Episodic ataxia type 2 (EA2) with interictal myokymia and focal dystonia.

Episodic ataxia type 1 and 2 (EA1 and EA2) are the most well-described of the episodic ataxias. They are autosomal dominantly inherited early-onset diseases characterized by attacks of cerebellar dysfunction. EA1 is clinically characterized by short episodes of ataxia with interictal myokymia, whereas EA2 is characterized by longer-lasting recurrent ataxia, slurred speech, and interictal nystagmus. We report on a patient with EA2 with interictal focal dystonia and also interictal myokymia, which is hitherto not reported as an interictal feature associated to EA2. The patient carries a previously described heterozygous pathogenic de novo frameshift variant in the CACNA1A gene, establishing the diagnosis of EA2. She had symptom onset at age 13 and from age 48 she developed interictal myokymia and focal dystonia as illustrated in Supplemental Movie S1. We conclude that interictal myokymia and focal dystonia may be interictal features associated to EA2 caused by the cerebellar pathophysiology of EA2. Episodes of ataxia were successfully treated with acetazolamide in low dose, whereas the interictal features were unresponsive to acetazolamide.

Dyssynergic Defecation and Other Evacuation Disorders.

Constipated patients are frequently referred to gastroenterologists for symptoms refractory to lifestyle modifications and laxatives. Dyssynergic defecation, the dyscoordination of rectoanal, abdominal, and pelvic floor muscles to facilitate defecation, is a major cause of refractory primary constipation. Understanding of the diagnosis, evaluation, and management of dyssynergic defecation and other evacuation disorders will allow providers to effectively manage these patients. This review focuses on the definition, pathophysiology, evaluation, and treatment of dyssynergic defecation and other evacuation disorders. Emerging treatments for these disorders include home biofeedback therapy for dyssynergic defecation and translumbosacral neuromodulation therapy for levator ani syndrome.

[Orientation disorder, ophthalmoplegia and ataxia in a 48-year-old male]. / Orientierungsstörung, Ophthalmoplegie und Ataxie bei einem 48-Jährigen.

This case report concerns a 48-year-old male patient presenting the classic clinical picture of Wernicke encephalopathy with orientation disorder, ophthalmoplegia and ataxia. Wernicke encephalopathy is a neurological emergency that should be treated immediately with high-dose intravenous thiamine for a week, if suspected. Recognition of the disease in the emergency room is essential. Due to the limited compliance in patients with alcohol-use disorder, early diagnosis can be challenging.

Update on the Treatment of Ataxia: Medication and Emerging Therapies.

While rehabilitation therapies always help patients with ataxia, there are currently no FDA-approved treatments for ataxia. Medications are available to treat symptoms that may complicate an ataxic illness, e.g., tremor, myoclonus, dystonia, and rigidity, which are discussed elsewhere in this volume. Spasticity, pain, fatigue, depression, sleep disturbances, cognitive decline, and bowel and bladder dysfunction, if they occur, all have multiple available drugs and therapies for symptomatic use. There is also an extensive literature on off-label uses of various medications to improve imbalance. The pipeline of emerging therapies for symptomatic and possible disease-modifying management of ataxia gives hope that we will soon see the first of many FDA-approved drugs for ataxic illnesses.

COQ2 nephropathy: a treatable cause of nephrotic syndrome in children.

BACKGROUND: Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q10 (CoQ10) deficiency. Pathogenic COQ2 variants are a cause of primary CoQ10 deficiency and present with phenotypes ranging from isolated nephrotic syndrome to fatal multisystem disease. CASE-DIAGNOSIS/TREATMENT: We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ10 levels prior to treatment. Pathologic findings varied from mesangial sclerosis to focal segmental glomerulosclerosis, with all patients having abnormal appearing mitochondria on kidney biopsy. In two of the three patients treated with CoQ10 supplementation, the nephrotic syndrome resolved; and at follow-up, both have normal renal function and stable proteinuria. CONCLUSIONS: COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ10 levels, as levels may be within normal range even with significant clinical disease. Early molecular diagnosis and specific treatment are essential in the management of this severe yet treatable condition.

The dilemma of diagnosing coenzyme Q10 deficiency in muscle.

