Clinical Spectrum and Genetic Mechanism of GLUT1-DS. Yasushi ITO (Tokyo Women s Medical University, Japan)

Transcription

1 Clinical Spectrum and Genetic Mechanism of GLUT1-DS Yasushi ITO (Tokyo Women s Medical University, Japan)

2 Glucose transporter type 1 (GLUT1) deficiency syndrome Mutation in the SLC2A1 / GLUT1 gene Deficiency of GLUT1 protein Impaired Glucose transport into the brain Failure of Energy production in the brain Impaired Brain functions (Metabolic Encephalopathy)

3 GLUT1 deficiency syndrome is characterized by l early-onset Epilepsy Paroxysmal abnormal eye movement, l subsequent Developmental delay, Paroxysmal / Static spasticity, ataxia, and dystonia, Other paroxysmal phenomena.

4 Phenotypic Spectrum of GLUT1-DS Mullen et al, 2010 Paroxysmal Exerciseinduced Dyskinesia Movement Disorder Epilepsy Idiopathic Generalized Epilepsy (IGE) Mild Mild Ataxia Epilepsy and Movement Disorder Focal Epilepsy Pharmacoresistant IGE Complex Movement Disorders with a combination of Ataxia, Spasticity, and Dystonia GLUT1 Encephalopathy Myoclonic- Astatic Epilepsy Intractable Infantile Seizures Severe Severe

5 Broad Clinical Spectrum of GLUT1-DS l Paroxysmal exercise-induced dyskinesia (PED) l Early-onset absence epilepsy (EOAE) l Myoclonic astatic epilepsy (MAE) l Alternating hemiplegia of childhood (AHC) l Dystonic tremor l Hemolytic anemia with Hereditary stomatocytoses

6 Phenotypic Spectrum of GLUT1-DS based on the hypothetical Residual GLUT1 Function in the Blood-Brain Barrier Wang et al, 2005 Phenotype Residual function Minimal % Mild Moderate (Classic) Severe Embryonic lethal Mutation / Remarks l heterozygous Missense mutation l triggered by Environmental factors that inhibit GLUT1 transport activity 50-75% l heterozygous Missense mutation 50% l hemizygote; Large deletion, Nonsense, Frameshift, and Splice-site mutation 25-50% l compound heterozygous mutation 0-25% l homozygous mutation

7 Relations between Genotype and Phenotype in GLUT1-DS patients Leen et al, 2010 Type A (n=21) B (n=30) C (n=6) Mutation Missense Nonsense, Frame shift, Splice site, or translation inhibition Multiple exon deletion Mild Mental Retardation 79% 26% Movement Disorders 63% 88% Early-onset Classical Phenotype 52% 63% 100% Non-Classical Phenotype 20% 14% 0%

8 Hereditary Pattern of GLUT1-DS l GLUT1-DS transmission is mostly sporadic, but several familial cases have also been reported. l Familial GLUT1-DS is mainly inherited in an autosomal dominant manner, but there are rare cases of autosomal recessive inheritance or parental mosaicism.

9 Activities of Daily Living (ADL) in Patients with GLUT1-DS A nationwide survey of GLUT1-DS in Japan (Male 23; Female 23: 3-35 yrs) Bathing Grooming Toile0ng Locomo0on Dressing Feeding Independence Preparing Watching Par0al assistance Total assistance 0% 20% 40% 60% 80% 100% 15% of patients needed total assistance to perform ADL, 30% needed partial assistance in all ADL except for eating, but 40% patients lead an independent life.

10 A Japanese Family Case with GLUT1-DS caused by S324L mutation in SLC2A1 Normal mentality, Infant-onset, pharmacosensitive partial epilepsy index case Mild mental retardation, Infant-onset, pharmacosensitive partial epilepsy, PED Mild ataxia 42y Case 2 16y 5y 3y Case 1 Case 3 Case 4 Borderline mentality, Infant-onset, pharmacosensitive generalized epilepsy, Adult-onset paroxysmal dystonia Moderate developmntal delay, No epilepsy

11 Clinical Summary of previously reported 15 Families with Autosomal dominant GLUT1-DS Family No. Anticipation of Mutation Age Phenotype Accel- Severity of eration ranges of Age Amino-acid Type (years) MR Epi PED Others MR Epi Sympt oms at onset PED in Upper Generation Reduced Penetrance 1 S324L Missence 3 to 42 ± ~ Ataxia +? ) 2 G91D Missence 10 to 46 + ~ Ataxia, Spascity + + +? 6) 7) 3 R126H Missence 8 to 78 - ~ Ataxia ) 8) 4 R126C Missence 1 & 31 ND + - Apnea, Abnormal eye movement ND ND +? 9) 5 G314S Missence 19 to 67 - ~ ? ) 10) 6 A275T Missence 7 to 44? - + Dystonia, Chorea? ) 7 S95I Missence 5 to 70 - ~ ?? ) 11) 8 R126C Missence 13 & Ataxia - - +? 2) 9 R93W Missence 10 &? - ~ Chorea + - +? 2) 10 S324L Missence 28 to 83 - ~ ± + + Ataxia + +? ) 12) 11 R223P Missence 22 to ? ) 12) 12 M344T Missence 14 &? + ~ Ataxia ) 13 c.18+1g>a Splice site 5 &? - ~ ) 14 c.746del; ins9 Deletion/ Insertion 15 Q282_S285del Deletion 9 to 60 - ~ & 16 + ~ Ataxia 2) Ref. No Hemolytic anemia ) 10) +, present; -, absent?, unclear; ND, not described; +++, severe MR; ++, moderate MR; +, mild MR: ±, bordeline mentality; -, normal mentality; MR, mental retardation; Epi, epilepsy; PED, paroxysmal exercise-induced dyskinesia.

12 Autosomal Recessive Familial GLUT1-DS % of 3-OMG RBC glucose uptake compared to an intra-assay control sample Family 1 Fa1 Mo1 Fa2 Mo2 87% Cousin 83% 84% Family 2 Pa2 66% Pa3 63% 52% ±8.94 Rotstein et al, 2010 Pa1 Phenotype Normal 36% Minimal / Mild Moderate / Classic Severe Embryonic lethal de novo mutation in the paternally derived allele

13 The GLUT1 Protein Transmembrane Configuration with the Locations of the R126L, K256V and R468W missense mutations Family 1 Family 2 Fa1 Mo1 Pa1 Fa2 Mo2 Pa2 Pa3 R126L ー / ー ー / ー +/ ー ー / ー ー / ー ー / ー ー / ー K256V ー / ー ー /+ +/+ ー / ー ー / ー ー / ー ー / ー R468W ー / ー ー /+ +/+ ー /+ ー /+ +/+ +/+ Uptake 100% 87% 36% 83% 84% 66% 63% Phenotype Healthy Healthy Severe Healthy Healthy Mild Minimal

14 The Brain Glucose Demands in Normal Children Fetus 3 to 4 yrs 10 s Adulthood

15 SUMMARY l In GLUT1-DS, there are variations in clinical phenotype and severity due to differences in gene mutations and residual function of GLUT1 protein. l Additionally, heterogeneity in clinical phenotype and severity is present not only among unrelated patients but also among patients within a family bearing the same autosomal dominant mutation. l The glucose demands of the brain vary with age. There are also agedependent differences in the symptoms. l Familial cases of GLUT1-DS may manifest asymptomatic to mild phenotypes in terms of intellectual disability and/or epilepsy in early generations, whereas more severe phenotypes and earlier onset ages appear in the next generations, showing an anticipation phenomenon. l Therefore, the mechanism of GLUT1-DS pathogenesis appears to be highly complex.