Epilepsy in NF1: Epidemiologic, Genetic, and Clinical Features. A Monocentric Retrospective Study in a Cohort of 784 Patients
Abstract
Simple Summary
Abstract
1. Introduction
2. Results and Discussion
2.1. Epidemiologic Data
2.2. Epileptic Phenotype
2.3. Neurological Comorbidities
2.4. Molecular Diagnosis
3. Materials and Methods
3.1. Patients
3.2. Follow-Up Protocol
3.3. Molecular Analysis
3.4. Statistical Analyses
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Total Cohort (784) | Patients without Epilepsy (747) | Patients with Epilepsy (37) | p-Value | |
---|---|---|---|---|
Sex (Females/Males) | 371/413 | 358/389 | 13/24 | 0.18 |
Mean age at first visit (months) | 58.25 | 57.59 | 69.57 | 0.10 < p < 0.20 |
SD 1: 43.7 | SD: 43.4 | SD: 49.4 | ||
Follow-up mean length (months) | 82 | 81 | 105 | 0.10 < p < 0.20 |
SD: 101 | SD: 101 | SD: 96 | ||
NF1 family history | 276 out of 742 (37.2%) | 267 out of 706 (37.8%) | 9 out of 36 (25%) | 0.1568 |
Mother/Father | 116/160 | 112/153 | 5/4 | |
Epilepsy family history | 17 out of 742 (2.29%) | 14 out of 706 (1.98%) | 3 out of 36 (8.3%) | 0.0389 |
ID-Sex | NF1 Mutation (NM_000267.3) | Neuro-Cognitive Phenotype | Brain MRI Imaging §,° | Type of Seizures |
---|---|---|---|---|
1-F | Not tested | LD | NA | Unknown |
2-M | c.3266delA p.(Gly1090fs*1095) Null | LD | OPG; UBOs | Focal (MO, IA) |
3-M | Not tested | LD+ADHD | Normal | Focal |
4-F | Not tested | Normal | UBOs | Generalized |
5-M | c.5471T > G p.(Ile1824Ser) Missense | mild ID, LD | Brainstem (pons)/left cerebellar peduncle nodular lesion; Hydrocephalus; UBOs | Combined generalized and focal |
6-M | c.2273_2274insT p.(Arg758Serfs*10) Null | DD, mild ID, LD | Low-grade astrocytoma (left frontal lobe) | Focal |
7-M | Not tested | DD | Hydrocephalus | Generalized |
8-M | Not tested | DD | Cerebral angioma (occipital lobe) § | Generalized (MO, TC) |
9-F | c.662G > A p.(Trp221*) Null | LD, ID, AD | Stroke; OPG; moyamoya; UBOs | Focal (MO) |
10-M | c.369delC p.(Cys124Valfs*41) Null | ID | Suprasellar lesion; OPG; UBOs | Focal |
11-M | c.3113 + 1G > A r.2991_3113del p.(Tyr998_Arg1038del) Splice site | DD, mild ID | OPG; UBOs | Generalized, (MO, myotonic-atonic) |
12-M | Not tested | Normal | NA | Generalized (MO, TC) |
13-F | c.5839 C > T p.(Arg1947*) Null | LD | Hydrocephalus; OPG; Absent MCA; Hypoplasic ICA | Generalized |
14-M | c.541C > T p.(Gln181*) Null | LD | UBOs | Generalized |
15-M | Not tested | NA (lost to FU at 6 months) | Left basal ganglia glioma; Hydrocephalus; OPG; UBOs | Unknown |
16-M | c.889-2A > G r.? p.? Splice site | DD, LD | UBOs | Focal (MO) |
17-M | c.532G > T p.(Glu178*) Null | DD | NA | Generalized (absence) |
18-F | c.6220_ 6221insCAACAATTCCCTT p.(Asp2074Alafs*29) Null | DD, mild ID, LD | Left centrum semiovalis signal alterations, compatible with perinatal brain injury °; UBOs | Spasms |
19-M | c.3233_3234insT p.(Leu1079Thrfs*10) Null | Normal | Low-grade cerebellar astrocytoma; left carotid-jugular arteriovenous fistula; UBOs | Focal |
