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. 2020 Feb:131:115142.
doi: 10.1016/j.bone.2019.115142. Epub 2019 Nov 6.

The skeletal phenotype of intermediate GM1 gangliosidosis: Clinical, radiographic and densitometric features, and implications for clinical monitoring and intervention

Carlos R Ferreira  1 , Debra S Regier  2 , Robin Yoon  3 , Kristen S Pan  4 , Jean M Johnston  5 , Sandra Yang  5 , Jürgen W Spranger  6 , Cynthia J Tifft  7
Affiliations

The skeletal phenotype of intermediate GM1 gangliosidosis: Clinical, radiographic and densitometric features, and implications for clinical monitoring and intervention

Carlos R Ferreira et al. Bone. 2020 Feb.

Abstract

GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in GLB1 encoding a lysosomal β-galactosidase. This disease is a continuum from the severe infantile form with rapid neurological decline to the chronic adult form, which is not life-limiting. The intermediate or type 2 form can be further classified into late infantile and juvenile forms. The frequency and severity of skeletal outcomes in late infantile and juvenile patients have not been characterized. Our goals are to describe the radiological skeletal abnormalities, bone mineral density (BMD), and frequency of fractures in patients with intermediate GM1 gangliosidosis. We evaluated 13 late infantile and 21 juvenile patients as part of an ongoing natural history study. Average time from onset of symptoms to diagnosis was 1.9 and 6.3 years for late infantile and juvenile patients, respectively. All late infantile patients had odontoid hypoplasia and pear-shaped vertebral bodies, the frequency of which was significantly different than in patients with juvenile disease (none and 14%, respectively). Juvenile patients had irregular endplates of the vertebral bodies (15/21), central indentation of endplates (10/21), and squared and flat vertebral bodies (10/21); all allowed radiographic differentiation from late infantile patients. Lumbar spine, femoral neck, and total hip BMD were significantly decreased (-2.1, -2.2, and -1.8 Z-scores respectively). Lumbar spine BMD peaked at 19 years, while distal forearm BMD peaked at 30 years. Despite low BMD, no patients exhibited fractures. We have demonstrated that all late infantile patients have some degree of odontoid hypoplasia suggesting the need for cervical spine evaluation particularly prior to anesthesia, whereas juvenile patients had variable skeletal involvement often affecting activities of daily living. Type 2 GM1 gangliosidosis patients have skeletal abnormalities that are both an early indication of their diagnosis, and require monitoring and management to ensure the highest possible quality of life.

Keywords: Beta-galactosidase deficiency; GM1 gangliosidosis type 2; Lysosomal storage disease; Skeletal dysplasia.

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Figures

Figure 1:
Figure 1:
Cervical spine radiographs in late infantile patients. A. Patient GSL013, 9 years. B. Patient GSL030, 3 years. C. GSL035, 4 years. In all patients, the odontoid process is underossified.
Figure 2:
Figure 2:
Lumbar spine radiographs in late infantile patients. A, B. Patient GSL0013 at 4 years and 9 years. The vertebral bodies have a pear-shaped ovoid appearance. Ossification of the anterior segments of the vertebral bodies is defective in the thoraco-lumbar junction leading to their hook-shape or an aspect of dorsal displacement. Note progression in 5 years consistent with clinical disease course C, D. Patient GSL007 at 6 and 10 years. Similar changes and progression are seen over time.
Figure 3:
Figure 3:
Pelvic radiographs in late infantile patients show hypoplasia of the infero-lateral portions of the ilia resulting in slanted acetabular roofs and wide ileo-acetabular angles. A. Patient GSL022, 3 years. The femoral necks are in valgus. The capital femoral epiphyses are well rounded and slightly large. B. Patient GSL023, 5 years. C. Patient GSL007, 6 years. D. Patient GSL072, 8 years. E. Patient GSL013, 4 years. The capital femoral epiphyses are dysplastic due to deficient ossification of their medial portions. F. Patient GSL013, 9 years. Compared to E, epiphyseal ossification has normalized, and the femoral necks are shorter.
Figure 4:
Figure 4:
Lumbar spine radiographs in juvenile patients. A. Patient GSL027, age 7 years. Normal spine. B. Patient GSL020, 12 years. The vertebral bodies are dorsally flat with irregular upper and lower margins. C. Patient GSL004, 12 years. The upper and lower endplates show central indentations. D. Patient GSL003, 18 years. The lumbar vertebral bodies are deformed with central indentations. The body of T12 is triangular resulting in an acute dorsolumbar kyphosis.
Figure 5:
Figure 5:
Pelvic radiographs in juvenile patients. A, B, C. Varying degrees of over-constricted lower ilia are seen with small acetabulae and subluxated femoral heads. The epiphyses are flat. A, patient GSL009, age 13 years. B, patient GSL010, 15 years. C, patient GSL003, 18 years. D. Patient GSL028, 19 years. In this patient the ilia are well developed with full acetabular coverage of the slightly flat femoral heads.
Figure 6:
Figure 6:
BMD Z-scores in patients with GM1 gangliosidosis.
Figure 7:
Figure 7:
Relationship between lumbar spine and distal forearm BMD and age: quadratic models. A, D. Cross-sectional regression models. B–C, E–F. Longitudinal changes in BMD with age. B, Change in lumbar spine BMD with age raw data and (C) predicted change in BMD based on mixed-effects model regression. E, Change in distal forearm spine BMD with age raw data and (F) predicted change in BMD based on mixed-effects model regression.
Figure 8:
Figure 8:
Relationship between total hip and femoral BMD and age: linear models. A, D. Cross-sectional regression models. B–C, E. Longitudinal changes in BMD with age. B, Change in total hip BMD with age raw data and (C) predicted change in BMD based on mixed-effects model regression. E, Change in femoral BMD with age raw data.
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