Mardian Emily B, Lines Matthew A, Moore Gregory P
Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Division of Metabolics and Newborn Screening, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
BMC Pediatr. 2020 Apr 20;20(1):177. doi: 10.1186/s12887-020-02085-x.
Lactic acidosis is a common finding in neonates, in whom mitochondrial dysfunction is often secondary to tissue hypoperfusion, respiratory failure, and/or sepsis. Primary (non-physiological) lactic acidosis is comparatively rare, and suggests the presence of an inborn error of mitochondrial energy metabolism. Optimal medical management and accurate prognostication requires the correct determination of the etiology of lactic acidosis in a given patient. Unfortunately, genetic diagnoses are rare and highly variable for neonates presenting with primary lactic acidosis; individual case reports may offer the most promise for treatment considerations. The mitochondrion is a complex molecular machine incorporating the products of > 1000 distinct nuclear genes. Primary lactic acidoses are therefore characterized by high genetic heterogeneity and a specific genetic diagnosis currently remains out of reach in most cases. Most mitochondriopathies with neonatal onset follow autosomal recessive inheritance and carry a poor prognosis. Here we detail the case of a father and daughter with dominantly-inherited, resolving (i.e. transient) neonatal hyperlactatemia due to complex IV deficiency. We found no other published descriptions of benign transient complex IV deficiency with autosomal dominant inheritance.
Both individuals presented as neonates with unexplained, marked lactic acidosis suggesting a primary mitochondrial disorder. Within the first weeks of life, elevated blood lactate levels normalized. Their clinical and developmental outcomes were normal. Biochemical studies in the proband showed multiple abnormalities consistent with a complex IV respiratory chain defect. Cultured skin fibroblasts showed an elevated lactate-to-pyruvate ratio, deficient complex IV activity, and normal pyruvate dehydrogenase and pyruvate carboxylase activities. Whole-exome sequencing of the proband and both parents did not identify a causative mutation.
We conclude that the proband and her father appear to have a dominant form of transient neonatal hyperlactatemia due to heterozygous changes in an as-yet unidentified gene. This transient neonatal complex IV deficiency should be considered in the differential diagnosis of primary neonatal hyperlactatemia; notable clinical features include autosomal-dominant inheritance and an apparently benign postnatal course. This report exemplifies the growing differential diagnosis for neonatal lactic acidosis and highlights the importance of both physician counselling and the use of family history in communicating with parents.
乳酸性酸中毒在新生儿中很常见，其线粒体功能障碍通常继发于组织灌注不足、呼吸衰竭和/或败血症。原发性（非生理性）乳酸性酸中毒相对罕见，提示存在线粒体能量代谢的先天性缺陷。最佳的医疗管理和准确的预后评估需要正确确定特定患者乳酸性酸中毒的病因。不幸的是，对于原发性乳酸性酸中毒的新生儿，基因诊断很少见且差异很大；个别病例报告可能为治疗考虑提供最大希望。线粒体是一种复杂的分子机器，包含1000多个不同核基因的产物。因此，原发性乳酸性酸中毒的特点是高度的遗传异质性，目前在大多数情况下仍无法进行特定的基因诊断。大多数新生儿期发病的线粒体病遵循常染色体隐性遗传，预后不良。在此，我们详细介绍了一例父女因复合体IV缺乏而导致显性遗传、可缓解（即短暂性）新生儿高乳酸血症的病例。我们未发现其他关于常染色体显性遗传的良性短暂性复合体IV缺乏的公开描述。
这两名患者均在新生儿期出现不明原因的明显乳酸性酸中毒，提示原发性线粒体疾病。在出生后的头几周内，血乳酸水平升高恢复正常。他们的临床和发育结果均正常。先证者的生化研究显示多项异常，与复合体IV呼吸链缺陷一致。培养的皮肤成纤维细胞显示乳酸与丙酮酸比值升高、复合体IV活性不足，丙酮酸脱氢酶和丙酮酸羧化酶活性正常。对先证者及其父母进行全外显子测序未发现致病突变。
我们得出结论，先证者及其父亲似乎因一个尚未确定的基因的杂合变化而患有显性形式的短暂性新生儿高乳酸血症。在原发性新生儿高乳酸血症的鉴别诊断中应考虑这种短暂性新生儿复合体IV缺乏；显著的临床特征包括常染色体显性遗传和明显良性的出生后病程。本报告例证了新生儿乳酸性酸中毒不断增加的鉴别诊断，并强调了医生咨询以及在与家长沟通中使用家族史的重要性。
