TSEN54 mutation in a child with pontocerebellar hypoplasia type 1

Abstract

Pontocerebellar hypoplasias (PCHs) are genetically deter-mined conditions characterized by disturbances ofmaturation of the ventral pontine nuclei and hemisphericcerebellar cortex. Characteristic clinical findings (such asprogressive microcephaly, the presence of spasticity, theoccurrence of dyskinesia), the possible involvement ofanterior horn cells (AHCs) of the spinal cord, and thepeculiar neuropathological features led to the identificationof two major forms, PCH1 and PCH2. In the past fewyears, mutations in genes encoding subunits of the tRNA-splicing endonuclease (TSEN) complex—TSEN54 in mostof the cases—were detected in patients who displayedclassical PCH2 features, or its allelic, more severe PCH4.The genetics of the phenotypically heterogeneous PCH1 isless clear, and, only recently, two genes were identified[2, 3, 5].In this work, a review of the archival clinical records ofthree sibs with early onset, complicated AHC disease, andneuropathological features of PCH in one, prompted us toanalyze the known genetic causes of PCH, after DNAretrieval from paraffin blocks [3].Phenotypic heterogeneity was present in this family(Fig. 1). The eldest child (II,2) had died at age 10 monthsand received a clinical diagnosis of Werdnig–Hoffmann-like disease (SMN1 gene was normal). His two sistersshowed microcephaly and hypotonia at birth, weak tendonreflexes and muscle retraction, multiple cranial nerveinvolvement, and optic nerve atrophy. Case II,4 died at age11 years, whereas the more severely affected child II,6 (theproband) died at 20 months because of respiratory failure.Electromyography (EMG) showed a denervation pattern inboth girls. The common TSEN54 mutation (i.e., c.919G[T/p.A307S) was found to be homozygous in case II,6,whereas it was not searched for in her relatives because ofthe lack of stored biological material. Neuropathologicalfindings in case II,6 (Fig. 2) showed normal size andgyration of both cerebral hemispheres. Both the ventralpons and the olivary profiles were shrunken. The cerebel-lum was remarkably small, with shallow hemispheric sulci;the left hemisphere was softened; only the anterior portionof the vermis was present. There was severe cell loss of theventral pontine nuclei and, to a less extent, of the rapheneurons. Transverse pontine fibers were also reduced,whereas long fiber tracts were preserved and properlymyelinated. Inferior olivary nuclei (ION) showed a normal,convoluted profile, with evidence, however, of neuronalcell loss. Arcuate nucleus was hypoplasic. Intense gliosis ofboth pontine and medullary structures was present. A largecystic lesion filled the centrum semiovale of the left cere-bellar hemisphere. The cerebellar folia were reduced innumber and size, and they were missing on the basal cer-ebellum. There was a dramatic loss of both internal granuleneurons and Purkinje cells, and some folia were completelydevoid of neurons. Thin axonal bundles could be detectedin the lamellae axis. Dentate nuclei remnants were detec-ted. Intense gliosis was spread over the cerebellar tissue.There was neuronal cell loss of the anterior horns of thecervical cord and moderate gliosis. Some neuronal cell losswas detected of the telencephalic cortex and thalamicnuclei. Myelination occurred properly throughout theneural structures.