CNS involvement in OFD1 syndrome: a clinical, molecular, and neuroimaging study.

BACKGROUND: Oral-facial-digital type 1 syndrome (OFD1; OMIM 311200) belongs to the expanding group of disorders ascribed to ciliary dysfunction. With the aim of contributing to the understanding of the role of primary cilia in the central nervous system (CNS), we performed a thorough characterization of CNS involvement observed in this disorder. METHODS: A cohort of 117 molecularly diagnosed OFD type I patients was screened for the presence of neurological symptoms and/or cognitive/behavioral abnormalities on the basis of the available information supplied by the collaborating clinicians. Seventy-one cases showing CNS involvement were further investigated through neuroimaging studies and neuropsychological testing. RESULTS: Seventeen patients were molecularly diagnosed in the course of this study and five of these represent new mutations never reported before. Among patients displaying neurological symptoms and/or cognitive/behavioral abnormalities, we identified brain structural anomalies in 88.7%, cognitive impairment in 68%, and associated neurological disorders and signs in 53% of cases. The most frequently observed brain structural anomalies included agenesis of the corpus callosum and neuronal migration/organisation disorders as well as intracerebral cysts, porencephaly and cerebellar malformations. CONCLUSIONS: Our results support recent published findings indicating that CNS involvement in this condition is found in more than 60% of cases. Our findings correlate well with the kind of brain developmental anomalies described in other ciliopathies. Interestingly, we also described specific neuropsychological aspects such as reduced ability in processing verbal information, slow thought process, difficulties in attention and concentration, and notably, long-term memory deficits which may indicate a specific role of OFD1 and/or primary cilia in higher brain functions.

The molecular basis of oral-facial-digital syndrome, type 1.

Oral-facial-digital syndrome type 1 (OFDI; OFD1; OMIM 311200) is a rare developmental disorder transmitted as an X-linked dominant condition with embryonic male lethality. OFD1 is characterized by malformation of the oral cavity, face, and digits. Central nervous system (CNS) abnormalities and cystic kidney disease can also be part of this condition. This disorder is due to mutations in the OFD1 gene that encodes a centrosomal protein localized at the basal bodies at the origin of primary cilia. Characterization of in vitro and in vivo models demonstrated that, similarly to what described for other ciliary proteins, Ofd1 inactivation is associated to defective sonic hedgehog (Shh) and canonical Wnt signaling pathways. Functional studies have demonstrated that OFD1 has a crucial role in the biology of primary cilia thus ascribing this pleiotropic disease to the growing number of disorders associated to dysfunction of primary cilia. OFD1 shares phenotypic similarities with this latter group of disorders, such as cystic kidneys, skeletal, and CNS abnormalities. Future studies will address whether all clinical manifestations of these diseases can be entirely explained by cilia dysfunction or may also be due to direct roles of the proteins involved.

Mutational spectrum of the oral-facial-digital type I syndrome: a study on a large collection of patients.

Oral-facial-digital type I (OFDI) syndrome is a male-lethal X-linked dominant developmental disorder belonging to the heterogeneous group of oral-facial-digital syndromes (OFDS). OFDI is characterized by malformations of the face, oral cavity, and digits. Central nervous system (CNS) abnormalities and cystic kidney disease can also be part of this condition. This rare genetic disorder is due to mutations in the OFD1 gene that encodes a centrosome/basal body protein necessary for primary cilium assembly and for left-right axis determination, thus ascribing OFDI to the growing number of disorders associated to ciliary dysfunction. We now report a mutation analysis study in a cohort of 100 unrelated affected individuals collected worldwide. Putative disease-causing mutations were identified in 81 patients (81%). We describe 67 different mutations, 64 of which represent novel mutations, including 36 frameshift, nine missense, 11 splice-site, and 11 nonsense mutations. Most of them concentrate in exons 3, 8, 9, 12, 13, and 16, suggesting that these exons may represent mutational hotspots. Phenotypic characterization of the patients provided a better definition of the clinical features of OFDI syndrome. Our results indicate that renal cystic disease is present in 60% of cases >18 years of age. Genotype-phenotype correlation did not reveal significant associations apart for the high-arched/cleft palate most frequently associated to missense and splice-site mutations. Our results contribute to further expand our knowledge on the molecular basis of OFDI syndrome.