Department of Pediatrics at the Institute for Genetic and Metabolic Diseases, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Pediatrics. 2012 Oct;130(4):e1034-9. doi: 10.1542/peds.2011-2711. Epub 2012 Sep 10.
Deficiency of β-1,4 mannosyltransferase (MT-1) congenital disorder of glycosylation (CDG), due to ALG1 gene mutations. Features in 9 patients reported previously consisted of prenatal growth retardation, pregnancy-induced maternal hypertension and fetal hydrops. Four patients died before 5 years of age, and survivors showed a severe psychomotor retardation. We report on 7 patients with psychomotor delay, microcephaly, strabismus and coagulation abnormalities, seizures and abnormal fat distribution. Four children had a stable clinical course, two had visual impairment, and 1 had hearing loss. Thrombotic and vascular events led to deterioration of the clinical outcome in 2 patients. Four novel ALG1 mutations were identified. Pathogenicity was determined in alg1 yeast mutants transformed with hALG1. Functional analyses showed all novel mutations representing hypomorphs associated with residual enzyme activity. We extend the phenotypic spectrum including the first description of deafness in MT1 deficiency, and report on mildly affected patients, surviving to adulthood. The dysmorphic features, including abnormal fat distribution and strabismus highly resemble CDG due to phosphomannomutase-2 deficiency (PMM2-CDG), the most common type of CDG. We suggest testing for ALG1 mutations in unsolved CDG patients with a type 1 transferrin isoelectric focusing pattern, especially with epilepsy, severe visual loss and hemorrhagic/thrombotic events.
β-1,4 甘露糖基转移酶（MT-1）缺陷型先天性糖基化障碍（CDG），由 ALG1 基因突变引起。先前报道的 9 例患者的特征包括产前生长迟缓、妊娠引起的母亲高血压和胎儿水肿。4 名患者在 5 岁之前死亡，幸存者表现出严重的精神运动发育迟缓。我们报告了 7 例精神运动发育迟缓、小头畸形、斜视和凝血异常、癫痫发作和脂肪分布异常的患者。4 名儿童的临床病程稳定，2 名儿童视力受损，1 名儿童听力受损。血栓形成和血管事件导致 2 名患者的临床预后恶化。发现了 4 个新的 ALG1 突变。在转化为 hALG1 的 alg1 酵母突变体中确定了致病性。功能分析表明，所有新突变均代表与残留酶活性相关的低功能突变体。我们扩展了表型谱，包括首次描述 MT1 缺陷型耳聋，并报告了轻度受影响的患者，可存活至成年。发育异常特征，包括脂肪分布异常和斜视，与磷酸甘露糖变位酶-2 缺陷型（PMM2-CDG）非常相似，后者是最常见的 CDG 类型。我们建议对 1 型转铁蛋白等电聚焦模式的未解决 CDG 患者进行 ALG1 突变检测，特别是有癫痫、严重视力丧失和出血/血栓事件的患者。
