AP4M1 相关性遗传性痉挛性截瘫的基因型-表型相关性及分子谱扩展。
Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia.
机构信息
Department of Molecular Neuroscience, Institute of Neurology, University College London, London, WC1N 3BG, UK.
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, WC1N 3BG, UK.
出版信息
Orphanet J Rare Dis. 2017 Nov 2;12(1):172. doi: 10.1186/s13023-017-0721-2.
BACKGROUND
Autosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients.
METHODS
We investigated a Greek HSP family using whole exome sequencing (WES).
RESULTS
A novel AP4M1A frameshift insertion, and a very rare missense variant were identified in all three affected siblings in the compound heterozygous state (p.V174fs and p.C319R); the unaffected parents were carriers of only one variant. Patients were affected with a combination of: (a) febrile seizures with onset in the first year of life (followed by epileptic non-febrile seizures); (b) distinctive facial appearance (e.g., coarse features, bulbous nose and hypomimia); (c) developmental delay and intellectual disability; (d) early-onset spastic weakness of the lower limbs; and (e) cerebellar hypoplasia/atrophy on brain MRI.
CONCLUSIONS
We review genotype-phenotype correlations and discuss clinical overlaps between different AP4-related diseases. The AP4M1 belongs to a complex that mediates vesicle trafficking of glutamate receptors, being likely involved in brain development and neurotransmission.
背景
AP4M1 突变导致的常染色体隐性遗传性痉挛性截瘫（HSP）是一种非常罕见的神经发育障碍，仅报道了少数几例患者。
方法
我们使用外显子组测序（WES）对一个希腊 HSP 家族进行了研究。
结果
在 3 位复合杂合子受影响的兄弟姐妹中均发现了一种新的 AP4M1A 移码插入和一种非常罕见的错义变异（p.V174fs 和 p.C319R）；未受影响的父母仅携带一种变体。患者受以下多种因素影响：（a）在生命的第一年发生的热性惊厥（随后发生癫痫性无热惊厥）；（b）独特的面部特征（例如，粗糙的特征、球状鼻子和表情缺失）；（c）发育迟缓伴智力障碍；（d）下肢痉挛性无力早发；（e）脑 MRI 显示小脑发育不良/萎缩。
结论
我们回顾了基因型-表型相关性，并讨论了不同 AP4 相关疾病之间的临床重叠。AP4M1 属于一种介导谷氨酸受体囊泡运输的复合物，可能参与脑发育和神经传递。
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