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Different rehabilitation models for persons diagnosed with disorders of consciousness have been proposed in Europe during the last decade. In Italy, the Ministry of Health has defined a national healthcare model, although, to date, there is a lack of information on how this has been implemented at regional level. The INCARICO project collected information on different regional regulations, analysing ethical aspects and mapping care facilities (numbers of beds and medical units) in eleven regional territories. The researchers found a total of 106 laws; differences emerged both between regions and versus the national model, showing that patients with the same diagnosis may follow different pathways of care. An ongoing cultural shift from a treatment-oriented medical approach towards a care-oriented integrated biopsychosocial approach was found in all the welfare and healthcare systems analysed. Future studies are needed to explore the relationship between healthcare systems and the quality of services provided.

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BACKGROUND AND PURPOSE: For many years deep brain stimulation (DBS) devices relied only on voltage-controlled stimulation (CV), but recently current-controlled devices have been developed and approved for new implants as well as for replacement of CV devices after battery drain. Constant-current (CC) stimulation has been demonstrated to be effective in new implanted parkinsonian and dystonic patients, but the effect of switching to CC therapy in patients chronically stimulated with CV implantable pulse generators (IPGs) has not been assessed. This report shows the results of a consecutive retrospective data collection performed at five Italian centers before and after replacement of constant-voltage with constant-current DBS devices, in order to verify the clinical efficacy and safety of this procedure. METHODS: Nineteen patients with Parkinson's disease or dystonic syndrome underwent DBS IPG CV/CC replacement. Clinical features and therapy satisfaction were assessed before surgery, 1 week after and 3 and 6 months after replacement. Programming settings and impedances were recorded before removing the CV device and when the CC IPGs were switched on. RESULTS: The clinical outcome of CC stimulation was similar to that obtained with CV devices and remained stable at 3 and 6 months of follow-up. Impedance values recorded for CV and CC IPGs were similar. Ninety-five percent of patients and physicians were satisfied with mixed implants. No adverse events occurred after IPG replacement. CONCLUSION: Replacing CV with CC IPGs is a safe and effective procedure. Longer follow-up is necessary to better clarify the impact of CC stimulation on clinical outcome after chronic stimulation in CV mode.

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BACKGROUND AND PURPOSE: The hereditary spastic paraplegias are a group of genetically heterogeneous neurodegenerative disorders, characterized by progressive spasticity and weakness of the lower limbs. Although conventional brain MR imaging findings are normal in patients with pure hereditary spastic paraplegia, microstructural alteration in the cerebral WM can be revealed with DTI. Concomitant investigation of multiple intrinsic diffusivities may shed light on the neurobiologic substrate of the WM degeneration pattern in patients with pure hereditary spastic paraplegia across the whole brain. MATERIALS AND METHODS: Tract-based spatial statistics analysis was performed to compare fractional anisotropy and mean, axial, and radial diffusivities of the WM skeleton in a group of 12 patients with pure hereditary spastic paraplegia and 12 healthy volunteers. Data were analyzed counting age and sex as nuisance covariates. The threshold-free cluster-enhancement option was applied, and the family-wise error rate was controlled by using permutation tests for nonparametric statistics. RESULTS: In pure hereditary spastic paraplegia, group widespread fractional anisotropy decreases and radial diffusivity and mean diffusivity increases (P < .05, corrected) were found. No voxelwise difference was observed for the axial diffusivity map. Percentage of voxels within the WM skeleton that passed the significance threshold were 51%, 41.6%, and 11.9%, respectively, for radial diffusivity, fractional anisotropy, and mean diffusivity clusters. An anteroposterior pattern with preferential decrease of fractional anisotropy in the frontal circuitry was detected. CONCLUSIONS: In patients with pure hereditary spastic paraplegia, alterations in multiple DTI indices were found. Radial diffusivity seems more sensitive to hereditary spastic paraplegia-related WM pathology and, in line with the lack of axial diffusivity changes, might indicate a widespread loss of myelin integrity. A decrease of fractional anisotropy alone in the frontal circuitry may reflect subtle disruption of the frontal connections.

