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OP10 – 2707: Childhood-onset ataxic gait solved by muscle biopsy
S4
EUROPEAN JOURNAL O F PAEDIATRIC NEUROLOGY
the NPCRS was administered by a single observer. All patients underwent brain MRI and midsaggital vermis relative diameter was obtained. Psychometric evaluations were available in 6 patients. Mann-Whitney U test was used to compare ICARS between patients and controls. To evaluate inter-observer agreement in patients’ ICARS, intraclass correlation coefficients (ICC) were calculated. ICARS Internal consistency was evaluated using Cronbach’s alpha. Spearman’s rank correlation coefficient test was used to correlate ICARS with NPCRS, midsaggital vermis relative diameter, and intelligence quotients (IQ). Results: ICARS and ICARS subscores differed between patients and controls (p<0.001). The ICCs for interobserver agreement of ICARS was “almost perfect” (ICC=0.99), with a “good” internal reliability (Cronbach’s alpha = 0.72). ICARS was significantly correlated with total NPCRS (rs 0.90, p<0.001). However, there was no agreement regarding categories of severity. Regarding neuroimaging, an inverse correlation between midsagittal vermis relative diameter and ICARS was found (rs −0.85, p=0.003). There was a negative correlation between ICARS and IQ (rs −0.94, p=0.005). All correlations remained significant when using corrected-by-age ICARS value. Conclusion: ICARS is a reliable instrument for assessment of PMM2-CDG patients, without significant inter-rater variability. Despite limited sample size, results hint a good correlation between functional cerebellar assessment, IQ and neuroimaging data. ICARS may represent a valuable tool to evaluate therapeutic interventions on cerebellum dysfunction in PMM2-CDG patients.
OP10 - 2707 Childhood-onset ataxic gait solved by muscle biopsy A. Jansen, C. Ceuterick-de Groote, T. Vanderhasselt, S. Seneca, K. Stouffs, L. De Meirleir. Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Brussels, Belgium Objective: The differential diagnosis of childhood-onset ataxia may be challenging, especially in the absence of brain MRI or lab abnormalities. We present a case where the findings of intra-axonal spheroids on muscle biopsy led to the diagnosis of atypical neuraxonal dystrophy (NAD) due to a compound heterozygous mutation in PLA2G6. Methods and results: The proband was referred for frequent falls at age 4 years. Acquisition of early developmental milestones was normal. Concerns were first expressed at age 3 years, when she developed an unsteady gait. On examination eye movements were slightly saccadic, gait ataxic, balance poor. She had mild proximal muscle weakness with positive sign of Gowers. Deep tendon reflexes were present. She was at times introverted and sometimes overfamiliar. Formal evaluation of development showed normal intelligence, normal speech and language development except for intermittent whispering, and confirmed poor coordination and balance. Visuo-spatial skills were normal. Brain MRI was normal and remained so after 3 years. EMG and nerve conduction studies, fundoscopy, lactate, alpha-foetoprotein and urinary catecholamines were normal. Friedreich ataxia and Pompe disease were excluded. Further concern about a possible myopathy led to muscle biopsy. Histological examination showed a predominance of type1 fibers. Extensive immunohistochemical testing was normal. Electron microscopy revealed intra-axonal spheroids in the peri- and endomysial myelinated nerve bundles as well as in the motor endplates. Neuroaxonal spheroids are present in >80% of cases with PLA2G6-associated neurodegeneration (PLAN) and is rarely seen in mitochondrial protein associated neurodegeneration (MPAN). Mutation analysis of PLA2G6 showed the compound heterozygous presence of the c.1021G>A (p.Ala341Thr) and c.2036G>T (p.Gly679Val) mutations in the patient, while both parents were heterozygous carriers, confirming the diagnosis of atypical NAD. Conclusion: This report highlights that childhoodonset gait ataxia with subtle behavioral and/or expressive speech abnormalities may be the presenting features of atypical NAD.
