Progressive Myoclonus Epilepsy Caused by a Homozygous Splicing Variant of SLC7A6OS.

Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected individuals from both families shared a rare, homozygous c.191A > G variant affecting a splice site in SLC7A6OS. Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a ~0.85cM shared genomic region on chromosome 16q encompassing the c.191A > G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss-of-function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2021;89:402-407.

Adult loss of Cacna1a in mice recapitulates childhood absence epilepsy by distinct thalamic bursting mechanisms.

Inborn errors of CACNA1A-encoded P/Q-type calcium channels impair synaptic transmission, producing early and lifelong neurological deficits, including childhood absence epilepsy, ataxia and dystonia. Whether these impairments owe their pathologies to defective channel function during the critical period for thalamic network stabilization in immature brain remains unclear. Here we show that mice with tamoxifen-induced adult-onset ablation of P/Q channel alpha subunit (iKOp/q) display identical patterns of dysfunction, replicating the inborn loss-of-function phenotypes and, therefore demonstrate that these neurological defects do not rely upon developmental abnormality. Unexpectedly, unlike the inborn model, the adult-onset pattern of excitability changes believed to be pathogenic within the thalamic network is non-canonical. Specifically, adult ablation of P/Q channels does not promote Cacna1g-mediated burst firing or T-type calcium current (IT) in the thalamocortical relay neurons; however, burst firing in thalamocortical relay neurons remains essential as iKOp/q mice generated on a Cacna1g deleted background show substantially diminished seizure generation. Moreover, in thalamic reticular nucleus neurons, burst firing is impaired accompanied by attenuated IT. Interestingly, inborn deletion of thalamic reticular nucleus-enriched, human childhood absence epilepsy-linked gene Cacna1h in iKOp/q mice reduces thalamic reticular nucleus burst firing and promotes rather than reduces seizure, indicating an epileptogenic role for loss-of-function Cacna1h gene variants reported in human childhood absence epilepsy cases. Together, our results demonstrate that P/Q channels remain critical for maintaining normal thalamocortical oscillations and motor control in the adult brain, and suggest that the developmental plasticity of membrane currents regulating pathological rhythmicity is both degenerate and age-dependent.

Prevalence and Improvement of Caine-Positive Wernicke-Korsakoff Syndrome in Psychiatric Inpatient Admissions.

BACKGROUND: Wernicke-Korsakoff Syndrome (WKS) resulting from thiamine deficiency is classically defined as including encephalopathy, ataxia, and ophthalmoplegia. Only 16% of autopsy-confirmed patients with WKS exhibit all three signs. Caine-positive WKS criteria include two or more of the following: nutritional deficiency, delirium or mild memory impairment, cerebellar dysfunction/ataxia, and oculomotor abnormalities. OBJECTIVE: We describe Caine-positive WKS prevalence among psychiatric inpatients and compare pretreatment-versus-posttreatment neurocognitive improvement to an unaffected group. METHODS: This 6-month quality-improvement evaluation included two-stage screening for Caine-positive WKS, administering high-dose intravenous thiamine (day 1: 1200 mg; days 2-4: 200 mg) with reexamination on day 5. We used descriptive statistics and fitted random effects models to examine rate-of-change differences in pre-/posttreatment Montreal Cognitive Assessment (MoCA), delayed 5-item recall, and gait/coordination scores between treated Caine-positive patients with WKS and untreated Caine-negative patients. RESULTS: Of 262 patients, 32 (12%) had Caine-positive WKS; 17 (53%) used alcohol currently. Treated Caine-positive WKS (n = 26) versus Caine-negative comparison (n = 34) before and after treatment observed a mean change (standard deviation) in the MoCA score of 3.6 (2.5) versus 1.8 (2.5) (P < 0.01); 5-item recall: 1.8 (1.4) versus 0.5 (1.4) (P < 0.001); gait/coordination scores: -0.6 (1.2) versus -0.1 (0.6) (P < 0.001). Oculomotor abnormalities were infrequent (n = 4 in Caine-positive WKS, n = 2 in Caine-negative comparison groups). CONCLUSIONS: Caine-positive WKS prevalence among psychiatric inpatients was 12%; only half used alcohol. Patients treated with high-dose thiamine demonstrated clinically significant neurocognitive improvement.

Dystonia-Ataxia with early handwriting deterioration in COQ8A mutation carriers: A case series and literature review.

