Significant differences in phenotype and age of onset in an SPG4 family caused by whole SPAST deletion combined with a hemizygous S44L modifier.

Hereditary spastic paraplegia type 4 (SPG4) is a neurodegenerative disorder with variable age of onset and severity. We report a patient with early-onset SPG4 resulting from compound heterozygosity for a full-gene SPAST deletion and partial DPY30 loss, together with the hemizygous NM_014946.6(SPAST):c.131 C > T p.(Ser44Leu) variant. Western blot showed a similar reduction in the M87 spastin isoform in all deletion-carrying relatives, including the proband, indicating that this reduction alone does not explain the marked difference in phenotype severity: relatives had mild symptoms, whereas the proband had an early-onset, severe phenotype. This co-occurrence of a whole-SPAST deletion, partial DPY30 loss, and a hemizygous phenotype-modifier variant in one individual has, to our knowledge, not been previously reported. We hypothesise that the p.(Ser44Leu)-modified spastin may add to the effect of SPAST haploinsufficiency to produce the more severe phenotype, though the precise mechanism remains unconfirmed.