Medical Genetics, Department of Pediatrics, Université de Sherbrooke-CHUS, Sherbrooke, QC, Canada.
CRCHUS, Sherbrooke, QC, Canada.
Mol Genet Genomic Med. 2019 Dec;7(12):e1000. doi: 10.1002/mgg3.1000. Epub 2019 Oct 26.
HSD10 mitochondrial disease (HSD10MD), originally described as a deficiency of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD), is a rare X-linked disorder of a moonlighting protein encoded by the HSD17B10. The diagnosis is usually first suspected on finding elevated isoleucine degradation metabolites in urine, reflecting decreased MHBD activity. However, it is now known that clinical disease pathogenesis reflects other independent functions of the HSD10 protein; particularly its essential role in mitochondrial transcript processing and tRNA maturation. The classical phenotype of HSD10MD in affected males is an infantile-onset progressive neurodegenerative disorder associated with severe mitochondrial dysfunction.
PATIENTS, METHODS, AND RESULTS: In four unrelated families, we identified index patients with MHBD deficiency, which implied a diagnosis of HSD10MD. Each index patient was independently investigated because of neurological or developmental concerns. All had persistent elevations of urinary 2-methyl-3-hydroxybutyric acid and tiglylglycine. Analysis of HSD17B10 identified a single missense variant, c.364C>G, p.Leu122Val, in each case. This rare variant (1/183336 alleles in gnomAD) was previously reported in one Dutch patient and was described as pathogenic. The geographic origins of our families and results of haplotype analysis together provide evidence of a founder effect for this variant in Quebec. Notably, we identified an asymptomatic hemizygous adult male in one family, while a second independent genetic disorder contributed substantially to the clinical phenotypes observed in probands from two other families.
The phenotype associated with p.Leu122Val in HSD17B10 currently appears to be attenuated and nonprogressive. This report widens the spectrum of phenotypic severity of HSD10MD and contributes to genotype-phenotype correlation. At present, we consider p.Leu122Val a "variant of uncertain significance." Nonetheless, careful follow-up of our patients remains advisable, to assess long-term clinical course and ensure appropriate management. It will also be important to identify other potential patients in our population and to characterize their phenotype.
HSD10 线粒体疾病（HSD10MD）最初被描述为 2-甲基-3-羟基丁酰辅酶 A 脱氢酶（MHBD）缺乏症，是一种由 HSD17B10 编码的具有多功能的线粒体蛋白的罕见 X 连锁疾病。该诊断通常首先根据尿液中升高的异亮氨酸降解代谢物来怀疑，这反映了 MHBD 活性降低。然而，现在已知临床疾病发病机制反映了 HSD10 蛋白的其他独立功能；特别是其在线粒体转录物加工和 tRNA 成熟中的基本作用。受影响男性中 HSD10MD 的典型表型是婴儿期起病的进行性神经退行性疾病，伴有严重的线粒体功能障碍。
患者、方法和结果：在四个无关的家庭中，我们鉴定了 MHBD 缺乏的索引患者，这提示了 HSD10MD 的诊断。由于存在神经或发育问题，每个索引患者都进行了独立的调查。所有患者的尿液中均持续升高 2-甲基-3-羟基丁酸和 tiglylglycine。HSD17B10 的分析在每种情况下均鉴定出单个错义变异 c.364C>G，p.Leu122Val。这种罕见的变体（gnomAD 中 1/183336 个等位基因）以前在一名荷兰患者中报道过，并被描述为致病性的。我们的家族的地理起源和单倍型分析结果共同证明了该变体在魁北克的起源。值得注意的是，我们在一个家庭中发现了一名无症状的半合子成年男性，而另一个独立的遗传疾病在另外两个家庭的先证者的临床表型中起了重要作用。
与 HSD17B10 中的 p.Leu122Val 相关的表型目前似乎较轻且无进展。本报告拓宽了 HSD10MD 表型严重程度的范围，并有助于基因型-表型相关性的研究。目前，我们认为 p.Leu122Val 是“意义未明的变异”。尽管如此，对我们的患者进行仔细随访仍然是明智的，以评估长期临床过程并确保进行适当的管理。识别我们人群中的其他潜在患者并描述其表型也很重要。