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INTRODUCTION: In a preceding article the state of Nutritional support (NS) in an Intensive Care Unit (ICU) was documented [Martinuzzi A et al. Estado del soporte nutricional en una unidad de Cuidados críticos. RNC 2011; 20: 5-17]. In this follow-up work we set to assess the impact of several organizational, recording and educational interventions upon the current state of NS processes. MATERIALS AND METHODS: Interventions comprised presentation of the results of the audit conducted at the ICU before the institution's medical as well as paramedical personnel; their publication in a periodical, peer-reviewed journal; drafting and implementation of a protocol regulating NS schemes to be carried out at the ICU; and conduction of continuous education activities on Nutrition (such as "experts talks", interactive courses, and training in the implementation of the NS protocol). The state of NS processes documented after the interventions was compared with the results annotated in the preceding article. Study observation window ran between March the 1st, 2011 and May 31th, 2011, both included. RESULTS: Study series differed only regarding overall-mortality: Phase 1: 40.0% vs. Phase 2: 20.5%; Difference: 19.5%; Z = 1.927; two-tailed-p = 0.054. Interventions resulted in a higher fulfillment rate of the prescribed NS indication; an increase in the number of patients receiving ≥ 80% of prescribed energy; and a reduction in the number of NS lost days. Mortality was (numerically) lower in patients in which the prescribed NS scheme was fulfilled, NS was early initiated, and whom received ≥ 80% of prescribed energy. Adopted interventions had no effect upon average energy intakes: Phase 1: 574.7 ± 395.3 kcal/24 h⁻¹ vs. Phase 2: 591.1 ± 315.3 kcal/24 h⁻¹; two-tailed-p > 0.05. CONCLUSIONS: Educational, recording and organizational interventions might result in a better conduction of NS processes, and thus, in a lower mortality. Hemodynamic instability is still the most formidable obstacle for initiating and completing NS.

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Introducción: En un artículo precedente se documentó el estado del Soporte nutricional (SN) en una Unidad de Terapia Intensiva (UTI) [Martinuzzi A y cols. Estado del soporte nutricional en una unidad de Cuidados críticos. RNC 2011; 20: 5-17]. En este trabajo de seguimiento nos propusimos evaluar el impacto de varias intervenciones educativas, registrales y organizativas hechas en la Unidad sobre el estado actual de los procesos del SN. Material y método: Las intervenciones incluyeron la presentación de los resultados de la auditoría hecha en la UTI ante el plantel médico y paramédico de la institución; la publicación de los mismos en una revista periódica, arbitrada por pares; la redacción e implementación de un protocolo normativo de los esquemas de SN a conducir en la UTI; y la celebración de actividades de educación continuada en Nutrición (como "charlas con expertos", cursos interactivos, y capacitación en la implementación del protocolo de SN). El estado de los procesos de SN documentado tras las intervenciones se comparó con los resultados anotados en el trabajo precedente. La ventana de observación del estudio se extendió entre el 1 de Marzo del 2011 y el 31 mayo del 2011, ambos incluidos. Resultados: Las series de estudio difirieron entre sí solo respecto de la mortalidad: Fase 1: 40.0% vs. Fase 2: 20,5%; Diferencia: 19,5%; Z = 1,927; p-de-2-colas = 0,054. Las intervenciones hechas resultaron en una mayor tasa de cumplimiento de la indicación prescrita de SN; un aumento en el número de enfermos que recibieron > 80% de la energía prescrita; y una reducción en el número de días de SN perdidos. La mortalidad fue (numéricamente) menor en los pacientes en los que se cumplió el esquema prescrito de SN, el SN se inició tempranamente, y que recibieron > 80% de la energía prescrita. Las intervenciones adoptadas no tuvieron efecto sobre los aportes promedio de energía: Fase 1: 574,7 ± 395,3 kcal/24 h-1 vs. Fase 2: 591,1 ± 315,3 kcal/24 h-1; p > 0,05. Conclusiones: Las intervenciones educativas, registrales y organizativas pueden resultar en una mejor conducción de los procesos de SN, y con ello, en una menor mortalidad. La inestabilidad hemodinámica sigue siendo el obstáculo más formidable en el inicio y mantenimiento del SN (AU)