20-M | c.204+1G > T r.100_204del p.(Val34_Met68del) Splice site | LD+ ADHD, BD, A | Brainstem (pons) capillary telangiectasia; UBOs | Generalized (absence) |
21-F | c.185delT p.(Leu62*) Null | DD, LD | UBOs | Generalized |
22-M | Not tested | mild ID | Olfactory cortex lesion; UBOs | Focal (MO) |
23-F | 17q11 microdeletion | LD | Brainstem low-grade lesion; UBOs | Focal |
24-F | c.4269+1G > A Splice site | Normal | Right thalamic lesion; periventricular nodular heterotopia; UBOs | Combined generalized and focal |
25-M | 17q11 microdeletion | mild ID | Hydrocephalus; Arnold Chiari I malformation; OPG; UBOs | Generalized |
26-F | c.1185+1 G > A r.1063_1185del p.(Asn355_Lys395del) Splice site | LD | Normal | Generalized (MO, TC) |
27-M | c.1945G > T p.(Glu649*) Null | mild ID | Incomplete hippocampal inversion °; OPG; UBOs | Combined generalized and focal |
28-M | c.82C > T p.(Gln28*) Null | Normal | UBOs | Focal (MO, clonic) |
29-M | Not tested | Normal | Cerebral cortical calcification ° (left parietal lobe) § | Unknown |
30-F | Negative (NGS+MLPA) | LD | Normal | Generalized (absence) |
31-M | Not tested | Normal | Subcortical signal enhancement; Lateral ventricles asymmetry; UBOs | Generalized (absence) |
32-M | c.3457_3460del p.(Leu1153Metfs*4) Null | Normal | OPG; lentiform nucleus low-grade lesion; UBOs | Focal (behavior arrest) |
33-M | c.2991-1G > A r.? p.? Splice site | ID | OPG; UBOs | Generalized (absence) |
34-F | c.7352delC p.(Pro2451Leufs*17) Null | DD | OPG; UBOs | Spasms |
35-M | Not tested | Normal | UBOs | Generalized |
36-F | Not tested | Normal | Left trigone hypodense lesion | Generalized (myoclonic absence) |
37-F | c.291delA p.(Gln97Hisfs*6) Null | Normal | UBOs | Generalized, (MO, TC) |
Nonepileptic Patients | Epileptic Patients | p-Value * | |
---|---|---|---|
Developmental delay and/or intellectual disability | 112 out of 747 (15%) | 14 out of 37 (37.8%) | 0.0009 * |
Learning disabilities with normal intellect | 113 out of 747 (15.1%) | 11 out of 37 (29.7%) | 0.0337 * |
Recurrent headache | 101 out of 747 (13.5%) | 13 out of 37 (35.1%) | 0.0011 * |
Pathologic imaging (except for UBOs) | 178 out of 378 (47.1%) | 24 out of 34 (70.6%) | 0.0114 * |
Hydrocephalus | 20 out of 378 (5.3%) | 5 out of 34 (14.7%) | 0.045 * |
Cerebral vasculopathies | 7 out of 378 (1.85%) | 5 out of 34 (14.7%) | 0.0015 * |
OPG | 132 out of 378 (34.9%) | 11 out of 34 (32.4%) | 0.8521 |
Brain neoplasia other than OPG (%) | 49 out of 378 (12.9%) | 10 out of 34 (29.4%) | 0.0177 * |
Other CNS anomalies | 34 out of 378 (9%) | 6 out of 34 (17.6%) | 0.124 |
UBOs | 193 out of 334 (57.8%) | 24 out of 32 (75%) | 0.062 |
p-Value | OR | 95% C.I. OR | ||
---|---|---|---|---|
Lower | Upper | |||
Sex | 0.294 | 1.514 | 0.697 | 3.288 |
NF1 family history | 0.970 | 0.985 | 0.432 | 2.241 |
Epilepsy family history | 0.970 | 1.043 | 0.113 | 9.632 |
Hydrocephalus | 0.042 | 3.293 | 1.043 | 10.403 |
