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A novel G8363A mutation in the mtDNA tRNA(Lys) gene was associated, in two unrelated families, with a syndrome consisting of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy. Muscle biopsies from the probands showed mitochondrial proliferation and partial defects of complexes I, III, and IV of the electron-transport chain. The G8363A mutation was very abundant (>95%) in muscle samples from the probands and was less copious in blood from 18 maternal relatives (mean 81.3% +/- 8.5%). Single-muscle-fiber analysis showed significantly higher levels of mutant genomes in cytochrome (c) oxidase-negative fibers than in cytochrome (c) oxidase-positive fibers. The mutation was not found in >200 individuals, including normal controls and patients with other mitochondrial encephalomyopathies, thus fulfilling accepted criteria for pathogenicity.

Background and Aims: Increased generation of reactive oxygen species and mitochondrial dysfunction may underlie the pathophysiology of Friedreich's ataxia, the most common inherited ataxia, due to GAA expansion in a [...]

Purpose: Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients.Methods: First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients.Results: 6.4% of ABCC6-negative PXE patients (n = 3) harboured biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE.Conclusion: CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization. [ABSTRACT FROM AUTHOR]

Abstract There are no data in Argentina on the response rates to first-line treatment of classical Hodgkin Lymphoma (cHL) outside clinical trials. A total of 498 patients from 7 public and private hospitals in Argentina were retrospectively examined. The median follow-up was 37.4 months (CI 95% 17.7–63.5). The median time from diagnosis to treatment was 22 days (IQR 14–42), which was significantly longer in public hospitals (49.3 (IC 95% 38.5–60.2) versus 32.5 (IC 95% 27–38); p = 0.0027). A total of 96.8% of patients were treated with ABVD.:84.3% achieved complete remission (CR) and 6.02% partial remission (PR), being the CR rate higher in private hospitals. End-of-treatment metabolic CR was achieved in 85.4% (n = 373). The interim PET scan was widely used in our cohort (70.5%; n = 351), but in only 23.3% (n = 116) was the treatment strategy response-adapted. The 5-year progression-free survival (PFS) was 76% (CI 95% 70–81). The 2 and 5-years-OS rates were 91% (CI 95% 88–94%) and 85% (CI 95% 80–89%), respectively. No differences in OS were found between public and private institutions (p = 0.27). This is one of the largest retrospective cHL cohorts reported. In Argentina ABVD is the chemotherapy regimen of choice and, although it is well tolerated, it is not exempt from toxicity. We showed that early initiation of treatment impacts the induction results. Although the use of PET scan is widespread, only a minority of patients was treated with respons- adapted strategies. The use of PET-guided treatment is strongly encouraged.

A compact description of coordinated muscle activity is provided by the factorization of electromyographic (EMG) signals. With the use of this approach, it has consistently been shown that multimuscle activity during human locomotion can be accounted for by four to five modules, each one comprised of a basic pattern timed at a different phase of gait cycle and the weighting coefficients of synergistic muscle activations. These modules are flexible, in so far as the timing of patterns and the amplitude of weightings can change as a function of gait speed and mode. Here we consider the adjustments of the locomotor modules related to unstable walking conditions. We compared three different conditions, i.e., locomotion of healthy subjects on slippery ground (SL) and on narrow beam (NB) and of cerebellar ataxic (CA) patients on normal ground. Motor modules were computed from the EMG signals of 12 muscles of the right lower limb using non-negative matrix factorization. The unstable gait of SL, NB, and CA showed significant changes compared with controls in the stride length, stride width, range of angular motion, and trunk oscillations. In most subjects of all three unstable conditions, >70% of the overall variation of EMG waveforms was accounted for by four modules that were characterized by a widening of muscle activity patterns. This suggests that the nervous system adopts the strategy of prolonging the duration of basic muscle activity patterns to cope with unstable conditions resulting from either slippery ground, reduced support surface, or pathology. [ABSTRACT FROM AUTHOR]

Several studies have demonstrated how cerebellar ataxia (CA) affects gait, resulting in deficits in multijoint coordination and stability. Nevertheless, how lesions of cerebellum influence the locomotor muscle pattern generation is still unclear. To better understand the effects of CA on locomotor output, here we investigated the idiosyncratic features of the spatiotemporal structure of leg muscle activity and impairments in the biomechanics of CA gait. To this end, we recorded the electromyographic (EMG) activity of 12 unilateral lower limb muscles and analyzed kinematic and kinetic parameters of 19 ataxic patients and 20 age-matched healthy subjects during overground walking. Neuromuscular control of gait in CA was characterized by a considerable widening of EMG bursts and significant temporal shifts in the center of activity due to overall enhanced muscle activation between late swing and mid-stance. Patients also demonstrated significant changes in the intersegmental coordination, an abnormal transient in the vertical ground reaction force and instability of limb loading at heel strike. The observed abnormalities in EMG patterns and foot loading correlated with the severity of pathology [International Cooperative Ataxia Rating Scale (ICARS), a clinical ataxia scale] and the changes in the biomechanical output. The findings provide new insights into the physiological role of cerebellum in optimizing the duration of muscle activity bursts and the control of appropriate foot loading during locomotion. [ABSTRACT FROM AUTHOR]

Objective.—To determine whether patients with migraine without aura with maternal “inheritance” are affected by a monosymptomatic form of the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) or carry the most common mitochondrial DNA (mtDNA) mutation associated with MELAS, namely the A3243G transition in the transfer RNA (tRNA)Leu(UUR) gene. Background.—The association between migraine and abnormal mitochondrial function has been suggested on clinical, biochemical, and neuroradiological grounds. Migraine attacks with vomiting and cerebral infarctions, most often in the posterior cerebral regions, which are reminiscent of complicated migraine, are typical features of MELAS. The observation that migrainous patients have affected mothers more often than affected fathers suggests a possible role for maternally transmitted genetic factors. Methods.—We studied 25 patients with migraine with aura whose mothers were also affected. A sensitive polymerase chain reaction restriction fragment length polymorphism analysis was used to detect mutated genomes. Conclusions.—We failed to detect the MELAS mutation, but migraine may still be associated with point mutations of mtDNA other than A3243G or with as-yet-unidentified nuclear DNA factors related to mitochondrial function. [ABSTRACT FROM AUTHOR]