Yanagisawa A, Bouchet C, Van den Bergh P Y K, Cuisset J-M, Viollet L, Leturcq F, Romero N B, Quijano-Roy S, Fardeau M, Seta N, Guicheney P
INSERM, U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Neurology. 2007 Sep 18;69(12):1254-60. doi: 10.1212/01.wnl.0000268489.60809.c4. Epub 2007 Jul 18.
Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance, often associated with CNS and ocular involvement. They are characterized by the abnormal glycosylation of alpha-dystroglycan, and caused by mutations in at least six genes encoding enzymes: FKTN, POMGNT1, POMT1, POMT2, FKRP, and LARGE. POMT2 mutations have recently been identified in Walker-Warburg syndrome and in a milder muscle-eye-brain disease-like form.
We studied mentally retarded patients with CMD, analyzed POMT2 by sequencing the coding regions, and also performed a haplotype analysis in all patients and their family members carrying the new POMT2 mutation.
We report three novel POMT2 mutations. One of these, p.Tyr666Cys, was homozygous in two unrelated patients and in a compound heterozygous state in others. All patients showed severe diffuse muscle weakness, microcephaly, severe mental retardation, and marked lordoscoliosis with hyperextended head. Elevated CK levels, cerebral cortical atrophy, and cerebellar vermis hypoplasia were constant findings. Mild cardiac abnormalities, focal white matter abnormalities, or partial corpus callosum hypoplasia were detected in single cases. Eye involvement was absent or mild. By genotype analysis, we defined a distinct 170kb haplotype encompassing POMT2 and shared by all the subjects harboring the mutation p.Tyr666Cys.
Our results broaden the clinical spectrum associated with POMT2 mutations, which should be considered in patients with CMD associated with microcephaly, and severe mental retardation with or without ocular involvement.
糖基化缺陷型肌营养不良症是一组常染色体隐性遗传的先天性肌营养不良症（CMD），常伴有中枢神经系统和眼部受累。其特征为α-肌营养不良蛋白聚糖糖基化异常，由至少六个编码酶的基因突变引起：FKTN、POMGNT1、POMT1、POMT2、FKRP和LARGE。最近在沃克-沃尔伯格综合征以及一种较轻的类似肌肉-眼-脑疾病的类型中发现了POMT2突变。
我们研究了患有CMD的智力发育迟缓患者，通过对编码区进行测序分析POMT2，并对所有携带新的POMT2突变的患者及其家庭成员进行单倍型分析。
我们报告了三个新的POMT2突变。其中一个，p.Tyr666Cys，在两名无亲缘关系的患者中为纯合子，在其他患者中为复合杂合子状态。所有患者均表现出严重的弥漫性肌无力、小头畸形、严重智力发育迟缓以及明显的脊柱前凸伴头部后仰。肌酸激酶水平升高、大脑皮质萎缩和小脑蚓部发育不全是常见表现。个别病例中检测到轻度心脏异常、局灶性白质异常或胼胝体部分发育不全。眼部无受累或受累较轻。通过基因型分析，我们确定了一个独特的170kb单倍型，其包含POMT2，且所有携带p.Tyr666Cys突变的受试者均共享该单倍型。
我们的结果拓宽了与POMT2突变相关的临床谱，对于伴有小头畸形、有或无眼部受累的严重智力发育迟缓的CMD患者应考虑该突变。
