PDF(Pubmed)
Abstract：
PU.1-mutated agammaglobulinemia (PU.MA) represents a recently described autosomal-dominant form of agammaglobulinemia caused by mutation of the SPI1 gene. This gene codes for PU.1 pioneer transcription factor important for the maturation of monocytes, B lymphocytes, and conventional dendritic cells. Only six cases with PU.MA, presenting with chronic sinopulmonary and systemic enteroviral infections, have been previously described. Accumulating literature evidence suggests a possible relationship between SPI1 mutation, microglial phagocytic dysfunction, and the development of Alzheimer\'s disease (AD).
We present a Caucasian female patient born from a non-consanguineous marriage, who was diagnosed with agammaglobulinemia at the age of 15 years when the immunoglobulin replacement therapy was started. During the following seventeen years, she was treated for recurrent respiratory and intestinal infections. At the age of 33 years, the diagnosis of celiac-like disease was established. Five years later progressive cognitive deterioration, unstable gait, speech disturbances, and behavioral changes developed. Comprehensive microbiological investigations were negative, excluding possible infective etiology. Brain MRI, 18FDG-PET-CT, and neuropsychological testing were suggestive for a diagnosis of a frontal variant of AD. Clinical exome sequencing revealed the presence of a novel frameshift heterozygous variant c.441dup in exon 4 of the SPI1 gene. Despite intensive therapy, the patient passed away a few months after the onset of the first neurological symptoms.
We describe the first case of PU.MA patient presenting with a rapidly progressive neurocognitive deterioration. The possible role of microglial dysfunction in patients with SPI1 mutation could explain their susceptibility to neurodegenerative diseases thus highlighting the importance of genetic testing in patients with inborn errors of immunity. Since PU.MA represents a newly described form of agammaglobulinemia, our case expands the spectrum of manifestations associated with SPI1 mutation.
We present a Caucasian female patient born from a non-consanguineous marriage, who was diagnosed with agammaglobulinemia at the age of 15 years when the immunoglobulin replacement therapy was started. During the following seventeen years, she was treated for recurrent respiratory and intestinal infections. At the age of 33 years, the diagnosis of celiac-like disease was established. Five years later progressive cognitive deterioration, unstable gait, speech disturbances, and behavioral changes developed. Comprehensive microbiological investigations were negative, excluding possible infective etiology. Brain MRI, 18FDG-PET-CT, and neuropsychological testing were suggestive for a diagnosis of a frontal variant of AD. Clinical exome sequencing revealed the presence of a novel frameshift heterozygous variant c.441dup in exon 4 of the SPI1 gene. Despite intensive therapy, the patient passed away a few months after the onset of the first neurological symptoms.
We describe the first case of PU.MA patient presenting with a rapidly progressive neurocognitive deterioration. The possible role of microglial dysfunction in patients with SPI1 mutation could explain their susceptibility to neurodegenerative diseases thus highlighting the importance of genetic testing in patients with inborn errors of immunity. Since PU.MA represents a newly described form of agammaglobulinemia, our case expands the spectrum of manifestations associated with SPI1 mutation.
摘要：
■PU.1突变的无丙种球蛋白血症（PU。MA）代表了最近描述的由SPI1基因突变引起的异丙种球蛋白血症的常染色体显性形式。该基因编码PU.1先锋转录因子，对单核细胞的成熟很重要，B淋巴细胞,和传统的树突状细胞。只有6例PU。MA,表现为慢性鼻肺和全身性肠病毒感染，之前已经描述过了。越来越多的文献证据表明，SPI1突变之间可能存在关系，小胶质细胞吞噬功能障碍，和阿尔茨海默病（AD）的发展。
■我们介绍了一名非近亲婚姻出生的白人女性患者，在开始免疫球蛋白替代疗法时，他在15岁时被诊断出患有无丙种球蛋白血症。在接下来的十七年里，她因反复呼吸道和肠道感染而接受治疗。33岁时,建立了乳糜泻的诊断。五年后进行性认知恶化，不稳定的步态,言语障碍,和行为的变化发展。综合微生物调查呈阴性，排除可能的感染性病因。脑部核磁共振,18FDG-PET-CT,和神经心理学测试提示诊断AD的额叶变体。临床外显子组测序显示，在SPI1基因的外显子4中存在一个新的移码杂合变体c.441dup。尽管有强化治疗,患者在首次出现神经系统症状几个月后去世。
■我们描述PU的第一种情况。表现为快速进行性神经认知恶化的MA患者。小胶质细胞功能障碍在SPI1突变患者中的可能作用可以解释他们对神经退行性疾病的易感性，从而突出了遗传检测在先天性免疫错误患者中的重要性。自PU。MA代表一种新描述的无丙种球蛋白血症，我们的病例扩展了与SPI1突变相关的表现谱.
■我们介绍了一名非近亲婚姻出生的白人女性患者，在开始免疫球蛋白替代疗法时，他在15岁时被诊断出患有无丙种球蛋白血症。在接下来的十七年里，她因反复呼吸道和肠道感染而接受治疗。33岁时,建立了乳糜泻的诊断。五年后进行性认知恶化，不稳定的步态,言语障碍,和行为的变化发展。综合微生物调查呈阴性，排除可能的感染性病因。脑部核磁共振,18FDG-PET-CT,和神经心理学测试提示诊断AD的额叶变体。临床外显子组测序显示，在SPI1基因的外显子4中存在一个新的移码杂合变体c.441dup。尽管有强化治疗,患者在首次出现神经系统症状几个月后去世。
■我们描述PU的第一种情况。表现为快速进行性神经认知恶化的MA患者。小胶质细胞功能障碍在SPI1突变患者中的可能作用可以解释他们对神经退行性疾病的易感性，从而突出了遗传检测在先天性免疫错误患者中的重要性。自PU。MA代表一种新描述的无丙种球蛋白血症，我们的病例扩展了与SPI1突变相关的表现谱.
