Degoutin Manon, Angelini Chloé, Bar Claire, El Khedoud Wahiba Amer, Barnerias Christine, Boulariah-Hadjou Razika, Estiar Mehrdad A, Ewenczyk Claire, Gan-Or Ziv, Lacombe Didier, Lefeuvre Claire, Majethia Purvi, Messaoud-Khelifi Mouna, Narayanan Dhanya Lakshmi, Rouleau Guy A, Suchowersky Oksana, Shukla Anju, Guillaud-Bataille Marine, Stevanin Giovanni, Goizet Cyril
Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France.
Université de Bordeaux, UFR Des Sciences médicales, Bordeaux, France.
Eur J Neurol. 2025 Jan;32(1):e70025. doi: 10.1111/ene.70025.
Heterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST.
Targeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder.
We describe 5 patients with pure HSP with a variable age of onset, mostly in infancy, and 4 patients with profound intellectual disability and progressively worsening tetrapyramidal syndrome. The patients' parents, heterozygous carriers of pathogenic SPAST variants, included both asymptomatic carriers and patients with classic forms of SPG4.
Biallelic variants of SPAST may explain cases of hereditary spastic paraplegia with autosomal recessive inheritance. Furthermore, some biallelic variants may also cause psychomotor regression with an infantile neurodegenerative disorder, associated with a tetrapyramidal syndrome, a new phenotype associated with the SPAST gene.
已知痉挛蛋白（SPAST）的杂合致病变异会导致遗传性痉挛性截瘫4型（SPG4），这是遗传性痉挛性截瘫最常见的形式，其特征为进行性双侧下肢痉挛，常伴有括约肌功能障碍。然而，文献中对携带SPAST双等位基因变异患者的描述非常少。
采用靶向桑格测序、基因panel测序和外显子组测序来确定6个无亲缘关系家庭中9例有遗传性痉挛性截瘫或婴儿神经退行性疾病症状患者的遗传病因。
我们描述了5例单纯遗传性痉挛性截瘫患者，发病年龄各异，大多在婴儿期发病，以及4例有严重智力障碍且四锥体束综合征进行性加重的患者。患者的父母是致病性SPAST变异的杂合携带者，包括无症状携带者和典型SPG4形式的患者。
SPAST的双等位基因变异可能解释常染色体隐性遗传的遗传性痉挛性截瘫病例。此外，一些双等位基因变异也可能导致伴有婴儿神经退行性疾病的精神运动发育迟缓，并伴有四锥体束综合征，这是一种与SPAST基因相关的新表型。
