Brain Malformation Testing

Similar to other types of pontocerebellar hypoplasias (PCH), subtypes PCH2 (OMIM 277470) and PCH4 (OMIM 225753) are characterized by small cerebellum and brainstem, variable neocortical atrophy, and abnormal mental and motor development.  In addition, patients with PCH2 exhibit progressive microcephaly from birth, extrapyramidal dyskinesia, chorea, and epilepsy.  PCH4, also known as fatal infantile olivopontocerebellar hypoplasia, is associated with a more severe course and an earlier lethality than PCH2.  Mutations in TSEN54 [OMIM 608755], encoding one of the noncatalytic subunits of the tRNA-splicing endonuclease complex, have recently been implicated in the etiology of PCH2A and PCH4.  Budde et al (2008) sequenced the TSEN54 gene in 58 patients from the Netherlands and other European countries, Brazil, and Israel.  3/3 patients with PCH4 had mutations detected in TSEN54, and 47/52 patients with PCH2 were homozygous for the p.A307S mutation.  Of these 47 patients, 31 shared European ancestry and a haplotype on which p.A307S arose as a founder mutation.

To date no deletions or duplications involving the TSEN54 gene as causative of pontocerebellar hypoplasia have been reported.

Bilateral frontoparietal polymicrogyria (BFPP) [OMIM #606854] is characterized by moderate-severe mental retardation, seizures, dysconjugate gaze, and characteristic radiological findings.  Mutations of the GPR56 [OMIM #604110] gene, or G-protein coupled receptor 56, have been identified in patients with BFPP.   Piao X, et al [2005] studied patients with BFPP along with some patients with other polymicrogyria syndromes.  All 29 patients with BFPP were found to be homozygous for GPR56 mutations.  However, no patients without the BFPP cortical distribution or without both white matter and posterior fossa changes were found to mutations in GPR56.

Deletions and/or duplications of the GPR56 gene as causative of disease have been reported.

Severe, de novo phenotype in females:  X-linked mental retardation and microcephaly with pontine and cerebellar hypoplasia [OMIM #300749] is characterized by severe or profound mental retardation (MR), microcephaly, and disproportionate pontine and cerebellar hypoplasia in females.  These mutations are typically de novo and thought to be lethal in males.

Mild, familial phenotype in males:  Affected males have mild to moderate MR, and carrier females seem to be unaffected.  In 2 families, MR was accompanied by nystagmus in multiple affected individuals.

CASK mutations were detected in 4/46 individuals with MIC-PCH including 3/13 females and 1/33 males.   A resequencing screen of X-chromosome coding exons in individuals from approximately 350 families with X-linked MR revealed CASK mutations in 4 families.

Deletions and/or duplications of the CASK gene as causative of disease have been reported.

The hallmark feature seen in patients with TUBB2B mutations is asymmetric polymicrogyria (PMG). PMG is a brain malformation with numerous small gyri separated by shallow sulci, creating a cobblestone appearance.  PMG in these patients is usually bilateral, asymmetric, and more striking in the frontal and temporal lobes.  Other findings on MRI include absence of the corpus callosum, abnormal basal ganglia and cerebellum, and hypoplasia of the brainstem.  Most patients also have microcephaly, severe mental retardation and seizures.   

Mutations of the TUBB2B gene have been identified in patients with asymmetrical PMG. Jaglin XH, et al [2009] reported four unrelated individuals and one fetus with asymmetrical PMG and de novo mutations in TUBB2B.  All mutations were missense mutations in highly conserved residues in exon 4.  These mutations result in haploinsufficiency and aberrant heterodimer assembly.   Mutations in TUBB2B are autosomal dominant and all mutations, to date, have been de novo.