Guillén-Navarro Encarna, Domingo-Jiménez María Rosario, Alcalde-Martín Carlos, Cancho-Candela Ramón, Couce María Luz, Galán-Gómez Enrique, Alonso-Luengo Olga
Orphanet J Rare Dis. 2013 Jun 25;8:92. doi: 10.1186/1750-1172-8-92.
Mucopolysaccharidosis type II (MPS II) is an inherited X-linked disease associated with a deficiency in the enzyme iduronate 2-sulfatase due to iduronate 2-sulfatase gene (IDS) mutations. Recent studies in MPS II carriers did not find clinical involvement, but these were mainly performed by anamnesis and patients' self-reported description of signs and symptoms. So although it is rare in heterozygous carriers, investigations in other types of inherited X-linked disorders suggest that some clinical manifestations may be a possibility. The aim of this study was to evaluate the clinical pattern in female carriers of MPS II and to determine whether clinical symptoms were associated with the X-chromosome inactivation (XCI) pattern and age.
Female carriers of MPS II were genetically identified by molecular analysis of IDS. The clinical evaluation protocol included pedigree analysis, a comprehensive anamnesis, complete physical examination, ophthalmological evaluation, brain-evoked auditory response, electrocardiogram, echocardiogram, pulmonary function tests, abdominal sonogram, skeletal survey, neurophysiological studies, blood cell counts and biochemistry, urine glycosaminoglycan (GAGs) quantification, karyotype and pattern of XCI.
Ten women were included in the study. The mean age of the participants was 40.2 ± 13.1 years. Six carriers presented a skewed XCI pattern, 3 of whom (aged 38, 42 and 52 years) had increased levels of GAGs in the urine and showed typical MPS II clinical manifestations, such as skeletal anomalies, liver abnormalities, carpal tunnel syndrome, recurrent ear infection, hypoacusia and more frequent severe odontological problems without coarse facial features.
This is the first study performing a comprehensive evaluation of heterozygous MPS II carriers. Our results provide evidence of possible progressive, age-dependent, mild clinical manifestations in MPS II female carriers with a skewed XCI pattern, most likely affecting the normal allele. Further comparative studies with systematized clinical examinations in larger age-stratified populations of MPS II female carriers are required.
II型黏多糖贮积症（MPS II）是一种遗传性X连锁疾病，由于艾杜糖醛酸2 -硫酸酯酶基因（IDS）突变导致艾杜糖醛酸2 -硫酸酯酶缺乏。近期对MPS II携带者的研究未发现临床受累情况，但这些研究主要通过问诊以及患者对体征和症状的自我报告描述进行。所以尽管在杂合子携带者中较为罕见，但对其他类型遗传性X连锁疾病的研究表明，可能存在一些临床表现。本研究的目的是评估MPS II女性携带者的临床模式，并确定临床症状是否与X染色体失活（XCI）模式及年龄相关。
通过对IDS的分子分析对MPS II女性携带者进行基因鉴定。临床评估方案包括系谱分析、全面问诊、完整体格检查、眼科评估、脑诱发电位听觉反应、心电图、超声心动图、肺功能测试、腹部超声、骨骼检查、神经生理学研究、血细胞计数及生化检查、尿糖胺聚糖（GAGs）定量、核型分析及XCI模式。
10名女性纳入本研究。参与者的平均年龄为40.2±13.1岁。6名携带者呈现偏态XCI模式，其中3名（年龄分别为38岁、42岁和52岁）尿中GAGs水平升高，并表现出典型的MPS II临床表现，如骨骼异常、肝脏异常、腕管综合征、反复耳部感染、听力减退以及更频繁出现的严重牙科问题，但无粗糙面容。
这是第一项对MPS II杂合子携带者进行全面评估的研究。我们的结果为具有偏态XCI模式的MPS II女性携带者可能存在的进行性、年龄依赖性轻度临床表现提供了证据，最有可能影响正常等位基因。需要在更大年龄分层的MPS II女性携带者群体中进行系统临床检查的进一步比较研究。
