The History of Cystinuria - Rare...
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HISTORY OF THE UNDERSTANDING
AND TREATMENT OF
CYSTINURIA
Matthew Lewis
Imperial
College London
International
Cystinuria
Foundation
A p o l l o P h y s i c i a n a n d A s c l e p i u s a n d H y g i e i a a n d P a n a c e a a n d a l l t h e g o d s a n d g o d d e s s e s , m a k i n g t h e m m y w i t n e s s e s , t h a t I w i l l f u l f i l l a c c o r d i n g t o m y a b i l i t y a n d j u d g m e n t t h i s o a t h a n d t h i s c o v e n a n t :
T o h o l d h i m w h o h a s t a u g h t m e t h i s a r t a s e q u a l t o m y p a r e n t s a n d t o l i v e m y l i f e i n p a r t n e r s h i p w i t h h i m , a n d i f h e i s i n n e e d o f m o n e y t o g i v e h i m a s h a r e o f m i n e , a n d t o r e g a r d h i s o f f s p r i n g a s e q u a l t o m y b r o t h e r s i n m a l e l i n e a g e a n d t o t e a c h t h e m t h i s a r t — i f t h e y d e s i r e t o l e a r n i t — w i t h o u t f e e a n d c o v e n a n t ; t o g i v e a s h a r e o f p r e c e p t s a n d o r a l i n s t r u c t i o n a n d a l l t h e o t h e r l e a r n i n g t o m y s o n s a n d t o t h e s o n s o f h i m w h o h a s i n s t r u c t e d m e a n d t o p u p i l s w h o h a v e s i g n e d t h e c o v e n a n t a n d h a v e t a k e n a n o a t h a c c o r d i n g t o t h e m e d i c a l l a w , b u t t o n o o n e e l s e .
I w i l l a p p l y d i e t e t i c m e a s u r e s f o r t h e b e n e f i t o f t h e s i c k a c c o r d i n g t o m y a b i l i t y a n d j u d g m e n t ; I w i l l k e e p t h e m f r o m h a r m a n d i n j u s t i c e .
I w i l l n e i t h e r g i v e a d e a d l y d r u g t o a n y b o d y i f a s k e d f o r i t , n o r w i l l I m a k e a s u g g e s t i o n t o t h i s e f f e c t . S i m i l a r l y I w i l l n o t g i v e t o a w o m a n a n a b o r t i v e r e m e d y . I n p u r i t y a n d h o l i n e s s I w i l l g u a r d m y l i f e a n d m y a r t .
I wi l l not use the knife, not even on suf ferers from stone, but wil l withdraw in favor of such men as are engaged in this work.
W h a t e v e r h o u s e s I m a y v i s i t , I w i l l c o m e f o r t h e b e n e f i t o f t h e s i c k , r e m a i n i n g f r e e o f a l l i n t e n t i o n a l i n j u s t i c e , o f a l l m i s c h i e f a n d i n p a r t i c u l a r o f s e x u a l r e l a t i o n s w i t h b o t h f e m a l e a n d m a l e p e r s o n s , b e t h e y f r e e o r s l a v e s .
W h a t I m a y s e e o r h e a r i n t h e c o u r s e o f t h e t r e a t m e n t o r e v e n o u t s i d e o f t h e t r e a t m e n t i n r e g a r d t o t h e l i f e o f m e n , w h i c h o n n o a c c o u n t o n e m u s t s p r e a d a b r o a d , I w i l l k e e p t o m y s e l f h o l d i n g s u c h t h i n g s s h a m e f u l t o b e s p o k e n a b o u t .
I f I f u l f i l l t h i s p a t h a n d d o n o t v i o l a t e i t , m a y i t b e g r a n t e d t o m e t o e n j o y l i f e a n d a r t , b e i n g h o n o r e d w i t h f a m e a m o n g a l l m e n f o r a l l t i m e t o c o m e ; i f I t r a n s g r e s s i t a n d s w e a r f a l s e l y , m a y t h e o p p o s i t e o f a l l t h i s b e m y l o t .
