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Case Reports
. 2014 Jan;71(1):41-7.
doi: 10.1001/jamaneurol.2013.4888.

Branching enzyme deficiency: expanding the clinical spectrum

Carmen Paradas  1 , Hasan O Akman  2 , Carolina Ionete  3 , Heather Lau  4 , Peter N Riskind  3 , David E Jones  3 , Thomas W Smith  5 , Michio Hirano  2 , Salvatore Dimauro  2
Affiliations
Case Reports

Branching enzyme deficiency: expanding the clinical spectrum

Carmen Paradas et al. JAMA Neurol. 2014 Jan.

Abstract

Importance: The neuromuscular presentation of glycogen branching enzyme deficiency includes a severe infantile form and a late-onset variant known as adult polyglucosan body disease. Herein, we describe 2 patients with adult acute onset of fluctuating neurological signs and brain magnetic resonance imaging lesions simulating multiple sclerosis. A better definition of this new clinical entity is needed to facilitate diagnosis.

Objectives: To describe the clinical presentation and progression of a new intermediate variant of glycogen branching enzyme deficiency and to discuss genotype-phenotype correlations.

Design, setting, and participants: Clinical, biochemical, morphological, and molecular study of 2 patients followed up for 6 years and 8 years at academic medical centers. The participants were 2 patients of non-Ashkenazi descent with adult acute onset of neurological signs initially diagnosed as multiple sclerosis.

Main outcomes and measures: Clinical course, muscle and nerve morphology, longitudinal study of brain magnetic resonance imaging, and glycogen branching enzyme activity and GBE1 molecular analysis.

Results: Molecular analysis showed that one patient was homozygous (c.1544G>A) and the other patient was compound heterozygous (c.1544G>A and c.1961-1962delCA) for GBE1 mutations. Residual glycogen branching enzyme activity was 16% and 30% of normal in leukocytes. Both patients manifested acute episodes of transient neurological symptoms, and neurological impairment was mild at age 45 years and 53 years. Brain magnetic resonance imaging revealed nonprogressive white matter lesions and spinocerebellar atrophy similar to typical adult polyglucosan body disease.

Conclusions and relevance: GBE1 mutations can cause an early adult-onset relapsing-remitting form of polyglucosan body disease distinct from adult polyglucosan body disease in several ways, including younger age at onset, history of infantile liver involvement, and subacute and remitting course simulating multiple sclerosis. This should orient neurologists toward the correct diagnosis.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ionete has received research support from Genzyme Corporation and Biogen Idec. Dr Lau has received research support from Genzyme Corporation, Biomarin, Shire, Amicus, and GlaxoSmithKline and has received compensation as a consultant to Pfizer. Dr Riskind has consulted for Genzyme Corporation and has received research support from Genzyme Corporation, Biogen Idec, sanofi-aventis, Roche, Genentech, Novartis, Teva Pharmaceuticals Industries LTD, Bayer, ACP, and EMD Serono. Dr Hirano has received honoraria as a member of the Athena Diagnostic Speakers’ Bureau. Dr Jones received research support from Biogen Idec, Genzyme Corporation, and Novartis; consulting compensation from Biogen Idec, Genzyme Corporation, and EMD Serono; and speaking honoraria from Biogen Idec, Novartis, EMD Serono, and Teva Pharmaceuticals Industries LTD. Dr DiMauro receives compensation as a member of the editorial board of MedLink Neurology. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Pedigrees of the 2 Families and Gene Mutations
Pedigrees of patient 1 (A) and patient 2 (B) and electropherograms showing the DNA sequences of GBE1 exon 12 in both patients and exon 15 in patient 2 (C). The nucleotide change causing the arginine to histidine substitution is indicated by an asterisk. The CA dinucleotide deletion leading to a premature stop codon is shown by the arrow. Square represents a male individual; circle, a female individual; shading, an affected individual; slash mark, a deceased individual; and central dot, a carrier. d. 3 y Indicates died at age 3 years.
Figure 2.
Figure 2.. Polyglucosan Bodies in Sural Nerve
A and B, Polyglucosan bodies appear faintly basophilic with hematoxylin-eosin stain (A) but show intensely positive reactions with periodic acid–Schiff stain (B). C, Polyglucosan bodies are surrounded by neural filament–positive material. D, Luxol fast blue staining for myelin also localizes polyglucosan bodies in neuronal axons (arrowhead). E and F, Electron micrographs show storage of thin filamentous material in the cytosol (E) and within a myelinated nerve fiber surrounded by several Schwann cell processes (F). Original magnification ×40 (B and C), ×60 (A and D), ×4000 (F), and ×6000 (E).
Figure 3.
Figure 3.. Brain Magnetic Resonance Imaging in Patient 2
Brain magnetic resonance images of patient 2 showed the typical cerebral and spinal pattern described in patients with adult polyglucosan body disease. A-H, Fluid-attenuated inversion recovery sequences showed symmetric hyperintense white matter lesions in the pyramidal tracts of the medulla (A), pons (B), cerebellar peduncles (C), and periventricular regions (D-G), as well as (to a lesser degree) in the external capsule and the posterior limb of the internal capsule (D) and in subcortical areas (H). I, Axial T1-weighted sequences showed medullary, spinal, and vermian atrophy. J, The T2-weighted images showed a similar but less well-defined pattern. K and L, The abnormal white matter areas had normal signal on T1-weighted images and showed no enhancement after contrast administration.
Figure 4.
Figure 4.. Longitudinal Study of Brain Magnetic Resonance Imaging in Patient 2
Sequential brain magnetic resonance images of patient 2 in 2006 (A, D, G, and I), 2008 (B and E), and 2012 (C, F, H, and J) showed mild increases in the size of white matter lesions in the cerebellar peduncles (C and F). All other lesions were unchanged during the follow-up period (G-J).
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