Autosomal dominant transmission of transient neonatal lactic acidosis: a case report

Lactic acid is an anaerobic metabolite that tends to accumulate whenever cellular respiration is inadequate to meet cellular energy requirements. Commonly, lactic acidosis reflects acquired mitochondrial dysfunction due to impaired tissue oxygenation (‘shock’). In neonates, hyperlactatemia is commonly observed in sepsis, hypoxic-ischemic injury, and congenital heart disease. When secondary, blood lactate levels mirror the patient’s clinical state, resolving with correction of the underlying disease process [1]. Primary lactic acidosis that is inappropriate to the clinical context suggests an inborn error of cellular energy metabolism. Collectively, these primary lactic acidoses are numerous. They are genetically heterogeneous with disorders of mitochondrial oxidative phosphorylation or pyruvate metabolism accounting for most cases. Because the mitochondrion is complex, comprising the products of > 1000 distinct nuclear genes, genetic diagnosis of primary mitochondrial disorders is rarely found, occurring only in ~ 25–50% of cases [2, 3]. With few exceptions (e.g. holocarboxylase synthetase deficiency, which is treatable with biotin, and pyruvate dehydrogenase deficiency, which is somewhat treatable with the ketogenic diet), specific treatments are lacking, and many patients die in infancy or childhood [4]. Here we detail the case of a father and daughter with dominantly-inherited, resolving (i.e. transient) neonatal hyperlactatemia due to transient complex IV deficiency. No previous description of such an autosomal dominant form of benign, transient complex IV appears to exist in the literature; this reiterates the increasing differential diagnosis for lactic acidosis in a neonate.

We describe a father and daughter with transient neonatal lactic acidosis, mild transient hepatic dysfunction, spontaneous clinical resolution, and no apparent developmental sequelae. Complex IV activity and lactate:pyruvate ratio were markedly abnormal in skin fibroblasts derived from the daughter. This disorder appears to represent an autosomal dominant (or, less likely, X-linked-dominant) form of transient complex IV deficiency caused by mutation of an as-yet unidentified nuclear gene.

Mitochondrial disorders are among the most common and heterogeneous inherited metabolic diseases in humans, with > 185 known (and several hundred unknown) genetic types [5, 6]. Inheritance is commonly autosomal recessive or maternal, but may be autosomal dominant or X-linked. Although most mitochondrial disorders are permanent (non-remitting), several previous papers do describe reversible infantile respiratory chain defects. They report their patients having neonatal or infantile presentations lasting weeks to months (e.g. one or more of hypotonia, liver failure, prolonged feeding difficulties, or respiratory insufficiency) with or without later sequelae such as feeding intolerance, hypotonia, hepatopathy, respiratory weakness, or motor delays in the context of a persisting myopathy [7‐9]. In contrast, the individuals presented in this report had both a relatively benign neonatal presentation and an apparently normal clinical outcome. Complex IV deficiency states are themselves genetically heterogeneous, with at least 20 distinct genetic causes [10]. Most pediatric-onset complex IV disorders are recessive, life-limiting conditions affecting the brain, cardiac muscle, liver, and other essential body systems. Although we are aware of a dominant form of SCO2 deficiency associated with severe myopia [11], and a matrilineally-inherited benign transient form caused by m.14674 T > C homoplasmy [8], we are not aware of any other published descriptions of benign transient complex IV deficiency with autosomal dominant inheritance.

Although rapidly becoming the first-line diagnostic test of choice for suspected mitochondrial disorders, WES results in a high-probability gene assignment in < 1/3 of individuals tested [12, 13]. This is in accord with the general WES-associated molecular diagnostic rate of 20–30% for other unsolved Mendelian disorders [14, 15]. Potential reasons for the modest molecular diagnostic rate are manifold. At present, we are aware of only 6000 human disease genes, and we suspect that there are many more with estimates of 6000–13,000 disease genes yet to be identified [16]. Furthermore, the variation responsible for the transient lactic acidosis may not be detectable by “exon” level methods such as variation in the non-coding region, a chromosomal deletion or duplication, complex chromosomal rearrangement(s) or expansion mutations. Technological advances such as whole-genome sequencing and RNA-Seq may resolve some of these issues and provide answers for the family in the near future.

The transient disorder described in this report should be considered a rare exception to the poor prognosis characteristic of most primary lactic acidoses [17]. In the absence of an accurate clinical and family history, transient primary hyperlactatemia may easily be mistaken for typical etiologies of lactic acidosis such as sepsis, congenital heart disease, and perinatal hypoxic-ischemic injury. Although uncommon, the condition presented here should be considered when counseling parents of neonates with primary lactic acidosis regarding prognosis. This case report emphasizes how the incorporation of parents, and their family history, may be vital to providing the most comprehensive overview of the neonate’s status and potential prognosis. Physicians also need to have this transient primary lactic acidosis on their differential diagnosis. While providing general supportive treatment for a primary lactic acidosis (e.g. vitamins that act as cofactors and antioxidants directed towards specific signs and symptoms), physicians can cautiously note to parents that their neonate may have a transient benign form of the clinical condition. Future genetic counselling and prenatal advice could prove useful for families as well [17]. Genetic counselling for inborn errors of metabolism varies by etiology, with this case presenting as an apparently dominant form resulting in a 50% chance of recurrence. Limitations for this case report include the need for future research required to elucidate the causative mutation and pathophysiology.