| #218000 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY; ACCPN | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| CHARLEVOIX DISEASE ANDERMANN SYNDROME POLYNEUROPATHY, SENSORIMOTOR, WITH OR WITHOUT AGENESIS OF THE CORPUS CALLOSUM CORPUS CALLOSUM, AGENESIS OF, WITH NEURONOPATHY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because autosomal recessive agenesis of the corpus callosum with peripheral neuropathy (ACCPN), also known as Andermann syndrome, is caused by mutations in the SLC12A6 gene (604878). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Andermann syndrome is an autosomal recessive motor and sensory neuropathy with agenesis of the corpus callosum associated with developmental and neurodegenerative defects and dysmorphic features. It has a high prevalence in the French Canadian population in the Charlevoix and Saguenay-Lac-Saint-Jean region of Quebec (Uyanik et al., 2006). Dupre et al. (2003) provided a comprehensive review of the disorder. Dobyns (1996) reviewed the many genetic causes of agenesis of the corpus callosum. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Naiman and Fraser (1955) described 2 sisters, and Ziegler (1958) described 2 brothers with agenesis of the corpus callosum associated with mental and physical retardation. Andermann et al. (1972) observed 2 brothers with mental retardation, areflexia and paraparesis. The authors postulated an anterior horn cell disease. The clinical picture was the same as in the sisters reported by Naiman and Fraser (1955) and the 2 families were French Canadian from the Charlevoix County in Quebec. Andermann et al. (1977) extended these studies to identify 45 patients in 24 sibships, descendants from a couple married in Quebec City, Charlevoix County, in 1657. Brain CT imaging demonstrated agenesis of the corpus callosum. Cao et al. (1977) reported 3 sibs, a male and 2 females, with severe mental retardation, spastic quadriplegia, microcephaly, and infantile spasms. Two sibs had agenesis of the corpus callosum on pneumoencephalogram. Other reports of familial agenesis of the corpus callosum consistent with autosomal recessive inheritance were published by Shapira and Cohen (1973) and Castro Gago et al. (1982). The former report concerned 2 affected sisters whose parents were more closely related than first cousins. The latter report concerned 2 sisters and 2 daughters of a paternal uncle of their father. The 2 sisters, studied at 6 years and 15 months of age, respectively, had progressive psychomotor regression, microcephaly, optic atrophy and seizures. CT scan showed absence of the corpus callosum, subcortical atrophy and gray substance heterotopy at the level of the ventricles. Larbrisseau et al. (1984) studied 15 cases and described a characteristic dysmorphic facies. The authors observed that progressive motor neuropathy led to loss of ambulation by adolescence and progressive scoliosis. Hauser et al. (1993) reported cases of agenesis of the corpus callosum with neuronopathy in a brother and sister in Vienna. Uyanik et al. (2006) reported 3 unrelated patients with Andermann syndrome; 1 was German and 2 Turkish. The German child presented at age 13 days with feeding difficulties and hypotonia. Over the next few months, she was found to have complete absence of the corpus callosum with ventricular enlargement and areflexia with an axonal and demyelinating peripheral neuropathy. Lumbar puncture showed increased CSF protein. At age 3 years, she had marked psychomotor retardation with inability to walk or speak. Mild facial dysmorphism was present, including hypertelorism, short nose, broad nasal root, and downplaced first toe and thumb. The second child, born of consanguineous Turkish parents, presented with diffuse hypotonic weakness, psychomotor retardation, and afebrile seizures. She had mild mental retardation, high-arched palate, elongated facies, esotropia of the right eye, ptosis, facial diplegia, areflexia, and distal wasting of the limbs. She had complete ACC and an axonal/demyelinating motor and sensory neuropathy with decreased nerve conduction velocities. The third child, born of second-degree Turkish cousins, had hypotonia and psychomotor retardation. He could walk with support at age 5 years and developed some speech. He had complete ACC and peripheral neuropathy but was less severely affected in the upper limbs. He also had bilateral diffuse white matter abnormalities, which had not previously been reported in this syndrome. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Casaubon et al. (1996) performed linkage studies with 120 microsatellite DNA markers to position the ACCPN gene to a 5-cM region on 15q13-q15, flanked by markers D15S1040 and D15S118. A maximum 2-point lod score of 11.1 was obtained with the markers D15S971 at a recombination fraction of 0.0. Haplotype analysis and linkage disequilibrium supported the existence of the previously suspected founder effect. The authors stated that this finding was the first step in the identification of the gene responsible for ACCPN, which may shed light on numerous conditions associated with progressive peripheral neuropathy or agenesis of the corpus callosum. Howard et al. (2002) typed 11 polymorphic markers on chromosome 15 in 231 individuals from 50 seemingly unrelated French Canadian ACCPN families. Haplotype analysis confirmed the presence of a founder haplotype, and recombination events reduced the ACCPN candidate interval to a region of approximately 2 cM or 1000 kb between markers D15S1040 and ACTC. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The K-Cl cotransporter KCC3, encoded by the SLC12A6 gene, maps within the ACCPN candidate region, prompting Howard et al. (2002) to screen that gene for mutations in individuals with ACCPN. Four distinct protein-truncated mutations (604878.0001-604878.0004) were found: 2 in the French Canadian population and 2 in non-French Canadian families. A 1-bp deletion (2436delG; 604878.0001) was determined to be a founder mutation in the French Canadian population. In 3 unrelated patients with Andermann syndrome, Uyanik et al. (2006) identified 4 different mutations in the SLC12A6 gene (604878.0005-704878.0008). Two were of Turkish descent, and 1 was German. Salin-Cantegrel et al. (2007) identified 2 mutations in exon 22 of the SLC12A6 gene (604878.0003; 604878.0009) in non-French Canadian patients with ACCPN, including families from Turkey, South Africa, Sudan, and the Netherlands. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Population Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| De Braekeleer et al. (1993) estimated that in the Saguenay-Lac-Saint-Jean region of northeastern Quebec the incidence at birth was 1 in 2,117 liveborns, and the carrier rate was 1 in 23 inhabitants. Remote consanguinity was found in several families, while the mean kinship coefficient was 2.7 times higher in the polyneuropathic group than in control groups. Genealogic reconstruction suggested that the high incidence is probably the result of founder effect and that a unique mutation accounts for most, if not all, of the cases known in this region. Howard et al. (2002) determined that a 1-bp deletion (2436delG) was a founder mutation in the French Canadian population. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Howard et al. (2002) found that mice with a targeted deletion of the Slc12a6 gene had a locomotor deficit, peripheral neuropathy, and a sensorimotor gating deficit, similar to the human disease. The findings suggested a critical role for SLC12A6 in the development and maintenance of the nervous system. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Battistella et al. (1987) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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