Primary deficiency of coenzyme Q10 (CoQ10) is a clinically and genetically heterogeneous group of autosomal recessive disorders that disrupt the complex biosynthetic pathway of this crucial molecule. Its main function is related to the mitochondrial oxidative phosphorylation where it shuttles electrons from complex I and complex II to complex III of the respiratory chain. Clinical manifestations of primary CoQ10 deficiency (PCQD) ranges from fatal neonatal onset multisystemic disease to a reasonably mild, late onset single system disease, of which the most common is steroid resistant nephrotic syndrome [1]. In general, PCQD patients benefit clinically from oral supplementation of high doses of CoQ10 but this is highly dependent on various factors including disease extent and severity, the age of diagnosis, and the age at which treatment is initiated [2]. Generally, early initiation of CoQ10 is expected to prevent or delay further progression of disease manifestations but it usually does not recover clinical damage that has already occurred.

COQ7 gene encodes for the enzyme 5 demethoxyubiquinone hydroxylase that catalyzes the hydroxylation of demethoxyubiquinone to 5-hydroxy-ubiquinone, a critical step in CoQ10 biosynthesis. Similar to other causes of PCQD, bi allelic mutations in COQ7 gene result in various clinical manifestations. Perhaps the most common phenotype is distal hereditary motor neuropathy either pure or complicated with other neurological deficits including upper motor neuron impairment, sensorineural hearing loss and ataxia [3, 4]. In the current issue of EJHG Pettenuzzo et al. report two sibling patients with compound heterozygous mutations in COQ7 gene [5]. This interesting study further extends the phenotypic spectrum of COQ7 gene defects to include fetal onset multisystemic disease with novel manifestation of prenatal and postnatal progressive gastrointestinal obstructions that required recurrent surgical interventions in both siblings. Early onset intestinal occlusions were not reported previously in PCQD syndromes. The current study should therefore raise the awareness of this uncommon manifestation that may be underdiagnosed. For example, we had a previous case of severe neonatal multisystemic disease due to COQ9 deficiency. The disease course was complicated by fulminant necrotizing enterocolitis that required several surgical interventions. This uncommon complication in a term neonate can represent an unrecognized gastrointestinal manifestation of PCQD (personal communication).

Notably, the correct diagnosis of the first sibling who succumbed at 14 months of age allowed immediate diagnosis at birth of the second sibling and supplementation with high dose CoQ10 already from birth. While too early to conclude, the disease course of the second sibling appears to be favorable compared to his deceased brother with near normal age appropriate, developmental milestones. This may be attributed to very early CoQ10 treatment but also to better surveillance and family awareness and alertness. Taken together, this study further emphasizes the importance of early genetic diagnosis in conditions like primary CoQ10 deficiency with available disease modifying therapies ideally before the development of irreversible neurological damage. The detailed fetal imaging descriptions of both siblings join only few previous reports and are highly valuable for clinicians for the early (ideally in utero) diagnosis of the severe end of PCQD syndromes. As a rule, the variable combination of intrauterine growth retardation with oligohydramnios, fetal cardiomegaly and/or cardiomyopathy, dysmorphic facial features, renal anomalies, brain malformations and echogenic bowel [6, 7] should raise the suspicion of PCQD syndromes and warrant comprehensive fetal genetic testing.

In the past the diagnosis of PCQD disorders relied on the biochemical assessment of CoQ10 content usually in skeletal muscle or cultured skin fibroblasts. This study required an invasive diagnostic procedure and a laborious usually time-consuming analysis that was carried in few specialized and highly experienced laboratories. The extended use in clinical practice of next generation sequencing technologies either in targeted genetic panels or non-targeted exome or genome sequencing significantly improved the diagnostic rate and shortened dramatically the delay in achieving correct diagnosis of rare genetic disorders. This has a considerable impact on the outcome of genetic diseases with potential treatment. Consequently, the current diagnosis of most PCQD patients is determined by the identification of pathogenic variants in the known CoQ10 biosynthetic genes using robust next generation sequencing. However, in cases with clinical or genetic ambiguity for example novel missense variants that are classified “variants of unknown significance” as in the siblings reported by Pettenuzzo et al. the utilization of classic biochemical studies in muscle tissue and cultured fibroblasts may permit reclassification of the variants in order to correctly diagnose PCQD. This example emphasizes the importance of available clinically approved certified laboratories with high experience in assessment of CoQ10 content and respiratory chain activity studies [8].

COQ7 phenotype-genotype correlation is complex and currently not completely understood. Moreover, the various factors that determine the clinical presentation are only partially related to the tissue CoQ10 production level. In general, pathogenic variants in PCQD associated genes including COQ7 are categorized as loss of function variants that result in either abnormal or significantly reduced protein. In agreement the levels of CoQ10 measured in the relevant tissue (skeletal muscle, cultured fibroblasts) are significantly decreased. However, additional factors yet to be determined and studied appear to play a role in the resulting phenotype. This may include tissue variability, the level of the defected gene product, tissue levels of CoQ10, accumulation of intermediate products proximal to the biosynthetic pathway block with a potential toxic effect etc. Additional studies that include precise detailed clinical descriptions with comprehensive genetic and biochemical investigations of the affected tissues are of great value.

In summary, the paper of Pettenuzzo et al. highlights COQ7 deficiency, an important member of a distinctive group of treatable mitochondrial diseases termed PCQD, with a special emphasis on fetal presentation and novel gastrointestinal manifestations. In addition, it underscores the significance of utilizing next generation sequencing technology combined with broad biochemical assessment for timely diagnosis and early initiation of effective disease modifying therapy.