PDF(Pubmed)
Abstract：
Biallelic pathogenic variants in MADD lead to a very rare neurodevelopmental disorder which is phenotypically pleiotropic grossly ranging from severe neonatal hypotonia, failure to thrive, multiple organ dysfunction, and early lethality to a similar but milder phenotype with better survival. Here, we report 5 patients from 3 unrelated Egyptian families in whom 4 patients showed the severe end of the spectrum displaying neonatal respiratory distress, hypotonia and chronic diarrhea while one patient presented with the mild form displaying moderate intellectual disability and myopathy. In addition, we observed distal arthrogryposis and nonspecific structural brain anomalies in all our patients. Interestingly, cerebellar and brainstem hypoplasia were noted in one patient. Whole exome sequencing identified three novel homozygous variants in the MADD gene: two likely pathogenic [c.4321delC p.(Gln1441ArgfsTer46) and c.2620 C > T p.(Arg874Ter)] and one variant of uncertain significance (c.4307 G > A, p.Arg1436Gln). The variants segregated with the disease in all available family members. Our findings confirm that arthrogryposis, genital, cardiac and structural brain anomalies are manifestations of MADD which expand the spectrum of MADD-related neurodevelopmental disorder. Moreover, they further highlight the convergence of MADD variants on different organ systems leading to complex phenotypes.
摘要：
MADD中的双等位基因致病变异导致一种非常罕见的神经发育障碍，这种疾病在表型上是多效性的，严重的新生儿张力减退，未能茁壮成长，多器官功能障碍,和早期的杀伤力相似但温和的表型，具有更好的存活率。这里,我们报告了来自3个无关埃及家庭的5名患者，其中4名患者表现出严重的频谱末端，显示新生儿呼吸窘迫，张力减退和慢性腹泻，而一名患者表现为轻度形式，表现为中度智力残疾和肌病。此外,我们在所有患者中观察到远端关节发育不良和非特异性脑结构性异常.有趣的是,1例患者出现小脑和脑干发育不全。全外显子组测序确定了MADD基因中的三个新的纯合变体：两个可能的致病性[c.4321delCp。（Gln1441ArgfsTer46）和c.2620C>Tp。（Arg874Ter）]和一个不确定意义的变体（c.4307G>A，p.Arg1436Gln)。变体在所有可用的家族成员中与疾病分离。我们的发现证实了关节病，生殖器,心脏和脑结构异常是MADD的表现,扩大了MADD相关神经发育障碍的范围.此外，他们进一步强调了MADD变异在不同器官系统上的趋同,导致复杂的表型.
