Transcript Nordic Society of Nephrology Meeting 2009 Helsinki Clinico-Pathological Conference 27.08.2009

Nordic Society of Nephrology
Meeting 2009 Helsinki
Clinico-Pathological Conference 27.08.2009
Presentation of a Case with Fabry Disease (FD)
Ole Wirta and Anne Räisänen-Sokolowski
•
Intralysosomal Accumulation of
1. Globotriaocylceramide (Gb3)
2. Digalactocylceramide
Xq22.1 and α-Galactosidase
 370 mostly family specifc mutations gene identified.
GLA is the only gene associated with FD Type of
mutations which are:
1. Missense and nonsense
2. Large and small rearrangements
3. Splicing defects
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(<50%)
(> 10%)
GLA mutations result in mRNA instability and/or truncated
α - galactosidase and reduced activity (<1%)
Genotype-Phenotype correlation largely unknown
Germ Cell mosaicism poses counselling problems
September 1994
Opthalmologic evaluation
• Visus 1.2/1.2
(1.5/1.5)
• Hyperopia
• Cornea verticillata
• (unrelated picture below)
March 2003
Evaluated for Primary Sterility
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An air stewardess born in 1973 (=30 years)
Length 178 cm, Weight 70 kg
BMI 22.1 , BSA 1.86
Chronic disease -, operations -,allergy –
Blood Group A Rh +
RR 95-110/60-75 mmHg
• Fabry Disease Carrier State +
– febrile/non-proximal extremity pain-episodes in childhood
Grandmother
Died from cancer
69 years of age
Analysis may include
1. Enzymatic
2. Genetic
3. Pedigree
Mother
1) α-galactosidase
within ref value
2) Mutation L311F
Patient
1) α-galactosidase
Not done
2) Mutation L311F
C10639T
Aunt
1) α-galactosidase
Reduced
2) Mutation L311F
Sister
1) α-galactosidase
within ref value
2) Mutation result ?
Ophtalmology 94-06
3)
1) Hyperopia
2) V 1.6/1.6
Cornea verticillata
Laboratory 03-09
Nephrology 03-09
3.
1. Microhematuria
2. Kidney biopsy
Neurology 04-09
Hyperfiltration/hypertrophy
1 Hematology 0
2) Blood chemistry 0
3) Immunoserology 0
1) Exam 0
2) MRI 0
3) ERT discussed
4) Follow-up organised
Obstetric 04-05
1)
Assisted pregnancy
2) Counselling
Cardiology 03-09
1)
Serial US
2) MRI
Ejection Fraction by Transthoracal Ultrasound
Wall Thicknesses by Transthoracal Ultrasound
14
60
12
50
10
40
8
30
6
Millimeters
per cent
70
20
4
10
2
0
0
12.6.2003
29.8.2005
20.09.2007
26.11.2008
IVS
PW
12.6.2003
29.8.2005
20.09.2007
26.11.2008
Prenatal testing
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Karyotype of Fetal Cells
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XY
GLA Mutation known
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Chorionic Villus Sampling (CVS)
Amniocentesis
Fetal Cell α-galA
Molecular testing of fetal cells
1.
2.
3.
Sequence Analysis/mutation scanning
Mutation Scanning + Exon
sequencing
Deletion Testing
1.
2.
3.
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Preimplantation genetic Diagnosis
(PGD)
In heterozygote females
Unknown mutation or
exonic/whole-gene deletion
In known mutations
Obstetric Events
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20.12.2004
gravitest + grav hbd 7+3
Assisted Pregnancy
Karyotype XX
4.8.2005
Succesful delivery
– Healthy girl
• Not tested by either enzyme activity or molecular dg.
Collected Urine Albumin Excretion Rate
24-H Urinary Protein Excretion Rate
30
400
Reference Value 11 ug/min
28
26
350
24
22
300
20
250
18
16
200
14
150
10
100
50
Pregnancy 11/2004- 8/2005
0
17.4.2005
12.6.2005
5.7.2005
5.9.2006
Serum Creatinine
58
Cu-Excretion Rate ug/min
mg/ 24-H
12
8
6
4
2
Pregnancy 11/04-5/05
0
3.9.2003
18.4.2005
5.1.2005
25.1.2008
24.7.2008
17.2.2008
17.10.2008
Urinary Erythrocytes / HPF
12
56
10
54
52
8
50
48
6
46
Number of
44
S-Creatinine (umol/l)
42
40
4
2
38
Pregnancy 11/04-8/2005
36
0
3.9.2003
4.1.2005
8.5.2003
28.8.2006
18.4.2005
14.1.2008
16.1.2007
17.10.2008
25.1.2008
17.2.2009
8.5.2003
18.4.2005
12.6.2003
25.1.2008
24.7.2008
19.2.2009
3.9.2003
13.6.2005
14.1.2008
10.6.2008
17.10.2008
Plasma Cystatine C
0,9
U-Osmolality
mosm/kg
0,8
0,7
700
468
490
537
0,6
0,5
0,4
0,3
Plasma Cystatine C
0,2
0,1
Pregnancy 11/04-8/05
0,0
14.1.2005
28.8.2006
14.01.2008
17.10.2008
18.4.2005
16.01.2007
25.01.2008
17.2.2008
US
3.9.2003
12.5/12.cm (R/L) RI 0.64-0.69
Cystoscopy 21.1.2004
unremarkable
US
10.06.2008
12.8/12.3 cm (R/L) RI 0.59-0.66
Flow 0.7-0.9 m/s
Kidney Biopsy was done11.06.2008
because of microhematuria
1. Common things are common
2. Diseases present in characteristic ways
3. A combination of two common disorders
is more frequent than
4. A rare disorder (that in fact exists)
•
A.J. Howie. Professor of Renal Pathology
