ADCK3‐related Coenzyme Q10 Deficiency: A Potentially Treatable Genetic Disease

Abstract

Background

Disorders related to dysfunction of coenzyme (CoQ₁₀) metabolism, including AarF domain containing kinase 3 gene (ADCK3) mutations, have received attention due to the potential for response to CoQ₁₀ supplementation.

Methods

We describe two new cases of neurological syndromes due to ADCK3 mutations that obtained striking benefit from CoQ10, and a third who did not. We also review 20 cases from the literature in which responses to CoQ10 were documented out of all 38 previously reported cases.

Results

Despite the remarkable responses in some cases with ataxia and movement disorders (myoclonus, dystonia, tremor), overall, we were not able to identify variables that predicted response to CoQ₁₀ supplementation.

Conclusions

Based on our experience and data from the literature, we recommend a minimum of 10 mg/kg/day of ubiquinone with titration up to 15 mg/kg/day, maintained at least for 6 months in order to obtain or exclude potential benefit from therapy.

Introduction

Neurological disorders due to mutations in genes leading to defects in coenzyme Q10 (CoQ₁₀) metabolism have gained attention due to the potential for clinical improvement after CoQ₁₀ supplementation.1 The AarF domain containing kinase 3 gene (ADCK3) is involved in CoQ₁₀ biosynthesis and regulation, and mutations in this gene lead to CoQ₁₀ deficiency through loss of function, resulting in mitochondrial dysfunction. Owing to advances in molecular genetic tests (i.e., whole‐exome sequencing [WES] or targeted gene panels using next‐generation sequencing [NGS]), variable phenotypic manifestations have been reported.2, 3, 4 Here we present two patients with a striking response to CoQ₁₀ replacement, and a third who failed to benefit from inconsistent therapy. In order to try to identify the associated phenotypes and clues that predict potential responses to CoQ₁₀ supplementation, we present these cases together with a literature review of 38 previously reported cases that had ADCK3 mutation disorders.

New Cases

Case One

A 25‐year‐old man, born from non‐consanguineous parents of Italian ancestry presented with tremor, reduced dexterity, incoordination, and abnormal posturing in his right hand at age 11. Symptoms progressed, slowly affecting handwriting and forcing him to switch certain activities to the left hand within five years of onset. He also developed dysarthria at age 12. Initial examination at age 13 showed hypometric saccades, scanning speech, and dystonic posturing with tremor solely in the right upper limb. Symptoms progressed insidiously, and at the age of 17, he developed mild thoracolumbar scoliosis and bilateral, asymmetric distal upper extremity tremor with mild dystonic posturing. At the age of 20, he noticed lower extremity tremor and gait ataxia (Video 1). An electrophysiological study confirmed dystonic tremor in the upper extremities. Therapeutic trials were unsuccessful, including tetrabenazine, trihexyphenidyl, benztropine, botulinum toxin A injections, primidone, clonazepam, and propranolol. WES revealed compound heterozygous variants in the ADCK3 gene, c.901C > T (p.Arg301Trp), c.1399‐3_1408del, confirmed by Sanger sequencing. This novel deletion affects the acceptor splice site of exon 12, which is likely to cause exon skipping. Testing of his parents confirmed that mutations are in trans. He was started on CoQ₁₀ supplementation 200mg twice a day for 6 months, followed by 3 months of 400 mg twice a day, presenting a remarkable response (Video 2), a resolution of tremor and improvement of limb and marked truncal dystonia.

Case Two

A 54‐year‐old woman, born to non‐consanguineous Ashkenazi Jewish parents, presented with long‐standing imbalance and incoordination since her teenage years leading to unsteady gait, falls, and an upper extremities tremor. Symptoms progressed slowly, but she continued to work and was independent until the age of 40 when the progression rate accelerated. At the age of 53, she presented with severe dysarthria, gait ataxia, and falls, requiring the use of a wheelchair. On examination, she had isolated pancerebellar features, including scanning dysarthria, appendicular dysmetria, truncal instability, titubation, and absent postural response. Gait was severely affected, wide‐based and tandem gait was impossible. Scale for the Assessment and Rating of Ataxia (SARA) score then was 17. Family history was negative for similar symptoms except for strong paternal heritage of deafness. NGS ataxia panel revealed compound heterozygous variants in the ADCK3 gene, c.1749_1751delCAC (p.Thr584del) exon 14, c.1532C > T (p.Thr511Met) exon 12. The patient was started on CoQ₁₀ supplementation with 200mg twice daily for 6 months followed by 3 months of 400 mg twice daily, presenting a remarkable improvement in ataxia overall, and has been able to walk independently with SARA score of 12.