Cerebellar ataxia is a hallmark of coenzyme Q10 (CoQ10) deficiency associated with COQ8A mutations. We present four patients, one with novel COQ8A pathogenic variants all with early, prominent handwriting impairment, dystonia and only mild ataxia. To better define the phenotypic spectrum and course of COQ8A disease, we review the clinical presentation and evolution in 47 reported cases. Individuals with COQ8A mutation display great clinical variability and unpredictable responses to CoQ10 supplementation. Onset is typically during infancy or childhood with ataxic features associated with developmental delay or regression. When disease onset is later in life, first symptoms can include: incoordination, epilepsy, tremor, and deterioration of writing. The natural history is characterized by a progression to a multisystem brain disease dominated by ataxia, with disease severity inversely correlated with age at onset. Six previously reported cases share with ours, a clinical phenotype characterized by slowly progressive or static writing difficulties, focal dystonia, and speech disorder, with only minimal ataxia. The combination of writing difficulty, dystonia and ataxia is a distinctive constellation that is reminiscent of a previously described clinical entity called Dystonia Ataxia Syndrome (DYTCA) and is an important clinical indicator of COQ8A mutations, even when ataxia is mild or absent.

Tocopherols, tocotrienols and tocomonoenols: Many similar molecules but only one vitamin E.

The aim of this article is to correct a very general error in scientific articles, in textbooks and in the Internet that has become an accepted fact. In this literature, the term "vitamin E″ is used for several similar molecules (both tocopherols and tocotrienols) that have never been shown to have vitamin property, i.e. a protective effect against the human deficiency disease. In fact, the name "vitamin E″ should only be used to define molecules that prevent the human deficiency disease "Ataxia with Vitamin E Deficiency" (AVED). Only one such molecule is known, α-tocopherol. This error may confuse consumers as well as medical doctors, who prescribe vitamin E without realizing that the current use of the name includes molecules of unknown, if not unwanted functions.

Real-time use of audio-biofeedback can improve postural sway in patients with degenerative ataxia.

Objective: Cerebellar ataxia essentially includes deficient postural control. It remains unclear whether augmented sensory information might help cerebellar patients, as the cerebellum underlies processing of various sensory modalities for postural control. Here, we hypothesized that patients with cerebellar degeneration can still exploit audio-biofeedback (ABF) of trunk acceleration as a real-time assistive signal to compensate for deficient postural control. Methods: Effects on postural sway during stance were assessed in an ABF intervention group versus a no-ABF disease control group (23 vs. 17 cerebellar patients) in a clinico-experimental study. A single-session ABF paradigm of standing plus short exergaming under ABF was applied. Postural sway with eyes open and eyes closed was quantified prior to ABF, under ABF, and post ABF. Results: Postural sway in the eyes closed condition was significantly reduced under ABF. Both benefit of ABF and benefit of vision correlated with the extent of postural sway at baseline, and both types of sensory benefits correlated with each other. Patients with strongest postural sway exhibited reduced postural sway also with eyes open, thus benefitting from both vision and ABF. No changes were observed in the no-ABF control group. Interpretation: Our findings provide proof-of-principle evidence that subjects with cerebellar degeneration are still able to integrate additional sensory modalities to compensate for deficient postural control: They can use auditory cues functionally similar to vision in the absence of vision, and additive to vision in the presence of vision (in case of pronounced postural sway). These findings might inform future assistive strategies for cerebellar ataxia.

Regressive pyridoxine-induced sensory neuronopathy in a patient with homocystinuria.

Pyridoxine (vitamin B6) is an essential vitamin playing a crucial role in amino acid metabolism. Pyridoxine is used for isoniazid side-effects prevention, pyridoxine-dependent epilepsy treatment and cystathionine beta-synthase deficiency (homocystinuria) treatment. However, vitamin B6 hypervitaminosis is neurotoxic and may provoke a progressive sensory neuronopathy (sensory ganglionopathy), usually when daily uptake is above 50 mg. We describe the case of a 30-year-old patient with homocystinuria who was treated with pyridoxine 1250-1750 mg/day for 20 years and developed progressive sensory neuropathy with ataxia and impaired sensation in the extremities. Electrodiagnostic testing demonstrated non-length-dependent abnormalities of sensory nerve potentials, and sensory ganglionopathy was diagnosed. Pyridoxine dosage was reduced to 500 mg/day, resulting in the disappearance of sensory symptoms and ataxia, and the normalisation of sensory nerve potentials. Our case indicates that pyridoxine-induced sensory ganglionopathy may be reversible, even after prolonged ingestion of high doses of vitamin B6 for more than 20 years.

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.

No laughing matter: subacute degeneration of the spinal cord due to nitrous oxide inhalation.

