Georgios Koutsis1, David S Lynch2, Arianna Tucci3, Henry Houlden2, Georgia Karadima4, Marios Panas4. 1. Neurogenetics Unit, 1st Department of Neurology, University of Athens Medical School, Eginition Hospital, Athens, Greece. Electronic address: gkoutsi2@otenet.gr. 2. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. 3. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milano, Italy. 4. Neurogenetics Unit, 1st Department of Neurology, University of Athens Medical School, Eginition Hospital, Athens, Greece.
Abstract
OBJECTIVES: To present a Greek family in which 5 male and 2 female members developed progressive spastic paraplegia. Plasma very long chain fatty acids (VLCFA) were reportedly normal at first testing in an affected male and for over 30 years the presumed diagnosis was hereditary spastic paraplegia (HSP). Targeted next generation sequencing (NGS) was used as a further diagnostic tool. METHODS: Targeted exome sequencing in the proband, followed by Sanger sequencing confirmation; mutation segregation testing in multiple family members and plasma VLCFA measurement in the proband. RESULTS: NGS of the proband revealed a novel frameshift mutation in ABCD1 (c.1174_1178del, p.Leu392Serfs*7), bringing an end to diagnostic uncertainty by establishing the diagnosis of adrenomyeloneuropathy (AMN), the myelopathic phenotype of X-linked adrenoleukodystrophy (ALD). The mutation segregated in all family members and the diagnosis of AMN/ALD was confirmed by plasma VLCFA measurement. Confounding factors that delayed the diagnosis are presented. CONCLUSIONS: This report highlights the diagnostic utility of NGS in patients with undiagnosed spastic paraplegia, establishing a molecular diagnosis of AMN, allowing proper genetic counseling and management, and overcoming the diagnostic delay that can be rarely caused by false negative VLCFA analysis.
OBJECTIVES: To present a Greek family in which 5 male and 2 female members developed progressive spastic paraplegia. Plasma very long chain fatty acids (VLCFA) were reportedly normal at first testing in an affected male and for over 30 years the presumed diagnosis was hereditary spastic paraplegia (HSP). Targeted next generation sequencing (NGS) was used as a further diagnostic tool. METHODS: Targeted exome sequencing in the proband, followed by Sanger sequencing confirmation; mutation segregation testing in multiple family members and plasma VLCFA measurement in the proband. RESULTS: NGS of the proband revealed a novel frameshift mutation in ABCD1 (c.1174_1178del, p.Leu392Serfs*7), bringing an end to diagnostic uncertainty by establishing the diagnosis of adrenomyeloneuropathy (AMN), the myelopathic phenotype of X-linked adrenoleukodystrophy (ALD). The mutation segregated in all family members and the diagnosis of AMN/ALD was confirmed by plasma VLCFA measurement. Confounding factors that delayed the diagnosis are presented. CONCLUSIONS: This report highlights the diagnostic utility of NGS in patients with undiagnosed spastic paraplegia, establishing a molecular diagnosis of AMN, allowing proper genetic counseling and management, and overcoming the diagnostic delay that can be rarely caused by false negative VLCFA analysis.
Authors: Chi-Lun Chang; Aubrey V Weigel; Maria S Ioannou; H Amalia Pasolli; C Shan Xu; David R Peale; Gleb Shtengel; Melanie Freeman; Harald F Hess; Craig Blackstone; Jennifer Lippincott-Schwartz Journal: J Cell Biol Date: 2019-06-21 Impact factor: 10.539