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2017 ; 89
(4
): 385-394
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DNM1 encephalopathy: A new disease of vesicle fission
#MMPMID28667181
von Spiczak S
; Helbig KL
; Shinde DN
; Huether R
; Pendziwiat M
; Lourenço C
; Nunes ME
; Sarco DP
; Kaplan RA
; Dlugos DJ
; Kirsch H
; Slavotinek A
; Cilio MR
; Cervenka MC
; Cohen JS
; McClellan R
; Fatemi A
; Yuen A
; Sagawa Y
; Littlejohn R
; McLean SD
; Hernandez-Hernandez L
; Maher B
; Møller RS
; Palmer E
; Lawson JA
; Campbell CA
; Joshi CN
; Kolbe DL
; Hollingsworth G
; Neubauer BA
; Muhle H
; Stephani U
; Scheffer IE
; Pena SDJ
; Sisodiya SM
; Helbig I
Neurology
2017[Jul]; 89
(4
): 385-394
PMID28667181
show ga
OBJECTIVE: To evaluate the phenotypic spectrum caused by mutations in dynamin 1
(DNM1), encoding the presynaptic protein DNM1, and to investigate possible
genotype-phenotype correlations and predicted functional consequences based on
structural modeling. METHODS: We reviewed phenotypic data of 21 patients (7
previously published) with DNM1 mutations. We compared mutation data to known
functional data and undertook biomolecular modeling to assess the effect of the
mutations on protein function. RESULTS: We identified 19 patients with de novo
mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic
parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A
common phenotype emerged that included severe to profound intellectual disability
and muscular hypotonia in all patients and an epilepsy characterized by infantile
spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome.
Two patients had profound global developmental delay without seizures. In
addition, we describe a single patient with normal development before the onset
of a catastrophic epilepsy, consistent with febrile infection-related epilepsy
syndrome at 4 years. All mutations cluster within the GTPase or middle domains,
and structural modeling and existing functional data suggest a dominant-negative
effect on DMN1 function. CONCLUSIONS: The phenotypic spectrum of DNM1-related
encephalopathy is relatively homogeneous, in contrast to many other genetic
epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant,
which is now one of the most common recurrent variants in epileptic
encephalopathies identified to date. Given the predicted dominant-negative
mechanism of this mutation, this variant presents a prime target for therapeutic
intervention.
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