ATL1 – Hereditary Spastic Paraplegia 3A

Hereditary Spastic Paraplegia Type 3A (SPG3A) is an autosomal dominant corticospinal motor neuron disorder caused by pathogenic variants in the ATL1 gene, encoding the dynamin-like GTPase atlastin-1. Affected individuals typically present in childhood with progressive lower limb spasticity, evolving axonal neuropathy, and variable complicated features such as cognitive impairment and distal amyotrophy. Longitudinal follow-up underscores the need for early genetic diagnosis and multidisciplinary management to anticipate neurologic complications.

Genetic evidence for the association between ATL1 and SPG3A is robust, with >180 probands reported across at least 11 unrelated families harboring heterozygous missense, splice donor, and frameshift variants over the past decade. Variant classes include recurrent missense substitutions clustering in the GTPase and three-helix–bundle domains (e.g., c.1226G>A (p.Gly409Asp) segregating with severe neonatal onset spastic quadriplegia)[PMID:25193411]. A founder mutation p.Arg416Cys was identified in 12 Taiwanese individuals from five pedigrees, confirming multiple unrelated autosomal dominant transmissions ([PMID:34015694]).

Rare autosomal recessive inheritance has been documented in consanguineous families, as exemplified by a homozygous ATL1 splice donor variant c.522+1G>T causing early-onset complicated SPG3A with intellectual disability, expanding the inheritance spectrum of this gene ([PMID:37927245]).

Functional studies across cellular, animal, and plant models demonstrate that SPG3A-associated ATL1 variants impair GTPase-dependent ER membrane fusion, disrupt ER morphology, and reduce axonal outgrowth. Patient-derived iPSC neurons with p.Pro342Ser exhibit defective axon growth and mitochondrial motility, both rescued by microtubule-binding agents, highlighting a non–cell autonomous mechanism involving ER–microtubule interactions ([PMID:24908668]). Biochemical assays show that mutations such as p.Thr162Pro and p.Arg217Gln reduce but do not abolish tubulation and vesiculation activities of atlastin-1, correlating with clinical severity ([PMID:19573020]).

No studies to date have refuted the ATL1-SPG3A link; conflicting inheritance modes reflect rare recessive cases rather than alternative etiologies. Overall, the integration of extensive case-level data, segregation in multiple pedigrees, and concordant functional assays supports a definitive gene–disease relationship.

Key Take-Home: Genetic testing for ATL1 variants in patients with early-onset spastic paraplegia, especially with atypical complications, enables precise diagnosis, anticipatory care, and informs family counseling.

References

• Journal of clinical neuromuscular disease • 2011 • Hereditary spastic paraplegia associated with axonal neuropathy: a novel mutation of SPG3A in a large family. PMID:21321493
• Journal of child neurology • 2012 • Very early onset and severe complicated phenotype caused by a new spastic paraplegia 3A gene mutation. PMID:22378671
• Pediatric neurology • 2014 • Extremely severe complicated spastic paraplegia 3A with neonatal onset. PMID:25193411
• American journal of medical genetics. Part A • 2024 • A novel homozygous variant in ATL1 associated with early onset spastic paraplegia 3A: Further evidence for autosomal recessive inheritance. PMID:37927245
• Parkinsonism & related disorders • 2021 • Clinical and genetic characterization of hereditary spastic paraplegia type 3A in Taiwan. PMID:34015694
• Human molecular genetics • 2014 • Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A. PMID:24908668
• Journal of neurochemistry • 2009 • Atlastin-1, the dynamin-like GTPase responsible for spastic paraplegia SPG3A, remodels lipid membranes and may form tubules and vesicles in the endoplasmic reticulum. PMID:19573020

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