Introduction: In a preceding article the state of Nutritional support (NS) in an Intensive Care Unit (ICU) was documented [Martinuzzi A et al. Estado del soporte nutricional en una unidad de Cuidados críticos. RNC 2011; 20: 5-17]. In this follow-up work we set to assess the impact of several organizational, recording and educational interventions upon the current state of NS processes. Materials and methods: Interventions comprised presentation of the results of the audit conducted at the ICU before the institution's medical as well as paramedical personnel; their publication in a periodical, peerreviewed journal; drafting and implementation of a protocol regulating NS schemes to be carried out at the ICU; and conduction of continuous education activities on Nutrition (such as "experts talks", interactive courses, and training in the implementation of the NS protocol). The state of NS processes documented after the interventions was compared with the results annotated in the preceding article. Study observation window ran between March the 1st, 2011 and May 31th, 2011, both included. Results: Study series differed only regarding overallmortality: Phase 1: 40.0% vs. Phase 2: 20.5%; Difference: 19.5%; Z = 1.927; two-tailed-p = 0.054. Interventions resulted in a higher fulfillment rate of the prescribed NS indication; an increase in the number of patients receiving > 80% of prescribed energy; and a reduction in the number of NS lost days. Mortality was (numerically) lower in patients in which the prescribed NS scheme was fulfilled, NS was early initiated, and whom received > 80% of prescribed energy. Adopted interventions had no effect upon average energy intakes: Phase 1: 574.7 ± 395.3 kcal/24 h-1 vs. Phase 2: 591.1 ± 315.3 kcal/24 h1; two-tailed-p > 0.05. Conclusions: Educational, recording and organizational interventions might result in a better conduction of NS processes, and thus, in a lower mortality. Hemodynamic instability is still the most formidable obstacle for initiating and completing NS (AU)

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BACKGROUND: The energy cost of locomotion (C) is a useful tool for quantifying the level of walking disability in the clinical evaluation of patients with cerebral palsy (CP). In addition to clinical condition, also age and velocity (v) can influence C, a fact that is often overlooked. AIM: To show: i) that C differs in the clinical subtypes of CP (hemiplegia or diplegia) and ii) that C should be measured at comparable speeds in CP patients and controls (of the same age). DESIGN: Controlled study. SETTING: Pediatric Rehabilitation Unit of "E. Medea" Scientific Institute (Conegliano, TV); Exercise Physiology Lab of University of Verona. POPULATION: Forty-three CP children (32 diplegic: Dg; 11 hemiplegic: Hg) and 20 healthy children (Cg) with an age range of 4-14 years. METHODS: C was measured as the ratio of net oxygen uptake to walking speed (at v from 1 to 6 km·h(-1)). The Locomotory index (LI) was calculated as the ratio of C in Dg/Hg and Cg (of the same age) at the same speed. RESULTS: C decreases with increasing speed in all groups but evolves differently in Hg and Dg: in the former C decreases by increasing age, becoming similar to that of Cg at 12-14 years; in the latter C does not change as a function of age being always larger than in Cg. CONCLUSION AND CLINICAL REHABILITATION IMPACT: Our data highlight the reduction in C with increasing speed and suggest a better prognosis of locomotion for Hg compared to Dg.

