Acquired cerebellar lesions in adults and children can lead to the development of a complex behavioural pattern termed 'Cerebellar Cognitive Affective Syndrome' (Schmahmann and Sherman, Brain, 1998; 121: 561-79), which is characterized by reduced cognitive efficiency associated with specific neuropsychological deficits (executive and visuospatial disorders), expressive language disorders (mild agrammatism and anomia) and affective disorders with blunting of affect. It is not known whether a symptomatological picture such as this can also be found in congenital cerebellar malformations. We studied the behavioural developmental profile of 27 patients including children and adults with congenital malformations confined to the cerebellum, the largest studied sample to date. Extensive clinical and neuropsychological investigations highlight the presence of a wide range of disorders supporting the important role played by the cerebellum in the acquisition of higher-order cognitive and affective skills. The type and extent of cerebral reorganization processes in the presence of malformative lesions are difficult to predict and may possibly account for the variability of clinical phenotypes. It is, therefore, more difficult to identify a syndromic picture defined as exactly as is the case with acquired lesions. However, the pattern of deficits that we document is in remarkable agreement with the general profile of the Cerebellar Cognitive Affective Syndrome. Malformations affecting the cerebellar vermis induce affective and social disorders and evolve towards more unfavourable pictures often associated with an autistic symptomatology. Malformations of cerebellar hemispheres are more frequently associated with selective neuropsychological deficits involving mainly executive functions and visuospatial and linguistic abilities. Motor deficits are generally less severe, and tend to improve slowly and progressively, in some cases reaching almost complete functionality. Finally, the overall favourable evolution with an onset of skills in advanced age in a consistent subset of subjects suggests that individual follow-ups should be performed in order to monitor the quality and stability of impairments and acquired abilities over time.

The terminal 22q13.3 deletion syndrome is characterized by severe expressive-language delay, mild mental retardation, hypotonia, joint laxity, dolichocephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpoint in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigations revealed that the translocation was reciprocal, with the chromosome 22 breakpoint within the 22q subtelomeric cosmid 106G1220 and the chromosome 12q breakpoint near STS D12S317. Using Southern blot analysis and inverse PCR, we located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and located the chromosome 22 breakpoint within exon 21 of the human homologue of the ProSAP2 gene. Short homologous sequences (5-bp, CTG[C/A]C) were found at the breakpoint on both derivative chromosomes. The translocation does not lead to the loss of any portion of DNA. Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the cerebral cortex and the cerebellum. The FLJ10659 gene is expressed in various tissues and does not show tissue-specific isoforms. The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome. ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses.

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17–74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.