Infantile onset of hereditary spastic paraplegia poorly predicts the genotype

Area of Science:

• Genetics
• Neurology
• Pediatrics

Background:

• Hereditary spastic paraplegia (HSP) onset varies widely, with infantile forms often misdiagnosed as cerebral palsy, especially without a family history.
• Mutations in the spastin gene (SPAST) causing infantile HSP are rare, typically linked to codominant mutations.
• The genetic basis of HSP is diverse, and infantile onset does not always predict the specific genotype.

Purpose of the Study:

• To report a novel de novo mutation in the SPAST gene causing infantile hereditary spastic paraplegia in a multi-generational family.
• To emphasize the diagnostic challenges and potential for misdiagnosis of infantile HSP.
• To raise awareness among pediatric neurologists regarding de novo mutations in HSP genes presenting in infancy.

Main Methods:

• Clinical evaluation of a family with successive generations affected by infantile onset spastic paraplegia.
• Genetic analysis to identify mutations in the SPAST gene.
• Review of previous diagnoses within the family, including cerebral palsy.

Main Results:

• A novel de novo mutation, 1537G>A (G471D), in the SPAST gene was identified as the cause of infantile onset HSP in the studied kindred.
• Three successive generations were affected, with several members previously diagnosed with cerebral palsy.
• The study confirms that infantile onset HSP can result from de novo mutations and may not follow typical inheritance patterns.

Conclusions:

• Infantile onset hereditary spastic paraplegia can be caused by de novo mutations in genes like SPAST.
• Misdiagnosis as cerebral palsy is common in infantile HSP, particularly when there is no family history.
• Pediatric neurologists should consider de novo mutations in HSP genes when evaluating infants with spasticity and no clear family history.