Mapping. Most patients with Andermann syndrome are found in the Charlevoix County and Saguenay-Lac-Saint-Jean region in the Province of Québec. Close to 250 cases have been identified (07; 05; 11). Genetic analysis demonstrates an autosomal recessive mode of inheritance. Genealogical studies reveal that 45 affected individuals in this region could be traced back to a French couple who married in Québec City in 1657, thus, demonstrating a founder effect. De Braekeleer and colleagues have shown that in the Saguenay-Lac-Saint-Jean region, the incidence at birth and the carrier rate, respectively, are 1 in 2117 liveborns and 1 in 23 inhabitants (11). Remote consanguinity was found in several families, but the mean kinship coefficient was 2.7 times higher in the syndromic group than in a control group. The genealogical reconstruction suggests that a unique mutation accounts for most, if not all, of the cases in that particular region. It is of interest that although the common ancestors carrying the gene for the condition originated in France, no case (so far) has been described in that country.
Casaubon and colleagues performed linkage studies using 120 microsatellite DNA markers in 14 French Canadian families and mapped the ACCPN locus to a region of 4cM on chromosome 15. Haplotype analysis and linkage disequilibrium confirm a founder effect (10). The haplotype analysis with 2 markers of chromosome 15q13-q15 has been performed on the affected siblings of an Algerian consanguineous family. The children were homozygous for both markers, again suggesting genetic homogeneity in this syndrome (24). The same has been found in 1 Turkish girl (14).
Though originally thought to be exclusively in the French Canadian population mainly in Quebec, many cases are now described in other ethnic groups. Outside French Canada, Andermann syndrome has also been identified in 1 Italian boy, 1 Spanish girl, 2 siblings from Austria, 2 siblings from Algeria, and 2 siblings from Tanzania (08; 20; 05; 13; 19). A new splice mutation in the SLC12A6 gene is also reported from Turkey (01), and a frameshift mutation in exon 20 of this gene is described in a Roma (gypsy) patient of nonconsanguineous parents (26). Siblings from India are reported with Andermann syndrome (18).
Animal models. A canine model of SLC12A6 mutation is available, but the truncating variants cause different clinical phenotypes between humans and dogs (34). A murine model of KCC3 expression produces motor-sensory neuropathy and callosal agenesis resembling Andermann syndrome in humans (17).
Molecular genetics. Howard and colleagues were able to identify the mutated gene SLC12A6, which encodes the K+-Cl- transporter KCC3 (22) and maps within the ACCPN candidate region. Four distinct protein-truncating mutations were found: 2 in the French Canadian population and 2 in non-French Canadian families. These authors suggest that loss-of-function mutations of SLC12A6, encoding KCC3, are responsible for the peripheral neuropathy associated with the syndrome, making Andermann syndrome the first hereditary sensorimotor neuropathy to be attributed to defects in an ion transporter. The same genetic defect is reported as a splice-site variant with motor sensory neuropathy but without agenesis of the corpus callosum (02), so that perhaps agenesis of the corpus callosum is not necessarily an obligatory morphological criterion of Andermann syndrome.
Uyanik and colleagues have reported 3 additional cases of Andermann syndrome of German and Turkish descent, 2 of which were found to have a different truncating mutation of KCC3 gene and 1 with a homozygous missense mutation of KCC3. The phenotype of this last case had all the usual features of Andermann syndrome except for the unusual findings on the MRI of disseminated white matter hyperintensities and a much milder motor-sensory neuropathy (33). Salin-Cantegrel and colleagues were interested in finding new mutations in non-French Canadian populations (28). These authors identified mutations in exon 22 of KCC3: a novel mutation (del + 2994-3003; E1015X) in 1 family, as well as a known mutation (3031C --> T; R1011X) found in 5 unrelated families and associated with 2 different haplotypes. This last mutation has also been found in a 5-year-old Turkish boy (12). Salin-Cantegrel and colleagues concluded that KCC3 mutations in exon 22 constitute a recurrent mutation site in this syndrome, regardless of ethnic origin, and are the most common cause in non-French Canadian families analyzed thus far. The same authors have reported a novel and more distal HMSN/ACC-truncating mutation (3402C à T; R1134X) in another patient, which eliminates only the last 17 residues of the protein (29). Within novel mutation, there are 10 KCC3 mutations identified, including 6 frameshift, 2 non-sense, and 2 missense mutations.
The same group conducted further research to understand the molecular mechanisms of the syndrome pathogenesis and the exact role of KCC3 in the development of the nervous system (30). They discovered that the C-terminal domain (CTD) of KCC3, which is lost in most of the syndrome-causing mutations, directly interacts with brain-specific creatine kinase (CK-B), an ATP-generating enzyme that is also a partner of KCC2. These authors concluded that this physical and functional association between the cotransporter and CK-B is, therefore, the first protein-protein interaction identified to be potentially involved in the pathophysiology of Andermann syndrome. In addition, Shekarabi and colleagues established that in a conditional KCC3 knockout mouse model, KCC3 is important for axon volume control (31). They also demonstrate that the neuropathic feature of HMSN/ACC are predominantly due to a neuronal KCC3 deficit whereas the auditory impairment secondary to a marked decrease in axonal tracts serving the auditory cortex is due to loss of non-neuronal KCC3 expression. The mouse model developed severe neuropathy, reduced sensitivity to inflammatory pain, hypoplasia of the corpus callosum, and an auditory impairment. This study suggests a role for KCC3 in callosal as well as central and peripheral nervous system maintenance. The identification of the mutated gene KCC3 allows a prenatal diagnosis. Further research by Ding and Delpire to establish the specific neuronal loss of KCC3 in knockout mouse lines has found that it involves the parvalbumin-positive neurons (15). This suggests a crucial role of these neurons in the development of the locomotor deficit. Deficiency in a related gene, NKCC1, caused disturbances in secretory epithelia, encephalopathy, and basal ganglionic and white matter abnormalities in sisters, but not Andermann syndrome, though the SLC12A2 mutations were responsible for the NKCC1 defect (32).