BACKGROUND: Coenzyme Q10 (CoQ10) is an important component of the mitochondrial respiratory chain (RC) and is critical for energy production. Although the prevalence of CoQ10 deficiency is still unknown, the general consensus is that the condition is under-diagnosed. The aim of this study was to retrospectively investigate CoQ10 deficiency in frozen muscle specimens in a cohort of ethnically diverse patients who received muscle biopsies for the investigation of a possible RC deficiency (RCD). METHODS: Muscle samples were homogenized whereby 600 ×g supernatants were used to analyze RC enzyme activities, followed by quantification of CoQ10 by stable isotope dilution liquid chromatography tandem mass spectrometry. The experimental group consisted of 156 patients of which 76 had enzymatically confirmed RCDs. To further assist in the diagnosis of CoQ10 deficiency in this cohort, we included sequencing of 18 selected nuclear genes involved with CoQ10 biogenesis in 26 patients with low CoQ10 concentration in muscle samples. RESULTS: Central 95% reference intervals (RI) were established for CoQ10 normalized to citrate synthase (CS) or protein. Nine patients were considered CoQ10 deficient when expressed against CS, while 12 were considered deficient when expressed against protein. In two of these patients the molecular genetic cause could be confirmed, of which one would not have been identified as CoQ10 deficient if expressed only against protein content. CONCLUSION: In this retrospective study, we report a central 95% reference interval for 600 ×g muscle supernatants prepared from frozen samples. The study reiterates the importance of including CoQ10 quantification as part of a diagnostic approach to study mitochondrial disease as it may complement respiratory chain enzyme assays with the possible identification of patients that may benefit from CoQ10 supplementation. However, the anomaly that only a few patients were identified as CoQ10 deficient against both markers (CS and protein), while the majority of patients where only CoQ10 deficient against one of the markers (and not the other), remains problematic. We therefore conclude from our data that, to prevent possibly not diagnosing a potential CoQ10 deficiency, the expression of CoQ10 levels in muscle on both CS as well as protein content should be considered.

Cerebral Manifestations of Mitochondrial Disorders.

This review aims at summarizing and discussing previous and recent findings concerning the cerebral manifestations of mitochondrial disorders (MIDs). MIDs frequently present as mitochondrial multiorgan disorder syndrome (MIMODS) either already at onset or later in the course. After the muscle, the brain is the organ second most frequently affected in MIMODS. Cerebral manifestations of MIDs are variable and may present with or without a lesion on imaging or functional studies, but there can be imaging/functional lesions without clinical manifestations. The most well-known cerebral manifestations of MIDs include stroke-like episodes, epilepsy, headache, ataxia, movement disorders, hypopituitarism, muscle weakness, psychiatric abnormalities, nystagmus, white and gray matter lesions, atrophy, basal ganglia calcification, and hypometabolism on 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron-emission tomography. For most MIDs, only symptomatic therapy is currently available. Symptomatic treatment should be supplemented by vitamins, cofactors, and antioxidants. In conclusion, cerebral manifestations of MIDs need to be recognized and appropriately managed because they strongly determine the outcome of MID patients.

[Functional Electrical Stimulation in a Case of Drop Foot and Atactic Gait: Expert Assessment of Contested Medical Aids]. / Funktionelle Elektrostimulation bei Fußheberschwäche und ataktischem Gangbild: Gutachterliches Vorgehen bei streitiger Hilfsmittelversorgung.

Expert medical opinions are necessary in pretrial cases and other legal matters. They act as means of evidence for administrative bodies and courts. It may be necessary to adapt the method of evaluation depending upon the issue or subject matter to be evaluated. We report on a social court case, which needed to answer the question of the medical necessity of a functional electrical stimulation orthosis prescribed to improve the function of a drop foot accompanied by an atactic gait disorder. The claimant suffered from a stroke, which had occurred several years before. Her aids were an ankle-foot-orthosis for foot lift and a wheeled walker. The current treatment was to be augmented by the disputed device. The statutory health insurance declined to meet the costs. They failed to find relevant benefits after analysis of video tapes of the patient's gait while using an electrical stimulation orthosis. The social court requested an expert opinion to answer the question as to whether or not there was a relevant functional benefit to using functional electrical stimulation over the existing orthosis or to an alternative treatment. Video documentation was desired by the court. We used the clinic's gait analysis laboratory, which is equipped with a gait course and the claimed video documentation. Standardised video documentation offers substantial advantages for answering forensic questions such as these. It assures reproducibility and comparability of all tested scenarios, with objectification of the individual advantages or limitations. This gain in both validity and reliability fulfills the scientific requirements placed upon an expert assessment.

Coenzyme Q10 analytical determination in biological matrices and pharmaceuticals.

