pathophysiology signs and symptoms old treatment prognosis...
TRANSCRIPT
![Page 1: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/1.jpg)
ALKAPTONURIA
PathophysiologySigns and symptoms
Old treatmentPrognosis
New treatment?
Harold W de Valk, endocrinologistZaira M. Barrientos, researcher
University Medical Centre UtrechtThe Netherlands
![Page 2: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/2.jpg)
Parts of the presentation
Background of the disease• Biochemical pathophysiology• Pathology• Genetics
Signs and symptoms Complications and prognosisThe Dutch surveyCurrent treatmentNew treatment• How to test effectivity, safety and toxicity in orphan drugs• What about NTBC?
Research & Development; outcome analysisConclusions
![Page 3: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/3.jpg)
Background of the disease
Deficiency of the enzyme homogentisic acid oxidaseAccumulation of homogentisic acid in blood, tissue and urine Rest activity can vary from person to person
![Page 4: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/4.jpg)
Biochemical pathway
Phenylalanine TyrosineTyrosine amino transaminase
Phenylalaninehydroxylase 4 Hydroxyphenylpyruvate
4-hydroxyphenylpyruvatedioxygenase (4-HPPD)
Homogentisic acid
Deficiency in Alkaptonuria
Homogentisate 1,2-dioxygenase
Maleylacetoacetate Maleylacetoacetate
Porphobilinogen isomerase
FumarylacetoacetateDeficiency in Hereditary
tyrosinaemia IFumarylacetoacetase
Fumarate +Acetoacetate Tricyclic acid cycle
![Page 5: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/5.jpg)
PathogenesisExcess HGA Excess HGA
in plasma Excess HGA
in urine
Polymers Binding to sulhydrylgroups
Genetic defect
Pathophysiologic pathway
Polyphenol oxidase in tissue
BQABinding to
collagen
Free radical damage
Cartilage damage Joint disease
![Page 6: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/6.jpg)
Genetics
Autosomal recessive diseaseMany DNA-mutationsDetected hot spots:• a valley in Slovakia• Dominican republic
− geographically and socially secluded area− non-paternity
Prevalence: 1/500.000 to 1/1.000.000• France (80 million): 80-160 patients• Les Pays Bas (16 million): 16-32 patients• European union (350 million): 350-700 patients
![Page 7: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/7.jpg)
Pathology Dark coloration of the cartilage
Loose fragments
Intra- and extracellular
deposits
Abnormalcollagen
Synovium involvement
Joint destruction
![Page 8: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/8.jpg)
Culture system
Human articular cartilage
4 days culture
DMEM + AHS + PSG
![Page 9: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/9.jpg)
Treatment
Homogentisic acid
Homogentisic acid and vit C
![Page 10: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/10.jpg)
Analysis
Cartilage matrix synthesisby proteoglycan synthesismeasured by35SO4 incorporation rateduring the last 4 hoursof culture
![Page 11: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/11.jpg)
Results
Propotional changes of the synthesis with regard to the controlgroup
0
20
40
60
80
100
120
140
160
0 10 100
concentration homogentisic acid (ug/ml)
%
30
![Page 12: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/12.jpg)
Signs, symptoms and complications (1)
Discoloration of fluids and tissues• Discoloration urine• Discoloration of sclerae• Discoloration of cerumen• Discoloration of sweat• Discoloration of cartilage
Joint disease at an early age− pain− limited mobility − inflammatory episodes
![Page 13: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/13.jpg)
Signs, symptoms and complications (2)
Renal calculiProstate calculiCardiac valve abnormalitiesConduction hearing lossRupture of the Achilles tendon
![Page 14: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/14.jpg)
Clinical evolution of alkaptonuriaA life’s time
Urine
Sclerae
Urinary Calculi
Joints
Valvular disease
![Page 15: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/15.jpg)
The Dutch survey
Research questions:• What is the prevalence• What are the clinical signs and symptoms• What about radiographic evaluation of the skeletal system• What about ultrasound evaluation of cardiac valves and
function• What about the current and previous therapy• First estimation of incidence of complications• Start of a (larger) follow-up study
![Page 16: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/16.jpg)
The Dutch survey
Recruitment of patients:• Contacting known professionals dealing with inborn errors
of metabolism• Contacting laboratories• Contacting siblings and other family members• Chance (1)
![Page 17: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/17.jpg)
The Dutch survey
Research protocol:• Written questionnaire completed by the patient• Physical examination• Radiographic evaluation:
