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 Neurometabolic Unit Unit 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

BH2 BH2

Tyrosine Tyrosine Tryptophan Tryptophan Phenylalanine Phenylalanine L L-

• Dopa

Dopa 5 5-

• HTP

HTP

Tyrosine Tyrosine

Dopamine Dopamine Serotonin Serotonin

qBH2 qBH2 BH4 BH4 HVA HVA 5 5-

• HIAA

HIAA B6 B6

O2

GTP GTP Dihydroneopterin Dihydroneopterin Triphosphate Triphosphate 6 6-

• Pyruvoyltetrahydropterin

Pyruvoyltetrahydropterin Tetrahydrobiopterin Tetrahydrobiopterin

Dihydroneopterin Dihydroneopterin

GTP GTP cyclohydrolase cyclohydrolase Pyruvoyl Pyruvoyl tetrahydroptein tetrahydroptein synthase synthase Aldose Aldose reductase reductase / /Sepiapterin Sepiapterin reductase reductase

P P3

3

BH4 Salvage BH4 Salvage

Tyr Tyr L L-

• Dopa

Dopa

BH4 BH4 qBH2 qBH2 DHPR DHPR

NADH NADH NAD NAD+

+

PCD +

PCD = pterin PCD = pterin carbinolamine carbinolamine dehydratase dehydratase DHPR = DHPR = dihydropteridine dihydropteridine reductase reductase

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 hypersalivation, swallowing difficulties, diurnal , swallowing difficulties, diurnal fluctuations of alertness, fluctuations of alertness, microcephaly microcephaly

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;

Treatment; Phe restriction Phe restriction. . 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

• Blood Spot DHPR

Blood Spot DHPR Caution Caution – – isolated CNS deficiency isolated CNS deficiency

Sepiapterin Sepiapterin Reductase Deficiency Reductase Deficiency

• Enzymatic and mutation analysis

Enzymatic and mutation analysis CSF Analysis CSF Analysis

• Serum

Serum prolactin prolactin

Neurochemical Neurochemical Evaluation Evaluation -

• CSF

CSF

• Determines degree of CNS pterin & monoamine

Determines degree of CNS pterin & monoamine deficiency. deficiency.

• Can identify pterin defects

Can identify pterin defects plus plus other disorders of

• ther disorders of

monoamine metabolism. monoamine metabolism.

• Monitors response to treatment.

Monitors response to treatment.

• HPLC + Electrochemical Detection.

HPLC + Electrochemical Detection.

• Tube 1

Tube 1 0.5ml 0.5ml HVA & 5

HVA & 5-

• HI AA

HI AA

• Tube 2

Tube 2 0.5ml 0.5ml 5

5-

• MTHF & PLP

MTHF & PLP

• Tube 3

Tube 3 1.0ml 1.0ml Pterins

Pterins

CSF CSF – – Sample Requirements Sample Requirements

(DTE/DETAPAC)

Collect at bedside and freeze immediately (not the form !) Collect at bedside and freeze immediately (not the form !)

