“Neurotransmitter” Disorders
Chemical Neurotransmission
• Neurotransmitters –Substances that upon release from nerve terminals, act on receptor sites at post-synaptic membranes to produce either excitation or inhibition of the target cell
BH2
Tyrosine
Tryptophan
Phenylalanine
L-Dopa
5-HTP
Tyrosine
Dopamine
Serotonin
qBH2qBH2BH4
HVA
5-HIAAPLP
O2
BH4
GTP
Dihydroneopterin Triphosphate
6-Pyruvoyltetrahydropterin
Tetrahydrobiopterin
Dihydroneopterin
GTP cyclohydrolase
Pyruvoyl tetrahydroptein synthase
Aldose reductase /Sepiapterin reductase
P3
-VE
BH4 Salvage
Tyr L-Dopa
BH4BH4 qBH2qBH2DHPRDHPR
NADHNADHNADNAD++
PCD+
PCD = pterin PCD = pterin carbinolaminecarbinolamine dehydratasedehydrataseDHPR = DHPR = dihydropteridinedihydropteridine reductasereductase
BH2BH2
• Tube 1 0.5ml HVA & 5-HIAA
• Tube 2 0.5ml 5-MTHF
• Tube 3 1.0ml Pterins
CSF – Sample Requirements
(DTE/DETAPAC)
Collect at bedside and freeze immediately (not the form !)Collect at bedside and freeze immediately (not the form !)
58-220985.1- Adult
89-3671851.10 – 5.00
68-4512500.67 – 1.00
63-5032710.34 - 0.66
199-6084170 - 0.335-HIAA
71-5652815.1- Adult
154-8674651.10 – 5.00
176-8515080.67 – 1.00
362-9555870.34 - 0.66
324-10987140 - 0.33HVA
Range MeanAge (years)Metabolite
nmol/L
Pediatr Res (1993) 34, 10-14
7-6519ALLNH2
0.4-13.95.6ALLBH2
9-39235.1- Adult
8-57331.10 – 5.00
19-56380.67 – 1.00
23-55370.34 - 0.66
27-105670 - 0.33BH4
Range MeanAge (years)Metabolite
nmol/L
Pediatr Res (1993) 34, 10-14
BH4 Deficiency
• Decreased spontaneous movements, mental
retardation, convulsions, disturbances of tone
and posture, drowsiness, irritability, abnormal
movements, recurrent hyperthermia, hyper-
salivation, swallowing difficulties, diurnal
fluctuations of alertness, microcephaly
With HyperphenylalaninemiaGTP cyclohydrolase I (GTPCH) deficiency;
Phe = 90-1200 umol/L
6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency;Phe = 240-2500 umol/L
Dihydropteridine reductase (DHPR) deficiency; Phe = 180-2500 umol/L
Pterin-4a-carbinolamine dehydratase (PCD) deficiency;Phe = 180-1200 umol/l
Without hyperphenylalaninemiaSepiapterin reductase deficiency (SR).
Dopa-responsive dystonia (DRD) due to GTPCH deficiency;
Disorders of BH4 metabolism
www.BH4.org
0
100
200
300
400
500
600
700
1.8 1.9
HVA5-HIAA
DHPR Deficiency – Response to Treatment
Age (Years)
nm
ol/L
GTP
Dihydroneopterin Triphosphate
6-Pyruvoyltetrahydropterin
Tetrahydrobiopterin
Sepiapterin Reductase Deficiency
Sepiapterin Reductase Deficiency
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)
5-HIAA: 2 (58- 220 nmol/L)
BH4: 11 (9- 39 nmol/L)
BH2: 64 (0.4- 13.9 nmol/L)
Total Neopterin: 19 (7- 65 nmol/L)
GTP
Dihydroneopterin Triphosphate
6-Pyruvoyltetrahydropterin
TetrahydrobiopterinBH2DHFR -Liver
L-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& marked impaitment of dopamine and serotonin turnover.
AD - DRD. Residual activity 2-20%.
