Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss

Marsh, AP; Lukic, V; Pope, K; Bromhead, C; Tankard, R; Ryan, MM; Yiu, EM; Sim, JC; Delatycki, MB; Amor, DJ; McGillivray, G; Sherr, EH; Bahlo, M; Leventer, RJ; Lockhart, PJ

Author(s): Marsh, AP; Lukic, V; Pope, K; Bromhead, C; Tankard, R; Ryan, MM; Yiu, EM; Sim, JC; Delatycki, MB; Amor, DJ; McGillivray, G; Sherr, EH; Bahlo, M; Leventer, RJ; Lockhart, PJ;
Details: Publication Year 2015-08,Volume 1,Issue #2,Page e16
Journal Title: Neurol Genet
Publication Type: Journal Article
Abstract: OBJECTIVE: To determine the molecular basis of a severe neurologic disorder in a large consanguineous family with complete agenesis of the corpus callosum (ACC), pontocerebellar hypoplasia (PCH), and peripheral axonal neuropathy. METHODS: Assessment included clinical evaluation, neuroimaging, and nerve conduction studies (NCSs). Linkage analysis used genotypes from 7 family members, and the exome of 3 affected siblings was sequenced. Molecular analyses used Sanger sequencing to perform segregation studies and cohort analysis and Western blot of patient-derived cells. RESULTS: Affected family members presented with postnatal microcephaly and profound developmental delay, with early death in 3. Neuroimaging, including a fetal MRI at 30 weeks, showed complete ACC and PCH. Clinical evaluation showed areflexia, and NCSs revealed a severe axonal neuropathy in the 2 individuals available for electrophysiologic study. A novel homozygous stopgain mutation in adenosine monophosphate deaminase 2 (AMPD2) was identified within the linkage region on chromosome 1. Molecular analyses confirmed that the mutation segregated with disease and resulted in the loss of AMPD2. Subsequent screening of a cohort of 42 unrelated individuals with related imaging phenotypes did not reveal additional AMPD2 mutations. CONCLUSIONS: We describe a family with a novel stopgain mutation in AMPD2. We expand the phenotype recently described as PCH type 9 to include progressive postnatal microcephaly, complete ACC, and peripheral axonal neuropathy. Screening of additional individuals with related imaging phenotypes failed to identify mutations in AMPD2, suggesting that AMPD2 mutations are not a common cause of combined callosal and pontocerebellar defects.
Publisher: American Academy of Neurology
Research Division(s): Population Health And Immunity
PubMed ID: 27066553
Publisher's Version: https://doi.org/10.1212/NXG.0000000000000014
Open Access at Publisher's Site: http://ng.neurology.org/content/1/2/e16.full
ARC Grants: ARC/FT100100764,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2016-04-28 02:06:56

Last Modified: 2016-04-28 02:13:44