19s (2015) S1 – S152
Free paper session 2: Epilepsy I OP11 - 2424 Genotype–phenotype correlations in patients with GRIN2A variants D.R.M. Vlaskamp, P.M.C. Callenbach, P. Rump, Y.J. Vos, T. Dijkhuizen, C.M.A. van Ravenswaaij-Arts, O.F. Brouwer. Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Objective: The GRIN2A gene has been associated with both benign childhood epilepsies and severe epileptic encephalopathies. This study evaluates the genotype–phenotype correlations in patients with GRIN2A variants. Methods: A systematic literature search was performed, identifying all patients reported before May 2014 with GRIN2A variants. Patients were classified in two groups based on their GRIN2A genotype. Group I genotypes had an expected detrimental effect on protein expression: nonsense, frameshift, splice site, or initiation codon sequence variants, translocations with breakpoints within GRIN2A, or deletions comprising GRIN2A. Group II genotypes were expected to result in an altered protein structure or function: missense or in-frame sequence variants. Results: Of 136 patients, 74 were included in group I and 62 in group II. Epilepsy was diagnosed in 86% of patients in both groups, with focal seizures being most common (82%). Benign epilepsy with centrotemporal spikes (BECTS) was significantly more often diagnosed in group II than in group I (51% versus 27%, p=0.03). Continuous spikes and waves during slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) occurred more often in group I than in group II (50% versus 37%), although not statistically significant (p=0.29). Mild to severe developmental problems related to speech and language (80%), cognition (66%), and motor skills (48%), and behavioural problems (61%) were present in both groups. Speech and language problems were significantly more often reported in group I than in group II (90% versus 69%, p=0.02), also in patients with no LKS/CSWS (94% versus 50%, p=0.01). Conclusion: GRIN2A variants are associated with a spectrum of epilepsies, mainly accompanied by language developmental problems. This epilepsy-aphasia syndrome spectrum ranges from relatively mild BECTS to more severe LKS/CSWS. This study shows that GRIN2A genotypes with an expected milder effect on protein function are associated with a relatively more benign phenotype including BECTS without language problems.
OP12 - 2577 Targeted resequencing in epileptic encephalopathies: diagnostic implications and genotype–phenotype correlations F. Zara, E. Gennaro, S. Vari, D. Coviello, P. Striano. Department of Neuroscience, Institute G. Gaslini, Genova, Italy Objective: To assess the diagnostic value of NGS target resequencing approach for epileptic encephalopathies. Methods: The diagnostic tool allows the screening of 20 genes which have been consistently associated with early-onset epileptic encephalopathy (EE): ALDH7A1, PNP0, ARHGEF9, ARX, SLC25A22, PLCB1, TBC1D24, PNKP, KCNT1, KCNQ2, SCN2A, SCN8A, STXBP1, SCN1A, PCDH19, CDKL5, SPTAN1, SLC2A1, ST3GAL3, GRIN2A). NGS have been performed by Ampliseq/Ion Torrent technology of at least 120X. Patients have been classified into 5 phenotypic classes: 1) EEs with onset in the first year of life; 2) infantile spasms/West syndrome 3) Dravet Syndrome 4) CSWS/LandauKleffner Syndrome 5) EEs with onset after the first year of life. Results: Fifty-four patients have been analyzed: class 1, n° 26; class 2, n° 10; class 3, n° 6; class 4, n° 4; class 5, n° 8. Pathogenetic effects of variants have been attributed according to i) segregation analysis (inherited vs transmitted; putative functional effect
EUROPEAN JOURNAL O F PAEDIATRIC NEUROLOGY
the NPCRS was administered by a single observer. All patients underwent brain MRI and midsaggital vermis relative diameter was obtained. Psychometric evaluations were available in 6 patients. Mann-Whitney U test was used to compare ICARS between patients and controls. To evaluate inter-observer agreement in patients’ ICARS, intraclass correlation coefficients (ICC) were calculated. ICARS Internal consistency was evaluated using Cronbach’s alpha. Spearman’s rank correlation coefficient test was used to correlate ICARS with NPCRS, midsaggital vermis relative diameter, and intelligence quotients (IQ). Results: ICARS and ICARS subscores differed between patients and controls (p<0.001). The ICCs for interobserver agreement of ICARS was “almost perfect” (ICC=0.99), with a “good” internal reliability (Cronbach’s alpha = 0.72). ICARS was significantly correlated with total NPCRS (rs 0.90, p<0.001). However, there was no agreement regarding categories of severity. Regarding neuroimaging, an inverse correlation between midsagittal vermis relative diameter and ICARS was found (rs −0.85, p=0.003). There was a negative correlation between ICARS and IQ (rs −0.94, p=0.005). All correlations remained significant when using corrected-by-age ICARS value. Conclusion: ICARS is a reliable instrument for assessment of PMM2-CDG patients, without significant inter-rater variability. Despite limited sample size, results hint a good correlation between functional cerebellar assessment, IQ and neuroimaging data. ICARS may represent a valuable tool to evaluate therapeutic interventions on cerebellum dysfunction in PMM2-CDG patients.