Phenylalanine Metabolism
GTP
BH4
p35
Phe Tyr
++veve --veve
GTP cyclohydrolase
Phenylalanine Loading TestPlasma Phenylalanine after 100mg/kg oral phenylalanine
0
200
400
600
800
1000
1200
0 1 2 3 4 5 6
Time (hrs)
Phe
(um
ol/L
)LLN Phe
ULN Phe
Phe
0
50
100
150
200
250
0 1 2 3 4 5 6
Time (hrs)
Tyr
(u
mo
l/L)
LLN Tyr
ULN Tyr
Tyr
0
2
4
6
8
10
12
0 1 2 3 4 5 6
Time (hrs)
Ph
e/T
yr r
atio LLN P/T ratio
ULN P/T ratio
P/T ratio
Phenylalanine load – DRD. DOB; 20/09/1966. Sample; 13/04/2004
Reported comment:‘Phe response slightly outside 95%CI and conversion to Tyr rather sluggish. These results do not exclude a pterin related defect.’
Low CSF neopterin,BH4, HVA and 5-HIAA
Outcome:GTP cyclohydrolasedeficiency….
Other Neurotransmitter Disorders
•Tyrosine Hydroxylase Def.•“Increased Dopamine turnover”•Aromatic Amino Acid Decarboxyalse Def.
•Pyridoxal Phosphate Def.•5-Methyltetrahydrofolate Def.
Tyrosine Hydroxylase Deficiency
Tyr Dopa Dopamine HVA
• Parkinsonian, ptosis, drooling, myoclonic jerks, severe head lag and trunkal hypotonia.
• L-Dopa marked and sustained improvement in hypokinesia and parkinsonian symptoms.
• Identified from CSF analysis; Normal pterin & 5-HIAA concentration. Very low HVA. Mutation analysis also available.
Tyrosine Hydoxylase Deficiency
Sex; Male. Dob; 17/05/2007. Sample; 27/02/2008
HVA: <10 (154-867 nmol/L)
5-HIAA: 137 (68 -451 nmol/L)
BH4: 36 (19-56 nmol/L)
BH2: 8 (0.4-13.9 nmol/L)
Total Neopterin: 9 (7-65 nmol/L)
Serum Prolactin 706 (86 – 324 mU/ml)
Tyrosine Hydroxylase Deficiency
Tyr Dopa Dopamine HVA
HVA: <10 (154-867 nmol/L)
Patient image has been removed
Tyrosine Hydroxylase Deficiency
Tyr Dopa Dopamine HVA
L-DOPA
Patient image has been removed
Increased Dopamine Turnover
First female child of consanguineous parents. 36 week gestation.Feeding difficulties from birth. 6 months reduced movements and failure to achieve milestones. 9 months able to smile but general paucity of movements. Rigidity of all limbs suggestive of dopamine deficiency. Left convergent squint but no abnormal eye movements detected.
HVA: 1705 ((154–867 nmol/L)
5-HIAA: 250 (89-367 nmol/L)
Pterin profile and 5-MTHF status unremarkable
Elevated urinary HVA
Serum Prolactin; 915 (<500 mU/ml)
Aromatic Amino Acid Decarboxylase Deficiency
Tyr L-Dopa Dopamine HVA
Trp 5-HTP Serotonin 5-HIAA
Clinical features resemble those of recessive BH4 deficiency; hypotonia, occulogyric crises, ptosis and paucity of spontaneous movement. Can be fatal
Urine: Vanillactic acid
CSF: Low HVA + 5Low HVA + 5--HIAA, but HIAA, but normalnormal pterin profile and accumulation pterin profile and accumulation of of 33--OO--methyldopamethyldopa. Enzymatic analysis possible on plasma.. Enzymatic analysis possible on plasma.
Treatment;Treatment; B6, MAOI & dopamine agonists.
