Department of Neurology, Mayo Clinic, Jacksonville, FL, USA; Division of Neurological and Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdansk, Gdansk, Poland; Neurology Department, St Adalbert Hospital, Copernicus PL Ltd., Gdansk, Poland.
Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA.
Parkinsonism Relat Disord. 2024 Apr;121:105894. doi: 10.1016/j.parkreldis.2023.105894. Epub 2023 Oct 10.
Recent developments in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and other disorders due to CSF1R variants led to the emergence of symptomatic and prophylactic treatment options. The growing body of knowledge on genetics, pathomechanisms, clinical, and radiological features in patients harboring CSF1R variants challenges the current concepts and terminology to define the disorders, in addition to bringing up new questions on genotype-phenotype relationships. Therefore, this paper discusses the present complexities and challenges in the research on ALSP due to CSF1R variants. We illustrate our new concepts with two cases that are compound heterozygotes for CSF1R variants. Although their clinical phenotype resembles ALSP, the diagnosis of brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) seems more appropriate based on their genotype. As the diagnostic classification dilemma cannot be resolved with currently used concepts and terminology on these disorders, we propose a new nomenclature of "CSF1R-related disorder" with subcategories of "early-onset (<18 years old) and late-onset (≥18 years old) forms". We highlight the heterogeneity of CSF1R variant carriers in age at onset, spectrum and severity of clinical presentation, and progression rate, even within the same family. We argue that multiple factors, including genetic architecture and environment, converge to result in an individual's disease phenotype.
最近，成人发病脑白质海绵状变性伴轴索性球体和色素性神经胶质病（ALSP）和其他因 CSF1R 变异引起的疾病的发展，导致出现了有症状和预防性的治疗选择。在携带 CSF1R 变异的患者中，遗传学、病理机制、临床和影像学特征的知识不断增加，这不仅对当前定义疾病的概念和术语提出了挑战，还提出了关于基因型-表型关系的新问题。因此，本文讨论了 CSF1R 变异引起的 ALSP 研究中的当前复杂性和挑战。我们用两个 CSF1R 变异的复合杂合子病例来说明我们的新概念。尽管他们的临床表现类似于 ALSP，但根据他们的基因型，脑异常、神经退行性变和骨发育不良（BANDDOS）的诊断似乎更合适。由于目前用于这些疾病的概念和术语无法解决诊断分类的困境，我们提出了一个新的命名法“CSF1R 相关疾病”，分为“早发（<18 岁）和晚发（≥18 岁）形式”两个亚类。我们强调了 CSF1R 变异携带者在发病年龄、临床表现的谱和严重程度以及进展速度方面的异质性，即使在同一家庭中也是如此。我们认为，包括遗传结构和环境在内的多种因素共同导致了个体的疾病表型。
