CLINICAL SIGNS SUGGESTIVE OF A NEUROMETABOLIC DISEASE. Bwee Tien Poll-The Amsterdam UMC The Netherlands

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1 CLINICAL SIGNS SUGGESTIVE OF A NEUROMETABOLIC DISEASE Bwee Tien Poll-The Amsterdam UMC The Netherlands

2 FRAMEWORK OF PRINCIPALS 1. Problem-oriented clinical approach 2. Biomarkers in plasma, urine, CSF 3. Mutations in genes 4. Next-generation sequencing 5. Internet

3 INITIAL INVESTIGATION INCLUDES STUDIES to determine the extent and degree of neurologic damage. Abnormalities outside the CNS. to ensure the early stages of treatable metabolic disorders are not missed, and studies to establish a baseline for monitoring the natural history of the condition

4 Presenting feature Acute Encephalopathy often occurs with little warning in previously healthy children or children with pre-existing medical condition may be missed because the early signs may be mistaken as a behavior disorder or more common disease often progresses rapidly, may fluctuate usually shows no focal neurologic deficits the likely causes are age dependent

5 The Acutely Sick Neonate When not taking oral feedings Start gluconeogenesis Start fatty acid oxidation Start protein breakdown Has a risk of dehydration But: Symptoms are similar to those of infections

6 Samples for Diagnosis 1. Urine (when critically ill) 2. Plasma (when critically ill) 3. Blood spots (DNA, tandem MS) 4. CSF when neurological symptoms 5. Skin biopsy (fibroblasts) 6. Other tissues (liver, muscle)

7

8

9 Example 1 / Clinical 2 day old male infant with fever, vomiting and respiratory distress. A.B. therapy, but he deteriorated. Convulsions coma ICU. Peritoneal dialysis and hemofiltration normalisation. Long-term successful treatment included a low-protein diet.

10 Example 1 / Routine Clinical Chemistry Blood glucose: 1.4 mmol/l Ketones: +++ Blood gasses: ph 7.35 bicarbonate 8.8 mmol/l Blood lactate: 3.1 mmol/l base excess meq/l Blood ammonia: 1380 µmol/l (controls < 100)

11 Example 1 / Diagnosis Plasma amino acids: Glutamine 565 µmol/l (c < 700) Urine organic acids: Methylmalonic acid mmol/mol creat (c < 18) Plasma carnitines: Free carnitine 5 µmol/l (c > 20) C 3 -carnitine 7 µmol/l (c < 1) Urine orotic acid: < 5 mmol/mol creat (normal)

12

13 Example 2 / Clinical 2 day old girl with vomiting, became lethargic. Convulsions and respiratory insufficiency ICU on day 5. Peritoneal dialysis on day 7 normalisation of hyperammonemia. Long-term treatment included a low-protein diet.

14 Example 2 / Routine Clinical Chemistry Blood glucose: 10.2 mmol/l Blood gasses: ph 7.32 bicarbonate 19 mmol/l Blood lactate: 8.1 mmol/l Liver enzymes: increased base excess -7.2 meq/l Blood ammonia: 882 µmol/l (controls < 100)

15 Example 2 / Metabolic Investigations Plasma amino acids : glutamine 3067 µmol/l (N ) citrulline 2876 µmol/l (N5-33) arginine 9 µmol/l (N12-166) Urine orotic acid : ++++ Urine citrulline : ++++ Urine lactate : ++

16 Citrullinemia, 8-day-old T2-weighted Diffusion-weighted ADC

17 Citrullinemia, 4 months old T2-weighted Fractional anisotropy Ammonia is neurotoxic and promotes cellular swelling and brain edema

18 Example 3 / Clinical Severe neonatal seizures Rythmic intra-uterine movements

19 EEG before pyridoxine

20 EEG during pyridoxine treatment

21 Pyridoxine-dependent Seizures Seizures are prominent and severe in the absence of any other significant abnormality. Characteristically, neonates present very early with intractable, generalized seizures and associated EEG abnormalities Often paroxysms of fetal movement during pregnancy Dramatic response to administration of vitamin B6 (pyridoxine): prompt cessation of seizures normalization of EEG abnormalities

22 The B6-dependent Disorders 1. Antiquitin defects (2-aminoadipicsemialdehyde inactivates B6) (AASDH-deficiency) 2. PNPO defects (no pyridoxalphosphate is formed) (Pyridox(am)ine phosphate oxidase deficiency 3. Cong.hypophosphatasia (reduced PLP uptake) 4. Hyperprolinemia II (PLP inactivation)

23 Inborn errors of Metabolism is a team sport Clinicians Clinical chemists Biochemical geneticists Dieticians Clinical geneticists

24 Presenting feature Chronic encephalopathy developmental regression seizures hard neurologic signs Abnormalities outside the CNS

