A Pathogenic Missense Variant (c.1617G>A, p.Met539Ile) in UBA1 Causing Infantile X-Linked Spinal Muscular Atrophy (SMAX2)

Abstract

Background: Infantile X-linked spinal muscular atrophy (SMAX2) is a rare type of spinal muscular atrophy associated with UBA1 variants.Methods: Clinical imaging and neurophysiological tests were performed on a Chinese patient with SMAX2. Further, focused panel sequencing of UBA1 was carried out on samples of both the proband and his maternal relatives.Results: The proband, a 4-year-old boy with the SMAX2 phenotype, suffered from reduced exercise capacity since infancy. His other symptoms included speech difficulties, severe nasal tone, reduced distal muscle strength, areflexia, and inadequate sucking ability. The brain MRI of the proband's showed normal results but the electromyography results showed multiple peripheral neurogenic lesions. Five male members of the proband's family were affected with the SMAX2 phenotype. They presented similar symptoms and had experienced a long and autonomous life. Molecular analysis revealed a novel missense variant (c.1617G>A, p.Met539Ile) in the exon 15 of UBA1. The proband's mother, as well as grandmother, carried the heterozygous missense UBA1 variant; whereas, the male patients from the family carried the hemizygotic variant. Conclusions:The affected members in this Chinese family showed unique features such as extended life span, no fractures, and cramps as compared with previously reported SMAX2 cases. The novel missense variant (c.1617G>A (p.Met539Ile) in UBA1 highlights the critical role of this gene in causing SMAX2 phenotype.

X-Linked Spinal Muscular Atrophy 2 due to a Synonymous Variant in the <b><i>UBA1</i></b> Gene in a Family with Novel Findings from Turkey

“…The study in mice with SMA1dependent SMA showed that AAV9-UBA1 gene therapy improved body weight, lifespan, and motor performance in mice [Powis et al, 2016] ). The missense variant c.1617G>A was also found in 3 individuals in a family described by Wang et al [2020]. These patients were milder affected when compared to other molecularly confirmed patients.…”

“…The majority of the cases previously reported had areflexia, progressive muscle weakness, and hypotonia with early onset. Five patients reported by Wang et al [2020] differed from the other patients by a long life span, dysarthria, mild muscle weakness, late-onset age, no bone fractures, contractures, respiratory distress, and no progression. Neuropathy was detected in approximately 33% of previously reported cases.…”

“…Among our patients, patient IV-4 reached the age of 37 months, the other patients (IV-1 and IV-3) died at the age of 30 and 29 months, respectively. Five patients from a family reported by Wang et al [2020] differ from the others in long lifespan, ranging from 5 to 86 years. Four of the 5 patients with previously reported c.1731C>T variant died within 2 years of age, suggesting that this variant may be associated with a poor prognosis [Greenberg et al, 1988;Jedrzejowska et al, 2015].…”

“…The prevalence of SMAX2 is unknown. To date, in only 9 families the diagnosis of SMAX2 has been confirmed by molecular genetic testing, although many cases of SMA with contractures and fractures have been reported [Greenberg et al, 1988;Ramser et al, 2008;Dlamini et al, 2013;Jedrzejowska et al, 2015;Shaughnessy et al, 2020;Wang et al, 2020]. In addition, Kosmicki et al [2017] demonstrated a missense variant c.199A>G (p.Met67Val) in a male patient with neurodevelopmental disorder, and Peng et al [2018] described a c.2501C>T (p.Pro834Leu) hemizygous missense variant in the UBA1 gene that was associated with West syndrome.…”

“…The prevalence is unknown. To date, 9 molecularly confirmed families have been reported [Greenberg et al, 1988;Ramser et al, 2008;Dlamini et al, 2013;Jedrzejowska et al, 2015;Shaughnessy et al, 2020;Wang et al, 2020].…”