Heterogeneity of coenzyme Q₁₀ deficiency: Patient Study and Literature Review

Abstract

CoQ₁₀ deficiency has been associated with five major clinical phenotypes: encephalomyopathy, severe infantile multisystemic disease, nephropathy, cerebellar ataxia, and isolated myopathy. Primary CoQ₁₀ deficiency is due to defects in CoQ₁₀ biosynthesis while secondary forms are due to other causes. Review of 149 cases, including our cohort of 76 patients, confirms that CoQ₁₀ deficiency is a clinically and genetically heterogeneous syndrome that predominantly begins in childhood and predominantly manifests as cerebellar ataxia. CoQ₁₀ measurement in muscle is the gold standard for diagnosis. Identification of CoQ₁₀ deficiency is important because it frequently responds to treatment. Causative mutations have been identified in a small proportion of patients.

INTRODUCTION

Coenzyme Q₁₀ (CoQ₁₀ or ubiquinone) deficiency in human is associated with clinically heterogeneous diseases.¹ Five major phenotypes have been described: 1) encephalomyopathy; 2) cerebellar ataxia; 3) infantile multisystemic form; 4) nephropathy; and 5) isolated myopathy (Table 1).

Table 1.

Clinical features of major forms of CoQ₁₀ deficiency

Syndrome	Number of cases (new cases)	Clinical features	Natural history	Responsible genes (numbers of patients/families)	References
Encephalomyopathy	4	Juvenile-onset mitochondrial myopathy, recurrent myoglobinuria, and encephalopathy	Slow progression of weakness	None known	4-6
Isolated myopathy	14 (4)	Juvenile or adult-onset muscle weakness, myoglobinuria, exercise intolerance, cramps, myalgias, elevated CK	Slow progression of weakness	ETFDH (7/5)	6-9
Nephropathy	11	Infantile or early childhood-onset steroid-resistant nephrotic syndrome.	May progress to renal failure. Encephalopathy may develop.	COQ2 (2/2),	2,10-19
		Infantile or juvenile-onset steroid- resistant nephrotic syndrome typically with congenital or juvenile- onset sensorineural deafness	Nephropathy typically progresses to renal failure. Seizures and ataxia may develop. May be fatal (2/8=25%)	COQ6 (8/4)
Infantile multisystemic disease	17 (2)	Infantile-onset psychomotor regression, encephalopathy, optic atrophy, retinopathy, hearing loss, renal dysfunction (mainly nephrotic syndrome). Less common: liver, cardiac, and pancreatic dysfunction and obesity.	Typically progresses rapidly with high mortality (11/17=65%)	COQ2 (4/3?), PDSS2 (1/1), COQ9 (1/1) PDSS1 (1/1), COQ6 (3/?)	14-18
Cerebellar ataxia	94 (23)	Typically juvenile-onset cerebellar ataxia. Multiple additional neurological and non-neurological manifestations may occur.	Slow or minimal progression of ataxia.	ADCK3 (22/13?), APTX (12/8?)	3,20-34
Atypical presentations	9 (5)	Adults with childhood-onset Leigh syndrome	Subacute progression.	None known	35-37
		Cardiofaciocutaneous syndrome	Uncertain.	BRAF (1/1)
		Neonatal hypotonia, infantile spasms	?	None known
		Adult-onset cerebellar ataxia and nephrotic syndrome	?	None known
		Childhood-onset encephalomyopathy, short stature, hearing loss and retinopathy	?	None known

METHODS

Seventy-six patients with CoQ₁₀ deficiency (36 previously unreported) were studied at the H. Houston Merritt Clinical Research Center, Columbia University Medical Center (CUMC), New York, NY, USA under CUMC Institutional Review Board protocols. CoQ₁₀ levels were measured in muscle, cultured fibroblasts, and/or lymphoblasts.^2,3 CoQ₁₀ levels reduced more than 2 SD below mean control values were considered deficient. Patients with CoQ₁₀ level decreased in one member of the family with similar phenotype and/or genetic mutation were considered to have CoQ₁₀ deficiency.

Dideoxy-sequencing was performed on all exons and flanking intronic regions of genes involved in CoQ₁₀ biosynthesis, associated with secondary CoQ₁₀ deficiencies, or encoding proteins with similar function, structure or both as proteins associated with CoQ₁₀ deficiency. In addition, PSAP encoding saposin B, a cytosolic protein that binds and transfers CoQ₁₀, and POLG were sequenced (eTable 1).

