Mandler Julia M, Härtl Johanna, Cordts Isabell, Sturm Marc, Hedderich Dennis M, Bafligil Cemsel, Baki Enayatullah, Becker Benedikt, Machetanz Gerrit, Haack Tobias B, Berthele Achim, Hemmer Bernhard, Deschauer Marcus
Department of Neurology, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, München, Germany.
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Mult Scler J Exp Transl Clin. 2024 Jul 24;10(3):20552173241263491. doi: 10.1177/20552173241263491. eCollection 2024 Jul-Sep.
Multiple sclerosis (MS) shares clinical/radiological features with several monogenic diseases that can mimic MS.
We aimed to determine if exome sequencing can identify monogenic diseases in patients diagnosed with MS according to the McDonald criteria thus uncovering them as being misdiagnosed.
We performed whole exome sequencing in a cohort of 278 patients with MS, clinically or radiologically isolated syndrome without cerebrospinal fluid-specific oligoclonal bands (CSF-OCBs) (n = 228), a positive family history of MS (n = 44), or both (n = 6), thereby focusing on individuals potentially more likely to have underlying monogenic conditions mimicking MS. We prioritized 495 genes associated with monogenic diseases sharing features with MS.
A disease-causing variant in was identified in one patient without CSF-OCBs, no spinal lesions, with non-response to immunotherapy, and a family history of dementia, thereby converting the diagnosis to cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Moreover, 18 patients (6.5% of total) carried variants of unclear significance.
Monogenic diseases being misdiagnosed as MS seem rare in patients diagnosed with MS according to the McDonald criteria, even in CSF-OCB negative cases. The detected pathogenic variant emphasizes CADASIL as a rare differential diagnosis and highlights the relevance of genetic testing in selected MS cases with atypical presentations.
多发性硬化症（MS）与几种可模仿MS的单基因疾病具有临床/放射学特征。
我们旨在确定外显子组测序是否能在根据麦克唐纳标准诊断为MS的患者中识别出单基因疾病，从而发现他们被误诊。
我们对278例MS患者进行了全外显子组测序，这些患者临床上或放射学上为孤立综合征且无脑脊液特异性寡克隆带（CSF-OCBs）（n = 228）、有MS家族史阳性（n = 44）或两者皆有（n = 6），从而聚焦于可能更易患有模仿MS的潜在单基因疾病的个体。我们对与具有MS特征的单基因疾病相关的495个基因进行了优先排序。
在一名无CSF-OCBs、无脊髓病变、对免疫治疗无反应且有痴呆家族史的患者中鉴定出一种致病变异，从而将诊断转变为伴有皮质下梗死和白质脑病的大脑常染色体显性动脉病（CADASIL）。此外，18名患者（占总数的6.5%）携带意义不明确的变异。
在根据麦克唐纳标准诊断为MS的患者中，被误诊为MS的单基因疾病似乎很少见，即使在CSF-OCB阴性的病例中也是如此。检测到的致病变异强调CADASIL作为一种罕见的鉴别诊断，并突出了基因检测在具有非典型表现的特定MS病例中的相关性。
