Pontocerebellar hypoplasia type 2 and TSEN2: review of the literature and two novel mutations.

Pontocerebellar hypoplasias (PCH) represent a heterogeneous group of autosomal recessive neurodegenerative disorders characterized by hypoplasia of the cerebellum and pons, variable cerebral involvement, microcephaly, severe delay in cognitive and motor development, and seizures. Seven different subtypes have been reported (PCH1-7) and mutations in three genes, TSEN2, TSEN34 and TSEN54 encoding three of four subunits of the tRNA splicing endonuclease complex have been found to underlie PCH2, PCH4 and PCH5. PCH2 is characterized by cerebellar hypoplasia affecting the hemispheres more severely than the vermis, progressive cerebral atrophy and microcephaly, dyskinesia, seizures, and death in early childhood. We describe a male patient with progressive microcephaly, severe hypotonia, and myoclonic-tonic seizures. Brain MRI confirmed microcephaly with simplified cortical gyration and revealed hypoplasia of the brainstem, cerebellum and cerebellar vermis. Sequencing of the TSEN2 gene detected the novel missense mutation c.934G > A (p.G312R) on one allele and the first nonsense mutation c.691C > T (p.Q231*) on the second allele. Although the cytosine-to-thymine transition results in introduction of a premature stop codon in the majority of annotated TSEN2 transcript variants, it could represent a splice site mutation (c.517-3C > T) in variant 4. However, by RT-PCR analysis we did not identify mRNAs representing TSEN2 transcript form 4 in leukocyte-derived RNA of the patient and healthy individuals. The clinical phenotype of the patient is comparable with PCH2. However, we noticed decreased cerebral volume with increased extra-axial cerebrospinal fluid spaces and wide-open Sylvian fissures indicating cerebral immaturity that might be associated with the TSEN2 null allele. We conclude that the severity of pontocerebellar hypoplasia in the patient fits PCH2, while the large involvement of the cerebrum better corresponds to PCH4 demonstrating the phenotypic spectrum of PCH2 and 4. To establish a possible genotype-phenotype correlation, more individuals with biallelic TSEN2 mutations need to be investigated.