Original articleEtiological heterogeneity of familial periventricular heterotopia and hydrocephalus
Introduction
Periventricular heterotopia represents a heterogeneous group of migrational disorders, characterized by nodules that are composed of neurons and positioned ectopically along the lateral ventricular walls. Prior studies have demonstrated an X-linked form of periventricular heterotopia (PH) caused by mutations in the filamin A gene (FLNA) [1], [2], [3]. Numerous other PH syndromes have associated findings of a cleft palate, frontal nasal dysplasia, sensorineural hearing loss, and celiac disease [4], [5], [6]. Given that mutations in FLNA can also lead to the otopalatodigital (OPD) spectrum of disorders with abnormalities in the brain, skeleton, viscera, urogenital tract, and craniofacial structures [7], some of these cases may represent an overlapping OPD-PH syndrome, although this remains uncertain. More recently, an autosomal recessive pattern of inheritance has also been seen in some families with PH and microcephaly, while other spontaneous cases show abnormalities of chromosome 5p [8], [9]. Further delineation of these various syndromes within the PH spectrum will provide greater refinement towards determining the genetic basis of these neurologic disorders.
PH associated with hydrocephalus has primarily been reported in sporadic cases. Perinatal trauma, probable prenatal onset seizure disorder (episodic rhythmic movements in utero) with additional findings of megalencephaly and lissencephaly [10], or bipolar disorder [11] have been seen with unilateral PH and hydrocephalus. A case of confluent bilateral heterotopia, hydrocephalus, and polymicrogyria resulted in early postnatal lethality [10]. A single individual from a pedigree with sensorineural hearing loss and hydrocephalus (Chudley-McCullough syndrome) also had associated findings of bilateral frontal nodular heterotopia [12]. While these various presentations suggest both heterogeneous and extrinsic causes leading to radiographic features of PHH, the current report of a familial disorder with similar findings argues for the existence of genetic causes of PH with hydrocephalus (PHH) within this spectrum of migrational disorders.
Here we describe three kindreds with PH alone or PH and hydrocephalus. One previously described family has a known FLNA mutation with hydrocephalus occurring in the setting of valproic acid exposure. This most likely represented valproate embryopathy. The second family showed suggestive linkage to the Xq28 region including the FLNA locus, although the inheritance pattern was not typical of this disorder and no mutation was detected on sequencing. Both genetic and molecular studies on the third pedigree clearly exclude FLNA as a causal gene, suggesting that PHH is an etiologically heterogeneous condition that can be caused by at least one as yet unidentified autosomal gene.
Section snippets
Case materials and methods
With the exception of the newborn child with PH and hydrocephalus (III-1), clinical descriptions of members from Family 1 have previously been published [1]. In Family 2, individuals across three generations were evaluated. They include the propositus (II-6), her affected offspring (III-1), her unaffected sister (II-8), and the sister's affected son (III-2). The unaffected parents of the propositus (I-1, I-2) were also included in the analyses. Individuals studied in Family 3 include two
Family 1 (Fig. 1)
The non-consanguineous Caucasian family is of Australian origin. The pedigree, except for the newborn child (III-1), has previously been described [1]. Affected individuals have characteristic bilateral PH (Fig. 2C) and a documented FLNA mutation (A–G substitution at exon 7 −2).
Since publication of the original report, the affected individual (Family 1, II-8) gave birth to a female (III-1). Her mother (II-8) was treated with valproic acid (1500 mg/day) and folate during the duration of the
Discussion
The current report describes three kindreds with periventricular heterotopia and variably associated hydrocephalus (PHH) that appear to represent a mixture of different causes both genetic and potentially non-genetic.
In Pedigree 1, hydrocephalus occurs for the first time in an infant [III-1] from a pedigree with PH and a known FLNA mutation. The affected infant's mother [II-8] was treated with valproate through the pregnancy, such that the new born's hydrocephalus and meningomyelocele may
Acknowledgements
We wish to thank Dr S. Berkovic for his comments on the manuscript. This work was supported by grants to CAW from the NINDS (5RO1 NS35129 and 1PO1NS40043), the March of Dimes, and the McKnight Foundation. CAW is an Investigator of the Howard Hughes Medical Institute. VLS is supported by a grant from the NIMH (1K08MH/NS63886-01). VLS is a Charles A. Dana fellow and CITP fellow for the Beth Israel Deaconess Medical Center and the Harvard/MIT Health Science and Technology.
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