Basal Ganglia Involvement in Mitochondrial Acetoacetyl-CoA Thiolase deficiency (T2).

Transcription

1 Basal Ganglia Involvement in Mitochondrial Acetoacetyl-CoA Thiolase deficiency (T2). Stéphanie Paquay Robert Debré Hospital Reference Center For Metabolic Diseases Paris, France

2 Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (MAT or T2) Key role of MAT in both isoleucine and ketone bodies metabolism (from Buhas et al 2013)

3 Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (T2) Acute ketoacidotic episodes: ph < 7,1, bicarbonate < 7 mmol/l, variable glycemia massive ketone bodies production Specific metabolites in urine organic acid analysis: 2MAA, 2M3HB, TG Blood acylcarnitine analysis : C5:1, C5-OH Enzyme assay Molecular diagnosis : ACAT 1 gene

4 Objectives Extrapyramidal signs observed without prior ketoacidotic events within two T2-deficient patients diagnosed through presymptomatic screening in already affected families. Review of a French cohort Relationship between neurological involvement and T2 deficiency?

5 Methods 26 patients Enzymatic assay in Lyon ( ) Collected data: Age at diagnosis and at end of follow-up Parental consanguinity Psychomotor development, clinical and radiological features During acute episode : supportive care, ph, bicarbonate, anionic gap, glycemia, NH3, lactate, ketonemia/ketonuria Urine organic acids, blood acylcarnitines profile Enzymatic assay Molecular analysis 2 groups based on normal / abnormal neurological examination

6 Results N e u r o l o g i c a l involvement 6/26 Absence of metabolic crisis 2/26 Ketoacidotic crisis 4/26 Neurological signs prior to the first decompensation : 2/4 Secondary neurological involvement 2/4

7 Clinical and radiological data for the 6/26 patients Presymptomatic with neurological diagnosis : abnormalities familial history Diagn Age End of Followup Consang Metabolic crisis # 1 5 m 8 y - - # 2 1 m 1 y + - # 3 2 m 3 y + + # 4 12 m 7 y - + Psychomotor Dvpt/Neurol. Examination Before acute E Psychomotor delay Axial hypotonia Psychomotor delay Axial hypotonia Dyskinesia # 5 24 m 13 y - + Normal After acute E Unchanged Unchanged Hypotonia Dyskinesia Dystonia # 6 11 m 19 y - + Normal Normal Evolution Motor delay Ataxia Dystonia Normal until 5 m. Hypotonia Dystonia Dystonia Improvement of dyskinesia Speech delay Dyspraxia Neurological sequelae 15 y Choreoathetosis Dystonia Brain MRI 6 y : T2/Flair hyperintensities in putamen 6 m : T2/Flair hyperintensities in putamen 11 m: T2/Flair hyperintensities in putamen 13 m : normal 28 m : T2 increased signal in putamen/ dentate nuclei 15 y : T2 high signal in pallidi and internal capsules

8 Results: 2 Patients with Neurological Signs Without Prior Ketoacidotic Events Patient #1: 8 years old Motor delay, frequent falls, ataxia, coordination disorders, Dystonic postures in upper limbs Other investigations unremarkable

9 Results: 2 Patients with Neurological Signs Without Prior Ketoacidotic Events Patient #2: 1-year old At the age of 5 months : axial hypotonia, dystonia, insufficient weight gain Other investigations unremarkable 9

10 Clinical and radiological data for the 6/26 patients with neurological abnormalities Neurological symptoms before the first crisis

11 Results: 2 Patients with Neurological Signs Before the First Ketoacidotic Episode Patient #3: 3 years old Psychomotor delay and axial hypotonia noted in the first months of life At the age of 5 months: bronchiolitis and first ketoacidotic event: ph 7,2, bicarbonate 9 mmol/l, glycemia 0,66 g/l. Rapid and favorable evolution with glucose infusion. Dystonic postures in upper right arm with closed fists. Other investigations unremarkable 11

12 Clinical and radiological data for the 6/26 patients with neurological abnormalities Neurological symptoms before the first crisis

13 Clinical and radiological data for the 6/26 patients with neurological abnormalities Neurological symptoms after the first crisis

14 Discussion T2 deficiency : Normal development or neurological sequelae after acute episode Our cohort : neurological findings and extrapyramidal signs in the absence of ketoacidotic events. What is known in the litterature?

15 Discussion 15

16 Physiopathological mechanisms : hypothesis? T2 : role in isoleucine metabolism >< SCOT! «Organic aciduria» 1. Toxicity of specific metabolites : role of 2-MAA et 2-MHB? Inhibition of energy metabolism by 2-methylacetoacetate and 2- methyl-3 hydroxybutyrate in cerebral cortex of developing rats». Rosa RB et al. J Inherit Metab 2005 Evidence that 2-methylacetoacetate induces oxidative stress in rat brain». Leipnitz G et al. Metab Brain Dis Cerebral vulnerability to oxidative stress Pathogenesis of CNS involvement in disorders of amino and organic acid metabolism. Kolker S et al, J Inherit Metab Dis

17 Discussion T2 deficiency : «An organic aciduria» Role of protein intake? T2 deficiency! accumulation of toxic isoleucine-derived acyl-coa esters in the brain mitochondria The protein intake could be responsible for an insidious cerebral toxicity Protein restriction prevents from neurological impairment? Usual practice «normal» protein intake + carnitine How much? An low-protein diet versus a «normal» protein intake? For how long? Vulnerability window during the 1 rst years? 17

18 Discussion Follow up : which monitoring tools? Correlation exists between the protein intake and body fluids excretion of T2 metabolites but intramitochondrial toxicity cannot be predicted based on the quantification of urine metabolites "Mild" genotype = detectable residual enzyme activity = "Mild" excretion but Our cohort : absence of genotype-phenotype correlation : great phenotypical variability within the same family 18

19 Conclusion 5/26 (19%) : neurological impairment and extrapyramidal signs without a clear relationship with a metabolic crisis T2 deficiency = in clinical practice not only as a ketolysis defect but also as an organic aciduria giving rise to a progressive and chronic cerebral intoxication Consider protein intake restriction : at least a «normal» protein diet + carnitine 19

20 Conclusion Neurological involvement in T2 deficiency as well as impact of protein intake on neurological impairment remain to be studied. Multicentric follow-up of newborns diagnosed through neonatal sreening could be useful to confirm the causality of this association Urine organic acid analysis could be performed in case of unexplained extrapyramidal signs since neonatal screening doesn t exclude the diagnosis 20

21 Acknowledgments M. Schiff Ch. Vianay-Saban P. de Lonlay D. Dobbelaere A. Fouilhoux N. Guffon F. Labarthe K. Mention G. Touati V. Valayannopoulos