The same SPAST deletion, very different courses in one family

A plain-language summary of a published scientific study. It is educational and does not replace medical advice.

The study: Vasova J et al., Neurogenetics, published online 27 August 2026[1]. A family case report. Only the abstract is freely available.

What the researchers studied

In SPG4, the age of onset and severity vary a great deal, even between relatives with the same variant[1,2]. The authors studied a family in which several members had a deletion of the whole SPAST gene on one of their two copies, together with partial loss of a neighbouring gene, DPY30[1]. The relatives had mild symptoms, but the patient through whom the family was identified had an early, severe form[1].

What they found

• The patient with the severe form also carried, on the remaining copy of SPAST, a variant known as a modifier: p.(Ser44Leu), S44L for short[1].
• Laboratory tests showed a similar reduction of one form of spastin (the M87 isoform) in all relatives with the deletion, including the patient. So this reduction alone does not explain the difference in severity[1].
• To the authors' knowledge, the combination of a whole-SPAST deletion, partial DPY30 loss and the S44L variant in one person had not been reported before[1].

What it means for families

The case shows why the course of the disease in a parent or relative does not necessarily predict the course in a child[2]. When a child is much more severely affected than relatives with the same variant, it is worth asking the clinical geneticist whether modifier variants such as S44L have been looked for.

What the study does not tell us yet

This is a single family. The authors propose that S44L-modified spastin adds to the effect of having only one working copy of the gene, but the exact mechanism is not confirmed[1].