Hereditary motor sensory neuropathy (HMSN/ACC) with agenesis of the corpus callosum (ACC) has been documented in the French-derived populations of Charlevoix and Saguenay/Lac St. Jean in Quebec, Canada, as well as a few sporadic families throughout the world. HMSN/ACC occurs because of loss-of-function mutations in the potassium-chloride cotransporter 3 (KCC3). In HMSN/ACC, motor deficits occur early in infancy with rapid and continual deterioration of motor and sensory fibers into juvenile and adulthood. Genetic work in mice has demonstrated that the disease is caused by loss of KCC3 function in neurons and particularly parvalbumin (PV)-expressing neurons. Currently, there are no treatments or cures for HMSN/ACC other than pain management. As genetic counseling in Quebec has increased as a preventative strategy, most individuals with HSMN/ACC are now adults. The onset of the disease is unknown. In particular, it is unknown if the disease starts early during development and whether it can be reversed by restoring KCC3 function. In this study, we used two separate mouse models that when combined to the PV-CreERT2 tamoxifen-inducible system allowed us to 1) disrupt KCC3 expression in adulthood or juvenile periods; and 2) reintroduce KCC3 expression in mice that first develop with a nonfunctional cotransporter. We show that disrupting or reintroducing KCC3 in the adult mouse has no effect on locomotor behavior, indicating that expression of KCC3 is critical during embryonic development and/or the perinatal period and that once the disease has started, reexpressing a functional cotransporter fails to change the course of HMSN/ACC.

Andermann syndrome (AS) is caused by mutation of SLC12A6 gene. It comprises severe progressive sensory and motor neuropathy with early onset, varying degree of agenesis of corpus callosum (ACC) and mental retardation. AS occurs occasionally among population outside the northeastern Quebec-Saguenay-Lac- St-Jean and Charlevoix regions, inhabited by French Canadians. None of the described patients were of Roma ethnic origin. We present an 8-month-old infant of Roma ethnic origin with AS, caused by a novel frame shift mutation c.2604delT,p.(Asp868GlufsTer11) in exon 20 of SLC12A6 gene. Our case presented with several atypical findings: clinical presentation resembling "spinal muscular atrophy plus" syndrome; tongue fasciculations, which are not reported in the literature; early contractures of the wrists; normal motor action potentials and preserved sensory action potentials. Our patient is the first of Roma origin from nonconsanguineous parents, which suggests that this mutation might be widespread in the Roma population, although screening for this mutation in 140 alleles from Roma individuals originating from the same geographic region did not reveal further carriers, implying the mutation is rare. We recommend that Roma patients presenting with the clinical phenotype of AS should be tested for this mutation primarily.

A pilot population-based carrier screening program started in 2010 in the Saguenay-Lac-Saint-Jean region of Quebec, Canada, for four recessive diseases with local founder effects (tyrosinemia type I, autosomal recessive spastic ataxia of Charlevoix-Saguenay, congenital lactic acidosis, and Andermann syndrome). The objective of this study was to describe the experience of carrier couples identified through this program. Semi-structured interviews were performed with carrier couples. Thematic analysis of interview transcripts was performed to identify emerging themes. Interviews were performed with 15 carrier couples (56% response rate). Carrier couples had little knowledge about the target diseases before being identified as carriers, despite pre-test education sessions. The main motivation for screening was a recommendation by a peer who had been screened, even for those with a positive family history of one of the target conditions. Couples perceived themselves at low risk of being a carrier couple, whatever their family history. Being found to be a carrier couple was initially a shock, illustrating how ill prepared they were for such a result, but carrier couples appreciated knowing their status. Our results emphasize the informational needs of couples to make informed decisions and the importance of post-test counseling for those with positive results. Our findings can inform counseling procedures in expanded carrier screening. © 2017 John Wiley & Sons, Ltd.