THE HIPPOCRATIC OATH
http://en.wikipedia.org/wiki/Hippocratic_Oath
ca. 460-370 BC
WILLIAM HYDE WOLLASTON
Chemist, physicist, and (briefly) physician
Notable contributions to science:
Developed the first physico-
chemical method for processing
platinum ore
Discoverer of two elements:
Palladium
Rhodium
Development of an improved electric battery
Inventor of the camera lucida
THE FIRST REPORTED CYSTINE STONES
First Published Report
July 5 th, 1810
William Hyde Wollaston presents his observation and analysis of two cystine stones to the Royal Society of London
Extracted from William Small, age 36
Observed by Wollaston sometime between 1805
and 1810
Originally part of a collection belonging to Guy’s
Hospital in London, formed by William Lucas Sr.
and Jr., successive surgeons to Guy’s from 1773
to 1824, during the course of their practice.
THE FIRST REPORTED CYSTINE STONES
THE FIRST REPORTED CYSTINE STONES
Alexander Marcet’s “An Essay on the Chemical History and
Medical Treatment of Calculus Disorders”, 2nd edition, 1819.
Names the substance “Cystic Oxide”
Taken from the bladder: cystic
Chemical observations: oxide
THE FIRST REPORTED CYSTINE STONES
+
“probably very rare”
“…one mass confusedly
crystallized throughout its
substance… yellowish
semi-transparency [and]
peculiar glistening
lustre…”
THE FIRST REPORTED CYSTINE STONES
Unable to describe the unique smell upon
burning, distinguishing it from other stone
types
RENAL ORIGIN
1817 - Stones reported in kidney
Alexander Marcet ’s Essay on the Chemical History and Medical Treatment of Calculus Disorders
Cystine staghorn used as evidence to conclusively state that kidney stones may form in the kidney lumen
“And as I am possessed of a calculus composed of cystic
oxyd… actually taken out of the kidney after death, there
can be no doubt… that all the varieties of calculi are liable
to originate in the kidneys…” (2nd edition, 1819)
(Guys Hospital physician from 1804 to 1819)
RENAL ORIGIN
Realization that “Cystic” is a misnomer
“The name renal or nephritic oxyd would
therefore be more appropriate. But unless
some great systematic object can be at stake,
there is so much less inconvenience incurred,
in chemical science, by retaining a name which
is not strictly accurate, than by changing
appellations which have been once established,
that I do not feel inclined to propose any new
name for the cystic oxyd.”
1817 – Marcet - observes for the first time a possible familial connection in cystine stone formation
Two brothers with cystine stones, possibly a third.
As more sibling (and one parent/child siblings) cases are recorded, the condition is often assumed to be inherited
FAMILIAL INHERITANCE
Chemist and London Physician
Notable contributions to science: Coined the term “convection” to
describe the heat transfer effect of currents
HCL in stomach juices
Classification of foods into carbohydrates, proteins, and fats
Hypothesized the existence of the proton (named after Prout by Ernest Rutherford in 1920) as the building block for atoms
WILLIAM PROUT
DISEASE PHYSIOLOGY
1823 – cystinuria due to a functional
disturbance in the kidneys
Cited by A. D. Stephens, Cystinuria
and its Treatment: 25 years
Experience at St. Bartholomew's
Hospital,
1820 – crystalluria and stone formation a consequence of excessive cystine excretion
130 years ahead of his time!
DISEASE PHYSIOLOGY
1823 – cystinuria due to a functional
disturbance in the kidneys
Cited by A. D. Stephens, Cystinuria
and its Treatment: 25 years
Experience at St. Bartholomew's
Hospital,
1820 – crystalluria and stone formation a consequence of excessive cystine excretion
130 years ahead of his time!