Metabolite Metabolite Age (years) Age (years) Mean Mean Range Range

HVA HVA

0 -

• 0.33

0.33 714 714 324 324-

• 1098

1098 0.34 0.34 -

• 0.66

0.66 587 587 362 362-

• 955

955 0.67 0.67 – – 1.00 1.00 508 508 176 176-

• 851

851 1.10 1.10 – – 5.00 5.00 465 465 154 154-

• 867

867 5.1 5.1-

• Adult

Adult 281 281 71 71-

• 565

565

5 5-

• HI AA

HI AA

0 -

• 0.33

0.33 417 417 199 199-

• 608

608 0.34 0.34 -

• 0.66

0.66 271 271 63 63-

• 503

503 0.67 0.67 – – 1.00 1.00 250 250 68 68-

• 451

451 1.10 1.10 – – 5.00 5.00 185 185 89 89-

• 367

367 5.1 5.1-

• Adult

Adult 98 98 58 58-

• 220

220

nmol/L nmol/L

Pediatr Res (1993) 34, 10-14

Metabolite Metabolite Age (years) Age (years) Mean Mean Range Range

BH4 BH4

0 -

• 0.33

0.33 67 67 27 27-

• 105

105 0.34 0.34 -

• 0.66

0.66 37 37 23 23-

• 55

55 0.67 0.67 – – 1.00 1.00 38 38 19 19-

• 56

56 1.10 1.10 – – 5.00 5.00 33 33 8 8-

• 57

57 5.1 5.1-

• Adult

Adult 23 23 9 9-

• 39

39

BH2 BH2

ALL ALL 5.6 5.6 0.4 0.4-

• 13.9

13.9

NH2 NH2

ALL ALL 19 19 7 7-

• 65

65

nmol/L nmol/L

Pediatr Res (1993) 34, 10-14

CSF CSF -

• Results

Results

HVA & 5 HVA & 5-

• HIAA + Pterins

HIAA + Pterins GTP GTP Cyclohydrolase Cyclohydrolase def def HVA & 5 HVA & 5-

• HIAA

HIAA PTP PTP Synthase Synthase def def HVA & 5 HVA & 5-

• HIAA

HIAA DHPR def DHPR def BH4 BH4 NH2 NH2 BH2 BH2

GTP GTP Dihydroneopterin Dihydroneopterin Triphosphate Triphosphate 6 6-

• Pyruvoyltetrahydropterin

Pyruvoyltetrahydropterin Tetrahydrobiopterin Tetrahydrobiopterin

Dihydroneopterin Dihydroneopterin

GTP GTP cyclohydrolase cyclohydrolase Pyruvoyltetrahydroptein Pyruvoyltetrahydroptein synthase synthase 2’ketoreductase/sepaiapterin 2’ketoreductase/sepaiapterin reductase reductase

P P3

3

• ve

ve

DHPR Deficiency DHPR Deficiency

Tyr Tyr L L-

• Dopa

Dopa

BH4 BH4 qBH2 qBH2 DHPR DHPR

NADH NADH NAD NAD+

+

BH2 BH2

• VE

Folate Metabolism Monoamine Metabolism

PCD PCD +

DOB; 20/01/06 . SAMPLE; 25/01/06 BH2; 106 (< 0.4 – 13.9 nmol/L)

100 100 200 200 300 300 400 400 500 500 600 600 700 700

1.8 1.8 1.9 1.9 HVA HVA 5 5-

• HIAA

HIAA

DHPR Deficiency DHPR Deficiency – – Response to Treatment Response to Treatment

Age (Years) Age (Years) nmol/L nmol/L

Sepiapterin Sepiapterin Reductase Deficiency Reductase Deficiency

• 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
• Am. J. Hum Genet. (2001) 69, 269-
• 277

277

GTP GTP Dihydroneopterin Dihydroneopterin Triphosphate Triphosphate 6 6-

• Pyruvoyltetrahydropterin

Pyruvoyltetrahydropterin Tetrahydrobiopterin Tetrahydrobiopterin

BH2 BH2 DHFR DHFR

Sepiapterin Sepiapterin Reductase Reductase Deficiency Deficiency

Sex; Male. Dob; 31/12/1987. Sample; 09/05/2003. Dystonia responsive to L-DOPA. No hyperphenylalaninaemia. DHPR normal.

HVA: HVA: 23 23 (71 (71-

• 565 nmol/ L)

565 nmol/ L) 5 5-

• HI AA:

HI AA: 2 2 (58 (58-

• 220 nmol/ L)

220 nmol/ L) BH4: BH4: 11 11 (9 (9-

• 39 nmol/ L)

39 nmol/ L) BH2: BH2: 64 64 (0.4 (0.4-

• 13.9 nmol/ L)

13.9 nmol/ L) Total Neopterin: Total Neopterin: 19 19 (7 (7-

• 65 nmol/ L)

65 nmol/ L)

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 L-

• Dopa Responsive Dystonia

Dopa Responsive Dystonia

• 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 L-

• Dopa Responsive Dystonia

Dopa Responsive Dystonia

• 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%.

