UBA1 – Infantile-Onset X-Linked Spinal Muscular Atrophy (SMAX2)

Infantile-onset X-linked spinal muscular atrophy (SMAX2) is a severe, early-lethal motor–sensory neuronopathy characterized by truncal hypotonia, areflexia, myopathic facies, flexion contractures and cryptorchidism in affected males. SMAX2 is inherited in an X-linked recessive manner due to loss-of-function variants in the ubiquitin-activating enzyme gene UBA1, which is essential for the ubiquitin–proteasome pathway.

Genetic evidence for the UBA1–SMAX2 association includes an initial report of a de novo hemizygous missense variant c.1670A>T (p.Glu557Val) identified in a male infant with hypotonia, areflexia and contractures (PMID:23518311). A Turkish family with two affected brothers harbored a hemizygous synonymous variant c.1731C>T (p.Asn577=) that altered splicing and reduced UBA1 expression (PMID:35707597). A Chinese pedigree with five affected males carried a novel c.1617G>A (p.Met539Ile) variant segregating in four additional affected relatives (PMID:32181232). Large-scale mutation screening across five families identified missense (p.Met539Ile, p.Ser547Gly) and synonymous (p.Asn577=) variants in exon 15, each segregating with disease in unrelated pedigrees (PMID:18179898). In total, ≥11 probands in 6 families demonstrate X-linked recessive inheritance with segregation in 6 additional relatives.

The variant spectrum in SMAX2 comprises missense substitutions (p.Glu557Val, p.Met539Ile, p.Ser547Gly) and splice-altering synonymous changes (p.Asn577=), all clustering within the active adenylation domain of UBA1. No recurrent or founder alleles have been reported. Carrier frequency is unknown given the rarity of SMAX2.

Functional studies support a loss-of-function mechanism via impaired adenylation activity and reduced UBA1 expression. The synonymous c.1731C>T (p.Asn577=) variant decreases UBA1 transcript levels and alters exon 15 methylation (PMID:18179898). In vitro adenylation assays reveal that p.Met539Ile and p.Ser547Gly significantly impair ubiquitin-adenylating activity while preserving thioester formation (PMID:29034082). The p.Met539Ile change also reduces enzyme function in patient-derived cells, confirming pathogenicity (PMID:32181232).

No conflicting reports have disputed the UBA1–SMAX2 link. The clustering of diverse variant types with consistent functional impairment, segregation in multiple families and concordant phenotypes provide strong clinical validity and diagnostic utility. UBA1 gene sequencing is recommended for male infants presenting with congenital hypotonia, areflexia and contractures.

Key Take-Home: UBA1 variants in exon 15 cause X-linked recessive SMAX2 by disrupting ubiquitin activation; early genetic diagnosis enables accurate counseling and supports future therapeutic development.

References

• Neuromuscular disorders • 2013 • Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene. PMID:23518311
• Molecular syndromology • 2022 • X-Linked Spinal Muscular Atrophy 2 due to a Synonymous Variant in the UBA1 Gene in a Family with Novel Findings from Turkey. PMID:35707597
• Frontiers in pediatrics • 2020 • A Pathogenic Missense Variant (c.1617G>A, p.Met539Ile) in UBA1 Causing Infantile X-Linked Spinal Muscular Atrophy (SMAX2). PMID:32181232
• American journal of human genetics • 2008 • Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy. PMID:18179898
• F1000Research • 2017 • Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy. PMID:29034082

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