C3H7NO3
1833, Jöns Jacob Berzelius (a founder of modern chemistry)
not an oxide!
proposes “cystin(e)”
1837, Baudrimont and Malaguti
Cystine contains sulphur
1838, Thaulow
Agrees with early Prout analysis, but replaces oxygen with sulphur to yield correct molecular formula
ADVANCEMENTS IN CHEMICAL
CHARACTERIZATION 1 830’S TO 1903
C3H7NO2S
1899, Morner
Discovers cystine in protein (amino acid!)
Finds hydrolized hair to be rich in cystine
1901, Embden
Cystine isolated from serum and egg albumins
1902 & 1903, Neuberg & Friedmann
Correct structural formula
1903, Erlenmeyer
Cystine synthesized
confirms proper structure
ADVANCEMENTS IN CHEMICAL
CHARACTERIZATION 1 830’S TO 1903
1876 – A. Niemann.
Review of previous cases, comments on familial disposition
1897, Pfeiffer
4 cystinuric children, parents were 1st cousins
1899, Cohn
Cystinuric mother,
normal father
6 of 10 children cystinuric (1 set of twins)
FAMILIAL INHERITANCE LATE 1800’S
1889 – Von Udranszky &
Baumann
Presence of diamines in cystinuric urine
ADDITIONAL AMINO ACIDS
Ornithine Putrescine
Cadaverine
Lysine
1905 – Alsberg & Folin Abnormally large “undetermined nitrogen”
content in cystinuric urine during starvation
1908 – Wolf & Shaffer Confirmed high undetermined nitrogen
attributed in part to presence of additional amino acids
Generalized aminoaciduria?
ADDITIONAL AMINO ACIDS
1911 – Ackermann & Kutscher Presence of crystaline lysine derivatives in cystinuric urine
Equivalent of ~ 0.1g lysine /L urine
1947 – Yeh et al. Found arginine and lysine to be ~10x normal in cystinuric urine
Specific additional aminoacidurias!
1951 - Confirmed by Dent and Rose added to definition of cystinuric condition
1951– Stein Ornithine found in excess
MORE ON ADDITIONAL AMINO ACIDS
PAPER CHROMATOGRAPHY OF AMINO
ACIDS IN URINE
Cys
Arg
Lys
Normal urine Cystinuric urine
Fanconi
Syndrome
Advanced
Cirrhosis of
the Liver
Dent and Rose, 1951
1908 – Archibald Garrod
(London Physician)
Inborn Errors of Metabolism
Cystinuria due to an “arrest” in cystine metabolism
Defective metabolic enzyme inherited
INBORN ERRORS OF METABOLISM
PAPER CHROMATOGRAPHY OF AMINO
ACIDS IN BLOOD PLASMA
Dent and Rose – 1949/1951
When paper chromatographic analysis is applied to blood plasma of cystinuric subjects, no gross overabundance of cystine could be observed
Rejection of Garrod’s Inborn Error Hypothesis
X
Subsequent studies demonstrating significantly reduced cystine in cystinuric plasma. Dent, Senior, Walshe, 1954
Arrow & Westall, 1958
Brigham, Stein, Moore, 1960
Frimpter, Horwith et al 1962
Rosenberg, 1965
Morin, Thompson, Jackson and Sass-Kortsak, 1971
Martensson et al 1990
No studies supporting normal plasma cystine since 1954
ADDITIONAL REPORTS OF PLASMA CYSTINE
IN CYSTINURIA
Bro
wn
an
d L
ewis
19
37
Den
t an
d R
ose
, 19
51
Stei
n 1
95
1
Fow
ler
et a
l 19
52
Den
t H
eath
cote
an
d J
oro
n 1
95
4
Den
t, S
enio
r, a
nd
Wal
she
19
54
Arr
ow
an
d W
esta
ll 1
95
8
Bri
gham
, Ste
in, M
oo
re 1
96
0
Frim
pte
r H
orw
ith
et.
