Abstract：
Monoallelic pathogenic HMBS variants are a well-established cause of acute intermittent porphyria (AIP), whereas biallelic pathogenic variants may cause HMBS-related leukoencephalopathy which remains a poorly characterized disorder. We describe an 8-year-old girl with hypotonia, hearing impairment, horizontal nystagmus, bilateral strabismus, impaired visual acuity, and optic nerve atrophy. She had no epilepsy but sleep electroencephalogram showed paroxysmal changes in the right hemisphere with secondary generalizations. Brain magnetic resonance imaging was unremarkable apart from a few small white matter hyperintensities. Exome sequencing (ES) initially prioritized a SCN3A c.3822G>A de novo variant whose sole causative role was eventually questioned as not fully compatible with symptoms. ES reanalysis revealed a homozygous c.674G>A HMBS variant. In the monoallelic form this variant is a known cause of AIP, whereas in trans with another HMBS pathogenic variant it was associated with the HMBS-related leukoencephalopathy in four individuals. Despite lack of signs/symptoms of porphyria, literature analysis suggested that HMBS c.674G>A likely contributed to the disease either as the sole cause or together with SCN3A c.3822G>A as a part of blended phenotype. Our report adds to the relatively small number of described cases of HMBS-related leukoencephalopathy and emphasizes that autosomal recessive form of HMBS disease can be present in the absence of porphyria symptoms.
摘要：
单等位基因致病性HMBS变异体是急性间歇性卟啉症（AIP）的公认原因，而双等位基因致病变异可能会导致HMBS相关白质脑病，这仍然是一种特征不清的疾病。我们描述了一个8岁的低张力女孩，听力障碍,水平眼球震颤,双侧斜视,视力受损，和视神经萎缩.她没有癫痫，但睡眠脑电图显示右半球出现阵发性变化，并伴有继发性概括。除了一些小的白质高强度外，脑磁共振成像并不明显。外显子组测序（ES）最初优先考虑SCN3Ac.3822G>A从头变体，其唯一的致病作用最终被质疑为与症状不完全相容。ES再分析显示纯合c.674G>AHMBS变体。在单等位基因形式中，该变体是AIP的已知原因，而与另一种HMBS致病变种的反式则与4例患者的HMBS相关白质脑病相关.尽管没有卟啉症的体征/症状，文献分析表明，HMBSc.674G>A可能是唯一原因或与SCN3Ac.3822G>A一起作为混合表型的一部分。我们的报告增加了相对较少的HMBS相关白质脑病的描述病例，并强调在没有卟啉症症状的情况下可能存在常染色体隐性形式的HMBS疾病。