In recent years, the analytical determination of coenzyme Q10 (CoQ10) has gained importance in clinical diagnosis and in pharmaceutical quality control. CoQ10 is an important cofactor in the mitochondrial respiratory chain and a potent endogenous antioxidant. CoQ10 deficiency is often associated with numerous diseases and patients with these conditions may benefit from administration of supplements of CoQ10. In this regard, it has been observed that the best benefits are obtained when CoQ10 deficiency is diagnosed and treated early. Therefore, it is of great value to develop analytical methods for the detection and quantification of CoQ10 in this type of disease. The methods above mentioned should be simple enough to be used in routine clinical laboratories as well as in quality control of pharmaceutical formulations containing CoQ10. Here, we discuss the advantages and disadvantages of different methods of CoQ10 analysis.

Coenzyme Q10 defects may be associated with a deficiency of Q10-independent mitochondrial respiratory chain complexes.

BACKGROUND: Coenzyme Q10 (CoQ10 or ubiquinone) deficiency can be due either to mutations in genes involved in CoQ10 biosynthesis pathway, or to mutations in genes unrelated to CoQ10 biosynthesis. CoQ10 defect is the only oxidative phosphorylation disorder that can be clinically improved after oral CoQ10 supplementation. Thus, early diagnosis, first evoked by mitochondrial respiratory chain (MRC) spectrophotometric analysis, then confirmed by direct measurement of CoQ10 levels, is of critical importance to prevent irreversible damage in organs such as the kidney and the central nervous system. It is widely reported that CoQ10 deficient patients present decreased quinone-dependent activities (segments I + III or G3P + III and II + III) while MRC activities of complexes I, II, III, IV and V are normal. We previously suggested that CoQ10 defect may be associated with a deficiency of CoQ10-independent MRC complexes. The aim of this study was to verify this hypothesis in order to improve the diagnosis of this disease. RESULTS: To determine whether CoQ10 defect could be associated with MRC deficiency, we quantified CoQ10 by LC-MSMS in a cohort of 18 patients presenting CoQ10-dependent deficiency associated with MRC defect. We found decreased levels of CoQ10 in eight patients out of 18 (45 %), thus confirming CoQ10 disease. CONCLUSIONS: Our study shows that CoQ10 defect can be associated with MRC deficiency. This could be of major importance in clinical practice for the diagnosis of a disease that can be improved by CoQ10 supplementation.

Cerebellar ataxia and severe muscle CoQ10 deficiency in a patient with a novel mutation in ADCK3.

Inherited ataxias are a group of heterogeneous disorders in children or adults but their genetic definition remains still undetermined in almost half of the patients. However, CoQ10 deficiency is a rare cause of cerebellar ataxia and ADCK3 is the most frequent gene associated with this defect. We herein report a 48 year old man, who presented with dysarthria and walking difficulties. Brain magnetic resonance imaging showed a marked cerebellar atrophy. Serum lactate was elevated. Tissues obtained by muscle and skin biopsies were studied for biochemical and genetic characterization. Skeletal muscle biochemistry revealed decreased activities of complexes I+III and II+III and a severe reduction of CoQ10 , while skin fibroblasts showed normal CoQ10 levels. A mild loss of maximal respiration capacity was also found by high-resolution respirometry. Molecular studies identified a novel homozygous deletion (c.504del_CT) in ADCK3, causing a premature stop codon. Western blot analysis revealed marked reduction of ADCK3 protein levels. Treatment with CoQ10 was started and, after 1 year follow-up, patient neurological condition slightly improved. This report suggests the importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult-onset cerebellar ataxia. Moreover, clinical stabilization by CoQ10 supplementation emphasizes the importance of an early diagnosis.

Coenzyme Q10 defects may be associated with a deficiency of Q10-independent mitochondrial respiratory chain complexes

BACKGROUND: Coenzyme Q10 (CoQ10 or ubiquinone) deficiency can be due either to mutations in genes involved in CoQ10 biosynthesis pathway, or to mutations in genes unrelated to CoQ10 biosynthesis. CoQ10 defect is the only oxidative phosphorylation disorder that can be clinically improved after oral CoQ10 supplementation. Thus, early diagnosis, first evoked by mitochondrial respiratory chain (MRC) spectrophotometric analysis, then confirmed by direct measurement of CoQ10 levels, is of critical importance to prevent irreversible damage in organs such as the kidney and the central nervous system. It is widely reported that CoQ10 deficient patients present decreased quinone-dependent activities (segments I + III or G3P + III and II + III) while MRC activities of complexes I, II, III, IV and V are normal. We previously suggested that CoQ10 defect may be associated with a deficiency of CoQ10-independent MRC complexes. The aim of this study was to verify this hypothesis in order to improve the diagnosis of this disease. RESULTS: To determine whether CoQ10 defect could be associated with MRC deficiency, we quantified CoQ10 by LC-MSMS in a cohort of 18 patients presenting CoQ10-dependent deficiency associated with MRC defect. We found decreased levels of CoQ10 in eight patients out of 18 (45 %), thus confirming CoQ10 disease. CONCLUSIONS: Our study shows that CoQ10 defect can be associated with MRC deficiency. This could be of major importance in clinical practice for the diagnosis of a disease that can be improved by CoQ10 supplementation.

