TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features.
To evaluate the phenotypic spectrum associated with mutations in TBC1D24.



We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24).



Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function.



TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.
Simona
S
Balestrini
Mathieu
M
Milh
Claudia
C
Castiglioni
Kevin
K
Lüthy
Mattea J
MJ
Finelli
Patrik
P
Verstreken
Aaron
A
Cardon
Barbara Gnidovec
BG
Stražišar
J Lloyd
JL
Holder
Gaetan
G
Lesca
Maria M
MM
Mancardi
Anne L
AL
Poulat
Gabriela M
GM
Repetto
Siddharth
S
Banka
Leonilda
L
Bilo
Laura E
LE
Birkeland
Friedrich
F
Bosch
Knut
K
Brockmann
J Helen
JH
Cross
Diane
D
Doummar
Temis M
TM
Félix
Fabienne
F
Giuliano
Mutsuki
M
Hori
Irina
I
Hüning
Hulia
H
Kayserili
Usha
U
Kini
Melissa M
MM
Lees
Girish
G
Meenakshi
Leena
L
Mewasingh
Alistair T
AT
Pagnamenta
Silvio
S
Peluso
Antje
A
Mey
Gregory M
GM
Rice
Jill A
JA
Rosenfeld
Jenny C
JC
Taylor
Matthew M
MM
Troester
Christine M
CM
Stanley
Dorothee
D
Ville
Magdalena
M
Walkiewicz
Antonio
A
Falace
Anna
A
Fassio
Johannes R
JR
Lemke
Saskia
S
Biskup
Jessica
J
Tardif
Norbert F
NF
Ajeawung
Aslihan
A
Tolun
Mark
M
Corbett
Jozef
J
Gecz
Zaid
Z
Afawi
Katherine B
KB
Howell
Karen L
KL
Oliver
Samuel F
SF
Berkovic
Ingrid E
IE
Scheffer
Fabrizio A
FA
de Falco
Peter L
PL
Oliver
Pasquale
P
Striano
Federico
F
Zara
Phillipe M
PM
Campeau
S M
SM
Sisodiya
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D049108:Cell Enlargement; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004569:Electroencephalography; D004827:Epilepsy / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D005260:Female; D020690:GTPase-Activating Proteins; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins; D016501:Neurites / Q000502:physiology; D010808:Physical Examination; D055815:Young Adult
D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C552551:TBC1D24 protein, human