al 1
96
2
Wes
tall
19
62
Frim
pte
r 1
96
3
Lon
do
n a
nd
Fo
ley,
19
65
, p
.12
9
Ro
sen
ber
g 1
96
5
Frim
pte
r, V
ann
ucc
i, Sh
ibu
ya 1
96
8
Mo
rin
, Tet
al
Thei
r an
d S
egal
19
78
Mar
ten
sso
n e
t al
19
90
Sega
l an
d T
hei
r 1
99
5
Palacin, Goodyer, Nunes, Gasparini OMMBID
Scriver 2008
Chillaron, Bertran, Palacin: MTD, 2003
Segal and Their 1995
Martensson et al 1990
Stephens 1989
Morin, Thompson, Jackson and Sass-Kortsak 1971
Frimpter, Vannucci, Shibuya 1968
Pruzanski 1966
Rosenberg 1965
London and Foley, 1965, p.129
Frimpter 1963
Westall 1962
Frimpter Horwith et. al 1962
Brigham, Stein, Moore 1960
Arrow and Westall 1958
Dent, Senior, and Walshe 1954
Dent Heathcote and Joron 1954
Fowler et al 1952 *
Stein 1951
Dent and Rose, 1951
normal normal / slightly low
abnormal
Plasma [cystine]
Data reporting
publications
Citing
Publications
1966 – Rosenberg, Downing,
Durant, and Segal
Three phenotypes of cystinuria based
on urinary excretion of cystine and
dibasic (lysine, arginine and ornithine)
amino acids of the obligate
heterozygous parent—type I, type II,
and type III.
“CLASSICAL” CLASSIFICATION
1999 - Feliubadaló, L. et al.
Type I (including patients formerly also classified as ‘type I’)
Nontype I (including former type II and type III)
Mixed type cystinuria (also known as type I/nontype I)
2002 - Dello Strologo, L. et al.
Enhansed genetic understanding...
Type A (if mutations are found in both SLC3A1 alleles)
Type B (if mutations are found in both SLC7A9 alleles)
Putative type AB (if one mutation is found in each gene)
MODERN CLASSIFICATION(S)
1994 - . Pras, E. et al. and
Calonge, M. J. et al.
Genetic and mutational analysis
studies show that mutations in
SLC3A1 cause cystinuria.
(SLC3A1 is a gene which codes for the
neutral and basic amino acid transport
protein rBAT)
1999 - Feliubadaló, L. et al.
Mutations in another gene - SLC7A9
can also cause cystinuria
(SLC7A9 is a gene which codes for a
subunit of rBAT named (b0, +AT)
ADVANCEMENT OF GENETIC AND
BIOCHEMICAL UNDERSTANDING
Pathophysiology and treatment of cystinuria
Josep Chillarón, Mariona Font-Llitjós, Joana
Fort, Antonio Zorzano, David S. Goldfarb,
Virginia Nunes
and Manuel Palacín
Two mouse models for study:
Mutation in Slc3a1 (rBAT)
Slc7a9 knockout (b0, +AT)
“Both mouse models produce cystine stones at high
rates and have morphological changes in kidney
architecture that result from obstruction and
inflammation .”
MODEL ORGANISMS FOR STUDY
TREATMENT
Water
Use for stone treatment predates cystinuria
Diuretics
Recommended by Prout in 1821, maybe earlier
Home remedies for pain and stone passage, warm bath, etc.
Prout, 1821, maybe earlier
Alkaline therapy
Henry, 1819; Prout, 1825
Concern with encouraging phosphate stones was known
Potassium citrate & bicarbonate used as early as 1880, Cantani
Successful dissolution of stones with K-Cit and K-bicarb 1914, Klemperer & Jacoby
Successful dissolution of stones, verified by x-ray
Protein restriction
As long as cys known to be in protein!
D-Pennicillamine, Thiola
Time for something new???