University College LondonHandbook of Renal
Biopsy. 2009
Masson trichrome
Masson trichrome
PAS
*
IgA
Dg: Fabry’s disease with concomitant IgA nephropathy
• The first report 36-yrs-old female in 1994 in Japan
(Yoshida et al. Nippon Jinzo Gakkai Shi 1994:36:11:1303)
• 4 other cases reported (3 F & 1 M)
(Kawamura et al. Clin Nephrol 1997:47: 71, Pisani et al: G Ital Nephrol 2005:21:385,
Whybra et al. Pediatr Nephrol 2006:21:1251)
• Fabry often subclinical, symptoms from IgA nephropathy
• It has been suggested that immunogenic galactocerebrosides can
accumulate and represent a long term antigenic stimulus and
induced autoimmune reaction
• As a consequence of the primary pathology of Fabry’s
disease, some patients may have increased susceptibility to
developing IgA nephropathy
Tampere University Hospital
Clinical Presentation of Subjects Diagosed with IGA-GN
Renal Failure; 18; 3%
Hematuria lone; 97; 16%
Nephritic sdr; 158; 25%
Proteinuria; 51; 8%
Nephrotic sdr; 37; 6%
Proteinuria & Hematuria; 259; 42%
Renal Pathology in Subjects Biopsied for Lone Hematuria
at the University Hospital in Tampere
1976-2007
110
100
90
80
70
60
50
40
30
Number of observ
20
10
0
AGN
ECGN
MesPGN
IGAGN
FPGN
DN
EPGN
MGN
MesSGN
IGMGN
GNnos
ATIN
AN
TBMD
CTIN
The incidence / 100 000 of specified biopsy indications
35
30
25
20
15
10
Renal Failure
Hematuria
Proteinuria
Nephrotic sdr
Hemat and proteinuria
Nephritic sdr
5
0
1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006
11.06.2008
Kidney Biopsy
1. Common things are common
2. Diseases present in characteristic ways
3. A combination of two common disorders
is more frequent than
4. A rare disorder (that in fact exists)
–
A.J. Howie. Professor of Renal Pathology University
College LondonHandbook of Renal Biopsy. 2009
5. (Do not forget a combination of a
common and a rare disorder )
Multisystem FD progression
Hemizygote (= Classic Variant in the Male , α-GAL-A <
1%)
1.
2.
3.
4.
5.
Attacks of pain and
distal acroparesthesia
worsened by triggering
factors
Cornea verticillata
Angiokeratomas
(bathing trunk
distribution)
Occlusive/trombotic
vascular events
Neurological, cardial
and renal organ
dysfunction
The Renal Variant of FD
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Age at onset
Age at death
Acroparesthesia
Hypohidrosis
Heart
Kidney
Alpha-gal A activity
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>25 years
> 60 years
-/+
-/+
LVH
ESRD
> 1%
FD in the Heterozygote
(= Carrier Female) (α-GAL-A >/< 1%)
• Clinical manifestation ranges from
asymptomatic to severe disease
• Random X-chromosome inactivation
– α-galactosidase residual activity overlapping
with normal
Pathogenesis of FD
• Intralysosomal
accumulation of neutral
glycosphingolipids (GSL)
– Globotriaosylceramid
(Gb3)
– Digalactocylceramide
• in various tissues
(multisystem disease)
• And various cells
– Endothelium (OVD)
– VSMC (LVH)
– Podocytes
(Proteinuria/Glomerulos
clerosis)
Clinical Presentation
Glomerulopathy
PU +/- HU
Distal Tubulopathy
Isosthenuria
Vasculopathy
CRF
Endothelial disease
OVD
• a) Light microscopy of the left kidney biopsy shows
obsolete glomeruli with the expanded mesangial matrix
• b) Vacuolization of the medial smooth muscle cells in an
arteriole
• c) Vacuolization of the endothelial cells of the afferent
arteriole. the swollen endothelium completely obliterates
the arteriolar lumen
Filtration Rate
• Creatinine clearance
22.5.2003
– 117 ml/min/1.73 m2
• OGTT
19.11.2008
– P-glucose 4.5-4.2 mmol/
• HbA1c 5.5 %
• Pt-Johexol test
– 125.7 ml/min/1.73 m2
9.11.2008
10.6.2008
High filtration rate and Large Kidneys
•
Documented in this patient
– Not-diabetes related
– Not pregnany related
– No evident cause
1. Related to Fabry carrier state !
2. Cause of secondary Hyperfiltrationhypertrophy related injury ?
3. Indication for ERT ?
Enzyme Replacement Therapy
Possible Indications in Female Carriers
• Proteinuria
– Increasing trend
– per se (even marginal)
• Pathology
– Non-slight findings
– Sclerosis/ Fibrosis
• Heart
– End-diastolic dysfunction
– Interstitial fibrosis
Enzyme Replacement Therapy
Recommendations in UpToDate
• In any subject with FD and renal
manifestations
Is This Patient with
Probably Renal Variant of FD and coincidental IGA-Nephropathy
at risk of ESRD
??
Is ERT indicated ?
What about ACEI/ARB ?
1.
2.
3.
4.
5.
6.
7.
Age at onset (=Diagnosis)
Age at death
Acroparesthesia
Hypohidrosis
Heart
Kidney
Alpha-gal A activity
1.
2.
3.
4.
5.
6.
7.
> 30 years
-------------------------LVH not found
FD related changes +
Unknown