OP10 - 2707 Childhood-onset ataxic gait solved by muscle biopsy A. Jansen, C. Ceuterick-de Groote, T. Vanderhasselt, S. Seneca, K. Stouffs, L. De Meirleir. Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Brussels, Belgium Objective: The differential diagnosis of childhood-onset ataxia may be challenging, especially in the absence of brain MRI or lab abnormalities. We present a case where the findings of intra-axonal spheroids on muscle biopsy led to the diagnosis of atypical neuraxonal dystrophy (NAD) due to a compound heterozygous mutation in PLA2G6. Methods and results: The proband was referred for frequent falls at age 4 years. Acquisition of early developmental milestones was normal. Concerns were first expressed at age 3 years, when she developed an unsteady gait. On examination eye movements were slightly saccadic, gait ataxic, balance poor. She had mild proximal muscle weakness with positive sign of Gowers. Deep tendon reflexes were present. She was at times introverted and sometimes overfamiliar. Formal evaluation of development showed normal intelligence, normal speech and language development except for intermittent whispering, and confirmed poor coordination and balance. Visuo-spatial skills were normal. Brain MRI was normal and remained so after 3 years. EMG and nerve conduction studies, fundoscopy, lactate, alpha-foetoprotein and urinary catecholamines were normal. Friedreich ataxia and Pompe disease were excluded. Further concern about a possible myopathy led to muscle biopsy. Histological examination showed a predominance of type1 fibers. Extensive immunohistochemical testing was normal. Electron microscopy revealed intra-axonal spheroids in the peri- and endomysial myelinated nerve bundles as well as in the motor endplates. Neuroaxonal spheroids are present in >80% of cases with PLA2G6-associated neurodegeneration (PLAN) and is rarely seen in mitochondrial protein associated neurodegeneration (MPAN). Mutation analysis of PLA2G6 showed the compound heterozygous presence of the c.1021G>A (p.Ala341Thr) and c.2036G>T (p.Gly679Val) mutations in the patient, while both parents were heterozygous carriers, confirming the diagnosis of atypical NAD. Conclusion: This report highlights that childhoodonset gait ataxia with subtle behavioral and/or expressive speech abnormalities may be the presenting features of atypical NAD.
19s (2015) S1 – S152
Free paper session 2: Epilepsy I OP11 - 2424 Genotype–phenotype correlations in patients with GRIN2A variants D.R.M. Vlaskamp, P.M.C. Callenbach, P. Rump, Y.J. Vos, T. Dijkhuizen, C.M.A. van Ravenswaaij-Arts, O.F. Brouwer. Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Objective: The GRIN2A gene has been associated with both benign childhood epilepsies and severe epileptic encephalopathies. This study evaluates the genotype–phenotype correlations in patients with GRIN2A variants. Methods: A systematic literature search was performed, identifying all patients reported before May 2014 with GRIN2A variants. Patients were classified in two groups based on their GRIN2A genotype. Group I genotypes had an expected detrimental effect on protein expression: nonsense, frameshift, splice site, or initiation codon sequence variants, translocations with breakpoints within GRIN2A, or deletions comprising GRIN2A. Group II genotypes were expected to result in an altered protein structure or function: missense or in-frame sequence variants. Results: Of 136 patients, 74 were included in group I and 62 in group II. Epilepsy was diagnosed in 86% of patients in both groups, with focal seizures being most common (82%). Benign epilepsy with centrotemporal spikes (BECTS) was significantly more often diagnosed in group II than in group I (51% versus 27%, p=0.03). Continuous spikes and waves during slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) occurred more often in group I than in group II (50% versus 37%), although not statistically significant (p=0.29). Mild to severe developmental problems related to speech and language (80%), cognition (66%), and motor skills (48%), and behavioural problems (61%) were present in both groups. Speech and language problems were significantly more often reported in group I than in group II (90% versus 69%, p=0.02), also in patients with no LKS/CSWS (94% versus 50%, p=0.01). Conclusion: GRIN2A variants are associated with a spectrum of epilepsies, mainly accompanied by language developmental problems. This epilepsy-aphasia syndrome spectrum ranges from relatively mild BECTS to more severe LKS/CSWS. This study shows that GRIN2A genotypes with an expected milder effect on protein function are associated with a relatively more benign phenotype including BECTS without language problems.
OP12 - 2577 Targeted resequencing in epileptic encephalopathies: diagnostic implications and genotype–phenotype correlations F. Zara, E. Gennaro, S. Vari, D. Coviello, P. Striano. Department of Neuroscience, Institute G. Gaslini, Genova, Italy Objective: To assess the diagnostic value of NGS target resequencing approach for epileptic encephalopathies. Methods: The diagnostic tool allows the screening of 20 genes which have been consistently associated with early-onset epileptic encephalopathy (EE): ALDH7A1, PNP0, ARHGEF9, ARX, SLC25A22, PLCB1, TBC1D24, PNKP, KCNT1, KCNQ2, SCN2A, SCN8A, STXBP1, SCN1A, PCDH19, CDKL5, SPTAN1, SLC2A1, ST3GAL3, GRIN2A). NGS have been performed by Ampliseq/Ion Torrent technology of at least 120X. Patients have been classified into 5 phenotypic classes: 1) EEs with onset in the first year of life; 2) infantile spasms/West syndrome 3) Dravet Syndrome 4) CSWS/LandauKleffner Syndrome 5) EEs with onset after the first year of life. Results: Fifty-four patients have been analyzed: class 1, n° 26; class 2, n° 10; class 3, n° 6; class 4, n° 4; class 5, n° 8. Pathogenetic effects of variants have been attributed according to i) segregation analysis (inherited vs transmitted; putative functional effect