• spine• hip• knee• shoulder
• Ultrasound evaluation of cardiac valves and function
![Page 18: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/18.jpg)
The Dutch survey
Results:• Number of patients: 40 (32 adults; 23 presented)• Prevalence: 1/400.000 subjects• Sex (n,%): 18/5 (78/22)• Age (years): 40 (16-72)• Early-diagnosed (n,%): 14 (61)• Late-diagnosed (n,%): 9 (39)• Joint replacement (n): 3• Spinal surgery (n): 1 • Cardio-vascular disease (n): 1
![Page 19: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/19.jpg)
Age at diagnosis
0
5
10
15
20
0-5
6-1
0
11-1
5
16-2
0
21-2
5
26-3
0
31-3
5
36-4
0
41-4
5
46-5
0
51-5
5
56-6
0
61-6
5
Age at diagnosis (years)
Num
ber
![Page 20: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/20.jpg)
Age at evaluation
0
5
10
15
200-2
0
21-4
0
41-6
0
61-8
0
Age at evaluation (years)
Num
ber
![Page 21: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/21.jpg)
The Dutch survey
Results:• Spinal pain: 16/23 patients 70%• Joint pain: 15/23 patients 65%
− shoulder 8/23 patients 35%− hip 11/23 patients 48%− knee 11/23 patients 48%
![Page 22: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/22.jpg)
The Dutch survey
Results:• 8 patients stopped working or changed job because of the
disease• No patients with renal calculi• 1 patient with prostate calculi• 2 patients with an Achilles tendon rupture• 5 patients with mild hearing loss• 1 patient with a valve replacement• No patients with coronary heart diseasetient
![Page 23: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/23.jpg)
Painful joint(s)
0
5
10
15
200-2
0
21-4
0
41-6
0
61-8
0
Age at evaluation (years)
Num
ber
of pat
ients
No jointsYes joints
![Page 24: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/24.jpg)
Pain according to joint involved
0
20
40
60
80
1000-2
0
21-4
0
41-6
0
61-8
0
Age at evaluation (years)
Per
centa
ge
of pat
ients
ShoulderHipKneeSpine
![Page 25: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/25.jpg)
First symptom large joints
0
20
40
60
80
100
0
10
20
30
40
50
60
70
80
Age (years)
Perc
enta
ge
![Page 26: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/26.jpg)
First symptom spine
0
20
40
60
80
100
0
10
20
30
40
50
60
70
80
Age (years)
Perc
enta
ge
![Page 27: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/27.jpg)
First symptom joints & spine
0
20
40
60
80
100
0
10
20
30
40
50
60
70
80
Age (years)
Perc
enta
ge
SpineJoints
![Page 28: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/28.jpg)
Difference between start of joint and spine problems
0
2
4
6
8
10
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9
10
Difference in years
Num
ber
![Page 29: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/29.jpg)
First symptom jointsaccording to time of diagnosis
0
20
40
60
80
100
0
10
20
30
40
50
60
70
80
Age (years)
Perc
enta
ge
EarlyLate
![Page 30: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/30.jpg)
First symptom spineaccording to time of diagnosis
0
20
40
60
80
100
0
10
20
30
40
50
60
70
80
Age (years)
Perc
enta
ge
EarlyLate
![Page 31: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/31.jpg)
First symptom joints with earlydiagnosis according to diet
0
20
40
60
80
100
0
10
20
30
40
50
60
70
80
Age (years)
Perc
enta
ge
Yes dietNo diet
p=0.3
![Page 32: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/32.jpg)
First symptom joints with earlydiagnosis according to vitamin C
0
20
40
60
80
100
0
10
20
30
40
50
60
70
80
Age (years)
Perc
enta
ge
Vit CNo Vit C
p=0.7
![Page 33: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/33.jpg)
First symptom spine with earlydiagnosis according to diet
0
20
40
60
80
100
0
10
20
30
40
50
60
70
80
Age (years)
Perc
enta
ge
Yes dietNo diet
p=0.7
![Page 34: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/34.jpg)
First symptom spine with earlydiagnosis according to vitamin C
0
20
40
60
80
100
0
10
20
30
40
50
60
70
80
Age (years)
Perc
enta
ge
Vit CNo Vit C
p=0.8
![Page 35: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/35.jpg)
The Dutch survey
Profession:• Construction 6• Student/teacher 3• Administration 3• Logistical support 3• Medical/paramedical 2• Security 1• Theatre 1• Dentist 1• Retired 3
Similar age-relations with construction workers
![Page 36: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/36.jpg)
The Dutch survey
Ultrasound evaluation:• Valve replacement in 1 patient• No abnormalities in all the others
![Page 37: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/37.jpg)
The Dutch survey
New events:5 joint replacements in 2 years
![Page 38: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/38.jpg)
The Dutch survey
Treatment:• Protein restriction at any time: 44%• Vitamin C at any time: 42%
![Page 39: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/39.jpg)
Current treatment
