Functional validation of novel variants in B4GALNT1 associated with early-onset complex hereditary spastic paraplegia with impaired ganglioside synthesis.

Abstract

Childhood-onset forms of hereditary spastic paraplegia are ultra-rare diseases and often present with complex features. Next-generation-sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where sufficient knowledge of the protein function and/or downstream pathways exists, functional studies in patient-derived cells can aid the interpretation of molecular findings. We here illustrate the case of a 13-year-old female who presented with global developmental delay and later mild intellectual disability, progressive spastic diplegia, spastic-ataxic gait, dysarthria, urinary urgency, and loss of deep tendon reflexes of the lower extremities. Exome sequencing showed a novel splice-site variant in trans with a novel missense variant in B4GALNT1 [NM_001478.5: c.532-1G>C/c.1556G>C (p.Arg519Pro)]. Functional studies in patient-derived fibroblasts and cell models of GM2 synthase deficiency confirmed a loss of B4GALNT1 function with no synthesis of GM2 and other downstream gangliosides. Collectively these results established the diagnosis of B4GALNT1-associated HSP (SPG26). Our approach illustrates the importance of careful phenotyping and functional characterization of novel gene variants, particularly in the setting of ultra-rare diseases, and expands the clinical and molecular spectrum of SPG26, a disorder of complex ganglioside biosynthesis.

• Authors: Julian Emanuel Alecu, Yuhsuke Ohmi, Robiul H Bhuiyan, Kei-Ichiro Inamori, Takahiro Nitta, Afshin Saffari, Hellen Jumo, Marvin Ziegler, Claudio Melo de Gusmao, Nutan Sharma, Shiho Ohno, Noriyoshi Manabe, Yoshiki Yamaguchi, Mariko Kambe, Keiko Furukawa, Mustafa Sahin, Jin-Ichi Inokuchi, Koichi Furakawa, Darius Ebrahimi-Fakhari
• Journal: American journal of medical genetics. Part A (Am J Med Genet A) Vol. 188 Issue 9 Pg. 2590-2598 (09 2022) ISSN: 1552-4833 [Electronic] United States
• PMID: 35775650 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2022 Wiley Periodicals LLC.

Chemical References

• Gangliosides

Topics

• Adolescent
• Child
• Female
• Gangliosides (genetics)
• Humans
• Mutation
• Pedigree
• Rare Diseases
• Spastic Paraplegia, Hereditary (diagnosis, genetics)