GM2 Activator Deficiency Caused by a Homozygous Exon 2 Deletion in GM2A

Abstract

GM2 activator (GM2A) deficiency (OMIM 613109) is a rare lysosomal storage disorder, with onset typically in infancy or early childhood. Clinically, it is almost indistinguishable from Tay-Sachs disease (OMIM 272800) or Sandhoff disease (OMIM 268800); however, traditionally available biochemical screening tests will most likely reveal normal results. We report a 2-year-old male with initially normal development until the age of 9 months, when he presented with developmental delay and regression. Workup at that time was unrevealing; at 15 months, he had abnormal brain MRI findings and a cherry red spot on ophthalmological examination. Family history and all laboratory studies were uninformative. The combination of a cherry red spot and developmental regression was strongly suggestive of a lysosomal storage disorder. Sequence analysis of GM2A did not reveal any pathogenic variants; however, exon 2 of GM2A could not be amplified by PCR, raising suspicion for a large, homozygous deletion. Subsequent copy number analysis confirmed a homozygous deletion of exon 2 in GM2A. This is the first reported case of GM2A deficiency being caused by a whole exon deletion. We describe previously unreported electron microscopy findings in this disease, thus expanding the clinical and variant spectrum for GM2 activator deficiency. These findings demonstrate the increased degree of suspicion required for diagnosis of this rare disorder. Brief Summary: This case of GM2 activator deficiency was caused by a homozygous deletion in GM2A, demonstrating the need to include exon level copy number analysis in any workup to fully exclude this disorder.

Keywords: Cherry red spot; Copy number analysis; Electron microscopy; GM2 activator deficiency; GM2A; Lysosomal storage disorder.

Fig. 1

(a) Electron microscopy from a skin biopsy of our patient. Axons with degenerative changes containing membrane bound debris (solid white arrows), areas of axonal retraction, and Schwann cell cytoplasm also filled with membrane bound debris (white outline arrows). Original magnification 6000x. (b) Electron microscopy from a skin biopsy of our patient. Cell with “zebra bodies” (solid white arrows), myelinosomes (white star), and granular membrane bound vesicles (outline arrow). This may represent a Schwann cell but definite myelin is not seen, so identification is uncertain. Original magnification 6000x

Fig. 2

Exon 2 deletion in GM2A. (a) Schematic representation of the deletion detected in the GM2A gene. The deleted region is represented with dotted lines whereas the intact region is represented with solid lines. The downward arrows indicate the breakpoints of the deletion. Also indicated are the intact (Black) and deleted (Gray) bases flanking each breakpoint. (b) Sequence alignment showing microhomology at the breakpoint junction. Patient sequence across the deletion breakpoint, as obtained by Sanger sequencing, was aligned to the reference sequences from both the 5′ breakpoint and the 3′ breakpoint. As shown in the figure, a 7 bp sequence, “AGCTGGG” was detected on either sides of the deletion. The deletion has been refined to be 6,142 bp long extending from and including chr5:g.150,636,648 to chr5:g.150,642,789. These results, together with the failure of PCR amplification of exon 2, confirm a homozygous deletion of exon 2 of the GM2A gene in this individual. Ref. reference, Seq sequence, Bkpt breakpoint