# Coenzyme Q at the Hinge of Health and Metabolic Diseases
## 4 CoQ Deficiency Syndrome
### Primary CoQ Deficiency
#### 4.1.2 Relationship of Primary CoQ Deficiency and Pathological Phenotype  
In order to clarify the relationship between _COQ_ mutations and phenotypes, recent revisions have been published [19; 50]. Many of the mutations directly affecting members of the CoQ-synthome produce effects on the central nervous system, being _COQ4_[110], _COQ5_[111], _COQ7_[112] and _COQ9_[102], the mutated genes that generate stronger developmental delays including motor, cognitive, speech, emotional, and social and communication skill dysfunctions [113]. Further, many of the mutations found in the members of the COQ-synthome have been associated with intellectual disability characterized by impaired intellectual and adaptive functioning. Further, many mutated COQ proteins have also been involved in epilepsy, hypotonia, and the peripheral nervous system, as well as sensory organ deficiencies such as hearing loss [19].  
Many of the mutations in COQ genes also affect kidney function. In general, renal dysfunction accompanied by altered morphological and physiological instability has been found especially in \(PDSS2\)[114], \(COQ2\)[115], \(COQ6\)[116], and COQ8B [117] patients. All these patients evolve to end-stage renal disease within childhood if not treated, indicating the severity of the mutations.  
Surprisingly, cardiac diseases are infrequent in primary CoQ\({}_{10}\)-deficient patients, despite the high importance of mitochondria in cardiac physiology. To date, the most commonly reported heart defect is hypertrophic cardiomyopathy that has been found more frequently in some \(COQ4\)[118] and \(COQ7\)[112] patients, and in a few \(PDSS2\)[114], \(COQ2\)[103], \(COQ9\)[102], and \(COQ8B\)[119] patients. Other functional heart defects include valvalopathies, cardiomegaly, septal defects, and heart hypoplasia, but no clear relationship between phenotype and mutation has been found [19; 50].  
Despite the importance of mitochondria in muscle physiology, muscle is relatively unaffected in these patients. In primary CoQ deficiency, isolated myopathy has been not found, although it is more common in secondary deficiency patients [100; 108]. However, myopathy in COQ patients has been reported but in association with a multisystemic phenotype and not always affecting all the patients with a specific mutation [19; 50]. The clearest muscle physiological defects are exercise intolerance, muscle weakness, and muscle fatigue, which are found more frequently in \(COQ8\) patients [120].  
Other clinical pathologies associated with these mutations include respiratory distress and apnea [118], and respiratory failure [121] but without a clear adsorption to a set of COQ mutations. Liver dysfunction has also been found in some \(COQ2\) patients as well as in some \(COQ8\) patients, but again without showing a clear pathological phenotype [19; 50].  
In general, it seems clear that neurological and renal dysfunctions in addition to hearing loss are the most common manifestations of COQ gene mutations. Other pathological manifestations can be a consequence of a different degree of sensibility to mitochondrial dysfunction depending on other factors or the equilibrium with other genes. Further research is needed, although the low number of patients with a specific mutation has made it impossible to establish a clear relationship between mutation and direct phenotypic characteristics to date.