Spastic Quadriplegia Resulting From a Pathogenic Variant in the SPAST Gene: A First Report

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• The SPAST gene encodes spastin, a protein crucial for microtubule dynamics.
• Mutations in SPAST are typically linked to autosomal dominant Spastic Paraplegia type 4 (SPG4), characterized by progressive lower limb spasticity.
• Severe neurological phenotypes associated with SPAST variants are uncommon.

Purpose of the Study:

• To report the first documented case of a rare pathogenic SPAST variant presenting with spastic quadriplegia.
• To highlight the expanded phenotypic spectrum of SPAST-related disorders.
• To underscore the diagnostic utility of genetic testing in complex neurodevelopmental cases.

Main Methods:

• Clinical case presentation of an adolescent with spastic quadriplegia.
• Genetic analysis to identify the specific SPAST variant (NM_014946.4: c.1507C>T; NP_055761.2: p. [Arg503Trp]).
• Review of literature for comparison of phenotypes associated with SPAST mutations.

Main Results:

• The patient exhibited spastic quadriplegia, severe intellectual disability, absent speech, dysphagia, and epilepsy.
• This presentation represents one of the most severe phenotypes reported for SPAST-related disorders.
• Genetic testing provided a definitive diagnosis, differentiating from a presumed etiology of perinatal asphyxia.

Conclusions:

• This case broadens the understanding of the phenotypic variability associated with SPAST gene mutations.
• Considering SPAST mutations is crucial for patients with atypical or severe neurodevelopmental presentations.
• Genetic diagnosis facilitates accurate prognosis, personalized care, and genetic counseling.