Conlon Tracey A, Fitzsimons Patricia E, Borovickova Ingrid, Kirby Fidelma, Murphy Sinéad, Knerr Ina, Crushell Ellen
National Centre for Inherited Metabolic Disorders Children's Health Ireland at Temple Street Dublin Ireland.
School of Medicine University College Dublin Dublin Ireland.
JIMD Rep. 2020 Jun 30;55(1):26-31. doi: 10.1002/jmd2.12146. eCollection 2020 Sep.
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG Co-A) synthase (mHS) deficiency is an autosomal recessive disorder of ketone body synthesis which has traditionally been associated with hypoketotic hypoglycemia, hepatomegaly and encephalopathy, presenting in early childhood following a period of fasting. We report the third case of mHS deficiency presenting in the absence of hypoglycemia, with profound biochemical abnormalities and further evidence of potential specific diagnostic biomarkers. A previously well, 20-month old, unvaccinated male, of nonconsanguineous Polish heritage, presented with encephalopathy, hepatomegaly, severe metabolic acidosis, and mild hyperammonemia following a brief intercurrent illness. The patient was reported to have taken colloidal silver prior to presentation, posing a further diagnostic challenge. Additionally, he developed features suggestive of hemophagocytic lymphohistiocytosis during treatment. While the patient was normoglycemic prior to dextrose administration, the sample was markedly lipemic, with significant hypertriglyceridemia detected. Urine organic acid analysis revealed dicarboxylic aciduria with 4-hydroxy-6-methyl-2-pyrone (4HMP) and the presence of three other previously reported putative biomarkers for mHS deficiency. Glutarate was markedly elevated in the initial chromatogram, with a mild increase in 3-hydroxyglutarate (3HG) persisting. Raised acetylcarnitine was detected on acylcarnitine profile. Molecular genetic analysis of the gene identified compound heterozygosity for known pathogenic mutations c.634G>A and c.1016+1G>A, confirming the diagnosis of mHS deficiency. This case provides further evidence that hypoglycemia is not invariably present in symptomatic mHS deficiency. We propose that elevated acetylcarnitine, triglycerides, and 3HG are additional biochemical features during acute presentations. With the expansion of novel biomarkers, further cases of this rare disorder may emerge.
线粒体3-羟基-3-甲基戊二酰辅酶A（HMG Co-A）合酶（mHS）缺乏症是一种常染色体隐性酮体合成障碍疾病，传统上与低酮性低血糖、肝肿大和脑病有关，在禁食一段时间后的幼儿期出现。我们报告了第三例无低血糖表现的mHS缺乏症病例，该病例有严重的生化异常以及潜在特异性诊断生物标志物的更多证据。一名20个月大、未接种疫苗、非近亲婚配的波兰裔男性，此前身体健康，在患一次短暂的并发疾病后出现脑病、肝肿大、严重代谢性酸中毒和轻度高氨血症。据报告，该患者在就诊前服用了胶体银，这给进一步诊断带来了挑战。此外，他在治疗期间出现了提示噬血细胞性淋巴组织细胞增生症的特征。虽然患者在给予葡萄糖前血糖正常，但样本明显脂血，检测到显著的高甘油三酯血症。尿有机酸分析显示二羧酸尿症伴4-羟基-6-甲基-2-吡喃酮（4HMP），以及其他三种先前报道的mHS缺乏症推定生物标志物。在初始色谱图中戊二酸明显升高，3-羟基戊二酸（3HG）持续轻度升高。酰基肉碱谱检测到乙酰肉碱升高。对该基因的分子遗传学分析确定了已知致病突变c.634G>A和c.1016+1G>A的复合杂合性，证实了mHS缺乏症的诊断。该病例进一步证明，有症状的mHS缺乏症并不总是出现低血糖。我们提出，乙酰肉碱、甘油三酯和3HG升高是急性发作期间的额外生化特征。随着新型生物标志物的不断发现，这种罕见疾病可能会出现更多病例。