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OBJECTIVE: Juvenile Idiopathic Arthritis (JIA) is the most common chronic pediatric rheumatic disease. It is recognized that only reliance on clinical signs of disease outcome is inadequate for understanding the impact of illness and its treatment on child's life and functioning. There is a need for a multidisciplinary and holistic approach to children with arthritis which considers both physical and emotional functioning. This study investigated the psychosocial functioning of children and adolescent with JIA and the disease-related changes in their family. METHODS: The sample consisted of 33 hospitalized patients, aged 6-16 years. Both parents and the children were given a number of questionnaire to fill out. Clinical information was extracted from the interviews. RESULTS: Self-reported psychological functioning (depression, anxiety, and behavior) was not different from the normal population; however significant psychological suffering was detected by the clinical interview. CONCLUSIONS: Children and adolescents with JIA do not show overt psychopathology by structured assessment; nevertheless a more clinically oriented holistic approach confirms JIA as a disrupting event causing relevant changes in the quality of life of the affected families.

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Caring for children in vegetative state (VS) or minimally conscious state (MCS) challenges parents and impacts on their well-being. This study aims to evaluate caregivers' health condition, coping, anxiety and depression levels, and how these issues relate to children's disability. 35 children with VS and MCS were administered the disability rating scale (DRS) and 35 caregivers completed the Coping Orientations to Problem Experiences, Short Form-12, Beck Depression Inventory, and the Spielberger State-Trait Anxiety Inventory-Y. Children were mainly males (68.6%), hosted at domicile (77.1%), and diagnosed with VS (60%), with anoxic aetiology (45.7%). Caregivers were mainly mothers (85.7%), married (82.9%), and housewives (51.4%); 60% declared financial difficulties, and 82.9% provided full-time assistance. 57.2% reported depressive symptoms, poor mental health, and high level of state and trait anxiety. "Problem-oriented" (P < 0.001) and "emotional-oriented" (P < 0.001), were more adopted than "potentially dysfunctional" ones. DRS scores (mean = 22.0; SD = 1.9) did not significantly correlate to any psychological measure. Rehabilitative programs for children with SV and SMC should also provide interventions on surrounding systems: improving the network of psychological support and social assistance may decrease the burden of caregivers and, in turn, improve caring abilities and children quality of life.

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Spastic paraplegia type 5 (SPG5) is caused by mutations in CYP7B1, a gene encoding the cytochrome P-450 oxysterol 7-α-hydroxylase, CYP7B1, an enzyme implicated in the cholesterol metabolism. Mutations in CYP7B1 were found in both pure and complicated forms of the disease with a mutation frequency of 7.7% in pure recessive cases. The mutation frequency in complex forms, approximately 6.6%, is more controversial and needs to be refined. We studied in more detail the SPG5-related spectrum of complex phenotypes by screening CYPB1 for mutations in a large cohort of 105 Italian hereditary spastic paraplegias (HSPs) index patients including 50 patients with a complicated HSP (cHSP) phenotype overlapping the SPG11- and the SPG15-related forms except for the lack of thin corpus callosum and 55 pure patients. Five CYP7B1 mutations, three of which are novel, were identified in four patients, two with a complex form of the disease and two with a pure phenotype. The CYP7B1 mutation frequencies obtained in both complicated and pure familial cases are comparable to the known ones. These results obtained extend the range of SPG5-related phenotypes and reveal variability in clinical presentation, disease course and functional profile in the SPG5-related patients while providing with some clues for molecular diagnosis in cHSP.

