Kevelam Sietske H, Neeleman Rochus A, Waisfisz Quinten, Friesema Edith C H, Langendonk Janneke G, van der Knaap Marjo S
From the Department of Child Neurology, Amsterdam Neuroscience (S.H.K., M.S.v.d.K.), and Department of Clinical Genetics (Q.W.), VU University Medical Center, Amsterdam; Department of Internal Medicine (R.A.N., J.G.L.), and Netherlands Porphyria Center, Center for Lysosomal and Metabolic Diseases, Department of Internal Medicine (E.C.H.F., J.G.L.), Erasmus MC, Rotterdam; and Department of Functional Genomics (M.S.v.d.K.), Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands.
Neurology. 2016 Sep 20;87(12):1258-65. doi: 10.1212/WNL.0000000000003129. Epub 2016 Aug 24.
To identify the genetic etiology of a distinct leukoencephalopathy with autosomal recessive inheritance in a single family.
We analyzed available MRIs and retrospectively reviewed clinical information and laboratory investigations. We performed whole-exome sequencing to find the causal gene variants.
We identified 3 family members with a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons. Cerebellar atrophy was noted in advanced disease stages. Clinical features were childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. Whole-exome sequencing revealed compound heterozygous missense variants in the HMBS gene, both associated with the autosomal dominant disorder acute intermittent porphyria. Sanger sequencing of 6 healthy siblings confirmed the bi-allelic location of the variants and segregation with the disease. Patients had a slight and moderate increase in urinary and plasma porphobilinogen and 5'-aminolevulinic acid, respectively, and a 50% to 66% decrease in hydroxymethylbilane synthase enzyme activity compared to normal.
Bi-allelic HMBS variants have been reported before as cause of severe encephalopathy with early childhood fatality in acute intermittent porphyria. Our cases demonstrate childhood onset, but milder and slower disease progression in middle-aged patients. With this, a novel phenotype can be added to the disease spectrum associated with bi-allelic HMBS variants: a leukoencephalopathy with early onset, slowly progressive neurologic symptomatology, and long life expectancy.
确定一个单一家族中具有常染色体隐性遗传的一种独特白质脑病的遗传病因。
我们分析了现有的磁共振成像（MRI），并回顾性地审查了临床信息和实验室检查结果。我们进行了全外显子组测序以寻找致病基因变异。
我们确定了3名家庭成员具有相似的MRI模式，其特征为脑室周围和大脑深部白质、丘脑及脑桥中部出现对称性信号异常。在疾病晚期出现小脑萎缩。临床特征为儿童期起病的缓慢进展性痉挛性截瘫、小脑共济失调、周围神经病变，2例患者伴有视神经萎缩以及垂直凝视和集合麻痹及眼球震颤。全外显子组测序揭示了HMBS基因中的复合杂合错义变异，这两种变异均与常染色体显性疾病急性间歇性卟啉症相关。对6名健康同胞进行的桑格测序证实了变异的双等位基因定位以及与疾病的分离。与正常情况相比，患者的尿和血浆中胆色素原和5'-氨基乙酰丙酸分别略有和中度升高，羟甲基胆色素合酶活性降低50%至66%。
双等位基因HMBS变异此前已被报道为急性间歇性卟啉症中导致严重脑病并在儿童早期死亡的原因。我们的病例显示为儿童期起病，但在中年患者中疾病进展较温和且缓慢。由此，可以在与双等位基因HMBS变异相关的疾病谱中增加一种新的表型：一种起病早、具有缓慢进展性神经症状且预期寿命长的白质脑病。
