Primary coenzyme Q10 deficiency (CoQ10 deficiency) is recognized as a mitochondrial respiratory chain disorder, stemming from a deficiency in CoQ10, a vital lipid component within the mitochondrial respiratory chain. This overview aims to equip clinicians with essential knowledge regarding the diagnosis and management of primary CoQ10 deficiency.
1. Clinical Characteristics of Primary Coenzyme Q10 Deficiency
Primary CoQ10 deficiency, also known as primary ubiquinone deficiency, is defined by reduced CoQ10 levels in tissues or cultured cells. This reduction is linked to biallelic pathogenic variants in one of the ten known genes essential for CoQ10 biosynthesis. The clinical presentation of primary CoQ10 deficiency is remarkably diverse, manifesting across a spectrum of phenotypes.
Broadening Clinical Manifestations
Historically, primary CoQ10 deficiency was categorized into five phenotypes: encephalomyopathy, cerebellar ataxia, severe infantile multisystem disease, steroid-resistant nephrotic syndrome, and isolated myopathy. However, this classification is now considered outdated. The clinical spectrum is far broader, with significant overlap and varied combinations of symptoms now recognized. Notably, isolated myopathy is rarely, if ever, confirmed in molecularly diagnosed primary CoQ10 deficiency; most muscle-related issues are linked to secondary CoQ10 deficiency.
The age of onset is also highly variable. COQ2-related CoQ10 deficiency, for instance, can manifest from birth to the seventh decade of life, highlighting the wide range of possible presentations.
The principal clinical manifestations, irrespective of the genetic cause, are detailed below, followed by specific phenotypic summaries for COQ2-, COQ8A-, and COQ8B-related CoQ10 deficiencies, which represent the most frequent genetic origins of this condition.
Principal Clinical Manifestations
Neurologic Manifestations: Central nervous system (CNS) involvement is a hallmark of primary CoQ10 deficiency. Encephalopathy, characterized by a wide range of brain involvement with diverse clinical and neuroradiologic features, is frequently observed. Neuroimaging in some patients may resemble Leigh syndrome or MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). Common neurologic signs include seizures, dystonia, spasticity, and intellectual disability.
The severity and onset age of neurologic symptoms vary greatly. At one end of the spectrum is fatal neonatal encephalopathy with hypotonia, while at the other end is a late-onset, slowly progressive multiple system atrophy (MSA)-like phenotype appearing in the seventh decade. This MSA-like presentation, marked by autonomic failure and combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction, has been specifically reported in families with COQ2-related CoQ10 deficiency.
Progressive cerebellar atrophy and ataxia, often accompanied by intellectual disability and seizures, are typical in COQ8A-related CoQ10 deficiency. Ataxia is also noted in COQ4-related cases.
Distal motor neuropathy has been reported in individuals with COQ7-related CoQ10 deficiency, and peripheral neuropathy in PDSS1-related CoQ10 deficiency. Due to the limited number of cases, generalizations about other specific neurologic manifestations remain challenging.
Renal Manifestations: Steroid-resistant nephrotic syndrome (SRNS) is a key renal feature and a notable aspect of mitochondrial disorders in the context of primary CoQ10 deficiency. Untreated SRNS typically progresses to end-stage kidney disease (ESKD). SRNS has been associated with variants in PDSS1, PDSS2, COQ2, COQ6, and COQ8B. Notably, SRNS has not yet been linked to variants in COQ4, COQ8A, and COQ9.
Renal involvement usually begins with proteinuria in infancy. The typical progression is from SRNS to ESKD, often followed by encephalomyopathy, seizures, stroke-like episodes, severe neurologic impairment, and potentially death. However, some individuals may present only with SRNS, with onset in the first or second decade, progressing slowly to ESKD without other systemic manifestations. Tubulopathy has been reported in COQ9-related CoQ10 deficiency shortly after birth in one case.
Cardiac Manifestations: Hypertrophic cardiomyopathy (HCM) has been observed in primary CoQ10 deficiency.
Ophthalmologic Manifestations: Retinopathy, sometimes isolated and adult-onset, is linked to variants in PDSS1, COQ2, COQ4, and COQ5. Optic atrophy has been reported in association with PDSS1-, PDSS2-, and COQ2-related CoQ10 deficiency.
Auditory Manifestations: Sensorineural hearing loss is common in COQ6-related CoQ10 deficiency and is also seen in some cases of COQ2– and PDSS1-related CoQ10 deficiency.
Muscle Findings: Muscle weakness and exercise intolerance are reported. Muscle biopsies might show non-specific signs such as lipid accumulation and mitochondrial proliferation. Muscle involvement is almost always accompanied by other extramuscular symptoms in primary CoQ10 deficiency.
