Neurotransmitter Disorders.
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1 Neurotransmitter Disorders
2 Chemical Neurotransmission Neurotransmitters Substances that upon release from nerve terminals, act on receptor sites at postsynaptic membranes to produce either excitation or inhibition of the target cell
3 Tyrosine O 2 L-Dopa Dopamine HVA Tryptophan 5-HTP PLP Serotonin 5-HIAA Phenylalanine Tyrosine BH4 qbh2 BH2
4 BH4
5 GTP GTP cyclohydrolase Dihydroneopterin Triphosphate P 3 Dihydroneopterin -VE Pyruvoyl tetrahydroptein synthase 6-Pyruvoyltetrahydropterin Aldose reductase /Sepiapterin reductase Tetrahydrobiopterin
6 BH4 Salvage Tyr BH4 PCD + DHPR L-Dopa qbh2 BH2 NAD + NADH PCD = pterin carbinolamine dehydratase DHPR = dihydropteridine reductase
7 CSF Sample Requirements Tube 1 0.5ml HVA & 5-HIAA Tube 2 0.5ml 5-MTHF Tube 3 1.0ml Pterins (DTE/DETAPAC) Collect at bedside and freeze immediately (not the form!)
8 nmol/l Metabolite Age (years) Mean Range HVA Adult HIAA Adult Pediatr Res (1993) 34, 10-14
9 nmol/l Metabolite Age (years) Mean Range BH Adult BH2 ALL NH2 ALL Pediatr Res (1993) 34, 10-14
10 BH4 Deficiency Decreased spontaneous movements, mental retardation, convulsions, disturbances of tone and posture, drowsiness, irritability, abnormal movements, recurrent hyperthermia, hypersalivation, swallowing difficulties, diurnal fluctuations of alertness, microcephaly
11 Disorders of BH4 metabolism With Hyperphenylalaninemia GTP cyclohydrolase I (GTPCH) deficiency; Phe = umol/l 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency; Phe = umol/l Dihydropteridine reductase (DHPR) deficiency; Phe = umol/l Pterin-4a-carbinolamine dehydratase (PCD) deficiency; Phe = umol/l Without hyperphenylalaninemia Sepiapterin reductase deficiency (SR). Dopa-responsive dystonia (DRD) due to GTPCH deficiency;
12 DHPR Deficiency Response to Treatment HVA 5-HIAA nmol/l Age (Years)
13 Sepiapterin Reductase Deficiency GTP Dihydroneopterin Triphosphate 6-Pyruvoyltetrahydropterin Tetrahydrobiopterin
14 Sepiapterin Reductase Deficiency Sex; Male. Dob; 31/12/1987. Sample; 09/05/2003. Dystonia responsive to L-DOPA. No hyperphenylalaninaemia. DHPR normal. HVA: 23 ( nmol/l) 5-HIAA: 2 ( nmol/l) BH4: 11 (9-39 nmol/l) BH2: 64 ( nmol/l) Total Neopterin: 19 (7-65 nmol/l)
15 GTP Dihydroneopterin Triphosphate 6-Pyruvoyltetrahydropterin BH2 DHFR -Liver Tetrahydrobiopterin
16 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%.
17 Phenylalanine Metabolism GTP p35 GTP cyclohydrolase +ve -ve Phe BH4 Tyr Phenylalanine Loading Test Plasma Phenylalanine after 100mg/kg oral phenylalanine
18 Phenylalanine load DRD. DOB; 20/09/1966. Sample; 13/04/ Phe (umol/l) LLN Phe ULN Phe Phe Tyr (umol/l) Time (hrs) LLN Tyr ULN Tyr Tyr Reported comment: Phe response slightly outside 95%CI and conversion to Tyr rather sluggish. These results do not exclude a pterin related defect Time (hrs) Low CSF neopterin, BH4, HVA and 5-HIAA Phe/Tyr ratio LLN P/T ratio ULN P/T ratio P/T ratio Outcome: GTP cyclohydrolase deficiency. Time (hrs)
19 Other Neurotransmitter Disorders Tyrosine Hydroxylase Def. Increased Dopamine turnover Aromatic Amino Acid Decarboxyalse Def. Pyridoxal Phosphate Def. 5-Methyltetrahydrofolate Def.
20 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.
