Lujan-Fryns綜合症

Lujan-Fryns綜合症（Lujan–Fryns syndrome、LFS）是一種X染色體伴性遺傳障礙，會導致輕度至中度智能障礙和類似於馬凡氏症候群的特徵。特徵包括高瘦身材和修長四肢。

歸因於MED12基因的錯義突變，該疾病以X連鎖顯性遺傳方式遺傳。

體徵和症狀
智力障礙通常從輕度到中度不等，但也有嚴重病例的報導。

相對常見的大腦異常，綜合症的是，因胚胎發育錯誤導致不存在連接左右兩個大腦半球的胼胝體。缺乏胼胝體會發現許多不良神經學影響，智力障礙的發生率約73%。

Additional alterations of psychopathology with behavioral manifestations that have been observed in LFS include: psychotic behavior, schizophrenia, hyperactivity and attention-deficit hyperactivity disorder, obsessive compulsive disorder,

The psychopathology of LFS usually exhibits schizophrenia. Marfanoid habitus describes a group of physical features common to Marfan syndrome.

In LFS, specific features identified as marfanoid include: a long, narrow face; with joint hyperextensibility, In LFS, hypernasality may also be caused by failure of the soft palate and uvula to reach the back wall of the pharynx (the interior cavity of the throat where swallowing generally occurs) during speech, a condition that can be associated with a submucosal cleft palate.

心臟
A number of features involving the heart have been noted in several LFS cases, the most significant being dilation of the aortic root, a section of the ascending aorta. As this presents a possible life-threatening consequence of LFS, routine cardiac evaluation methods such as echocardiogram are implemented when the disorder is first diagnosed, along with MRI scans of the brain to screen for suspected agenesis of the corpus callosum. Missense mutations are genetic point mutations in which a single nucleotide in the genetic sequence is exchanged with another one. This leads to an erroneously substitution of a particular amino acid in the protein sequence during translation. The missense mutation in the MED12 gene, that causes LFS, is identified as p.N1007S.

The Mediator complex is required for polymerase II transcription and acts as a bridge between the polymerase II enzyme and different gene-specific transcription factors. Mediator can contain up to 30 subunits, but some of the subunits are only required for regulation of transcription in particular tissues or cells. Currently, the exact mechanism by which dysfunction of MED12 results in LFS and its associated neuropsychopathic and physical characteristics is unclear. Marfanoid habitus, a highly arched palate and several other features of LFS can be found with Marfan syndrome, a connective tissue disorder. In zebrafish, a mutation in MED12 was found to be responsible for the mutant motionless (mot). Zebrafish with the mot mutation have neuronal and cardiovascular defects, although not all types of neurons are affected. Introduction of human MED12 mRNA into the zebrafish restores normal development. MED12 is also a critical coactivator for the gene SOX9, which is involved in the developmental regulation of neurons, cartilage and bone. In the zebrafish, MED12 defects cause maldevelopment of vertebrate embryonic structures such as the neural crest, which would alter function of the autonomic and peripheral nervous systems; and they also cause malformations of cell types serving as precursors to cartilage and bone, such as osteocytes. Some features found in LFS, like agenesis of the corpus callosum and cartilage-related craniofacial anomalies, are similar to defects found in zebrafish with MED12 and associated mutations.

與其他遺傳病的相似之處
An individual exhibiting intellectual disability and other symptoms similar to LFS was found to have a terminal deletion of the subtelomeric region in the short arm of chromosome 5. Fryns (2006) suggests a detailed examination of chromosome 5 with FISH should be performed as part of the differential diagnosis of LFS. UPF3B is part of the nonsense-mediated mRNA decay (NMD) complex, which performs mRNA surveillance, detecting mRNA sequences that have been erroneously truncated (shortened) by the presence of nonsense mutations. Mutations in UPF3B alter and prevent normal function of the NMD pathway, resulting in translation and expression of truncated mRNA sequences into malfunctioning proteins that can be associated with developmental errors and intellectual disability. Individuals from two families diagnosed with LFS and one family with FGS were found to have mutations in UPF3B, confirming that the clinical presentations of the different mutations can overlap. Common features shared by both LFS and FGS include X-linked intellectual disability, hyperactivity, macrocephaly, corpus callosum agenesis and hypotonia.

綜合症與錯義突變 p.N1007S 相關，而 FGS 與錯義突變 p.R961W 相關。 As both disorders originate from an identical type of mutation in the same gene, while exhibiting similar, yet distinct characteristics; LFS and FGS are considered to be allelic. The initial observation of suspected X-linked intellectual disability with Marfanoid features and craniofacial effects such as a high-arched palate was described by Lujan et al. in 1984.

In the report, four affected male members of a large kindred (consanguinous family) were noted.

参见
*Fragile X syndrome
*Aarskog syndrome
*Coffin–Lowry syndrome
*FG syndrome

參考
延伸閱讀
[https://www.ncbi.nlm.nih.gov/books/NBK1676/ GeneReview/NIH/UW entry on MED12*-Related Disorders]
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外部鏈接