Prognosis: Prognostic data are limited due to the rarity of primary CoQ10 deficiency. It is generally a progressive condition with variable progression rates and tissue involvement, dependent on the specific gene affected and the severity of CoQ10 deficiency. Severe multisystem CoQ10 deficiency in children often has a poor prognosis, with death occurring in the neonatal period or within the first year of life. Later-onset disease may show better response to high-dose oral CoQ10 supplementation, which can alter the disease course by slowing kidney disease progression and preventing neurologic manifestations in individuals with biallelic pathogenic variants in COQ2, COQ6, COQ8B, or PDSS2.
Phenotypes of COQ2-, COQ8A-, and COQ8B-Related Coenzyme Q10 Deficiencies
COQ2 Deficiency: Clinical presentations in COQ2 deficiency vary widely in severity and onset age. The main features include SRNS, which can be infantile-onset rapidly progressing to ESKD, or later-onset with slow progression. Adult-onset retinitis pigmentosa can occur as an isolated finding or alongside late-onset multiple system atrophy.
COQ8A Deficiency: COQ8A deficiency typically presents with muscle weakness and reduced exercise tolerance between 18 months and three years, followed by cerebellar ataxia, a predominant clinical feature with significant cerebellar atrophy on MRI. The course of ataxia varies, from progressive to apparently self-limited. Ataxia may be nonprogressive from childhood or progressive, starting in the second decade and worsening.
COQ8B Deficiency: COQ8B deficiency commonly manifests as SRNS in the first or second decade, frequently progressing to ESKD. Some individuals also exhibit mild intellectual disability, occasional seizures, and retinitis pigmentosa.
Laboratory Findings
Serum or plasma lactate concentration: May be elevated in severe neonatal-onset cases, but normal levels do not rule out primary CoQ10 deficiency.
Cerebrospinal fluid lactate concentration: May be more sensitive than serum levels, but can also be normal.
2. Genetic Causes of Primary Coenzyme Q10 Deficiency
Ten genes are currently known to be associated with primary CoQ10 deficiency. Further genes may yet be identified.
Genes Associated with Primary Coenzyme Q10 Deficiency and Their Clinical Features
| Gene 1 | # of Families with CoQ10 Deficiency Attributed to Gene | Clinical Features |
|---|---|---|
| Kidneys | Heart | |
| COQ2 | >10 | SRNS |
| COQ4 | >10 | |
| COQ5 5 | 2 | |
| COQ6 | >10 | SRNS 6 |
| COQ7 | >10 | |
| COQ8A | >10 | |
| COQ8B | >10 | SRNS 6 |
| COQ9 | 2 | Tubulopathy |
| PDSS1 | 10 | SRNS |
| PDSS2 | 3 | SRNS |
1 Genes are listed in alphanumeric order. 2 Encephalopathy: broad brain involvement, varied features. 3 Adult-onset MSA-like phenotype. 4 Severe hypotonia, respiratory insufficiency, cerebellar hypoplasia, progressive neurologic deterioration, spasticity, ID. 5 COQ5 and ataxia link needs confirmation. 6 COQ6– & COQ8B-related cases ascertained by SRNS; broader phenotype possible. 7 COQ8A-related CoQ10 deficiency = autosomal recessive spinocerebellar ataxia 9 or SCAR9 (OMIM 612016).
Caption: Table 1. Genes associated with primary Coenzyme Q10 deficiency and their related clinical features, including impact on kidneys, heart, eyes, hearing, neurological and muscular systems.
3. Differential Diagnosis of Primary Coenzyme Q10 Deficiency
It is crucial to consider primary CoQ10 deficiency in patients presenting with mitochondrial encephalomyopathy, steroid-resistant nephrotic syndrome, retinitis pigmentosa, unexplained ataxia, or motor neuropathy, as it is a treatable condition with high-dose oral CoQ10 supplementation.
Secondary CoQ10 deficiencies occur due to pathogenic variants in genes not directly involved in CoQ10 biosynthesis. Distinguishing between primary and secondary CoQ10 deficiency requires molecular genetic testing. Causes of secondary CoQ10 deficiency include respiratory chain defects (see Primary Mitochondrial Disorders Overview), multiple acyl-CoA dehydrogenase deficiency, and ataxia with oculomotor apraxia type 1.
4. Evaluation Strategies to Identify the Genetic Cause of Primary Coenzyme Q10 Deficiency in a Proband
Identifying the specific genetic cause of primary CoQ10 deficiency is essential for targeted treatment, prognosis discussions, and genetic counseling. Evaluation typically includes medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
Medical history: Suspect primary CoQ10 deficiency in individuals with clinical or neuroradiologic signs of mitochondrial encephalomyopathy, steroid-resistant nephrotic syndrome (especially with neurologic symptoms), retinitis pigmentosa, unexplained ataxia, or motor neuropathy.
Physical examination: No pathognomonic signs exist for primary CoQ10 deficiency. A thorough general and neurologic examination is necessary.
