Abstract
BackgroundHeterozygous 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.MethodsSanger 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.ResultsThirty-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.ConclusionsWe 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.
Highlights
Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH)
For 5 of the remaining index patients the carrier status of their mothers or daughter was only recognized during family studies at an age between 16 and 65 years, where none of those carrier relatives so far had experienced seizures or other clinical abnormalities previously associated with FLNA mutations
In our cohort no instances of stillbirths or late abortion were recorded, nor were milder affected male siblings with clinical findings of the FLNA phenotypic spectrum. This further strengthens the previously proposed hypothesis that (I) most hemizygous truncating FLNA mutations lead to predominantly early abrogation of intrauterine development [22], as might have been the case in the 3 miscarriages around the 12th week of gestation of patient # I/1 from family 32. (II) Our data from this large cohort further confirm, that FLNA-associated PVNH in liveborn males is rare and may only be compatible with postnatal development in the presence of critical amounts of correct functional full length cDNA either due to hypomorphic alleles, incomplete splice effects or somatic mosaicism for truncating mutations functionally similar to the situation in heterozygous female mutation carriers [4]
Summary
Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). The most frequent symmetric manifestation of periventricular nodular heterotopia (PVNH) is located along the walls of both lateral ventricles predominantly in females and results from heterozygous loss of function mutations in the X-linked FLNA gene [3, 4]. It is associated with high intrauterine and perinatal lethality in hemizygous males presumably from excessive bleeding, on rare occasions boys and adult hemizygous male carriers of FLNA mutations have been reported [4, 5]. Penetrance in heterozygous FLNA mutation carriers is reduced and asymptomatic PVNH may be detected through predictive carrier testing or incidentally in cerebral MR imaging as the only manifestation of a FLNA mutation
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