25 Presenting feature Seizures Onset early in life Association with other neurologic signs (e.g. eye, muscle, movement, retardation) Complex partial or myoclonic seizures Resistance to conventional anticonvulsent therapy (e.g. GLUT1)

26 Neuronal ceroid lipofuscinoses, late infantile form Onset 2-4 yrs with seizures, myoclonus, progressive regression, ataxia, RP

27 Late infantile NCL retinal degeneration optic nerve atrophy thread-like arteries ERG extinguished VEP very enlarged

28 Polymerase-γ metabolism: both ends of the clinical spectrum

29 Pat. DK 17 yr

30 Clinical features Patient BW Patient DK Birth Age 17 y Hypotonia Myoclonus Deafness Status epilepticus resistent Neuropathy to treatment Retardation Vomiting, feeding problems MRI normal Cortex, thalamus, cerebellum MRS-NL Death 4 y Death 17 y

31 Patient BW Patient DK CSF: protein g/l 5.8; ; 1.27; 1.62; 2.05 Lactate mmol/l Pyruvate mmol/l 0.12 L/P 23 OGTT: Lactate mmol/l (T180) L/P increased

32 DK

33 DK

34 Polymerase-γ (POLG) gene Nuclear Maintenance mtdna > 60 mutations ~ human disease Early neonatal life late middle age Spectrum of phenotypes PEO Ataxia, neuropathy Myoclonus, epilepsy Hepatocerebral syndrome (Alpers)

35 Leigh-like encephalomyopathy and mild methylmalonic aciduria: a mtdna depletion syndrome

36 Patient 1 y 5 m T2W Hyperintensity of putamen and caudate

37 SUCLA-2 defect Cognitive and motor dysfunction Severe hypotonia Sensory hearing defect Neuropathy

38 Basic biochemical findings Blood (mmol/l) lactate (C< 2.0) pyruvate (C< 0.10) 3-OH-butyrate 0.50 (C<0.2) acetoacetate 0.14 (C< 0.1) CSF (mmol/l) lactate 3.7 (C<2.3) pyruvate 0.23 (C< 0.13)

39 Metabolic findings Urine MMA (mmol/mol) (C<10) HIVA (mmol/mol) (C<50) Plasma MMA (µm) 8.4 (C < 0.4) propionylcarn (µm) 6.9 (C<0.9) MMA-carn (µm)* 0.17 (C<0.08) *may also contain succinylcarnitine

40 SUCLA-2 defect Succinyl-CoA Pi ADP Homozygous for a c.977 G>A (G326D) missense mutation which may affect the structure and function of the SUCLA-2 protein CoA Succinate ATP SUCLA-2 codes for succinyl-coa synthetase which catalyzes the formation of succinate and ATP from succinyl- CoA and ADP in the TCA cycle in a reversible manner.

41 Both glucose and branched-chain amino acids will have an effect on the citric acid cycle. Defects of succinyl-coa synthase will therefore be aggravated by protein and carbohydrate feeding

42 Summary SUCLA-2 defect Early infantile Leigh-like encephalomyopathy Deafness Severe muscle hypotonia Progressive movement disorder Lactic acidosis Mild MMA Abnormal carnitine ester profile

43 Presenting feature Leukodystrophy Motor difficulties Common feature of many IEM presenting with chronic encephalopathy including Central leukodystrophy only or central + peripheral

44 Lysosomal leukodystrophy Infantile metachromatic leukodystrophy (0.5-3 yrs) * Motor difficulties * Peripheral neuropathy * Spasticity * Painful, irritable

45

46 Polyneuropathy + Regression + Spastic pareses = Metachromatic leukodystrophy

47 Pre Next Generation Sequencing test methods - Phenotyping patient in detail - Differential diagnosis - Directed molecular analysis - Diagnosis - Counseling - effort / time / means for initial phenotyping - low throughput / expensive molecular testing

48 Clinical diversity of genetic peroxisomal disorders Zellweger syndrome Neonatal adrenoleukodystrophy Infantile Refsum disease Rhizomelic chondrodysplasia punctata And many more Isolated peroxisomal β-oxidation defect X-ALD X- AMN

49

50 METABOLIC DISEASES OF THE NERVOUS SYSTEM 1. Disorders of intermediary metabolism interference with numerous pathways endogenous intoxication interference with neurotransmitter synthesis 2. Disorders involving subcellular organelles storage substances - interference with the function / survival of neural cells inducing deficiency of metabolites interference with other pathways or metabolic processes 3. Disorders of metallic metabolism 4. Others

51 Post Next Generation Sequencing test methods - Minimal phenotyping patient - Consent - NGS - Causative mutation - Diagnosis - Counseling - No major effort / time / means for initial phenotyping - No initial differential diagnosis - High throughput / cheaper molecular testing

52 Multisystem Disease with neurologic features INHERITED METABOLIC DISEASES

53 What do patients (or parents) want to know 1. What do I have? 2. What causes it? 3. What are the consequences and natural history? 4. What can be done about it?

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