PLP
Tyrosine
Tryptophan
L-Dopa
5-HTP
Dopamine
SerotoninBH4
HVA
5-HIAAPLP
AADC
3-Methyldopa
Vanillactic acid
Aromatic Amino Acid DecarboxylaseDeficiency
Male. Dob; 28/08/2007.Sample; 10/01/2008
Floppy, episodes of dystonia, developmental delay
HVA 47 (362-955 nmol/L)5-HIAA 14 (63- 503 nmol/L)3-Methyldopa 1170 (<300 nmol/L)PLP 32 (23-87 nmol/L)
Plasma AADC Activity 0.7 (36 -129 pmol/min/ml)
Serum Prolactin 900 (85 – 250 mU/ml)
Tyrosine
Tryptophan
L-Dopa
5-HTP
Dopamine
SerotoninBH4
HVA
5-HIAAPLP
AADC
3-Methyldopa
Vanillactic acid
Vitamin B6 Metabolism
Pyridoxine-5’- phosphate Pyridoxamine-5’- phosphate
Pyridoxal-5’- phosphate
N
CH2OH
HO
H3C
CH2OPO3H2
CH2OPO3H2
CH2OPO3H2
N
CH2NH2
HO
H3C
N
CHO
HO
H3C
PNPOPNPO
PNPO = Pyridox(am)ine-5’-oxidase
PNPO Deficiency
• Neonatal epileptic encephalopathy
•• Fetal distress, prenatal seizures, low Apgar
•• Pseudo AADC deficiency – Not consistent
•• Glycine & Threonine – Not consistent
• Vanillactate excretion – Consistent ?
PNPO Deficiency
CSF (PLP)CSF (PLP)
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16Age (Years)
PLP
(nm
ol/L
)
CSF 5-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 Folate Deficiency - Neurological syndrome associated with low CSF 5-MTHF and normal peripheral folate.
Cerebral Folate Deficiency
•Presentation 4 – 6 months after birth with irritability and sleep disturbance
•Deceleration of head growth (6 – 18 months)•Psychomotor retardation, sometimes followed
by regression.•Cerebellar ataxia•Pyramidal tract signs in lower limbs•Dyskinesis•Epileptic seizures
•Sub group – autistic features
Cerebral Folate Deficiency•Production of blocking auto-antibodiesagainst folate receptor ?? Produced by exposure to soluble folate binding proteins in human or bovine milk ?? (Ramekers et al., 2005).
•Milk free diet down regulates folatereceptor auto-immunity (Ramekers et al., 2008).
•Blocking auto-antibodies not present in allpatients with cerebral folate deficiency.
N
N
N
NH
NH2
NH
O
NH
O OH
OH
O
OH CH3
5-Methyltetrahydrofolate
•CSF deficiency documented in mitochondrial disorders
•Responsive to folinic acid
•25% of ETC defects associated with CSF 5-MTHF deficiency
•No apparent correlation with magnitude of defect
5MTHFEndocytosis
Folate PolyglutamatePool
5MTHFFR1
RFC
sFR1
-ve
PLASMA CSF
1 2
O2
._5MTHF ???
CSF 5-MTHF Deficiency & Mitochondrial Disorders
5-MTHF
F. 15 yrs 29 (46 - 160 nmol/L)M. 9 yrs 5 (72 – 172 nmol/L)M. 8 yrs 44 (72 – 172 nmol/L)F. 2 yrs 17 (52 - 178 nmol/L)F. 6 yrs 7 (72 – 172 nmol/L)
•Leads to brain specific folate deficiency
•Loss of function mutations in the FOLR1.
•Gene coding for the FR
•AR disorder manifests in late infancy with Severe developmental regression, movement disturbances,epilepsy and leukodystrophy
•Beneficial effect of folinic acid.
CSF 5-Methyltetrahydrofolate
•DHPR deficiency
•Long term L-dopa administration
L-DOPA 3-Methyldopa
Dopamine
COMT
10 year old female
GTP cyclohydrolase deficiency
62 (72-172 nmol/L)
Secondary Causes
• Hypoxia• Neurodegeneration• Epilepsy• Gaucher Disease• Mitochondrial Disease • Drugs• Sample Processing
Top Related