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Transfer of Expertise on Rare Metabolic Diseases in Adults

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Transfer of Expertise on Rare Metabolic Diseases in Adults ALKAPTONURIA Pathophysiology Signs and symptoms Old treatment Prognosis New treatment? Harold W de Valk, endocrinologist Zaira M. Barrientos, researcher University Medical Centre Utrecht The Netherlands Parts of the presentation Background of the disease • Biochemical pathophysiology • Pathology • Genetics Signs and symptoms Complications and prognosis The Dutch survey Current treatment New treatment • How to test effectivity, safety and toxicity in orphan drugs • What about NTBC? Research & Development; outcome analysis Conclusions Background of the disease Deficiency of the enzyme homogentisic acid oxidase Accumulation of homogentisic acid in blood, tissue and urine Rest activity can vary from person to person Biochemical pathway Phenylalanine Tyrosine Tyrosine amino transaminase Phenylalanine hydroxylase 4 Hydroxyphenylpyruvate 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) Homogentisic acid Deficiency in Homogentisate 1,2-dioxygenase Alkaptonuria Maleylacetoacetate Maleylacetoacetate Porphobilinogen isomerase Fumarylacetoacetate Deficiency in Hereditary Fumarylacetoacetase tyrosinaemia I Fumarate + Acetoacetate Tricyclic acid cycle Genetic defect Pathophysiologic pathway Pathogenesis Excess HGA Excess HGA Excess HGA in plasma in urine Polyphenol Polymers Binding to oxidase in tissue sulhydrylgroups BQA Binding to collagen Free radical damage Cartilage damage Joint disease Genetics Autosomal recessive disease Many DNA-mutations Detected 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 Pathology Dark coloration of the cartilage Loose fragments Synovium involvement Intra- and extracellular deposits Joint destruction Abnormal collagen Culture system Human articular cartilage 4 days culture DMEM + AHS + PSG Treatment Homogentisic Homogentisic acid acid and vit C Analysis Cartilage matrix synthesis by proteoglycan synthesis measured by 35 SO4 incorporation rate during the last 4 hours of culture Results Propotional changes of the synthesis with regard to the controlgroup 160 140 120 100 % 80 60 40 20 0 0 30 10 100 concentration homogentisic acid (ug/ml) 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 Signs, symptoms and complications (2) Renal calculi Prostate calculi Cardiac valve abnormalities Conduction hearing loss Rupture of the Achilles tendon Clinical evolution of alkaptonuria A life’s time Urine Sclerae Urinary Calculi Joints Valvular disease 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 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) 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 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 Number 10 15 20 0 5 0-5 6-10 11-15 Age atdiagnosis 16-20 Ag e atd 21-25 i 26-30 ag n o 31-35 s i s ( 36-40 y ear 41-45 s ) 46-50 51-55 56-60 61-65 Age at evaluation 20 15 r e b 10 m Nu 5 0 60 80 40 20 0- 41- 61- 21- Age at evaluation (years) 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% 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 Painful joint(s) 20 s ent i 15 t a p f No joints 10 Yes joints er o 5 mb u N 0 80 40 60 20 0- 61- 21- 41- Age at evaluation (years) Pain according to joint involved 100 s t n e i 80 t pa Shoulder f 60 Hip o Knee ge 40 a t Spine n e 20 c r e P 0 60 80 40 20 0- 41- 61- 21- Age at evaluation (years) Percentage 100 20 40 60 80 0 0 First symptomlarge joints 10 20 30 Ag e ( y ear 40 s ) 50 60 70 80 Percentage 100 20 40 60 80 0 0 10 First symptomspine 20 30 Ag e ( y ear 40 s ) 50 60 70 80 First symptom joints & spine 100 80 e 60 tag Spine n e Joints c r 40 Pe 20 0 0 50 60 70 80 10 20 30 40 Age (years) Number 10 Difference between startofjointand 4 6 8 0 2 -10 -9 -8 -7 -6 spine problems -5 -4 D i -3 ffe r -2 e n -1 c e i 0 n y 1 e ar 2 s 3 4 5 6 7 8 9 10 First symptom joints according to time of diagnosis 100 80 e 60 tag Early n e Late c r 40 Pe 20 0 0 50 60 70 80 10 20 30 40 Age (years) First symptom spine according to time of diagnosis 100 80 e 60 tag Early n e Late c r 40 Pe 20 0 0 50 60 70 80 10 20 30 40 Age (years) First symptom joints with early diagnosis according to diet 100 p=0.3 80 e 60 tag Yes diet n e No diet c r 40 Pe 20 0 0 50 60 70 80 10 20 30 40 Age (years) First symptom joints with early diagnosis according to vitamin C 100 p=0.7 80 e 60 tag Vit C n e No Vit C c r 40 Pe 20 0 0 60 70 80 10 20 30 40 50 Age (years) First symptom spine with early diagnosis according to diet 100 p=0.7 80 e 60 tag Yes diet n e No diet c r 40 Pe 20 0 0 50 60 70 80 10 20 30 40 Age (years) First symptom spine with early diagnosis according to vitamin C 100 p=0.8 80 e 60 tag Vit C n e No Vit C c r 40 Pe 20 0 0 60 70 80 10 20 30 40 50 Age (years) 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 The Dutch survey Ultrasound evaluation: • Valve replacement in 1 patient • No abnormalities in all the others The Dutch survey New events: 5 joint replacements in 2 years The Dutch survey Treatment: • Protein restriction at any time: 44% • Vitamin C at any time: 42% Current treatment Protein restriction High doses of vitamin C Genetic defect Site of intervention PR Pathogenesis Excess HGA Excess HGA Excess HGA in plasma in urine Polyphenol Polymers Binding to oxidase in tissue sulhydrylgroups BQA Vit C Binding to collagen Free radical damage Cartilage damage Joint disease Current treatment Protein restriction • Difficult to maintain at higher ages and less effective Dietary manipulations in alkaptonuria 4 ) l / g YOUNG 2 OLD HGA ( y a n i r U 0 Usual diet Protein restriction Liberal protein intake Diet 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? 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 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 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? 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) Site of action of NTBC Phenylalanine Tyrosine Tyrosine amino transaminase Phenylalanine hydroxylase 4 Hydroxyphenylpyruvate 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) Homogentisic acid Homogentisate 1,2-dioxygenase Maleylacetoacetate Maleylacetoacetate Porphobilinogen isomerase Fumarylacetoacetate Fumarylacetoacetase Fumarate
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