Objective

X-linked myopathy with excessive autophagy (XMEA) linked to the VMA21 gene leads to autophagy failure with progressive vacuolation and atrophy of skeletal muscles. Current knowledge of this rare disease is limited. Our objective was to define the clinical, radiological, and natural history of XMEA.

Methods

We conducted a retrospective study collecting clinical, genetic, muscle imaging, and biopsy data of XMEA patients followed in France and reviewed the literature for additional cases.

Results

Eighteen males had genetically confirmed XMEA in France, carrying four different VMA21 variants. Mean age at disease onset was 9.4 ± 9.9 (range 1–40) years. In 14/18 patients (77.8%), onset occurred during childhood (< 15 years); however in four patients, the disease started in adulthood. Patients had anterior and medial compartment thigh muscle weakness, distal contractures (56.3%), elevated CK levels (1287.9 ± 757.8 U/l) and autophagic vacuoles with sarcolemmal features on muscle histopathology. Muscle MRI (n = 10) showed a characteristic pattern of lower limb muscle involvement. In 11 patients, outcome measures were available for an average follow-up period of 10.6 ± 9.8 years and six of them show disease progression. Mean change of functional outcomes was 0.5 ± 1.2 points for Brooke and 2.2 ± 2.5 points for Vignos score, 7/16 patients (43.8%) needed a walking aid and 3/16 (18.8%) were wheelchair-bound (median age of 40 years old, range 39–48). The variant c.164-7 T > G was associated with a later onset of symptoms. Respiratory insufficiency was common (57.1%) but cardiac involvement rare (12.5%).

Interpretation

XMEA has variable age of onset, but a characteristic clinical, histopathological, and muscle imaging presentation, guiding the diagnosis. Although slowly, motor disability progresses with time, and relevant genotype–phenotype correlations will help design future clinical trials.

中文翻译：

---

过度自噬的 X 连锁肌病的表型变异和自然史

客观的

与VMA21基因相关的过度自噬 X 连锁肌病 (XMEA)会导致自噬失败，并伴有进行性空泡化和骨骼肌萎缩。目前对这种罕见疾病的了解有限。我们的目标是定义 XMEA 的临床、放射学和自然史。

方法

我们进行了一项回顾性研究，收集了法国 XMEA 患者的临床、遗传、肌肉成像和活检数据，并回顾了其他病例的文献。

结果

在法国，18 名男性已被基因证实为 XMEA，携带四种不同的VMA21变体。发病时的平均年龄为 9.4 ± 9.9（范围 1-40）岁。 14/18 名患者 (77.8%) 发病于儿童时期（< 15 岁）；然而，有四名患者的疾病是在成年后开始的。患者大腿前、内侧肌无力，远端挛缩（56.3%），CK水平升高（1287.9±757.8 U/l），肌肉组织病理学上出现具有肌膜特征的自噬空泡。肌肉 MRI（n  = 10）显示下肢肌肉受累的特征模式。 11 名患者的平均随访时间为 10.6 ± 9.8 年，其中 6 名患者出现疾病进展。 Brooke 功能结果的平均变化为 0.5 ± 1.2 分，Vignos 评分为 2.2 ± 2.5 分，7/16 名患者 (43.8%) 需要助行器，3/16 (18.8%) 需要坐轮椅（中位年龄 40 岁）岁，范围 39-48）。变体 c.164-7 T > G 与较晚出现的症状相关。呼吸功能不全常见（57.1%），但心脏受累罕见（12.5%）。

解释

XMEA 的发病年龄各不相同，但具有特征性的临床、组织病理学和肌肉影像学表现，可指导诊断。虽然运动障碍进展缓慢，但会随着时间的推移而进展，相关的基因型-表型相关性将有助于设计未来的临床试验。