Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.
Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
J Neurol Neurosurg Psychiatry. 2014 Sep;85(9):1024-8. doi: 10.1136/jnnp-2013-306981. Epub 2014 Feb 12.
Autosomal-recessive hereditary spastic paraplegias (AR-HSP) consist of a genetically diverse group of neurodegenerative diseases characterised by pyramidal tracts dysfunction. The causative genes for many types of AR-HSP remain elusive. We tried to identify the gene mutation for AR-HSP with cerebellar ataxia and neuropathy.
This study included two patients in a Japanese family with their parents who are first cousins. Neurological examination and gene analysis were conducted in the two patients and two normal family members. We undertook genome-wide linkage analysis employing single nucleotide polymorphism arrays using the two patients' DNAs and exome sequencing using one patient's sample.
We detected a homozygous missense mutation (c.4189T>G, p.F1397V) in the lysosomal trafficking regulator (LYST) gene, which is described as the causative gene for Chédiak-Higashi syndrome (CHS). CHS is a rare autosomal-recessive syndrome characterised by hypopigmentation, severe immune deficiency, a bleeding tendency and progressive neurological dysfunction. This mutation was co-segregated with the disease in the family and was located at well-conserved amino acid. This LYST mutation was not found in 200 Japanese control DNAs. Microscopic observation of peripheral blood in the two patients disclosed large peroxidase-positive granules in both patients' granulocytes, although they had no symptoms of immune deficiency or bleeding tendency.
We diagnosed these patients as having adult CHS presenting spastic paraplegia with cerebellar ataxia and neuropathy. The clinical spectrum of CHS is broader than previously recognised. Adult CHS must be considered in the differential diagnosis of AR-HSP.
常染色体隐性遗传性痉挛性截瘫（AR-HSP）由一组遗传异质性的神经退行性疾病组成，其特征是锥体束功能障碍。许多类型的 AR-HSP 的致病基因仍未被发现。我们试图鉴定具有小脑共济失调和神经病的 AR-HSP 的基因突变。
本研究纳入了一个日本家庭的两名患者及其父母（他们是表亲）。对两名患者和两名正常家庭成员进行了神经学检查和基因分析。我们对两名患者的 DNA 进行了全基因组连锁分析，使用单核苷酸多态性微阵列，对一名患者的样本进行了外显子测序。
我们在溶酶体转运调节因子（LYST）基因中检测到一个纯合错义突变（c.4189T>G，p.F1397V），该基因被描述为 Chédiak-Higashi 综合征（CHS）的致病基因。CHS 是一种罕见的常染色体隐性遗传综合征，其特征为色素减退、严重免疫缺陷、出血倾向和进行性神经功能障碍。该突变与家族中的疾病共分离，且位于高度保守的氨基酸位置。该 LYST 突变未在 200 例日本对照 DNA 中发现。对两名患者的外周血进行显微镜观察发现，两名患者的粒细胞中均存在大量过氧化物酶阳性颗粒，尽管他们没有免疫缺陷或出血倾向的症状。
我们诊断这两名患者为具有小脑共济失调和神经病的痉挛性截瘫的成人 CHS。CHS 的临床谱比以前认识到的更广泛。在 AR-HSP 的鉴别诊断中必须考虑到成人 CHS。
