DEVELOPMENTAL DISORDERS OF THE CEREBELLUM

Despite progress in cerebellar embryology, neuroimaging and molecular genetics, the pathogenesis of cerebelllar malformations is still poorly understood. Selected examples are reviewed. Cerebellar agenesis is extremely rare. All non-syndromic cases are sporadic, patients show neurological and cognitive impairment. Pontocerebellar hypoplasias (PCH) are a group of recessively inherited malformations with prenatal onset degeneration. Neuroimaging is identical in PCH1 and PCH2. PCH2 is more prevalent than type 1 (with anterior horn cell degeneration). Variants (other forms?) with milder course are known. Rhombencephalosynapsis (RS) is characterized by vermian agenesis, fusion of cerebellar hemispheres and dentate nuclei. Aspart form the exceptional Gomez-Lopez-Hernandez syndrome, RS is a sporadic disorder. Children with isolated RS may have normal development. Patients with associated malformations have variable impairments. Unilateral cerebellar hypoplasia (aplasia) is most likely not a malformation, but a form of disruption. Affected children present with developmental delay. Cerebellar hypoplasias (CH), involving vermis and hemispheres, are often seen in siblings, suggesting recessive inheritance, but the genetic basis is still unknown. Children present with hypotonia and delay, followed by ataxia and cognitive impairment. MRI reveals remarkable intra- and inter-familial variability. CH may occur in several clinical syndromes (e.g. Ritscher-Schinzel, PHACE). Joubert syndrome (JS) is the best studied mid-hindbrain malformation. Consistent clinical findings are early hypotonia, developmental delay, ataxia, and cognitive impairment; breathing abnormalities, oculomotor apraxia, and retinal dystrophy are frequent. The Molar Tooth Sign (MTS) on axial MRI through the midbrain is an essential diagnostic feature. However MTS is also found in other related cerebello-oculo-renal syndromes (e.g. Senior-Löken, COACH). JS is genetically heterogeneous: loci were mapped to 9q34.4 and 11p11.2-q12.3; in a third locus on 6q23 AHI1-gene mutations were identified, rare patients have NPHP1-gene deletions. Further loci are awaited. Genotype-phenotype correlations are being established.