Case Three

A 33‐year‐old man, born from consanguineous Kuwaiti parents, had a history of global developmental delay. He started to walk at the age of 18 months and always had problems with coordination. Intellectual disability required special education and symptoms deteriorated to the extent that he was functionally dependent for all activities of the daily living at age 20. From the motor perspective, he presented isolated pancerebellar features, including head titubation, dysmetria, dysdiadochokinesia, wide‐based stance/gait, and inability to perform tandem gait. Other aspects of the neurological examination were normal. Brain MRI revealed severe cerebellar atrophy. Muscle mitochondrial respiratory chain activity was normal in complexes I and II, citrate synthase and cytochrome c oxidase, and muscle CoQ₁₀ was mildly decreased. ADCK3 gene was analyzed using Sanger sequencing, revealing the homozygous mutation, c.913G>T; p.D305Y, exon 7. Under inconsistent use of CoQ₁₀ supplementation with 400 mg twice a day for 2 years, the SARA scores had not improved (9 to 10), and symptoms progressed.

The clinical and biological findings of the three patients are summarized in Table 1.

Table 1.

Summary of the clinical, radiological, and biological findings of the three patients

	Patient 1	Patient 2	Patient 3
Age of onset, y	11	10	5
Age of examination, y	15	54	33
Sex	Male	Female	Male
Race/ethnicity	Italian	Ashkenazi Jewish	Kuwaiti
First sign	Focal dystonia	Gait ataxia	Gait and limb ataxia
Ataxia	+	++	++
Cognition	Normal	Impaired	Impaired
Other findings	Axial tremor and dystonia, scoliosis	No	No
Tendon reflexes	Normal	Normal	Normal
Disease course	Progression for 10 years, then stabilize	Slowly progressive until the age of 40 then more rapid progression	Slowly progressive
Brain MRI	No cerebellar atrophy at age 25	Cerebellar atrophy at age 40	Severe cerebellar atrophy at age 33
NCV	Normal	Not available	Normal
Muscle CoQ10 level (ug/g) 1	22.38 (low)	14.54 (low)	15.91 (low)
Mutation	Compound heterozygous: c.901C>T (p.Arg301Trp), c.1399‐3_1408del	Compound heterozygous: c.1749_1751delCAC (p.Thr584del) in exon 14, c.1532C>T (p.Thr511Met) in exon 12	Homozygous, c.913G>T; p.D305Y, at exon 7

Abbreviations: CoQ₁₀, coenzyme Q10; MRI, magnetic resonance imaging; NCS, nerve conduction studies.

Reference range: ¹23.63–48.11 ug/g

Methods and Results

We performed a literature review of English language papers published in PubMed using the keywords “coenzyme Q10 deficiency,” “kinase 3 gene mutation,” “ADCK3 mutations,” and “autosomal recessive cerebellar ataxias.”

From a total of 38 cases, we reviewed twenty‐three, including our three new cases, where a response to CoQ₁₀ was described. Patient characteristics are shown in Table 2.2, 3, 4, 5, 6, 7, 8, 9

Table 2.

The response to CoQ₁₀ supplementations of our patients and previously reported ADCK3 mutated patients

