PDF(Pubmed)
Abstract：
Spastic paraplegia type 3A (SPG3A) is the second most common form of hereditary spastic paraplegia (HSP). This autosomal-dominant-inherited motor disorder is caused by heterozygous variants in the ATL1 gene which usually presents as a pure childhood-onset spastic paraplegia. Affected individuals present muscle weakness and spasticity in the lower limbs, with symptom onset in the first decade of life. Individuals with SPG3A typically present a slow progression and remain ambulatory throughout their life. Here we report three unrelated individuals presenting with very-early-onset (before 7 months) complex, and severe HSP phenotypes (axial hypotonia, spastic quadriplegia, dystonia, seizures and intellectual disability). For 2 of the 3 patients, these phenotypes led to the initial diagnosis of cerebral palsy (CP). These individuals carried novel ATL1 pathogenic variants (a de novo ATL1 missense p.(Lys406Glu), a homozygous frameshift p.(Arg403Glufs*3) and a homozygous missense variant (p.Tyr367His)). The parents carrying the heterozygous frameshift and missense variants were asymptomatic. Through these observations, we increase the knowledge on genotype-phenotype correlations in SPG3A and offer additional proof for possible autosomal recessive forms of SPG3A, while raising awareness on these exceptional phenotypes. Their ability to mimic CP also implies that genetic testing should be considered for patients with atypical forms of CP, given the implications for genetic counseling.
摘要：
痉挛性截瘫3A型(SPG3A)是遗传性痉挛性截瘫(HSP)的第二常见形式。这种常染色体显性遗传性运动障碍是由ATL1基因的杂合变异引起的，通常表现为纯儿童期发作的痉挛性截瘫。受影响的个体表现出下肢肌肉无力和痉挛，在生命的头十年出现症状。患有SPG3A的个体通常呈现缓慢的进展并且在其一生中保持走动。在这里，我们报告了三个不相关的个体，他们表现出非常早发病（在7个月之前）复杂，和严重的HSP表型(轴向低张力，痉挛性四肢瘫痪,肌张力障碍,癫痫发作和智力残疾)。对于3名患者中的2名，这些表型导致脑瘫（CP）的初步诊断。这些个体携带新的ATL1致病变体（从头ATL1错义p。（Lys406Glu），纯合移码p。（Arg403Glufs*3）和纯合错义变体（p。Tyr367His)).携带杂合移码和错义变体的父母无症状。通过这些观察,我们增加了关于SPG3A基因型-表型相关性的知识，并提供了可能的常染色体隐性形式的SPG3A的额外证据，同时提高对这些特殊表型的认识。他们模仿CP的能力也意味着对于非典型形式的CP患者应考虑进行基因检测。考虑到遗传咨询的意义。
