Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

中文翻译：

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定义接头蛋白复合物 4 相关遗传性痉挛性截瘫的临床、分子和影像谱


编码衔接蛋白复合物 4 (AP-4) 亚基的基因中的双等位基因功能丧失变异导致儿童期发病和复杂遗传性痉挛性截瘫的典型但知之甚少的形式：SPG47 ( AP4B1 )、SPG50 ( AP4M1 ）、SPG51（ AP4E1 ）和 SPG52（ AP4S1 ）。在这里，我们报告了来自 101 个家庭的 156 名患者的临床、影像和分子数据的详细横断面分析。入组患者具有不同的种族背景，年龄范围广泛（1.0-49.3 岁）。症状出现时的平均年龄为 0.8 ± 0.6 岁 [标准差 (SD)，范围 0.2–5.0]，诊断时的平均年龄为 10.2 ± 8.5 岁（SD，范围 0.1–46.3）。我们定义了一组核心特征：早发性发育迟缓，伴有运动里程碑延迟和显着言语迟缓（50％非言语）；中度至重度智力障碍；婴儿期轻度肌张力减退，随后出现痉挛性截瘫（平均年龄：8.4 ± 5.1 岁，SD），随后出现四肢瘫痪（平均年龄：16.1 ± 9.8 岁，SD）；产后小头畸形（83%）；足部畸形（69%）；以及部分顽固性癫痫（66%）。在最后一次随访中，36% 的人在协助下行走（平均年龄：8.9 ± 6.4 岁，SD），54% 的人依赖轮椅（平均年龄：13.4 ± 9.8 岁，SD）。 56% 的患者出现过刻板大笑，这可能与假性延髓情绪一致。神经影像学的主要特征包括胼胝体薄（90%）、脑室扩大（65%）（通常伴有阴道头畸形）和脑室周围白质信号异常（68%）。在一部分患者中发现了铁沉积和多小脑回。 AP4B1相关的SPG47和AP4M1相关的SPG50占大多数病例。大约三分之二的患者是近亲父母所生，82% 携带纯合变异。存在超过 70 种独特的变异，其中大多数是移码突变或无义突变。为了跟踪整个年龄范围内的疾病进展，我们定义了通过多种评级量表衡量的疾病严重程度与疾病持续时间之间的关系。我们发现，大多数患者在 3 岁之前出现癫痫，与较差的运动结果相关。通过探索基因型-表型相关性，我们发现疾病严重程度和主要表型在四种亚型中分布均匀，从而确定 SPG47、SPG50、SPG51 和 SPG52 具有共同的表型，即“AP-4 缺乏综合征”。通过描绘整个年龄范围内 AP-4 相关遗传性痉挛性截瘫的核心临床、影像和分子特征，我们的结果将有助于早期诊断，为受影响的家庭提供咨询和预期指导，并帮助确定未来介入试验的终点。