References	Molecular genetic mutation	Symptoms	CoQ10 level	Amount and duration of CoQ10 (ubidecarenon)	SARA before treatment	SARA after treatment	Other changes
Our patients
	comp. htz c.1399‐3_1408del, at exon 12	Dystonia, ataxia	Decreased	200 mg BID, 6 m, then 400 mg BID, 3 m	6	5	Resolved in tremor, improved dystonia and ataxia
	comp. htz in‐frame deletion, c.1749_1751delCAC, p.Thr584Met, at exon 14	Ataxia	Decreased	200 mg BID, 6 m, then 400 mg BID, 3 m	17	12	Able to walk independently
	hmz c.913G>T; p.D305Y, at exon 7	Ataxia	Decreased	Inconsistent with 400 mg BID, 2 y	9	10	Tremors worsen
Previously reported patients
5	comp. htz c.[815G>A]+[1812_1813insG] exons 6 + 15 p.[Gly272Asp]+[Glu605Glyfs*125]	Exercise intolerance, ataxia, hand dystonia	Decreased	250 mg TID, 15 y	15.5	NA	Improvement in exercise intolerance and vomiting
5	comp. htz c.[637C>T]+[815G>T] exons 4 + 6 p.[Arg213Trp]+[Gly272Val]	Delayed development, ataxia, hand dystonia, myoclonus	NA	175 mg BID, 8 y	NA	NA	No improvement
5	comp. htz c.[637C>T]+[815G>T] exons 4 + 6 p.[Arg213Trp]+[Gly272Val]	Delayed development, ataxia	NA	175 mg BID, 13 m	NA	NA	No improvement
2	comp. htz c.[811C>T], p.[Arg271Cys] c.[910G>A], p.[Ala304Thr]	Ataxia, mild dystonia	Normal	300 mg/d, 6 m	NA	NA	No improvement
2	hmz c.[911C>T], p.[Ala304Val]	Ataxia, myoclonus, epilepsy	Decreased	300 mg/d, 6 m	NA	NA	No improvement
2	hmz c.[895C>T], p.[Arg299Trp]	Delayed development, ataxia, epilepsy	Normal	200 mg/d, 2 m	NA	NA	No improvement
2	comp. htz c.[1286A>G], p.[Tyr429Cys]	Delayed development, ataxia	Decreased	200 mg/d, 2 m	NA	NA	No improvement
6	hmz c.1042C>T, p.R348	Epilepsy, ataxia	Decreased	10 mg/kg/d, 6 m	NA	NA	Improvement in ataxia
7	comp. htz c.[1523T>C] exon13 + del exons 3 to 15 p.[Phe508Ser]	Hand dystonia, ataxia, tremor and myoclonus	NA	100 mg TID, 15 m	9.5	6.5	Improvement in dystonia, myoclonus, and ataxia
7	comp. htz c.[895C>T]+[1358delT] exons 7 and 11 p.[Arg299Trp]+[Leu453Argfs*24]	Gait ataxia and tremor at 12	Normal	100 mg TID, 8 m	11.5	NA	Improvement in tremor
7	hmz c.[811C>T] exon 6 p.[Arg271Cys]	Truncal ataxia, dystonia, chorea	Decreased	30 mg/kg/d, 3 y	NA	NA	No improvement
7	hmz c.[589‐3C>G] intron 3 p.[Leu197Valfs*20]	Gait ataxia	NA	400 mg TID, 12 m	7	7	No improvement
7	hmz c.[589‐3C>G] intron 3 p.[Leu197Valfs*20]	Gait ataxia	NA	400 mg TID, 12 m	10	9	Improvement in ataxia
7	hmz c.[1081‐1_1082dupGTA] intron 8 / exon 9 p.[Gln360_Tyr361ins*]	Ataxia, transient chorea	NA	400 mg BID, 12 m	15	NA	No improvement
3	comp. htz c.1750_1752delACC, p. Thr584delACC p.P502R	Delayed development, ataxia, psychiatric	NA	20 kg/mg/d, 6 y	NA	NA	Improvement in motor skills
4	hmz c.1844_1845insG, p.Ser616Leufs*114	Myoclonus, tremor, ataxia	Decreased	200 mg BID, 6 m	17	13	Improvement in myoclonus, tremor, and ataxia
9	hmz c.895C > T, p.Arg99Trp	Epilepsy, ataxia	Decreased	300 mg TID, 6 m	7	NA	No improvement
	comp. htz c.895C > T, p.Arg229Trp, c.1732T > G, p.Phe578Val	Epilepsy, stroke‐like, ataxia	Decreased	300 mg TID, 6 m	11	6	Improvement in ataxia
	hmz c.895C > T, p.Arg299Trp	Ataxia, epilepsy	NA	Deoxyubiquinone 1000 mg/d, 4 y	33	NA	No improvement
8	hmz c.[1511_1512delCT], p.Ala504fs	Ataxia	Decreased	400 mg/d, 1 y	13	10	Improvement in ataxia

Abbreviations: BID, twice a day; comp. htz, compound heterozygous; CoQ₁₀, coenzyme Q10; hmz, homozygous; m, month; NA, Not available; SARA, Scale for the assessment and rating of ataxia; TID, three times a day; y, year.

Eleven patients (50%) reported clinical benefit from CoQ₁₀ supplementation. Ataxia was the symptom that showed the greatest response (eight patients [36.4%]), followed by other movement disorders such as dystonia, myoclonus, and tremor (four patients [18.1%]). One patient described a benefit in exercise intolerance and vomiting, and another showed improved motor skills. Fourteen (63.6%) had CoQ₁₀ levels reported from muscle or fibroblast; seven (31.8%) of them showed decreased levels. All the responders received variable dosages of ubiquinone, ranging from a total daily dose of 300 to 1200 mg, and duration, ranged from six months to 15 years. There were no consistent correlations between clinical phenotype, genotype, and response to treatment.

