Functional validation of novel variants in B4GALNT1 associated with early‐onset complex hereditary spastic paraplegia with impaired ganglioside synthesis. Issue 9 (1st July 2022)

• Record Type: Journal Article
• Authors: Alecu, Julian Emanuel; Ohmi, Yuhsuke; Bhuiyan, Robiul H.; Inamori, Kei‐ichiro; Nitta, Takahiro; Saffari, Afshin; Jumo, Hellen; Ziegler, Marvin; de Gusmao, Claudio Melo; Sharma, Nutan; Ohno, Shiho; Manabe, Noriyoshi; Yamaguchi, Yoshiki; Kambe, Mariko; Furukawa, Keiko; Sahin, Mustafa; Inokuchi, Jin‐ichi; Furakawa, Koichi; Ebrahimi‐Fakhari, Darius
• Is Part Of: American journal of medical genetics. Volume 188:Issue 9(2022)
• Page Start: 2590
• Page End: 2598
• Publication Date: 2022-07-01
• Subjects: gangliosides -- hereditary spastic paraplegia -- inborn error of metabolism -- neurodegeneration -- spastic paraplegia 26 -- spasticity; Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.62880
• Languages: English
• ISSNs: 1552-4825

Abstract

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.