L L-

• Dopa Responsive Dystonia

Dopa Responsive Dystonia

• Lowish

Lowish CSF concentrations of : CSF concentrations of :-

• BH4

BH4 Neopterin. Neopterin. HVA. HVA.

• I mpaired phenylalanine tolerance.

I mpaired phenylalanine tolerance.

Plasma Phenylalanine after Plasma Phenylalanine after 100mg/kg oral Phenylalanine 100mg/kg oral Phenylalanine

Time (Hours) Time (Hours)

1 2 3 4 5 6 500 1000 1500 DRD DRD CONTROLS CONTROLS *** *** ***

Phenylalanine ( Phenylalanine (umol umol/L) /L)

Tyrosine Hydroxylase Deficiency Tyrosine Hydroxylase Deficiency

Tyr Tyr Dopa Dopa Dopamine Dopamine HVA HVA

• Parkinsonian, ptosis, drooling, myoclonic jerks,

Parkinsonian, ptosis, drooling, myoclonic jerks, severe head lag and trunkal hypotonia. severe head lag and trunkal hypotonia.

• L

L-

• Dopa marked and sustained

Dopa marked and sustained improvement in hypokinesia and parkinsonian improvement in hypokinesia and parkinsonian symptoms. symptoms.

• I dentified from

I dentified from CSF analysis CSF analysis; ; Normal pterin & 5 Normal pterin & 5-

• HI AA concentration. Very low HVA.

HI AA concentration. Very low HVA. Mutation Mutation analysis also available. analysis also available.

Tyrosine Tyrosine Hydoxylase Hydoxylase Deficiency Deficiency

Sex; Female. Sex; Female. Dob Dob; 12/04/2000. Sample; 14/12/2001 ; 12/04/2000. Sample; 14/12/2001

HVA: HVA: 22 22

(154 (154-

• 867 nmol/L)

867 nmol/L)

5 5-

• HIAA:

HIAA: 165 165

( 89 ( 89-

• 367 nmol/L)

367 nmol/L)

BH4: BH4: 47 47

(8 (8-

• 57 nmol/L)

57 nmol/L)

BH2: BH2: 10 10

(0.4 (0.4-

• 13.9 nmol/L)

13.9 nmol/L)

Total Neopterin: Total Neopterin: 11 11

(7 (7-

• 65 nmol/L)

65 nmol/L)

Aromatic Amino Acid Decarboxylase Deficiency Aromatic Amino Acid Decarboxylase Deficiency

Tyr Tyr L L-

• Dopa

Dopa Dopamine Dopamine HVA HVA Trp Trp 5 5-

• HTP

HTP Serotonin Serotonin 5 5-

• HIAA

HIAA

Clinical features resemble those of recessive BH4 deficiency; Clinical features resemble those of recessive BH4 deficiency; hypotonia, hypotonia, occulogyric

• cculogyric crises, ptosis and paucity of spontaneous

crises, ptosis and paucity of spontaneous

• movement. Can be fatal
• movement. Can be fatal

Urine Urine: : Vanillactic Vanillactic acid acid CSF CSF: Low HVA + 5 : Low HVA + 5-

• HIAA, but

HIAA, but normal normal pterin profile and accumulation pterin profile and accumulation

• f
• f 3

3-

• O

O-

• methyldopa
• methyldopa. Enzymatic analysis possible on

. Enzymatic analysis possible on plasma plasma. . Treatment; B6, MAOI & dopamine agonists. Treatment; B6, MAOI & dopamine agonists.