Family history: Autosomal recessive inheritance is typical (e.g., affected siblings, parental consanguinity). However, absence of family history does not exclude the diagnosis.
Diagnosis is primarily confirmed through molecular genetic testing, though biochemical testing can be supportive in certain situations.
Molecular Genetic Testing Options
Molecular genetic testing can involve gene-targeted testing (multigene panel) or comprehensive genomic testing (exome or genome sequencing). Gene-targeted testing is suitable when specific genes are suspected, while comprehensive genomic testing is useful when the likely gene is unknown.
Option 1: Gene-Targeted Testing
Multigene panel for steroid-resistant nephrotic syndrome, mitochondrial disorders of nuclear origin, retinitis pigmentosa, ataxia, or peripheral neuropathy, including the ten genes listed in Table 1, is highly effective. This approach limits the identification of variants of uncertain significance and pathogenic variants in unrelated genes. Panel content and diagnostic sensitivity vary by laboratory and may evolve. Some labs offer custom panels or phenotype-focused exome analysis. Methods include sequence analysis, deletion/duplication analysis, and other non-sequencing tests.
Option 2: Comprehensive Genomic Testing
Comprehensive genomic testing, such as exome sequencing or genome sequencing, is an option when the implicated gene is not known. Exome sequencing is most common, while genome sequencing is also feasible. This approach avoids the need to pre-select specific genes.
Biochemical Testing in Diagnosis
Biochemical testing was historically primary for CoQ10 deficiency diagnosis, but now mainly serves to support molecular genetic testing results or to establish diagnosis when molecular testing is inconclusive. Biochemical tests can distinguish CoQ10 deficiency from other mitochondrial disorders but cannot differentiate between primary and secondary CoQ10 deficiency.
Plasma CoQ10 levels are not diagnostically reliable as they reflect dietary intake, not endogenous production. Tissue CoQ10 measurements, such as in muscle or fibroblasts, are more direct but are not routinely available and normal levels do not exclude the diagnosis. Therefore, biochemical testing is no longer a first-line diagnostic tool due to these limitations and the availability of genetic testing.
5. Management of Primary Coenzyme Q10 Deficiency
Currently, there are no published clinical practice guidelines for managing primary CoQ10 deficiency.
Evaluations Following Initial Diagnosis
To assess the extent of the disease and the needs of a newly diagnosed individual, the following evaluations are recommended if not already performed:
| System/Concern | Evaluation | Comment |
|---|---|---|
| Encephalopathy | – Neurologic status assessment by pediatric neurologist – Brain MRI | Check for signs of Leigh syndrome or MELAS. |
| Adult-onset neurologic complications | Assess for autonomic dysfunction & movement disorders (parkinsonism, cerebellar ataxia, pyramidal signs). | |
| Neuromuscular | Orthopedics / physical medicine & rehab / PT & OT eval | Assess gross & fine motor skills, contractures, need for medical equipment. |
| Developmental assessment | Motor, adaptive, cognitive, & speech-language eval. Early intervention/special education eval. | |
| Intellectual disability | Educational placement eval. | |
| Seizures | EEG | |
| Peripheral neuropathy | Assess muscle strength & reflexes, exercise tolerance. Consider EMG & nerve conduction studies for COQ7-related cases. | |
| Gastrointestinal/Feeding | Gastroenterology / nutrition / feeding team eval | Assess gastrointestinal dysmotility, aspiration risk, nutritional status. Consider gastrostomy tube for dysphagia/aspiration risk. |
| Hearing loss | Audiometry for SNHL. | |
| Retinopathy | Ophthalmologic eval & electroretinogram. | Assess retinopathy & optic atrophy, need for low vision services. |
| Cardiac | Cardiac eval, echocardiography. | Assess for HCM. |
| Steroid-resistant nephrotic syndrome | Renal eval for proteinuria, kidney function. | |
| Ethics consultation | Clinical ethics services | Address health care decisions in child’s best interest and family values. |
| Genetic counseling | Genetics professionals 1 | Pedigree, inform family about nature, inheritance, implications for medical and personal decisions. |
| Family support & resources | Assess need for community/online resources, social work, home nursing. | Parent to Parent, social work, home nursing referrals. |
1 Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider.
Caption: Table 2. Recommended evaluations for individuals diagnosed with primary Coenzyme Q10 deficiency to determine the extent of the condition and required support.
Treatment of Manifestations
There is no cure for primary CoQ10 deficiency, but management focuses on treatment and supportive care.
Pharmacologic Treatment
Coenzyme Q10 supplementation: High-dose oral CoQ10 supplementation (5-50 mg/kg/day) can be effective. Soluble formulations may be more bioavailable. Early treatment is crucial to limit disease progression and potentially reverse some symptoms, although established severe damage may be irreversible. Response varies based on genetic defect, disease severity, and other factors. COQ6-related deficiency shows particularly good response in renal manifestations. Data on other gene-related deficiencies are limited.