Cerebral vasculopathies | 0.006 | 6.173 | 1.673 | 22.781 |
OPG | 0.755 | 0.878 | 0.389 | 1.983 |
Non OPG Neoplasia | 0.413 | 1.503 | 0.567 | 3.983 |
Nonepileptic NF1 Patients (n = 747) | Epileptic NF1 Patients (n = 37) | ||
---|---|---|---|
Untested | 214 | 4 | |
(% of cohort) | (28.6) | (10.8) | |
At least one test | 525 | 31 | |
(% of cohort) | (70.2) | (83.8) | |
Tested for 17q11 microdeletion only | 61 | 6 | |
(% of cohort) | (8.2) | (18.2) | |
p-value | |||
17q11 microdeletion | 22 | 2 | |
(% of cohort) | (2.9) | (5.4) | 0.3145 |
(% of confirmed molecular defects) | (4.9) | (8.3) | 0.3533 |
Identified mutation | 421 | 22 | |
(% of cohort) | (56.3) | (59.4) | |
(% of MLPA and NGS analyses) | (90.7) | (88) | |
Nonsense or frameshift mutation | 264 | 15 | |
(% of cohort) | (35.3) | (40.5) | 0.5981 |
(% of confirmed molecular defects) | (59.6) | (62.5) | 0.8339 |
Missense mutation | 64 | 1 | |
(% of cohort) | (8.6) | (2.7) | 0.3545 |
(% of confirmed molecular defects) | (14.4) | (4.2) | 0.2276 |
Splicing mutation | 69 | 6 | |
(% of cohort) | (9.2) | (16.2) | 0.6128 |
(% of confirmed molecular defects) | (15.6) | (25) | 0.2494 |
In frame mutation | 8 | ||
(% of cohort) | (1.1) | - | 1 |
(% of confirmed molecular defects) | (1.8) | ||
Exonic/multiexonic deletion | 12 | ||
(% of cohort) | (1.6) | - | 1 |
(% of confirmed molecular defects) | (2.7) | ||
Other | 4 | ||
(% of cohort) | (0.5) | - | 1 |
(% of confirmed molecular defects) | (0.9) | ||
No causative mutation or CNV detected | 43 | 3 | |
(% of tested patients) | (8.2) | (9.1) |
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Sorrentino, U.; Bellonzi, S.; Mozzato, C.; Brasson, V.; Toldo, I.; Parrozzani, R.; Clementi, M.; Cassina, M.; Trevisson, E. Epilepsy in NF1: Epidemiologic, Genetic, and Clinical Features. A Monocentric Retrospective Study in a Cohort of 784 Patients. Cancers 2021, 13, 6336. https://doi.org/10.3390/cancers13246336
Sorrentino U, Bellonzi S, Mozzato C, Brasson V, Toldo I, Parrozzani R, Clementi M, Cassina M, Trevisson E. Epilepsy in NF1: Epidemiologic, Genetic, and Clinical Features. A Monocentric Retrospective Study in a Cohort of 784 Patients. Cancers. 2021; 13(24):6336. https://doi.org/10.3390/cancers13246336
Chicago/Turabian StyleSorrentino, Ugo, Silvia Bellonzi, Chiara Mozzato, Valeria Brasson, Irene Toldo, Raffaele Parrozzani, Maurizio Clementi, Matteo Cassina, and Eva Trevisson. 2021. "Epilepsy in NF1: Epidemiologic, Genetic, and Clinical Features. A Monocentric Retrospective Study in a Cohort of 784 Patients" Cancers 13, no. 24: 6336. https://doi.org/10.3390/cancers13246336
APA StyleSorrentino, U., Bellonzi, S., Mozzato, C., Brasson, V., Toldo, I., Parrozzani, R., Clementi, M., Cassina, M., & Trevisson, E. (2021). Epilepsy in NF1: Epidemiologic, Genetic, and Clinical Features. A Monocentric Retrospective Study in a Cohort of 784 Patients. Cancers, 13(24), 6336. https://doi.org/10.3390/cancers13246336