A novel non-invasive sampling method using buccal mucosa cells for determination of coenzyme Q10.

Coenzyme Q10 (CoQ10) is an important cofactor in the mitochondrial respiratory chain and a potent endogenous antioxidant. CoQ10 deficiency is often associated with numerous diseases, and patients can benefit from CoQ10 supplementation, being more effective when diagnosed and treated early. Due to the increased interest in CoQ10 deficiency, several methods for CoQ10 analysis from plasmatic, muscular, fibroblast, and platelet matrices have been developed. These sampling techniques are not only highly invasive but also too traumatic for periodic clinical monitoring. In the present work, we describe the development and validation of a novel non-invasive sampling method for quantification of CoQ10 in buccal mucosa cells (BMCs) by microHPLC. This method is suitable for using in a routine laboratory and useful for sampling patients in pediatry. CoQ10 correlation was demonstrated between BMCs and plasma levels (Spearman r, 0.4540; p < 0.001). The proposed method is amenable to be applied in the post treatment monitoring, especially in pediatric patients as a non-invasive sample collection. More studies are needed to assess whether this determination could be used for diagnosis and if this matrix could replace the traditional ones.

Primary coenzyme Q10 deficiency presenting as fatal neonatal multiorgan failure.

Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 µM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis.

Genetic bases and clinical manifestations of coenzyme Q10 (CoQ 10) deficiency.

Coenzyme Q(10) is a remarkable lipid involved in many cellular processes such as energy production through the mitochondrial respiratory chain (RC), beta-oxidation of fatty acids, and pyrimidine biosynthesis, but it is also one of the main cellular antioxidants. Its biosynthesis is still incompletely characterized and requires at least 15 genes. Mutations in eight of them (PDSS1, PDSS2, COQ2, COQ4, COQ6, ADCK3, ADCK4, and COQ9) cause primary CoQ(10) deficiency, a heterogeneous group of disorders with variable age of onset (from birth to the seventh decade) and associated clinical phenotypes, ranging from a fatal multisystem disease to isolated steroid resistant nephrotic syndrome (SRNS) or isolated central nervous system disease. The pathogenesis is complex and related to the different functions of CoQ(10). It involves defective ATP production and oxidative stress, but also an impairment of pyrimidine biosynthesis and increased apoptosis. CoQ(10) deficiency can also be observed in patients with defects unrelated to CoQ(10) biosynthesis, such as RC defects, multiple acyl-CoA dehydrogenase deficiency, and ataxia and oculomotor apraxia.Patients with both primary and secondary deficiencies benefit from high-dose oral supplementation with CoQ(10). In primary forms treatment can stop the progression of both SRNS and encephalopathy, hence the critical importance of a prompt diagnosis. Treatment may be beneficial also for secondary forms, although with less striking results.In this review we will focus on CoQ(10) biosynthesis in humans, on the genetic defects and the specific clinical phenotypes associated with CoQ(10) deficiency, and on the diagnostic strategies for these conditions.

Association between coenzyme Q10 and glucose transporter (GLUT1) deficiency.

BACKGROUND: It has been demonstrated that glucose transporter (GLUT1) deficiency in a mouse model causes a diminished cerebral lipid synthesis. This deficient lipid biosynthesis could contribute to secondary CoQ deficiency. We report here, for the first time an association between GLUT1 and coenzyme Q10 deficiency in a pediatric patient. CASE PRESENTATION: We report a 15 year-old girl with truncal ataxia, nystagmus, dysarthria and myoclonic epilepsy as the main clinical features. Blood lactate and alanine values were increased, and coenzyme Q10 was deficient both in muscle and fibroblasts. Coenzyme Q10 supplementation was initiated, improving ataxia and nystagmus. Since dysarthria and myoclonic epilepsy persisted, a lumbar puncture was performed at 12 years of age disclosing diminished cerebrospinal glucose concentrations. Diagnosis of GLUT1 deficiency was confirmed by the presence of a de novo heterozygous variant (c.18+2T>G) in the SLC2A1 gene. No mutations were found in coenzyme Q10 biosynthesis related genes. A ketogenic diet was initiated with an excellent clinical outcome. Functional studies in fibroblasts supported the potential pathogenicity of coenzyme Q10 deficiency in GLUT1 mutant cells when compared with controls. CONCLUSION: Our results suggest that coenzyme Q10 deficiency might be a new factor in the pathogenesis of G1D, although this deficiency needs to be confirmed in a larger group of G1D patients as well as in animal models. Although ketogenic diet seems to correct the clinical consequences of CoQ deficiency, adjuvant treatment with CoQ could be trialled in this condition if our findings are confirmed in further G1D patients.