B6 B6

Tyrosine Tryptophan L-Dopa 5-HTP Dopamine Serotonin

BH4 HVA 5-HIAA PLP

AADC

3-Methyldopa Vanillactic acid

Aromatic Amino Acid Aromatic Amino Acid Decarboxylase Decarboxylase Deficiency Deficiency

Sex; Sex; Male Male Dob Dob; 02/03/1998. Sample; 05/07/2001 ; 02/03/1998. Sample; 05/07/2001

HVA HVA 52 52 (154 (154-

• 867 nmol/L)

867 nmol/L) 5 5-

• HIAA

HIAA 22 22 ( 89 ( 89-

• 367 nmol/L)

367 nmol/L) 3 3-

• Methyldopa

Methyldopa 589 589 ( < 50 nmol/L) ( < 50 nmol/L)

Pyridox Pyridox(am) (am)ine ine-

• 5’

5’-

• Oxidase

Oxidase Deficiency Deficiency

Pyridoxine-5’- phosphate

Pyridoxamine-5’- phosphate

Pyridoxal-5’- phosphate

N CH2OH HO H3C

CH2OPO3H2 CH2OPO3H2 CH2OPO3H2

N CH2NH2 HO H3C

N CHO HO H3C

PNPO

PNPO PNPO = Pyridox(am)ine-5’-oxidase

CH2OPO3H2 CH2OPO3H2

PNPO Deficiency PNPO Deficiency

• Neonatal epileptic encephalopathy

Neonatal epileptic encephalopathy

• Fetal

Fetal distress, prenatal seizures, low distress, prenatal seizures, low Apgar Apgar. .

• Lactate (blood, CSF), pseudo AADC deficiency

Lactate (blood, CSF), pseudo AADC deficiency

• Pyridoxal

Pyridoxal phosphate (CSF) phosphate (CSF) Glycine Glycine & & Threonine Threonine (blood, CSF) (blood, CSF)

PNPO Deficiency PNPO Deficiency

CSF (PLP) CSF (PLP)

10 20 30 40 50 60 70 80 90 100 2 4 6 8 10 12 14 16

Age (Years) PLP (nmol/L)

CSF 5 CSF 5-

• MTHF Deficiency

MTHF Deficiency

• DHPR deficiency
• MTHFR deficiency
• AADC deficiency
• 3-Phosphoglycerate dehydrogenase def
• Rett syndrome
• Aicardi Goutieres
• Mitochondrial disorders
• L-dopa treatment
• Methotrexate
• Anticonvulsants
• Steroids
• Co-trimoxazole

Cerebral Cerebral Folate Folate Deficiency Deficiency

• Neurological syndrome associated with low CSF 5-MTHF

and normal peripheral folate.

• Decreased transport/increased turnover ?

20 children reviewed: 4 months unrest, irritability, sleep disturbances followed by psychomotor retardation, cerebellar ataxia, spastic paraplegia & dyskinesia. Autistic features. Epilepsy in 33% of cases. Visual disturbances around 3 years. Imaging; atrophy of frontotemporal regions and periventricular demyelination in 7 children.

Oral folinic acid associated with favourable clinical response

5-MTHF

34.4

42.0 – 119.6 nmol/L

CSF Analysis CSF Analysis

• Pterin defects +

Pterin defects + sepiapterin sepiapterin reductase def. reductase def.

• Tyrosine hydroxylase deficiency.

Tyrosine hydroxylase deficiency.

• Aromatic amino acid decarboxylase deficiency.

Aromatic amino acid decarboxylase deficiency.

• Disorders of B6 metabolism.

Disorders of B6 metabolism.

• 5

5-

• MTHF deficiency.

MTHF deficiency.

• Monitor response to treatment.

Monitor response to treatment.

• Tryptophan hydroxylase deficiency ?

Tryptophan hydroxylase deficiency ?

• Immune response activation (

Immune response activation (neopterin neopterin) )

• Be aware of secondary causes

Be aware of secondary causes ! !