BACKGROUND: Whilst the dangers of 'legal highs' have been widely publicised in the media, very few cases of the neurological syndrome associated with the inhalation of nitrous oxide (N2O) have been reported. Here we set out to raise awareness of subacute degeneration of the spinal cord arising from recreational N2O use so that formal surveillance programs and public health interventions can be designed. METHODS: Case series documenting the clinical and investigational features of ten consecutive cases of subacute degeneration of the spinal cord presenting to a hospital with a tertiary neurosciences service in East London. RESULTS: Sensory disturbance in the lower (± upper) limbs was the commonest presenting feature, along with gait abnormalities and sensory ataxia. MRI imaging of the spine showed the characteristic features of dorsal column hyperintensity on T2 weighted sequences. Serum B12 levels may be normal because subacute degeneration of the spinal cord in this situation is triggered by functional rather than absolute B12 deficiency. DISCUSSION: A high index of suspicion is required to prompt appropriate investigation, make the diagnosis and commence treatment early. This is the largest reported series of patients with subacute degeneration of the spinal cord induced by recreational use of N2O. However, the number of patients admitted to hospital likely represents the 'tip of the iceberg', with many less severe presentations remaining undetected. After raising awareness, attention should focus on measuring the extent of the problem, the groups affected, and devising ways to prevent potentially long-term neurological damage.

Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway.

Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Here, we show that lack of CoQ in human skin fibroblasts causes impairment of hydrogen sulfide oxidation, proportional to the residual levels of CoQ. Biochemical and molecular abnormalities are rescued by CoQ supplementation in vitro and recapitulated by pharmacological inhibition of CoQ biosynthesis in skin fibroblasts and ADCK3 depletion in HeLa cells. Kidneys of Pdss2kd/kd mice, which only have ~15% residual CoQ concentrations and are clinically affected, showed (i) reduced protein levels of SQR and downstream enzymes, (ii) accumulation of hydrogen sulfides, and (iii) glutathione depletion. These abnormalities were not present in brain, which maintains ~30% residual CoQ and is clinically unaffected. In Pdss2kd/kd mice, we also observed low levels of plasma and urine thiosulfate and increased blood C4-C6 acylcarnitines. We propose that impairment of the sulfide oxidation pathway induced by decreased levels of CoQ causes accumulation of sulfides and consequent inhibition of short-chain acyl-CoA dehydrogenase and glutathione depletion, which contributes to increased oxidative stress and kidney failure.

Evaluation of the effectiveness of biofeedback therapy for functional constipation in children.

BACKGROUND/AIMS: Defecation disorders are one of the most common problems in pediatric gastroenterology. Treatment includes changes in the diet, pharmacotherapy, and biofeedback therapy. The aim of the present study was to evaluate the effectiveness of biofeedback therapy as assessed by clinical improvement as well as by changes in manometric parameters in children with constipation and pelvic floor dyssynergia (PFD). MATERIALS AND METHODS: A total of 44 children with constipation and PFD hospitalized between 2000 and 2015 were enrolled in this retrospective study. All patients underwent anorectal manometry, and in case of diagnosed PFD, the patient qualified for biofeedback therapy. Amplitudes between extreme and basic pressures during defecation maneuvers in the first and last sessions as well as the difference between them were compared between groups with and without clinical improvement after the last session. RESULTS: A clinical improvement was achieved in 38 (86%) patients. There were no significant differences found in the amplitudes in the first session (mmHg), 94, 65, 115 vs. 112, 55, 170 (median, first quartile, third quartile, respectively; NS: not significant); last session, 36, 27, 52 vs. 41, -38, 66, respectively; or between them, 71, 11, 124 vs. 81, 17, 109, respectively, in the group with versus the group without clinical improvement, respectively. CONCLUSION: Biofeedback therapy has high clinical efficacy, and despite the lack of manometric improvement, it should be used as a treatment method in children in whom dietary and pharmacological procedures do not work, even if we consider the exercises more as a form of psychological training.

Deep brain stimulation or thalamotomy in fragile X-associated tremor/ataxia syndrome? Case report.

We present the case of a 66-year-old man who has been treated for essential tremor since the age of 58. He developed mild cerebellar gait ataxia seven years after tremor onset. Moderate, global brain atrophy was identified on MRI scans. At the age of 68, only temporary tremor relief could be achieved by bilateral deep brain stimulation of the ventral intermedius nucleus of the thalamus. Bilateral stimulation of the subthalamic nucleus also resulted only in transient improvement. In the meantime, progressive gait ataxia and tetraataxia developed accompanied by other cerebellar symptoms, such as nystagmus and scanning speech. These correlated with progressive development of bilateral symmetric hyperintensity of the middle cerebellar peduncles on T2 weighted MRI scans. Genetic testing revealed premutation of the FMR1 gene, establishing the diagnosis of fragile X-associated tremor/ataxia syndrome. Although this is a rare disorder, it should be taken into consideration during preoperative evaluation of essential tremor. Postural tremor ceased two years later after thalamotomy on the left side, while kinetic tremor of the right hand also improved.

Coenzyme Q biosynthesis in health and disease.