CLINICAL FEATURES

Since the first description of human ubiquinone deficiency, 113 patients have been reported (Tables 1-3). Of 455 patients’ samples referred to our center for possible CoQ₁₀ deficiency from 1997 to 2010, 76 patients (64 families) had CoQ₁₀ deficiency; 40 were previously described. The reported patients and our 36 new patients comprised 149 cases: 4 encephalomyopathy, 14 isolated myopathy, 17 infantile-onset multisystemic disease, 11 nephropathy (with our without sensorineural hearing loss), 94 cerebellar ataxia, and 9 patients with atypical presentations.

Table 3.

Clinical response to CoQ10 supplementation in major forms of CoQ₁₀ deficiency

Syndrome	CoQ10 doses and duration	Response to therapy
Encephalomyopathy
Isolated myopathy
Isolated nephropathy
Infantile multisystemic disease
Cerebellar ataxia
Atypical presentations

Onset was predominantly in childhood (<13 years old: 82%) including 23% in infancy (<12 months old). Onset during adolescence (13-18 years-old: 7%) and adulthood (>18 years-old: 11%) were uncommon. The mortality rate was low (8%) and mainly seen in the infantile multisystemic and renal forms.

The encephalomyopathic form of CoQ₁₀ deficiency manifesting as a triad of mitochondrial myopathy, recurrent myoglobinuria, and encephalopathy, has been reported in 4 patients (eTable 2).^4-6 Neurological features included cerebellar ataxia, seizures, mental retardation, delayed motor development; progressive external ophthalmoplegia and ptosis.

The myopathic form of CoQ₁₀ deficiency presents with muscle weakness, myoglobinuria, exercise intolerance, cramps, myalgia, and elevated CK. This condition has been described in 10 patients.^6-9 We have identified 4 additional patients (eTable 3).

Among the 17 patients (including 2 new patients) with the infantile multisystemic form, the combination of encephalopathy and nephropathy has been the most common presentation (eTable 4).^2,10-16 Neurological manifestations are: psychomotor regression, ataxia, hypotonia, seizures, pyramidal syndrome, optic atrophy and retinopathy, deafness and Leigh syndrome. The renal involvement is mainly nephrotic syndrome but occasionally tubulopathy. Three patients required kidney transplantation.^15,17 In addition, liver, cardiac and pancreatic involvement, and obesity have been described in literature and in our cohort.^10,12,18 Eleven patients (65%) died in early infancy, and causes of death were opportunistic infections, kidney failure, encephalopathy, or multi-organ failure. Early onset isolated steroid resistant nephrotic syndrome (SRNS), due to collapsing glomerulopathy and focal segmental glomerulosclerosis (FSGS), has been reported in 2 patients.¹⁴ Moreover, the association between SRNS with sensorineural hearing loss has been described in patients with mutations in the CoQ₁₀ biosynthetic gene, COQ6; however, CoQ₁₀ level was not measured in these patients (eTable 5).¹⁶

Cerebellar ataxia is the most common phenotype, with 94 patients (including 23 new patients) (eTable 6).^3,19-33 Other manifestations include neuropathy, seizures, mental retardation, migraine, psychiatric disorders, muscle weakness and exercise intolerance, congenital hypotonia, upper motor neuron signs, dystonia and chorea, ptosis and ophthalmoplegia, retinitis pigmentosa, optic atrophy, oculomotor apraxia, deafness, lipomas, Dandy-Walker syndrome, agenesis of corpus callosum, hypogonadism and other endocrinological problems, hypoalbuminemia, and hypercholesterolemia.

Among the patients classified as “atypical cases”, there are two adult sisters with childhood onset Leigh-syndrome, growth retardation, infantilism, ataxia, deafness, and lactic acidosis, ³⁴ a 4-year-old Moroccan girl with cardiofaciocutaneous syndrome (CFC),³⁵ two unrelated patients with neonatal hypotonia and infantile spasm (one reported)³⁶, two Portuguese sisters with adult-onset cerebellar ataxia and nephrotic syndrome, and a 16-year-old girl with onset at age 4 years of exercise intolerance, fatigue, recurrent headaches, short stature, deafness, retinopathy and mental retardation. One new patient is the father of a child with cerebellar ataxia (P119 in eTable 6), with mild CK elevation, but normal examination and brain MRI.

DIAGNOSIS

Initial biochemical evaluation of patients with suspected CoQ₁₀ deficiency should include blood lactate measurement, although normal values do not exclude ubiquinone deficiency. Muscle biopsies occasionally show mitochondrial proliferation or lipid droplets, but can be normal or show only non-specific changes.

