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Nelson Tang primary carnitine deficiency slides
- 1. Disorders of carnitine and fatty acid oxidation pathway in Chinese 香港華人的生化遺傳病 -脂肪酸氧化作用缺陷症 鄧亮生 Nelson LS Tang, MD, FRCPA Chemical Pathology, The Chinese University of Hong Kong 香港中文大学 化学病理系教授 澳洲病理医学院 遗传学 考官
- 2. Nelson Tang Patients and family Paediatricians Prof. TF Fok J Hui KL Cheung Genetics / Chemical Pathology Nelson Tang Eric LK Law WH Lau Dietitian Phyllis Yau Joint Metabolic Clinic since 1997 Prince of Wales Hospital / CUHK
- 3. Nelson Tang Fatty acid oxidation (CH3)3-N-CH2-CH-CH2-COOH OH Long-Chain - FA Plasma membrane inner mitochondria membrance High affinity transport Low affinity transport Acyl-CoA Acyl-Carnitine Carnitine Acyl-Carnitine LCAD MCAD SCAD Acyl-CoA Acyl-CoA EH HAD KAT Acetyl-CoA FADETFETF-DH CoQ Electron transport chain CPT 1 CPT 2 Outer mitochondrial membrance Translocase
- 4. Nelson Tang Carnitine transporter defect Normal Carnitine transporter defect Carnitine transporter
- 5. Nelson Tang Case History • A blood sample and urine sample collected at the time of admission • Serum free carnitine: 9 umol (22-50) • Total carnitine: 12 umol • Urine organic acid: – dicarboxylic aciduria with little ketone
- 6. Nelson Tang Carnitine loading test- kidney maximal carnitine reabsorption capacity 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100 Filtered load CONTROL MOTHER FATHER Renalexcretionoffreecarnitine (umol/LGFR) Plasma free carnitine concentration (umol/L) Max. Reabsorption capacity Renal excretion threshold Normal control
- 7. Nelson Tang Discovery of the gene, OCTN2 • 1999, We discovered the gene responsible for this disease (US and Japan groups about the same time). • The gene encodes for a plasma membrane carnitine transporter. • Mutations leads to primary carnitine deficiency
- 8. Nelson Tang Is it just an incidental case ? • Is primary carnitine deficiency like other rare IMD just happened to be picked up in one family in Chinese ?
- 9. Nelson Tang Prevalence of primary carnitine deficiency in Taiwan • Many cases were sent here for confirmatory mutation analysis • Many cases diagnosed over 10+ years • Roughly 50,000 cases screened in the collaborating center in Taipei each year • Estimated incidence : 1 in 60,000 newborns • Similar to predicted incidence (Tang, 2002)
- 10. Nelson Tang Founder mutation of primary carnitine deficiency in Chinese • New cases were diagnosed in Hong Kong, Macau, Taiwan • Sharing a common mutation (R254X: 50% of mutations found in Chinese) • Different from mutations found in Caucasians
- 11. Nelson Tang Estimated incidence of Primary carnitine deficiency • 1 in 40,000 to 1 in 60,000 due to the founder mutation alone • So true incidence will be higher • Expanded study of 10 other Taiwan patients • R254X was found in >50% of patients
- 12. Nelson Tang • ? Recurrent mutation events, happened independently • Same founder mutation but traveled across Continents
- 13. Nelson Tang Primary carnitine deficiency Can Newborn screening pick it up? • Yes or No. • By Low C0 (free carnitine) • Sensitivity of only ~50% – “Two of 4 babies subsequently diagnosed clinically with the carnitine transporter defect had a free carnitine level in the neonatal blood sample low enough to be detected by screening. “ – Wilchen et al 1999 (Australia)
- 14. Nelson Tang Prognosis • Is good on life long high-dose carnitine supplement • Could lead to sudden death if carnitine supplement is stopped.
- 15. Nelson Tang What is the Chinese term for Carnitine ? • 肉毒碱 before 1999 • I translated it into a new name 卡尼丁 during a press conference.
- 16. Nelson Tang What is new ?
- 17. Nelson Tang Mother has disesae • Among those newborns screening positive for a low carnitine (confirmed at re-test) in NBS • 50% are patients with PCD • New Phenotype Defined • 50% are carrier only but their mothers are undiagnosed patients of PCD • Maternal PCD
- 18. Nelson Tang Maternal PCD • Asymptomatic / undiagnosed adult women • Give birth to a child (uneventful pregnancy) • Child picked up by NBS for low carnitine • Family study revealed the diagnosis • Mostly a Biochemical (Laboratory) defined phenotype
- 19. Nelson Tang Maternal PCD • These mother also had very low carnitine levels • i.e genuine deficiency • Are they symptomatic ? – Mostly asymptomatic.
- 20. Nelson Tang Why (and how) are maternal PCD asymptomatic ?
- 21. Nelson Tang Maternal PCD: specific mutation • All except one are carrier of S467C • This mutation was first reported in Japanese (1999)
- 22. Nelson Tang S467C has substanital residual activity • Koizumi et al 1999
- 23. Nelson Tang What FOAD are found in Southern Chinese? 1. Primary Carnitine deficiency 卡尼丁缺乏症 2. Glutaric aciduria type 2 (ETF chain) defects 戊二酸血症第2型 3. Carnitine translocase deficiency 卡尼丁穿透障礙 4. VLCAD極長鏈醯輔酶Α去氫酶缺乏症 5. SCAD短鏈羥基醯輔酶Α去氫酶缺乏症
- 24. Nelson Tang Fatty acid oxidation (CH3)3-N-CH2-CH-CH2-COOH OH Long-Chain - FA Plasma membrane inner mitochondria membrance High affinity transport Low affinity transport Acyl-CoA Acyl-Carnitine Carnitine Acyl-Carnitine LCAD MCAD SCAD Acyl-CoA Acyl-CoA EH HAD KAT Acetyl-CoA FADETFETF-DH CoQ Electron transport chain CPT 1 CPT 2 Outer mitochondrial membrance Translocase
- 25. Nelson Tang What is Carnitine called in Chinese ? • Called 肉毒碱 before 1999 • I translated it into a new name 卡尼丁 during a press conference.
- 26. Nelson Tang 卡尼丁 becomes standard terminology