Ineffective or unvalidated treatments: Ubiquinol (reduced CoQ10), short-chain quinone analogs like idebenone, and bypass therapies with quinone ring analogs have not shown validated benefits and may be detrimental.
Supportive Care
Multidisciplinary supportive care is vital to improve quality of life, maximize function, and reduce complications.
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Fatal Neonatal Encephalopathy Phenotype | ||
| Nutrition/Feeding | Feeding team: nutritionist, gastroenterologist | Nasogastric tube, gastrostomy tube. |
| Steroid-resistant nephrotic syndrome | Nephrologist | Refer to Steroid-Resistant Nephrotic Syndrome Overview, Management. ACE inhibitors with CoQ10 may be used for proteinuria. Kidney transplant for ESKD. |
| Respiratory insufficiency | Pulmonologist | Tracheostomy & artificial ventilation may be needed. |
| Neuromuscular | Physical therapy | Maintain muscle strength & mobility, prevent contractures, adaptive positioning devices. |
| Seizures | Neurologist, standard ASM treatment | Monitor medication levels, parent/caregiver education. |
| Sensorineural hearing loss | Hearing loss specialists | Refer to Genetic Hearing Loss Overview. |
| Cardiomyopathy | Standard treatment protocols | |
| Retinopathy | Ophthalmologist & low vision services | |
| Other Neurologic Phenotypes | ||
| Peripheral neuropathy | Refer to Charcot-Marie-Tooth Hereditary Neuropathy Overview. | |
| Cerebellar ataxia | Refer to Hereditary Ataxia Overview. | |
| Dystonia | Standard care | |
| Spasticity |
ASM = anti-seizure medication
Caption: Table 3. Treatment strategies for different manifestations of primary Coenzyme Q10 deficiency based on phenotype.
Developmental Delay / Intellectual Disability Management
For developmental delay and intellectual disability, early intervention programs (ages 0-3 years) are recommended, including occupational, physical, speech, and feeding therapy, special education, and sensory impairment specialists. Developmental preschool (ages 3-5 years) through public school districts is advised, with IEPs developed for qualifying children. Consultation with a developmental pediatrician is crucial for all ages to ensure access to community, state, and educational resources. IEP services, 504 plans, and Developmental Disabilities Administration enrollment should be considered.
Surveillance
Ongoing monitoring is essential, tailored to the genetic cause and individual manifestations. Regular evaluations should include:
- For adult-onset neurologic findings or isolated SRNS: assessment for autonomic dysfunction and movement disorders every 1-2 years.
- Urine analysis for proteinuria and kidney function assessment.
- Ophthalmologic evaluation and electroretinogram for retinopathy.
- Hearing evaluation for sensorineural hearing loss.
Cardiac evaluation should be performed at diagnosis, but routine periodic evaluation is not needed unless cardiac involvement is documented, as cardiomyopathy is mainly seen in severe neonatal-onset cases.
Evaluation of Relatives at Risk
Given the importance of early CoQ10 supplementation, evaluating siblings of a proband with primary CoQ10 deficiency is recommended to identify and treat affected sibs early.
6. Genetic Counseling
Primary CoQ10 deficiency is typically inherited in an autosomal recessive manner.
Mode of Inheritance and Risk to Family Members
Parents of a proband: Parents are presumed heterozygotes (carriers). Molecular genetic testing is recommended to confirm carrier status and for recurrence risk assessment. If only one parent is a carrier, consider possibilities like a de novo variant or non-paternity.
Sibs of a proband: If both parents are carriers, each sib has a 25% risk of being affected, 50% risk of being a carrier, and 25% risk of being unaffected and not a carrier.
Offspring of a proband: Offspring are obligate heterozygotes (carriers).
Other family members: Sibs of parents have a 50% risk of being carriers.
Carrier Detection and Prenatal/Preimplantation Genetic Testing
Carrier testing for at-risk relatives is possible once familial pathogenic variants are identified. Prenatal and preimplantation genetic testing are options when pathogenic variants are known in the family. DNA banking should be considered for probands without confirmed molecular diagnoses for future testing advancements.
Resources
GeneReviews provides links to disease-specific and umbrella support organizations and registries for individuals with CoQ10 deficiency and their families.
Chapter Notes
Author Notes
Experts in primary CoQ10 deficiency diagnosis and research are available for consultation and collaboration, particularly regarding variants of uncertain significance and families without identified causative variants through molecular genetic testing.
Acknowledgments
This work is supported by various grants and foundations dedicated to genetic and mitochondrial disease research.
Author History
List of authors and their roles/dates of contribution.
Revision History
Revision dates and summary of updates.
References
Literature Cited
List of cited literature references from the original article.
