Disorders of Dopamine & Disorders of Dopamine & Serotonin - PowerPoint PPT Presentation

Disorders of Dopamine & Disorders of Dopamine & Serotonin Metabolism Serotonin Metabolism Simon Heales Simon Heales Neurometabolic Unit Unit Neurometabolic A CPA accredited & SAS Laboratory A CPA accredited & SAS Laboratory National Hospital (UCLH Trust) National Hospital (UCLH Trust) Queen Square Queen Square London WC1N 3BG London WC1N 3BG

O 2 Tyrosine Tyrosine L- -Dopa Dopa L Dopamine Dopamine HVA HVA B6 B6 Tryptophan Serotonin Tryptophan Serotonin 5- -HTP HTP 5 5- -HIAA HIAA 5 Phenylalanine Phenylalanine Tyrosine Tyrosine BH2 qBH2 BH2 qBH2 BH4 BH4

GTP GTP GTP cyclohydrolase cyclohydrolase GTP P 3 P 3 Dihydroneopterin Triphosphate Triphosphate Dihydroneopterin Dihydroneopterin Dihydroneopterin Pyruvoyl tetrahydroptein tetrahydroptein synthase synthase Pyruvoyl 6- -Pyruvoyltetrahydropterin Pyruvoyltetrahydropterin 6 Aldose reductase Aldose reductase / /Sepiapterin Sepiapterin reductase reductase Tetrahydrobiopterin Tetrahydrobiopterin

BH4 Salvage BH4 Salvage Tyr L- -Dopa Dopa Tyr L PCD + qBH2 qBH2 BH4 BH4 DHPR DHPR NAD + + NADH NAD NADH PCD = pterin carbinolamine carbinolamine dehydratase dehydratase PCD = pterin DHPR = dihydropteridine dihydropteridine reductase reductase DHPR =

BH4 Deficiency BH4 Deficiency Decreased spontaneous movements, mental Decreased spontaneous movements, mental • • retardation, convulsions, disturbances of tone retardation, convulsions, disturbances of tone and posture, drowsiness, irritability, abnormal and posture, drowsiness, irritability, abnormal movements, recurrent hyperthermia, movements, recurrent hyperthermia, hypersalivation, swallowing difficulties, diurnal , swallowing difficulties, diurnal hypersalivation fluctuations of alertness, microcephaly microcephaly fluctuations of alertness,

BH4 Deficiency BH4 Deficiency Hyperphenylalaninaemia. Hyperphenylalaninaemia. • • Neurological impairment due to :- - Neurological impairment due to : • • -Decreased DA and 5 Decreased DA and 5- -HT metabolism. HT metabolism. - -Impaired NO metabolism ? Impaired NO metabolism ? - Treatment; Phe restriction Phe restriction. . Treatment; • • Monoamine replacement. Monoamine replacement. Folinic acid (DHPR deficiency) Folinic acid (DHPR deficiency) BH4 BH4

Diagnosis Diagnosis • Detection of Detection of hyperphenylalaninaemia hyperphenylalaninaemia • • Plasma/urine pterin profile Plasma/urine pterin profile • • Serum Serum prolactin prolactin • • Blood Spot DHPR Blood Spot DHPR • Caution – – isolated CNS deficiency isolated CNS deficiency Caution Sepiapterin Reductase Deficiency Reductase Deficiency Sepiapterin • Enzymatic and mutation analysis Enzymatic and mutation analysis • CSF Analysis CSF Analysis

Neurochemical Evaluation Evaluation - - CSF CSF Neurochemical Determines degree of CNS pterin & monoamine Determines degree of CNS pterin & monoamine • • deficiency. deficiency. Can identify pterin defects plus plus other disorders of other disorders of Can identify pterin defects • • monoamine metabolism. monoamine metabolism. Monitors response to treatment. Monitors response to treatment. • • HPLC + Electrochemical Detection. HPLC + Electrochemical Detection. • •

CSF – – Sample Requirements Sample Requirements CSF HVA & 5- -HI AA HI AA Tube 1 0.5ml HVA & 5 Tube 1 0.5ml • • 5- -MTHF & PLP MTHF & PLP Tube 2 0.5ml 5 Tube 2 0.5ml • • Pterins Tube 3 1.0ml Pterins Tube 3 1.0ml • • (DTE/DETAPAC) Collect at bedside and freeze immediately (not the form !) Collect at bedside and freeze immediately (not the form !)

nmol/L nmol/L Metabolite Age (years) Mean Range Metabolite Age (years) Mean Range HVA HVA 0 - 0 - 0.33 0.33 714 714 324- 324 -1098 1098 0.34 - - 0.66 0.66 587 362- -955 955 0.34 587 362 0.67 – – 1.00 1.00 508 176- -851 851 0.67 508 176 1.10 – – 5.00 5.00 465 154- -867 867 1.10 465 154 5.1- - Adult Adult 281 71- -565 565 5.1 281 71 5- 5 -HI AA HI AA 0 - - 0.33 0.33 417 199- -608 608 0 417 199 0.34 - 0.34 - 0.66 0.66 271 271 63- 63 -503 503 0.67 – – 1.00 1.00 250 68- -451 451 0.67 250 68 1.10 – – 5.00 5.00 185 89- -367 367 1.10 185 89 5.1- - Adult Adult 98 58- -220 220 5.1 98 58 Pediatr Res (1993) 34, 10-14

nmol/L nmol/L Metabolite Age (years) Mean Range Metabolite Age (years) Mean Range BH4 BH4 0 - 0 - 0.33 0.33 67 67 27- 27 -105 105 0.34 - - 0.66 0.66 37 23- -55 55 0.34 37 23 0.67 – – 1.00 1.00 38 19- -56 56 0.67 38 19 1.10 – – 5.00 5.00 33 8- -57 57 1.10 33 8 5.1- - Adult Adult 23 9- -39 39 5.1 23 9 BH2 BH2 ALL 5.6 0.4- -13.9 13.9 ALL 5.6 0.4 NH2 NH2 ALL ALL 19 19 7- 7 -65 65 Pediatr Res (1993) 34, 10-14