Protein restrictionHigh doses of vitamin C
![Page 40: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/40.jpg)
PathogenesisExcess HGA Excess HGA
in plasma Excess HGA
in urine
Polymers Binding to sulhydrylgroups
Genetic defect
PR
Site of intervention
Polyphenol oxidase in tissue
Vit CBQABinding to
collagen
Free radical damage
Cartilage damage Joint disease
![Page 41: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/41.jpg)
Current treatment
Protein restriction• Difficult to maintain at higher ages and less effective
![Page 42: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/42.jpg)
Dietary manipulations in alkaptonuria
0
2
4
Usual diet Protein restriction Liberal proteinintake
Diet
Urin
ay H
GA
(g/l)
YOUNGOLD
![Page 43: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/43.jpg)
Current treatment
Protein restriction• Difficult to maintain at higher ages and less effective
High doses of vitamin C• High doses may even be pro-oxidative
→ What is the evidence→ Does it justify the burden of treatment?
![Page 44: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/44.jpg)
Case report
• A male (FZ) born 28-8-1963• Referred by paediatrician from the AMC Amsterdam• First diagnosis made within the first year: discoloration of
urine• Period of treatment with vitamin C and protein restriction until
12th year• Surgery left knee (meniscus)• Second diagnosis made in 1998 (35 year) with the first
operation because of a lumbar hernia nuclei pulposi
![Page 45: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/45.jpg)
Case report
• No other complications related to alkaptonuria• Physical examination: dark cerumen, darkened helices• Limited mobility in all directions of the shoulder joints• Increased kyphosis of the spine• No other abnormalities• Radiographic examinination:
– Cervical spine: little exophytes– Thoracic spine: no abnormalities– Lumbo-sacral spine: discopathy all levels with subchondral
sclerosis– SI-joints normal– Hips: no abnormalities– Knee: some narrowing of the joint space
• Ultrasound: no evidence of valve abnormalities
![Page 46: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/46.jpg)
Case report
• Urine: large excretion of homogentisic acid• Referral to the dept. of Neurology: radicular syndrome, no
substrate?• MRI: multiple sequesters• 2001: Surgery• No great improvement in symptoms.• His questions:
– What does the future hold?– What is the best treatment?– Which professions would be advisable?
![Page 47: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/47.jpg)
New treatment
NTBC (Nitisinone)
• Initially tested as a herbicide• Inhibits competitively an upstream enzyme:
4-hydroxyphenylpyruvate dioxygenase (4-HPPD)• Inhibits the overproduction of homogentisic acid • Lower plasma homogentisic acid levels and no urinary
homogentisic acid production• Recently obtained the orphan drug designation form
EMEA (European Medicine Evaluation Agency)
![Page 48: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/48.jpg)
Site of action of NTBC
Phenylalanine TyrosineTyrosine amino transaminase
Phenylalaninehydroxylase 4 Hydroxyphenylpyruvate
4-hydroxyphenylpyruvatedioxygenase (4-HPPD)
Homogentisic acid
Homogentisate 1,2-dioxygenase
Maleylacetoacetate Maleylacetoacetate
Porphobilinogen isomerase
Fumarylacetoacetate
Fumarylacetoacetase
Fumarate +Acetoacetate Tricyclic acid cycle
![Page 49: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/49.jpg)
PathogenesisExcess HGA Excess HGA
in plasma Excess HGA
in urine
Polymers Binding to sulhydrylgroups
Genetic defect
NTBC
PR
Site of intervention
Polyphenol oxidase in tissue
Vit CBQABinding to
collagen
Free radical damage
Cartilage damage Joint disease
![Page 50: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/50.jpg)
(Orphan) drug developmentPhase 1:• Testing in the laboratory to get some estimation of the
drug doses required• Toxicity: reproductive system• Testing in healthy volunteers whether it is not
directly lethal
Phase 2:• A: Dose finding study in patients• B: Longer term exposure in patients
Phase 3:• Testing against usual care in a randomized trial
Phase 4:• Treatment in larger patients groups and/or for longer
periods (post-marketing surveillance)
![Page 51: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/51.jpg)
(Orphan) drug developmentAim of the procedures:
• Development of a pharmacological agent• Known effectiveness• Known risks:
− adverse events (specific, non-specific)− reproductive toxicity (female, male)− teratogenic risk
• Costs of use (final price at the counter)
![Page 52: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/52.jpg)
NTBC development (1)
Phase 1:• Testing in the laboratory to get some estimation of the
drug doses requiredData from the tyrosinaemia experience? 1 mg/kg? Less?
