Andermann Syndrome in a Pakistani Family Caused by a Novel Mutation in SLC12A6

Abstract

Agenesis of the corpus callosum with peripheral neuropathy (ACCPN) or Andermann syndrome is an autosomal recessive condition caused by mutations in SLC12A6. The neurodegenerative features are characterized primarily by severe and progressive polyneuropathy, with eventual loss of ambulation and limited lifespan. We report two siblings with Andermann syndrome from a consanguineous Pakistani family with severe global developmental delays, sensory-motor polyneuropathy, and complete agenesis of the corpus callosum, associated with a homozygous c.745+2T>A mutation in SLC12A6. This sequence change is predicted to inactivate the donor splice site and abolish correct splicing of intron 6, yielding an abnormally truncated protein. This is the first report of Andermann syndrome in patients of Pakistani origin, which supports the pan-ethnic incidence of this condition.

Keywords

neuropathy - SLC12A6 - corpus callosal agenesis

• References

• 1 Dupré N, Howard HC, Mathieu J , et al. Hereditary motor and sensory neuropathy with agenesis of the corpus callosum. Ann Neurol 2003; 54 (01) 9-18
• 2 Uyanik G, Elcioglu N, Penzien J , et al. Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome. Neurology 2006; 66 (07) 1044-1048
• 3 Howard HC, Mount DB, Rochefort D , et al. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet 2002; 32 (03) 384-392
• 4 De Braekeleer M, Dallaire A, Mathieu J. Genetic epidemiology of sensorimotor polyneuropathy with or without agenesis of the corpus callosum in northeastern Quebec. Hum Genet 1993; 91 (03) 223-227
• 5 Demir E, Irobi J, Erdem S , et al. Andermann syndrome in a Turkish patient. J Child Neurol 2003; 18 (01) 76-79
• 6 Salin-Cantegrel A, Rivière JB, Dupré N , et al. Distal truncation of KCC3 in non-French Canadian HMSN/ACC families. Neurology 2007; 69 (13) 1350-1355
• 7 Rudnik-Schöneborn S, Hehr U, von Kalle T, Bornemann A, Winkler J, Zerres K. Andermann syndrome can be a phenocopy of hereditary motor and sensory neuropathy—report of a discordant sibship with a compound heterozygous mutation of the KCC3 gene. Neuropediatrics 2009; 40 (03) 129-133
• 8 Lourenço CM, Dupré N, Rivière JB , et al. Expanding the differential diagnosis of inherited neuropathies with non-uniform conduction: Andermann syndrome. J Peripher Nerv Syst 2012; 17 (01) 123-127
• 9 Degerliyurt A, Akgumus G, Caglar C, Bilguvar K, Caglayan AO. A new patient with Andermann syndrome: an underdiagnosed clinical genetics entity?. Genet Couns 2013; 24 (03) 283-289
• 10 Mercado A, Mount DB, Gamba G. Electroneutral cation-chloride cotransporters in the central nervous system. Neurochem Res 2004; 29 (01) 17-25
• 11 Lucas O, Hilaire C, Delpire E, Scamps F. KCC3-dependent chloride extrusion in adult sensory neurons. Mol Cell Neurosci 2012; 50 (3-4): 211-220
• 12 Race JE, Makhlouf FN, Logue PJ, Wilson FH, Dunham PB, Holtzman EJ. Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter. Am J Physiol 1999; 277 (6 Pt 1): C1210-C1219
• 13 Boettger T, Rust MB, Maier H , et al. Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO J 2003; 22 (20) 5422-5434
• 14 Shekarabi M, Moldrich RX, Rasheed S , et al. Loss of neuronal potassium/chloride cotransporter 3 (KCC3) is responsible for the degenerative phenotype in a conditional mouse model of hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum. J Neurosci 2012; 32 (11) 3865-3876
• 15 Kahle KT, Flores B, Bharucha-Goebel D , et al. Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter. Sci Signal 2016; 9 (439) ra77