Coenzyme Q (CoQ, or ubiquinone) is a remarkable lipid that plays an essential role in mitochondria as an electron shuttle between complexes I and II of the respiratory chain, and complex III. It is also a cofactor of other dehydrogenases, a modulator of the permeability transition pore and an essential antioxidant. CoQ is synthesized in mitochondria by a set of at least 12 proteins that form a multiprotein complex. The exact composition of this complex is still unclear. Most of the genes involved in CoQ biosynthesis (COQ genes) have been studied in yeast and have mammalian orthologues. Some of them encode enzymes involved in the modification of the quinone ring of CoQ, but for others the precise function is unknown. Two genes appear to have a regulatory role: COQ8 (and its human counterparts ADCK3 and ADCK4) encodes a putative kinase, while PTC7 encodes a phosphatase required for the activation of Coq7. Mutations in human COQ genes cause primary CoQ(10) deficiency, a clinically heterogeneous mitochondrial disorder with onset from birth to the seventh decade, and with clinical manifestation ranging from fatal multisystem disorders, to isolated encephalopathy or nephropathy. The pathogenesis of CoQ(10) deficiency involves deficient ATP production and excessive ROS formation, but possibly other aspects of CoQ(10) function are implicated. CoQ(10) deficiency is unique among mitochondrial disorders since an effective treatment is available. Many patients respond to oral CoQ(10) supplementation. Nevertheless, treatment is still problematic because of the low bioavailability of the compound, and novel pharmacological approaches are currently being investigated. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

Comparison of motor praxis and performance in children with varying levels of developmental coordination disorder.

The praxis test is a less well-documented method to determine functional manifestations of childhood dyspraxia. For this study, children aged 6-8years were recruited as follows: 17 children with DCD, 18 at risk of DCD and 35 without obvious problems in motor coordination. The Movement Assessment Battery for Children (MABC-2) was used to measure motor performance and identify the motor incoordination. This study developed a battery of tests to assess limb praxis using a praxis imagery questionnaire, gesture representation, and questions about knowledge of object use. In the comparison of subtests within the praxis test, significant differences were observed across groups on the praxis imagery questionnaire and gesture representation tests but not on knowledge of object use. Similar results were observed in the correlation analyses, in which a weak relationship between MABC-2 and praxis tests was observed. The DCD group had lower scores on the praxis imagery questionnaire, whereas the group at risk of DCD had lower scores on most gesture production tests. Our study provides a better understanding of the nature of the childhood dyspraxia and sheds light on its effect on motor coordination to identify praxis tests with specific clinical meanings in children with movement disorders.

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.

Selenium and coenzyme Q10 interrelationship in cardiovascular diseases--A clinician's point of view.

A short review is given of the potential role of selenium deficiency and selenium intervention trials in atherosclerotic heart disease. Selenium is an essential constituent of several proteins, including the glutathione peroxidases and selenoprotein P. The selenium intake in Europe is generally in the lower margin of recommendations from authorities. Segments of populations in Europe may thus have a deficient intake that may be presented by a deficient anti-oxidative capacity in various illnesses, in particular atherosclerotic disease, and this may influence the prognosis of the disease. Ischemic heart disease and heart failure are two conditions where increased oxidative stress has been convincingly demonstrated. Some of the intervention studies of anti-oxidative substances that have focused on selenium are discussed in this review. The interrelationship between selenium and coenzyme Q10, another anti-oxidant, is presented, pointing to a theoretical advantage in using both substances in an intervention if there are deficiencies within the population. Clinical results from an intervention study using both selenium and coenzyme Q10 in an elderly population are discussed, where reduction in cardiovascular mortality, a better cardiac function according to echocardiography, and finally a lower concentration of the biomarker NT-proBNP as a sign of lower myocardial wall tension could be seen in those on active treatment, compared to placebo.

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.

Pyridoxine-induced sensory ataxic neuronopathy and neuropathy: revisited.

High dose pyridoxine is neurotoxic. Previous case reports were sparse and little is known about the clinical and electrodiagnostic findings. Three patients with pyridoxine-induced sensory ataxic neuropathy were studied and a review of the involved literature was performed. Three patients, aged 80, 83 and 83 years old, presented with sensory ataxia for 3-8 months. Examination showed signs of polyneuropathy and sensory ataxia. Six hundred milligrams of pyridoxine was consumed each day for 3-10 years, in the form of vitamin B1-6-12 combination tablet. Investigations for other causes of neuropathy were unremarkable. Blood levels of vitamin B6 were markedly elevated at 104.6, 81.4 and 66.9 times of upper normal limits. Electrodiagnostic tests showed symmetric axonal sensory polyneuropathy in two patients. Two years after vitamin discontinuation, all patients showed no significant improvement in the neuropathy and gait. In conclusion, consumption of high dose pyridoxine can cause sensory neuronopathy and axonal sensorimotor polyneuropathy, leading to sensory ataxia which may not be reversible.