• ToxicityReproductive system?Ocular abnormalities: partially depending on the degree of elevation of the plasma tyrosine level (>500-600 μmol/l).Reversible. Animals: in rats and beagle, but not in mice or rabbits.
![Page 53: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/53.jpg)
NTBC development (2)
Phase 1:• Safety
Not lethal in man• Pharmacology:
Non-competitive inhibitorT½ nitisinone: 54 hoursT½ tyrosine: 7 days!
![Page 54: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/54.jpg)
NTBC development (3)
Phase 2:• Proper dose finding in patients:
2003 • Extension study with multiple dosing
2003
Phase 3:• Proper randomized, placebo-controlled clinical trial
2004
Phase 4
Compassionate use: with consent of the patient incases of a mortal disease
![Page 55: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/55.jpg)
A clinical research effort in alkaptonuria
Nice idea, but…..• Alkaptonuria is a rare disease• Complications in alkaptonuria develop slowly• Do we use NTBC and/or other strategies?• Where does the funding come from? • How about collaboration with industry?
Hypercholesterolaemia? After statinsErectile dysfunction? After viagraFabry? After α- or β-galactosidase
![Page 56: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/56.jpg)
Partir (from Paris) c’est mourir un peu, mais…...
![Page 57: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/57.jpg)
ne pas rêver c’est être complètement mort
![Page 58: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/58.jpg)
Short outline of the clinical research programme
• Description of the currently known patients (survey), initially in the Netherlands with later a European extension
• Follow-up to describe prognosis and event rate: outcome analysis of unselected patients
• Pre-clinical testing of NTBC• Clinical testing of NTBC
![Page 59: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/59.jpg)
Why is outcome analysis inunselected patient groups so extremely important?
![Page 60: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/60.jpg)
Design
• Inclusion of all Dutch women with type 1 diabetes mellitus becoming pregnant in a period of 12 months
• Participation of all Dutch hospitals (118)– Internist– Gynaecologist– Diabetes-nurse– (Patients themselves)
• Completing questionnaires (internist, gynaecologist, paediatrician, and patient)
• Study duration of 4 years
![Page 61: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/61.jpg)
Preconceptional care and knowledge
• 84% of pregnancies are planned• 70% start with folic acid before conception• HbA1c at 10 weeks pregnancy: 72% < 7.0%• Problempopulation: lower education, foreign extraction
![Page 62: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/62.jpg)
HbA1c at 10 weeks 0
2040
6080
4,5 5,0 5,5 6,0 6,5 7,0 7,5 8,0 8,5 9,0
N
%
![Page 63: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/63.jpg)
Frequency and risk factors for severe hypoglycaemia (SH) in the first trimester
Preconceptional 1e trimester
Frequency SH (episodes/4 mts)SH (all episodes) 0.9 ± 2.4 2.6 ± 6.3 *Hypoglycaemic coma 0.3 ± 1.3 0.7 ± 3.7 *
Proportion of women:SH (all) 25% 41% *Uncomplicated SH 16% 22% *Coma 9% 19% *
* p<0.001N=278
![Page 64: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/64.jpg)
Complications (1)congenital abnormalities
• Major 4.9%• Minor 3.4%• Total 8.3% (95% CI 5.3-11.3%; 2%, P<0.05)
• Unplanned vs. planned pregnancies: major 10.4% vs. 3.8% (P=0.05)
![Page 65: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/65.jpg)
HbA1c at 10 weeks and congenital abnormalities
4,2
7,5
9,4
0
2
4
6
8
10
12
4.0-6.0% 6.1-7.0% >7.0%
% C% CAA
![Page 66: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/66.jpg)
Complications (2)
• Perinatal mortality: 2.8% (95% CI 1.0-4.6%; 0.9%, P<0.05)– CM (n=4), IUVD (n=2), PE (n=2), asphyxia (n=1)– 2 late neonatal mortality
• Maternal mortality: n=2 (0.6%; 0.01%, P<0.05)– Severe hypoglycaemia at 17 weken– Amnion fluid embolism durante partu