ANO10 mutations cause ataxia and coenzyme Q10 deficiency.

Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.

Nitrogen-bisphosphonate therapy is linked to compromised coenzyme Q10 and vitamin E status in postmenopausal women.

BACKGROUND: Nitrogen-bisphosphonates (N-BPs) are the most widely used drugs for bone fragility disorders. Long-term or high-dose N-BP use is associated with unusual serious side effects such as osteonecrosis of the jaw, musculoskeletal pain, and atypical fractures of long bones. It has escaped notice that the pathway N-BPs block is central for the endogenous synthesis of coenzyme Q10, an integral enzyme of the mitochondrial respiratory chain and an important lipid-soluble antioxidant. Our objective was to assess the coenzyme Q10 and antioxidant status in relation to N-BP exposure in women with postmenopausal osteoporosis. METHODS: Seventy-one postmenopausal women (age, 73.5 ± 5.5 y) with osteoporosis and no other malignancy were included in this cross-sectional study. Seventeen were treatment naive, 27 were on oral N-BP, and 27 were on i.v. N-BP. RESULTS: Vitamin E γ-tocopherol levels (µmol/mL) were significantly reduced in N-BP users [oral, H(2) = 18.5, P = .02; i.v., H(2) = 25.2, P < .001; mean rank comparisons after Kruskal-Wallis test). Length of time (days) of N-BP exposure, but not age, was inversely associated with the coenzyme Q10/cholesterol ratio (µmol/mol) (ß = -0.27; P = .025), which was particularly low for those on i.v. N-BP (mean difference = -35.0 ± 16.9; 95% confidence interval, -65.2 to -4.9; P = .02). CONCLUSION: The degree of N-BP exposure appears related to compromised coenzyme Q10 status and vitamin E γ-tocopherol levels in postmenopausal women with osteoporosis. This phenomenon may link to certain adverse N-BP-associated effects. Confirmation of this would suggest that therapeutic supplementation could prevent or reverse certain complications of long-term N-BP therapy for at-risk individuals.

Characterization of CoQ10 biosynthesis in fibroblasts of patients with primary and secondary CoQ10 deficiency.

Primary coenzyme Q10 (CoQ10) deficiencies are associated with mutations in genes encoding enzymes important for its biosynthesis and patients are responsive to CoQ10 supplementation. Early treatment allows better prognosis of the disease and therefore, early diagnosis is desirable. The complex phenotype and genotype and the frequent secondary CoQ10 deficiencies make it difficult to achieve a definitive diagnosis by direct quantification of CoQ10. We developed a non-radioactive methodology for the quantification of CoQ10 biosynthesis in fibroblasts that allows the identification of primary deficiencies. Fibroblasts were incubated 72 h with 28 µmol/L (2)H3-mevalonate or 1.65 mmol/L (13)C6-p-hydroxybenzoate. The newly synthesized (2)H3- and (13)C6- labelled CoQ10 were analysed by high performance liquid chromatography-tandem mass spectrometry. The mean and the reference range for (13)C6-CoQ10 and (2)H3-CoQ10 biosynthesis were 0.97 (0.83-1.1) and 0.13 (0.09-0.17) nmol/Unit of citrate synthase, respectively. We validated the methodology through the study of one patient with COQ2 mutations and six patients with CoQ10 deficiency secondary to other inborn errors of metabolism. Afterwards we investigated 16 patients' fibroblasts and nine showed decreased CoQ10 biosynthesis. Therefore, the next step is to study the COQ genes in order to reach a definitive diagnosis in these nine patients. In the patients with normal rates the deficiency is probably secondary. In conclusion, we have developed a non-invasive non-radioactive method suitable for the detection of defects in CoQ10 biosynthesis, which offers a good tool for the stratification of patients with these treatable mitochondrial diseases.