Copy Number Variation in the GBE1 Gene is not the Cause of Adult Polyglucosan Body Disease in a Symptomatic Heterozygote. (P05.031)

Abstract

Objective: To determine whether DNA copy number variation in the GBE1 gene can contribute to the molecular pathogenesis of Adult Polyglucosan Body Disease (APBD). Background APBD is a progressive neurodegenerative disorder with onset after the fifth decade characterized by gait ataxia, spastic paraplegia, posterior column sensory loss, bladder dysfunction, and variable cognitive disturbances. MRI of the brain shows cortical/cerebellar volume loss, white matter changes, and an atrophic cervical spinal cord. Inheritance is autosomal recessive via mutation of the glucan (1,4-alpha-), branching enzyme 1 (also known as Glycogen-branching enzyme), GBE1 . Inactivating mutations lead to a fatal childhood-onset liver disorder, glycogen storage disease type IV. Mutations that reduce activity lead to milder forms, including APBD, associated with the formation of insoluble polyglucosan bodies in the central and peripheral nervous system. Homozygous or compound heterozygous missense mutations are the most common genetic variations seen. Design/Methods: A 51 year old man of Ashkenazi Jewish heritage presented to our tertiary care center with difficulty walking beginning insidiously at age 36, falls at age 46, and bladder incontinence at age 48. Examination showed lower extremity spasticity, distal sensory loss, and a spastic ataxic gait. MRI showed T2/FLAIR hyperintensities throughout the brain, cerebellum, and brainstem with a thin cervical spinal cord. Sural nerve biopsy revealed polyglucosan bodies and muscle enzymatic activity was significantly reduced to approximately 40% of normal (p=0.029). GBE1 gene sequencing identified a heterozygous c.986A>C (p.Tyr329Ser) missense mutation but no other sequence variants. Results: To assess whether DNA structural variation was responsible for this observation, we performed quantitative PCR evaluating the GBE1 locus in this patient and identified no abnormal structural variation on the opposite allele. Conclusions: Here we demonstrate DNA copy number variation is not the mechanism for the molecular pathogenesis of APBD in this patient, although this may still be a consideration in other patients lacking confirmation of a molecular diagnosis by GBE1 sequencing. Supported by: NIMH K08MH86297 (BLF) and the UCLA Program in Neurogenetics. Disclosure: Dr. Fogel has received personal compensation for activities with the American Physician Institute for Advanced Professional Studies. Dr. Botros has nothing to disclose.