Mutations of TSEN and CASK genes are prevalent in pontocerebellar hypoplasias type 2 and 4

Sir, Pontocerebellar hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments (Barth, 2000). Recently in two subtypes, PCH type 2 (associated with dyskinesia and/or dystonia and variable degrees of spasticity) and PCH type 4 (a more severe phenotype associated with perinatal symptoms, ventilator dependency and early death), mutations have been identified in three of the four different subunits of the transfer RNA-splicing endonuclease complex (TSEN54, TSEN34 and TSEN2) (Budde et al., 2008). Mutations in the calcium/calmodulin-dependent serine protein kinase (CASK) gene have also been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia (Najm et al., 2008). Namavar et al. (2011) reported on a series of 169 patients affected with PCH and identified mutations in TSEN54 or RARS2 genes in 106 individuals. The authors display a strong correlation between TSEN54 mutations and a ‘dragonfly-like’ cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. They also show that homozygosity for the common c.919G>T (p.Ala307Ser) missense mutation in TSEN54 is clinically associated with a PCH2 phenotype whereas the presence of a nonsense or splice site mutation is associated with a PCH4 phenotype.