Reduced biochemical activities of respiratory chain complexes, in particular, complexes I+III (NADH:cytochrome c oxidoreductase) and II+III (succinate:cytochrome c oxidoreductase) in muscle suggest CoQ₁₀ deficiency, although activities of these enzymes may be normal particularly when the deficiency is mild. Reduction of these enzyme activities and deficiency of CoQ₁₀ in skin fibroblasts can be an important confirmation of ubiquinone deficiency; however normal levels do not exclude deficiency in muscle. Direct measurement of CoQ₁₀ in skeletal muscle by high performance liquid chromatography is the most reliable test for the diagnosis. In contrast, plasma concentrations of ubiquinone are significantly influenced by dietary uptake, therefore not reliable. Measurements of CoQ₁₀ in peripheral blood mononuclear cells (MNC) has detected deficiency in a small number of patients; however, correlations with muscle CoQ₁₀ measurements in a larger cohort of patients will be necessary to assess clinical utility of MNC ubiquinone levels.

Morphological and biochemical findings differ in the various clinical forms. In patients with the encephalomyopathic, myopathic, or infantile multisystemic forms, muscle biopsies have typically revealed abnormal mitochondrial proliferation (RRF or excessive SDH histochemical activity) and lipid accumulation as well as reduced biochemical activities of respiratory chain enzyme complexes I+III and II+III while all muscle samples showed decreased CoQ₁₀ levels. In contrast, fibroblast CoQ₁₀ levels have varied and was normal in one patient with encephalomyopathy, but low in 1/2 with the myopathic form and 7/8 with the infantile multisystemic form.

In two patients with isolated nephropathy, CoQ₁₀ levels and respiratory chain enzyme activities were reduced in either fibroblasts or muscle. RRF-like were observed in the only patient who underwent muscle biopsy.¹⁴

In patients with the ataxic form, muscle biopsies revealed mitochondrial proliferation, COX-negative fibers, or lipid accumulation in 15/49, and reduced respiratory chain enzyme activities in 27/51. Levels of CoQ₁₀ were low in muscle, but reduced in 18/30 fibroblasts.

GENETICS

Primary CoQ₁₀ deficiency is due to mutations in genes involved in CoQ₁₀ biosynthesis (Figure 1). Secondary deficiencies include diseases caused by mutations in genes unrelated to ubiquinone biosynthesis, for example aprataxin (APTX) gene, causing ataxia and oculomotor apraxia,^21,27,28,30 electron-transferring-flavoprotein dehydrogenase gene (ETFDH), causing isolated myopathy,⁹ and BRAF gene, causing CFC syndrome.³⁵ Moreover, CoQ₁₀ deficiency has been reported in association with mitochondrial DNA mutations.¹

Figure 1.

Biosynthesis of coenzyme Q₁₀ (CoQ₁₀). Mutations in CoQ₁₀ biosynthetic genes (indicated by red ovals) cause primary CoQ₁₀ deficiency. CoQ₁₀ transport electrons from mitochondrial respiratory chain complexes I and II to complex III.

In most cases, family history suggests autosomal recessive inheritance. Pathogenic mutations have been reported in 63 patients (Table 1).

No mutations have been described among the encephalomyopathic patients. Except for the patients reported by Gempel in 2007,⁹ we did not find other mutations in ETFDH in our cohort of patients with isolated myopathy, indicating that other genes can be responsible for this phenotype.

Most patients with the infantile-onset multisystemic variant have genetically confirmed primary CoQ₁₀ deficiency. Mutations have been described in COQ2 (3 patients)^13,14,18, PDSS2 (1 patient)², COQ9 (1 patient)¹¹, PDSS1 (2 patients)¹⁸, and COQ6 (3 patients)¹⁶. Interestingly, two patients with isolated nephrotic syndrome have COQ2 mutations.^13,14 Thus, patients with COQ2 mutations have presented with either infantile multisystemic syndrome or isolated nephropathy. There are three potential explanations for the divergent phenotypes. First, variations in the phenotypes may be due to genetic or environmental modifiers. Second, patients with isolated nephropathies may develop multisystemic disease later in life. Third, CoQ₁₀ treatment may have altered the clinical course of the disease by preventing neurological complications in both patients with only renal disease. In contrast, in 9 patients, mutations in COQ6 gene have been associated with kidney involvement (nephrotic syndrome, and nephrolithiasis) and sensorineural hearing loss.¹⁶ A subgroup of patients with juvenile-onset cerebellar ataxia have primary CoQ₁₀ deficiency due to mutations in the ADCK3 gene (22 patients).^{3,25,29,31-33} Secondary forms have been described in association with mutations in the APTX gene (12 patients) including four affected members of one family that we studied.^21,27,28,30 The majority of patients with cerebellar ataxia and CoQ₁₀ deficiency still lack molecular diagnosis.