• Macrosomia (>p90) 56.1%(>p97.7)(>p97.7) 30.4%30.4%
![Page 67: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/67.jpg)
Birth weight children of mothers with type 1 diabetes
0
5
10
15
20
25
30
35
< 2.3 2.3-10 10-25 25-50 50-75 75-90 90-97.7 >97.7
geboortegewicht in percentielen
%
![Page 68: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/68.jpg)
Conclusions
1. Periconceptional preparation often good2. HbA1c in the majority of women in the ‘safe’ area3. Still increased frequency of congenital abnormalities, also
within the ‘safe’ area (HbA1c 6-7%)4. Very high frequency of macrosomia5. High frequency of neonatal morbidity6. High frequency of maternal severe hypoglycaemia7. Strongly increased maternal mortality
![Page 69: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/69.jpg)
So what now?
1. Is an HbA1c between 6-7% really safe?2. Is HbA1c a good index of the complexity of glycaemic
control: Glucose-variability3. Should ‘defensive’ forces be strengthened (anti-oxidantia?)4. Should we give different information?5. Type 1 diabetes and pregnancy is still not a won race.6. The goals of the St. Vincentdeclaration are not met, may be
this is simple not, and who knows never possible.
![Page 70: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/70.jpg)
‘Safe’ HbA1c: 6.0-7.0% (n=5)
-5,0
0,0
5,0
10,0
15,0
20,0
12:00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM
Time
Glu
cose
Con
cent
ratio
n (m
mol
/L)
-5,0
0,0
5,0
10,0
15,0
20,0
12:00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM
Time
Glu
cose
Con
cent
ratio
n (m
mol
/L)
-5,0
0,0
5,0
10,0
15,0
20,0
12:00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM
Time
Glu
cose
Con
cent
ratio
n (m
mol
/L)
-5,0
0,0
5,0
10,0
15,0
20,0
12:00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM
Time
Glu
cose
Con
cent
ratio
n (m
mol
/L)
-5,0
0,0
5,0
10,0
15,0
20,0
12:00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM
Time
Glu
cose
Con
cent
ratio
n (m
mol
/L)
![Page 71: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/71.jpg)
Outcome analysis in unselected patient groups is so extremely important because it
it provides adequate information on the results of the current therapyit can provide new insights leading to new ideasit can lead to the development of or use of new pharmacological or non-pharmacological treatmentsit can discard mythsit can give valuable information of the life situation of patientsIt can identify patients groups at highest risk
![Page 72: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/72.jpg)
Conclusions
Alkaptonuria may be more frequent than 1/500.000No current effective treatmentImpact on life after the end of the third decadeFurther clinical epidemiologic studies are required with outcome analysis and assessment of event rateEuropean collaboration is wantedNTBC offers a new and exciting pharmacological treatment possibilityBut it remains a ‘normal’ drug with possible serious side effects, used in a non-life-threatening diseaseEuropean collaboration is wanted
![Page 73: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/73.jpg)
LE FIN
![Page 74: Pathophysiology Signs and symptoms Old treatment Prognosis …ec.europa.eu/health/ph_projects/2000/rare_diseases/fp... · 2006. 10. 31. · Biochemical pathway Phenylalanine Tyrosine](https://reader033.vdocuments.mx/reader033/viewer/2022060711/60771a845ac35740ca7d407c/html5/thumbnails/74.jpg)
This report was produced by a contractor for Health & Consumer Protection Directorate General and represents the views of the contractor or author. These views have not been adopted or in any way approved by theCommission and do not necessarily represent the view of the Commission or the Directorate General for Health and Consumer Protection. The European Commission does not guarantee the accuracy of the dataincluded in this study, nor does it accept responsibility for any use made thereof.