CSF - - Results Results CSF HVA & 5- -HIAA + Pterins HIAA + Pterins GTP GTP Cyclohydrolase Cyclohydrolase def def HVA & 5 HVA & 5- -HIAA HIAA HVA & 5 PTP Synthase Synthase def def PTP BH4 BH4 NH2 NH2 HVA & 5- -HIAA HIAA HVA & 5 DHPR def DHPR def BH2 BH2

GTP GTP GTP cyclohydrolase cyclohydrolase GTP P 3 P 3 Dihydroneopterin Triphosphate Triphosphate Dihydroneopterin Dihydroneopterin Dihydroneopterin Pyruvoyltetrahydroptein synthase synthase Pyruvoyltetrahydroptein -ve ve - 6- -Pyruvoyltetrahydropterin Pyruvoyltetrahydropterin 6 2’ketoreductase/sepaiapterin reductase 2’ketoreductase/sepaiapterin reductase Tetrahydrobiopterin Tetrahydrobiopterin

DHPR Deficiency DHPR Deficiency Tyr L- -Dopa Dopa Tyr L PCD PCD + BH2 qBH2 BH2 DHPR qBH2 DHPR BH4 BH4 NAD + + NADH NAD NADH -VE DOB; 20/01/06 . SAMPLE; 25/01/06 Folate Metabolism BH2; 106 (< 0.4 – 13.9 nmol/L) Monoamine Metabolism

DHPR Deficiency – – Response to Treatment Response to Treatment DHPR Deficiency 700 700 600 600 HVA HVA 500 500 5- -HIAA HIAA 5 nmol/L nmol/L 400 400 300 300 200 200 100 100 0 0 1.8 1.9 1.8 1.9 Age (Years) Age (Years)

Sepiapterin Reductase Deficiency Reductase Deficiency Sepiapterin • 2 patients (14 & 9 year old males) 2 patients (14 & 9 year old males) • Progressive psychomotor retardation, dystonia • Progressive psychomotor retardation, dystonia • No • No Hyperphenylalaninaemia Hyperphenylalaninaemia • Normal urinary pterins • Normal urinary pterins • Low CSF HVA, 5 • Low CSF HVA, 5- -HIAA. Elevated BH2 HIAA. Elevated BH2 Am. J. Hum Genet. (2001) 69, 269- -277 277 Am. J. Hum Genet. (2001) 69, 269

GTP GTP Dihydroneopterin Triphosphate Triphosphate Dihydroneopterin 6- -Pyruvoyltetrahydropterin Pyruvoyltetrahydropterin 6 Tetrahydrobiopterin Tetrahydrobiopterin BH2 BH2 DHFR DHFR

Sepiapterin Reductase Reductase Deficiency Deficiency Sepiapterin Sex; Male. Dob; 31/12/1987. Sample; 09/05/2003. Dystonia responsive to L-DOPA. No hyperphenylalaninaemia. DHPR normal. HVA: 23 (71- -565 nmol/ L) 565 nmol/ L) HVA: 23 (71 5- -HI AA: HI AA: 2 (58- -220 nmol/ L) 220 nmol/ L) 5 2 (58 BH4: 11 (9- -39 nmol/ L) 39 nmol/ L) BH4: 11 (9 BH2: 64 (0.4- -13.9 nmol/ L) 13.9 nmol/ L) BH2: 64 (0.4 Total Neopterin: 19 (7- -65 nmol/ L) 65 nmol/ L) Total Neopterin: 19 (7

Outcome of Current treatment Outcome of Current treatment • Restoration of monoamine turnover by L Restoration of monoamine turnover by L- -DOPA & 5 DOPA & 5- -HTP HTP • • Resolution of major but not all neurological signs Resolution of major but not all neurological signs • • Some cases severe developmental delay persists Some cases severe developmental delay persists • • Poor response and variation may be due to Poor response and variation may be due to • -Severity of metabolic defect Severity of metabolic defect - -Irreversible brain damage occurring Irreversible brain damage occurring in in utero utero - -Failure to Correct primary defect Failure to Correct primary defect - -NO Metabolism NO Metabolism -

L- -Dopa Responsive Dystonia Dopa Responsive Dystonia L • Typical onset in first decade • Typical onset in first decade - - dystonic dystonic equinus equinus posturing of the feet that spreads to other posturing of the feet that spreads to other extremities. extremities. • Can present later with parkinsonian • Can present later with parkinsonian features. features. • Marked diurnal fluctuation. • Marked diurnal fluctuation. • Response to L • Response to L- -Dopa appears complete Dopa appears complete and enduring. and enduring. • Has been misdiagnosed as cerebral palsy. • Has been misdiagnosed as cerebral palsy.

L- -Dopa Responsive Dystonia Dopa Responsive Dystonia L • Hereditary progressive dystonia (Segawa et al., 1971). • Autosomal Dominant – Female predominance (4:1). • GTP cyclohydrolase – a causitive gene (Ichinose et al., 1994) Mutations in gene cause at least 2 disorders :- AR – present within 6 months, hyperphenylalaninaemia & neurological dysfunction. AD - DRD. Residual activity 2-20%.