CSF1R突变引起常染色体显性遗传CSF1R相关白质脑病,伴有轴突球状体和色素胶质细胞(CSF1R-ALSP)和常染色体隐性遗传性脑异常,神经变性,和肌营养不良症(BANDDOS)。前者越来越被认可,并引入了疾病改善疗法;然而,后者的文献很少。这篇综述分析了BANDDOS,并讨论了与CSF1R-ALSP的异同。我们系统地检索和分析了临床,遗传,放射学,以及先前报道的病理数据和我们的BANDDOS病例。我们确定了19例BANDDOS患者(根据PRISMA2020指南进行文献检索:n=16,我们的材料:n=3)。我们发现了11个CSF1R突变,包括拼接(n=3),错觉(n=3),废话(n=2),和内含子(n=2)变体和一个内框缺失。所有突变都破坏了酪氨酸激酶结构域或导致无义介导的mRNA衰变。材料是异质的,所提供的信息是指对特定症状有足够数据的患者数量,结果,或执行的程序。最初的症状发生在围产期(n=5),婴儿期(n=2),童年(n=5),和成年期(n=1)。7/17例存在畸形特征。神经系统症状包括言语障碍(n=13/15),认知能力下降(n=12/14),痉挛/刚度(n=12/15),肌腱反射过度活跃(n=11/14),病理性反射(n=8/11),癫痫发作(n=9/16),吞咽困难(n=9/12),发育迟缓(n=7/14),婴儿张力减退(n=3/11),和视神经萎缩(n=2/7)。在13/17例中观察到骨骼畸形,属于肌硬化障碍-派尔疾病谱。脑异常包括白质改变(n=19/19),钙化(n=15/18),call体发育不全(n=12/16),脑室增宽(n=13/19),丹迪-沃克复合体(n=7/19),和皮质异常(n=4/10)。三个病人在婴儿期死亡,两个在童年,和一个年龄不明的案例。一个单一的大脑尸检证实了多个大脑异常,没有call体,没有小胶质细胞,轴突球状体严重白质萎缩,胶质增生,和许多营养不良性钙化。总之,BANDDOS出现在围产期或婴儿期,具有先天性脑异常的破坏性过程,发育迟缓,神经功能缺损,骨硬化,和畸形特征。在临床上有明显的重叠,放射学,BANDDOS和CSF1R-ALSP之间的神经病理学方面。因为两种疾病都在同一个连续统一体,有机会将CSF1R-ALSP中的可用疗法应用于BANDDOS。
CSF1R mutations cause autosomal-dominant CSF1R-related
leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) and autosomal-recessive brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). The former is increasingly recognized, and disease-modifying therapy was introduced; however, literature is scarce on the latter. This
review analyzes BANDDOS and discusses similarities and differences with CSF1R-ALSP.We systematically retrieved and analyzed the clinical, genetic, radiological, and pathological data on the previously reported and our cases with BANDDOS. We identified 19 patients with BANDDOS (literature search according to the PRISMA 2020 guidelines: n = 16, our material: n = 3). We found 11 CSF1R mutations, including splicing (n = 3), missense (n = 3), nonsense (n = 2), and intronic (n = 2) variants and one inframe deletion. All mutations disrupted the tyrosine kinase domain or resulted in nonsense-mediated mRNA decay. The material is heterogenous, and the presented information refers to the number of patients with sufficient data on specific symptoms, results, or performed procedures. The first symptoms occurred in the perinatal period (n = 5), infancy (n = 2), childhood (n = 5), and adulthood (n = 1). Dysmorphic features were present in 7/17 cases. Neurological symptoms included speech disturbances (n = 13/15), cognitive decline (n = 12/14), spasticity/rigidity (n = 12/15), hyperactive tendon reflex (n = 11/14), pathological reflexes (n = 8/11), seizures (n = 9/16), dysphagia (n = 9/12), developmental delay (n = 7/14), infantile hypotonia (n = 3/11), and optic nerve atrophy (n = 2/7). Skeletal deformities were observed in 13/17 cases and fell within the dysosteosclerosis - Pyle disease spectrum. Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10). Three patients died in infancy, two in childhood, and one case at unspecified age. A single brain autopsy evidenced multiple brain anomalies, absence of corpus callosum, absence of microglia, severe white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications.In conclusion, BANDDOS presents in the perinatal period or infancy and has a devastating course with congenital brain abnormalities, developmental delay, neurological deficits, osteopetrosis, and dysmorphic features. There is a significant overlap in the clinical, radiological, and neuropathological aspects between BANDDOS and CSF1R-ALSP. As both disorders are on the same continuum, there is a window of opportunity to apply available therapy in CSF1R-ALSP to BANDDOS.