THERAPY

Patients with CoQ₁₀ deficiency showed variable responses to CoQ₁₀ treatment (Table 3). We recommend oral supplementation doses up to 2,400 mg daily in adult patients and up to 30mg/kg daily in pediatric patients, divided into three doses per day.

In patients with encephalomyopathy, muscle symptoms improved after therapy.^4-6 In one of our patients, muscle symptoms and seizures resolved, CK and lactic acid normalized, and a muscle biopsy showed CoQ₁₀ level normalization.⁶ In contrast, another patient, developed cerebellar ataxia.⁵

Six patients with pure myopathy^6-9 (including one unreported) improved after CoQ₁₀ supplementation, while 2 patients with ETFDH mutations improved only after addition of riboflavin (100 mg/day).⁹

In some patients with the infantile multisystemic form, CoQ₁₀ supplementation has halted progression of the encephalopathy and improved the myopathy.¹⁷ One patient with a homozygous COQ2 mutation, on therapy showed neurological but not renal improvement, and underwent kidney transplant, but his sister, with isolated nephropathy, received coenzyme Q₁₀ and has had progressive recovery of renal function, reduced proteinuria and no neurological manifestations.^13-15 In contrast, a patient with a homozygous COQ9 mutation, on therapy, had reduction of blood lactate, but neurological and cardiac worsening, and died at age 2 years.¹¹ Similarly, despite treatment, a patient with PDSS2 mutations developed intractable seizures and died at age 8 months² and a patient with infantile-onset Leigh syndrome, hepatopathy, and hypertrophic cardiomyopathy after initial clinical improvement, died at age 3 years. Published data for 2 patients with mutations in COQ6 gene noted decreased proteinuria in both patients after CoQ₁₀ treatment, but hearing improved only in one patient.¹⁶

Response to CoQ₁₀ supplementation in patients with cerebellar ataxia is also variable. Three patients with mutations in ADCK3 gene showed mild clinical improvement after treatment,^3,31,32 but 7 patients carrying mutations in the same gene did not improve,^25,33 and another patient, despite dramatic muscle improvement, developed tremor, myoclonic jerks, and cerebellar atrophy.^24,25 In 3 siblings with mutations in APTX gene, CoQ₁₀ supplementation was associated with clear improved ambulation, and resolution of seizures in one patient.²¹ Nevertheless, another patient with APTX mutations did not improve after therapy.²⁸ Improvement in muscle but not neurological signs and symptoms has been noted in one new and 2 reported patients.^19,20 A reduction in ICARS score in 9 patients with unknown genetic defect and in one patient with ADCK3 gene mutations has been documented.^23,26,31 Eleven patients with undefined molecular defect did not respond to therapy.^22,32

Among the clinically atypical cases of CoQ₁₀ deficiency, two sisters with Leigh syndrome and one patient with CFC syndrome improved after CoQ₁₀ supplementation.^34,35 One patient with neonatal hypotonia and infantile spasm showed no improvement.³⁶

CONCLUSIONS

It is important to identify CoQ₁₀ deficiency as this condition often responds to supplementation. The diagnosis can be made by direct measurement of CoQ₁₀ in muscle, and reinforced by the presence of reduced biochemical activities of respiratory chain complexes, in particular, complexes I+III and II+III. Molecular genetic testing has revealed causative mutations in a small proportion of patients indicating that screening for DNA mutations is not yet effective for diagnosing CoQ₁₀ deficiency. Our observations not only highlight the clinical heterogeneity of CoQ₁₀ deficiency, but also the genetic heterogeneity that is likely related to the large number of proteins involved in ubiquinone biosynthesis and regulation and of secondary CoQ₁₀ deficiencies. Clinical improvement after CoQ₁₀ supplementation was documented in many patients, but treatment protocols have not been standardized, and results have not been uniform. Progress in our knowledge of the genetic bases of CoQ₁₀ deficiencies may help us develop a more accurate molecular classification of this syndrome, while additional studies of the pathogenesis of CoQ₁₀ deficiency may lead to more effective therapies.

Table 2.

Laboratory features of major forms of CoQ₁₀ deficiency

Syndrome	Blood lactate	Serum CK	Muscle Histology	Mitochondrial respiratory chain enzyme activities	CoQ10 levels
Encephalomyopathy
Isolated myopathy
Isolated nephropathy
Infantile multisystemic disease
Cerebellar ataxia
Atypical presentations