transporter
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CYSTINURIA - GENETICS

• SLC3A1
• 2p16.7-p21
• Heavy subunit rBAT
• Type 1 Cystinuria
• 104614

• SLC7A9
• 19q13.1-q13.2
• Light subunit b0,AT
• Non-Type 1 Cystinuria
• 604144

Gene Symbol Locus Protein Phenotype MIM
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CYSTINURIA - COMMENT

• Two centuries of inquiry.
• An example of dynamic metabolism involving
  solute traffic here to there.
• Garrod, none the less, was on an appropriate
  path
• dynamic metabolism.
• A new type of inborn error the inborn error of
  transport.

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PENTOSURIA - 1Garrods perfect sport

• A condition with persistent excessive urinary
  loss of a pentose sugar without any apparent
  clinical consequences.
• Behaves as a Mendelian recessive (MIM 260800).
• Behaves as an inborn error of metabolism
  affecting a normal metabolite (L()-xylulose) and
  a normal enzyme (xylulose reductase (E.C.
  1.1.1.10)) in a normal pathway for glucuronic
  acid oxidation.

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PENTOSURIA - 2

• A benign condition as revealed in survival
  studies.
• The condition clusters in Ashkanazi Jews with
  estimated allele frequency of 0.0127.

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PENTOSURIA - 3The locus, the gene and the
expression of the enzyme

• The Gene symbol is DCXR
• Cloned and mapped to human chromosome 17 (MIM
  608347).
• Expressed in two forms
• The major isozyme, in cytosol and mitochondria,
  is missing in Pentosuria.
• DCXR is expressed prominently in kidney with
  possible role in osmoregulation.

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PENTOSURIA - 4

• Xylulose reductase is in a superfamily of
  short-chain dehydrogenase/reductase enzymes.
• It functions as a homotetramer with
• Conserved residues for catalytic function,
  subunit interaction and coenzyme (NADP/NADPH)
  binding.

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PENTOSURIA 5crystal structure determined at
1.96 Å resolution (El-Kabbani et al. 2004)
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ALBINISM - 1 That Albinism is congenital and
persists through life is self-evident. The
condition is obvious and its rarity in man is
also evident. It stands to reason that an error
of metabolism which persists from birth into
adult and even into advanced life must needs be
relatively innocuous. (Garrod, 1908) Or,
Albinism is another sport.
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ALBINISM - 2

• Garrod finds evidence for recessive inheritance
  in the form of Albinism seen by him. He sees it
  as an inborn error of metabolism.
• The evidence suggests that he was observing
  Oculocutaneous Albinism (MIM 203100).
• Garrod is lucky he picked a consistent single
  phenotype.

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ALBINISM - 3

• Garrod faces opposition. Karl Pearson (1911)
  denies Garrods interpretation, stating there is
  no definite proof of Mendelism applying to any
  living form at present.
• Garrods proposal for Mendelism in Albinism
  eventually supported by data (Hogben 1931).
• Albinism has locus and allelic heterogeneity
  (Trevor-Roper 1952 King et al. 2008).

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ALBINISM 4

• OCA Maps to the TYR locus, chromosome 11q14-q21.
• The gene encodes Tyrosinase (E.C. 1.14.18.1)
  which hydroxylates tyrosine to form DOPA quinone
  in the pathway leading to mature melanosomic
  melanin.
• Tyrosinase deficiency is complete in OCA Type 1A
  (MIM 203100, 606933) and partial in OCA Type 1B
  (MIM 606952, 606933).

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THE HEDGEFOX OVERVIEW

• No quality is so universal in the appearance of
  things, as diversity and variety
• (Montaigne, essay on EXPERIENCE).

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LEGACIESFox Report - 1

• Each charter inborn error of metabolism has
  acquired
• Its own chromosomal locus
• Cloned gene
• Set of mutations
• A protein gene product with a crystal structure
• Discernable metabolic consequences

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LEGACIESFox Report - 2

• The charter IEMs are not true sports, they have
  consequences for health, thus there are
  implications for
• Counselling
• Diagnosis
• Treatment
• SSIEM is a Legacy of Garrods work .
• Orphan diseases and orphan drugs are components
  of the legacy.

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SOME HEDGEFOX PERSPECTIVES

• Nothing makes sense in biology except in the
  light of evolution (Th. Dobzhansky).
• Examples
• DNA structure and function
• Genome projects
• The Human Variome Project and GWAS
• The genotype-phenotype problem (dbGaP)
• The ENCODE project
• etc

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AN ERA Of OMES
GENOME
EPIGENOME
TRANSCRIPTOME
PHENOME
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Scriver CR et al. Metabolism 34868-873, 1985.
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HEDGEFOX METABOLISM

• Kacser and Burns, The Molecular Basis of
  Dominance, Genetics, 97 639-666, 1981.
• Hartman et al., Principles for the buffering of
  genetic variation, Science, 291 1001-1004, 2001.
• Oltvai and Barabasi, Lifes complexity pyramid,
  Science, 298 763-764, 2002.

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(Goh et al., PNAS 104 8685-8690, 2007)
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• What can I know.
• And with that knowledge what ought I do.
• (Immanuel Kant, 1724-1804)
• Although the word is common to all, most people
  live as if each had a private intelligence of
  ones own.
• (Heraclitus 513 B.C.)

Sarkissian and Scriver fecit PowerPoint