Discussion

Two of our three patients with ADCK3 gene mutations showed clinical improvement after short‐term CoQ₁₀ supplementation, similar to other reports;2, 3, 4, 5, 6, 7, 8, 9 however, potential longer‐term impact upon disease progression remains unclear. Given the heterogeneity of diseases caused by genetic mutations resulting in a CoQ₁₀ deficiency, responses to supplementation are varied. So far, one prospective longer‐term, open‐label study, evaluating response to CoQ₁₀ supplementation in patients with congenital cerebellar ataxia of unknown origin, was performed.10 This study followed two groups of seven cases, one group with low muscle CoQ₁₀ and another with normal levels. Both had similar levels of disability at baseline and were treated with CoQ₁₀ 30 mg/kg/day with International Cooperative Ataxia Rating Scale (ICARS) determined at baseline and after 3, 6, 12, and 24 months. At the end of 24 months, the group with low muscle CoQ₁₀ levels showed a statistically significant reduction of ICARS, including posture, gait, and kinetic function scores compared to baseline. The group with normal muscle CoQ₁₀ levels did not show improvements, except for two patients. There were no intergroup differences in variables that may influence response including age at therapy start, disease severity, and treatment compliance. The only patient with a proven genetic abnormality on further screening had an ADCK3 gene mutation, and did not respond better compared to those without genetic abnormalities, suggesting the possibility that muscle CoQ₁₀ levels, not the type of genetic mutation, is a better predictor of supplementation response. Unfortunately, the degree of reduction in muscle CoQ₁₀ levels was not accounted for and should be considered as an important variable in future studies. All our cases had reduced muscle CoQ₁₀; however, one did not benefit from therapy.

A limited number of publications have described immediate and dramatic responses of movement disorders to CoQ₁₀ supplementation. Mignot et al.7 reported twelve patients with biallelic mutations in the ADCK3 gene, and of the six patients who had detailed CoQ₁₀ supplementation response records, only two with dystonia, tremor, and myoclonus showed a dramatic and long‐lasting improvement after 6 months of treatment with 300 mg a day. Liu et al.4 reported a patient's dramatic improvement in myoclonus and speech after 3 months of CoQ₁₀ 400mg a day supplementation, which was sustained after 6 months. Of note, improvements in gait ataxia were more evident after 6 months of therapy, suggesting that longer treatment may be needed to improve ataxia.

Here, we added data from our patients to published cases that had adequate clinical and paraclinical documentation, with critical attention to the dose, duration, and response to CoQ₁₀ supplementation. In concordance with some of the reports from the literature, case one responded remarkably with respect to tremor and dystonia, while case two showed a substantial improvement in ataxia, to the extent that she was able to walk after using a wheelchair for years. All responders received CoQ₁₀ supplementation for at least 6 months; however, the response did not clearly correlate with the daily dosage with the caveat that only two reports described supplementation with regard to bodyweight while all others mention an absolute daily dose, ranging from 300 to 1200 mg a day. Overall, the response to CoQ₁₀ supplementation in patients with ADCK3 gene mutation was not uniform. In part, this may be due to different factors, especially the lack of standardized dosages, duration of CoQ₁₀ replacement, and variable details of outcome measurements.

Our experience highlights the importance of the diagnosis of this rare condition given that the neurological status of some patients may be improved with therapy. Indeed, we recommend a therapeutic trial of CoQ₁₀ supplementation in patients with ataxia of unknown etiology, starting with a dose of 5 mg/kg up to a maximum of 15 mg/kg total daily dose, maintained for a minimum of 6 months.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

A.C.: 1A, 1C, 3A

M.R.‐L.: 1A, 3B

E.S.: 2B, 3C

M.T.: 2B, 3C

A.E.L.: 1A, 3B

R.P.M.: 1A, 1B, 1C, 3C

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. The patient's informed consent was obtained.

Funding Sources and Conflict of Interest: The authors report no sources of funding and no conflicts of interest relevant to this work.

Financial Disclosures for the previous 12 months: The authors report no sources of funding and no conflicts of interest.

Supporting information

Supplemental Video 1. At the age of 23 his ataxia symptoms were subtle, and the scale for the assessment and rating of ataxia (SARA) score was 6.

Supplemental Video 2. After 6 months of supplementation with CoQ₁₀ 200 mg twice a day followed by 3 months of 400 mg twice a day, the SARA score reduced to 5 and his symptoms and signs have not shown significant progression overall since then. Moreover, he had improvement in dystonia, especially in axial dystonia resulting scoliosis.