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2015 ; 10
(ä): 134
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47 patients with FLNA associated periventricular nodular heterotopia
#MMPMID26471271
Lange M
; Kasper B
; Bohring A
; Rutsch F
; Kluger G
; Hoffjan S
; Spranger S
; Behnecke A
; Ferbert A
; Hahn A
; Oehl-Jaschkowitz B
; Graul-Neumann L
; Diepold K
; Schreyer I
; Bernhard MK
; Mueller F
; Siebers-Renelt U
; Beleza-Meireles A
; Uyanik G
; Janssens S
; Boltshauser E
; Winkler J
; Schuierer G
; Hehr U
Orphanet J Rare Dis
2015[Oct]; 10
(ä): 134
PMID26471271
show ga
BACKGROUND: Heterozygous loss of function mutations within the Filamin A gene in
Xq28 are the most frequent cause of bilateral neuronal periventricular nodular
heterotopia (PVNH). Most affected females are reported to initially present with
difficult to treat seizures at variable age of onset. Psychomotor development and
cognition may be normal or mildly to moderately impaired. Distinct associated
extracerebral findings have been observed and may help to establish the diagnosis
including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve
disease and aortic dissection, chronic obstructive lung disease or chronic
constipation. Genotype-phenotype correlations could not yet be established.
METHODS: Sanger sequencing and MLPA was performed for a large cohort of 47
patients with Filamin A associated PVNH (age range 1 to 65 years). For 34
patients more detailed clinical information was available from a structured
questionnaire and medical charts on family history, development, epileptologic
findings, neurological examination, cognition and associated clinical findings.
Available detailed cerebral MR imaging was assessed for 20 patients. RESULTS:
Thirty-nine different FLNA mutations were observed, they are mainly truncating
(37/39) and distributed throughout the entire coding region. No obvious
correlation between the number and extend of PVNH and the severity of the
individual clinical manifestation was observed. 10 of the mutation carriers so
far are without seizures at a median age of 19.7 years. 22 of 24 patients with
available educational data were able to attend regular school and obtain
professional education according to age. CONCLUSIONS: We report the clinical and
mutation spectrum as well as MR imaging for a large cohort of 47 patients with
Filamin A associated PVNH including two adult males. Our data are reassuring in
regard to psychomotor and cognitive development, which is within normal range for
the majority of patients. However, a concerning median diagnostic latency of 17
to 20 years was noted between seizure onset and the genetic diagnosis, intensely
delaying appropriate medical surveillance for potentially life threatening
cardiovascular complications as well as genetic risk assessment and counseling
prior to family planning for this X-linked dominant inherited disorder with high
perinatal lethality in hemizygous males.
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