SPG4related

SPG4-related refers to hereditary spastic paraplegia type 4, the most common form of autosomal dominant hereditary spastic paraplegia. It is caused by pathogenic variants in the SPAST gene, located on chromosome 2q37. The SPAST gene encodes spastin, a microtubule-severing ATPase that participates in axonal transport and organelle dynamics.

Clinical features typically begin with progressive stiffness and weakness of the legs (lower-limb predominant spastic paraparesis), leading to a climbing or wide-based gait. Babinski sign, hyperreflexia, and spasticity are common. Onset ranges from childhood to adulthood and progression is usually slow; urinary urgency and pain may occur in some individuals.

Genetics: SPG4 is autosomal dominant, with considerable inter- and intrafamilial variability. Most cases are due to loss-of-function variants in SPAST; de novo mutations account for a subset. Both missense and truncating variants as well as copy-number changes have been reported.

Pathophysiology: Spastin participates in severing microtubules, a key step in neuronal remodeling and axonal transport. Impaired spastin function leads to degeneration of long corticospinal tract axons, contributing to the pyramidal signs and length-dependent weakness characteristic of SPG4-related HSP.

Diagnosis: Suspected from clinical features and family history; confirmed by genetic testing of SPAST. MRI may show non-specific white-matter changes and regional atrophy; imaging is mainly used to exclude other causes. Genetic testing helps with counseling and family planning.

Management is supportive and multidisciplinary. Physical and occupational therapy maintain mobility; oral antispasmodics (e.g., baclofen, tizanidine) or botulinum toxin can reduce spasticity; orthotic devices and assistive devices aid gait. Genetic counseling is recommended; there is no disease-modifying therapy currently.