Familial Progressive Sensorimotor Neuropathy with Agenesis of the Corpus callosum (Andermann Syndrome): A Clinical, Neuroradiological and Histopathological Study

Abstract

Three siblings from consanguineous parents, originating from Tanzania, presented with symptoms of complete or partial agenesis of the corpus callosum. Two males had in addition a sensorimotor neuropathy, moderate mental retardation and skeletal dysmorphism (Andermann syndrome). A study of sural nerve biopsies revealed thickening of the perineurium and reduction in the number of large myelinated fibres with axonal degeneration. Muscle biopsies showed neurogenic atrophy. The Andermann syndrome is autosomal recessive and almost exclusively confined to the region of Charlevoix and Saguenay-Lac-St-Jean (Quebec, Canada). Moreover in families with the Andermann syndrome, no siblings with only agenesis of the corpus callosum have been described.

Human and Murine Phenotypes Associated with Defects in Cation-Chloride Cotransport

“…Although originally described from a single county in the Province of Quebec, Canada, the disorder may also be found in other populations with high rates of consanguinity (40). This progressive neuropathy is significant in its early onset and severity.…”

“…ACCPN patients demonstrate both muscle weakness and decreased nerve velocities. Ultrastructural analyses of nerve and muscle reveals demyelination with axonal degeneration and neurogenic atrophy of the muscle (40,126).…”

Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter

“…K + influx is presented in picomoles of K + per milligram of protein per minute and plotted for both isotonic and hypotonic conditions. K + uptake was significantly increased upon WNK/SPAK inhibition in untransfected and transfected cells [repeated-measures two-way ANOVA; F(15, 40) = 38.43, P < 0.0001]. KCC3-Thr 991 Ala–transfected cells exhibited significantly higher activity than WT KCC3 in all conditions [F(5, 40) = 813.9, P < 0.0001].…”

“…ACCPN patients and KCC3 knockout (KO) mice exhibit severe peripheral nerve degeneration (11, 14–17); however, ACCPN patients also exhibit severe brain phenotypes, including mal-development of the corpus callosum, hydrocephalus, developmental delay, mental retardation, and seizures (14, 15). GOF mutations in KCC3 have not been identified in any organism, and the clinical consequences of overactive KCC3 in vivo are unknown.…”

Fine mapping the candidate region for peripheral neuropathy with or without agenesis of the corpus callosum in the French Canadian population

“…6 Reports of ACCPN patients in other parts of the world are rare and have yet to be confirmed as true ACCPN cases; these reports originate from countries such as Austria 7 , Italy 8 , Spain 9 , and Oman. 10 Using linkage analysis, Casaubon et al 11 initially mapped the ACCPN locus to a 4 cM interval on chromosome 15q13 -15. We have since collected additional families and tested 11 polymorphic markers on chromosome 15.…”