Summary
In their 2011 study “Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia”, Namavar et al. demonstrated the connection between genetic findings on the one hand, and brain abnormalities seen in imaging as well as clinical symptoms of patients with pontocerebellar hypoplasia on the other.
Background
It had already been established that changes in certain genes are associated with specific forms of pontocerebellar hypoplasia.
Mutations in the TSEN genes (TSEN54, TSEN34, TSEN2) were known to cause PCH2 and PCH4.
(TSEN = tRNA splicing endonuclease subunit)
Methods
A cohort of 169 patients with clinical pontocerebellar hypoplasia was genetically examined. In 106 patients, mutations were found in one of the TSEN genes or in the RARS2 gene. To determine how the severity of disease (as reflected in imaging and clinical symptoms) correlated with genetic changes, this group of 106 patients with confirmed genetic abnormalities was compared to the 63 patients who met the clinical criteria for pontocerebellar hypoplasia but had no mutations in these genes.
Results
Namavar et al. identified a strong correlation between TSEN54 mutations and a dragonfly-like appearance of the cerebellum on MRI. The cerebellum appeared flattened and markedly reduced in size, particularly affecting the hemispheres, while the central vermis was relatively less affected.
Clinically, patients with TSEN54 mutations showed dyskinesia and/or dystonia, various forms of spasticity (sometimes a pure generalized spasticity), irritability after birth, cortical visual impairment, and profound motor and cognitive impairment. These findings are consistent with PCH2.
More severe TSEN mutations led to early death, contractures, polyhydramnios (excess amniotic fluid during pregnancy), and respiratory difficulties. In MRI, these cases also showed marked cortical immaturity, consistent with PCH4.
Conclusion
The study demonstrated that PCH2 and PCH4 represent a spectrum of mutations, primarily involving TSEN54.
The strong correlation between genetic (genotype), clinical (phenotype), and neuroradiological findings facilitates early clinical diagnosis and underscores the importance of genetic testing.
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