Clinical and genetic variability of oculodentodigital dysplasia

To the Editor: Oculodentodigital dysplasia (ODDD, OMIM 164200) is a rare autosomal dominant inherited disorder affecting the development of face, eyes, teeth, and limbs. A key finding is syndactyly III affecting fingers V and IV, sometime also the fingers IV and III and toes. Other typical signs include microphthalmos, a small nose, hypotrichosis, and abnormal dentition. In addition, several patients develop neurological problems in adulthood, mostly a spastic paraparesis associated with white matter hyperintensity onMR imaging (1). The syndrome is caused by mutations of the gene GJA1 encoding for connexin-43 (2–4). In most cases, missense mutations in the 50-end of the GJA1 gene were found. The phenotypes range from syndactyly III alone to ODDD without syndactyly (3, 4). Although neurological symptoms are underdiagnosed due to the late occurrence in the course of the disease, it is clear that some families are not affected by neurological symptoms (2). Here, we describe four GJA1 mutations in ODDD patients, two of which were associated with a spastic paraparesis and one with a developmental and language disorder. Families 1 and 2 were described previously (1, 5). However, in family 1, no attention was paid to neurological symptoms (5). Patient 1-1 had the first symptoms in her thirties (Table 1). T2weightedMRI of the brain disclosed a hyperintensive signal in the white matter adjacent to the posterior horns. Visual-, auditory-, and somatosensory-evokedpotentialswere delayed. Patient 1-2 (daughter of 1-1) suffered from occasional faecal incontinence at the age of 15, but there were no other neurological symptoms. Visualand auditory-evoked potentials were abnormal. In patient 4-1, attention deficit and impaired language developmentwere observed at the age of 3. For genotyping, the coding sequence of the GJA1 gene was amplified and sequenced as describedbefore (2). In 20 healthy subjects, in three unaffected sisters of patient 1-1, and in the parents of patients 3-1 and 4-1, none of the described mutations was found. ODDD is a pleiotropic syndrome involving several tissues such as the white matter of the nervous system, in which connexin-43 is forming gap junctions. Heterozygote mutations of one GJA1 allele are generally thought to exert a dominant negative effect on the function of multisubunit gap junctions (6, 7). This explains the dominant inheritance of the disorder. The function and interaction partners of connexin-43 vary with the tissue (8). Thus, a specific mutation may affect gap junctions in only a subset of connexin-43 expressing tissues. Indeed, the presentation of ODDD differs between families and possibly depends on the specific connexin-43 mutation. In our teenage patient 3-1 and in a Danish family, missense mutations of codon 96 were not associated with a neurological phenotype although our patient may still be too young to manifest neurological symptoms (9). Neurological signs were also missing with other mutations (S18P, A40V, Q49K, F52dup, Y98C, E110D, and R202H) (2, 10). However, we have detected three mutations in patients with neurological symptoms (spastic paraparesis in patients 1-1, 2-1; developmental disorder in patient 4-1), adding to a number of previously described missense mutations linked to neurological signs (Y17S, G22E, K23T, L90V, K102N, I130T, K134E, G138R, V216L, K134N, and R148Q) (2, 3). Thus, mutations associated with neurological symptoms are spread over the N-terminal part of connexin-43 and cannot be localized to a certain domain of the protein. Expression of ODDD-associated connexin-43 mutations in a glial cell line resulted in non-functional connexin hemichannels and gap junction functions regardless of whether the particular mutant is associated with neurological dysfunction (11). Thus, up to now it is unclear which factors determine whether a mutation leads to neurological symptoms or not. Most mutations are specific for a family. Of the four mutations we have detected, only L113P (T338C) has been described before (3). In addition, previous reports and two of our patients (3-1, 4-1) demonstrate that new mutations occur in the gene.