21 Tyrosine Hydoxylase Deficiency Sex; Male. Dob; 17/05/2007. Sample; 27/02/2008 HVA: <10 ( nmol/l) 5-HIAA: 137 ( nmol/l) BH4: 36 (19-56 nmol/l) BH2: 8 ( nmol/l) Total Neopterin: 9 (7-65 nmol/l) Serum Prolactin 706 ( mu/ml)
22 Tyrosine Hydroxylase Deficiency Tyr Dopa Dopamine HVA Patient image has been removed HVA: <10 ( nmol/l)
23 Tyrosine Hydroxylase Deficiency Tyr Dopa Dopamine HVA L-DOPA Patient image has been removed
24
25 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 ( nmol/l) 5-HIAA: 250 ( nmol/l) Pterin profile and 5-MTHF status unremarkable Elevated urinary HVA Serum Prolactin; 915 (<500 mu/ml)
26
27 Aromatic Amino Acid Decarboxylase Deficiency Tyr L-Dopa Dopamine HVA PLP 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 + 5-HIAA, 5 but normal pterin profile and accumulation of 3-O-methyldopa.. Enzymatic analysis possible on plasma. Treatment; B6, MAOI & dopamine agonists.
28 Vanillactic acid 3-Methyldopa Tyrosine Tryptophan BH4 L-Dopa 5-HTP AADC PLP Dopamine Serotonin HVA 5-HIAA
29 Aromatic Amino Acid Decarboxylase Deficiency Male. Dob; 28/08/2007. Sample; 10/01/2008 Floppy, episodes of dystonia, developmental delay HVA 47 ( nmol/l) 5-HIAA 14 ( nmol/l) 3-Methyldopa 1170 (<300 nmol/l) PLP 32 (23-87 nmol/l) Serum Prolactin 900 ( mu/ml) Plasma AADC Activity 0.7 ( pmol/min/ml)
30 Vanillactic acid 3-Methyldopa Tyrosine Tryptophan BH4 L-Dopa 5-HTP AADC PLP Dopamine Serotonin HVA 5-HIAA
31 Vitamin B 6 Metabolism Pyridoxine-5 - phosphate CH 2 OH Pyridoxamine-5 - phosphate CH 2 NH 2 HO CH 2 OPO 3 H 2 HO CH 2 OPO 3 H 2 H 3 C N H 3 C N Pyridoxal-5 - phosphate PNPO CHO PNPO HO H 3 C N CH 2 OPO 3 H 2 PNPO = Pyridox(am)ine-5 -oxidase
32 PNPO Deficiency Neonatal epileptic encephalopathy Fetal distress, prenatal seizures, low Apgar Pseudo AADC deficiency Not consistent Glycine & Threonine Not consistent Vanillactate excretion Consistent?
33 PNPO Deficiency
34 CSF (PLP) PLP (nmol/l) Age (Years)
35 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.
36 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
37 Cerebral Folate Deficiency Production of blocking auto-antibodies against folate receptor?? Produced by exposure to soluble folate binding proteins in human or bovine milk?? (Ramekers et al., 2005). Milk free diet down regulates folate receptor auto-immunity (Ramekers et al., 2008). Blocking auto-antibodies not present in all patients with cerebral folate deficiency.
38 5-Methyltetrahydrofolate H 2 N N H N N N O OH CH 3 HN H N O H O O O H 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
39 PLASMA CSF 5MTHF FR1 -ve Endocytosis 1 2 RFC 5MTHF Folate Polyglutamate Pool sfr1 O 2._ 5MTHF???
40 CSF 5-MTHF Deficiency & Mitochondrial Disorders 5-MTHF F. 15 yrs 29 ( nmol/l) M. 9 yrs 5 ( nmol/l) M. 8 yrs 44 ( nmol/l) F. 2 yrs 17 ( nmol/l) F. 6 yrs 7 ( nmol/l)
41 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.
42 CSF 5-Methyltetrahydrofolate DHPR deficiency Long term L-dopa administration L-DOPA COMT 3-Methyldopa 10 year old female Dopamine GTP cyclohydrolase deficiency 62 ( nmol/l)
43 Secondary Causes Hypoxia Neurodegeneration Epilepsy Gaucher Disease Mitochondrial Disease Drugs Sample Processing
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