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BACKGROUND: Recently, the efficacy of functional electrical stimulation (FES) cycling have been demonstrated on the improvement of strength and motor control in adults with stroke. FES-cycling, providing a repetitive goal-oriented task, could facilitate cortical reorganization and utilization of residual cortico-spinal pathways. These benefits could be more enhanced in children because of the greater plasticity and flexibility of their central nervous system. AIM: The aim of the present case report study was to explore the feasibility of FES-cycling in children with cerebral palsy (CP) and to provide a set of instrumental measures able to evaluate the effects of this novel treatment on cycling and walking ability. DESIGN: Interventional study. SETTING AND POPULATION: Two ambulant outpatient children with diplegic CP were recruited by the "E. Medea" Scientific Institute. METHODS: Patients followed a FES-cycling treatment for 30 minutes a day, 3 days a week for 7 weeks. Pre and post treatment tests were performed, namely clinical measures and electromyographic, kinematic and oxygen expenditure analysis during gait and cycling. RESULTS: The treatment was safe, feasible and well accepted by the 2 children. After treatment both patients achieved a more symmetrical muscular strategy during voluntary cycling and gait and a significant reduction of muscle co-contractions during cycling. These improvements were corroborated by a decrease in oxygen expenditure during the post test for one of the two children, the less impaired, implying a better exploiting of bi-articular muscles. CONCLUSION AND CLINICAL REHABILITATION IMPACT: FES-cycling is feasible and safe and it may be an alternative rehabilitation method for diplegic CP patients. The set of instrumental measurements proposed seems to be a valuable tool for functional assessment to identify subclinical anomalies and improvements on cycling and gait in CP patients.

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Spastic paraplegia type 10 (SPG10) is an autosomal dominant form of hereditary spastic paraplegia (HSP) due to mutations in KIF5A, a gene encoding the neuronal kinesin heavy chain implicated in anterograde axonal transport. KIF5A mutations were found in both pure and complicated forms of the disease; a single KIF5A mutation was also detected in a CMT2 patient belonging to an SPG10 mutant family. To confirm the involvement of the KIF5A gene in both CMT2 and SPG10 phenotypes and to define the frequency of KIF5A mutations in an Italian HSP patient population, we performed a genetic screening of this gene in a series of 139 HSP and 36 CMT2 affected subjects. We identified five missense changes, four in five HSP patients and one in a CMT2 subject. All mutations, including the one segregating in the CMT2 patient, are localized in the kinesin motor domain except for one, falling within the stalk domain and predicted to generate protein structure destabilization. The results obtained indicate a KIF5A mutation frequency of 8.8% in the Italian HSP population and identify a region of the kinesin protein, the stalk domain, as a novel target for mutation. In addition, the mutation found in the CMT2 patient strengthens the hypothesis that CMT2 and SPG10 are the extreme phenotypes resulting from mutations in the same gene.

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In this study we assessed ΔG'(ATP) hydrolysis, cytosolic [ADP], and the rate of phosphocreatine recovery using Phosphorus Magnetic Resonance Spectroscopy in the calf muscle of a group of patients affected by glycogen myo-phosphorylase deficiency (McArdle disease). The goal was to ascertain whether and to what extent the deficit of the glycogenolytic pathway would affect the muscle energy balance. A typical feature of this pathology is the lack of intracellular acidosis. Therefore we posed the question of whether, in the absence of pH decrease, the rate of phosphocreatine recovery depends on the amount of phosphocreatine consumed during exercise. Results showed that at the end of exercise both [ADP] and ΔG'(ATP) of patients were significantly higher than those of matched control groups reaching comparable levels of phosphocreatine concentration. Furthermore, in these patients we found that the rate of phosphocreatine recovery is not influenced by the amount of phosphocreatine consumed during exercise. These outcomes provide experimental evidence that: i) the intracellular acidification occurring in exercising skeletal muscle is a protective factor for the energy consumption; and ii) the influence of pH on the phosphocreatine recovery rate is at least in part related to the kinetic mechanisms of mitochondrial creatine kinase enzyme.

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BACKGROUND: Hereditary spastic paraplegia (HSP) with thin corpus callosum (HSP-TCC) is a frequent subtype of complicated HSP clinically characterised by slowly progressive spastic paraparesis with cognitive impairment and thin corpus callosum (TCC). SPG11, the gene associated with the major locus involved, encodes spatacsin, a protein of unknown function. METHODS: Different types of mutations were identified in patients with the complex form of HSP (cHSP) including TCC. We screened a series of 45 index patients with different types of cHSP with (n = 10) and without (n = 35) TCC. RESULTS: Ten mutations, of which five are novel, were detected in seven patients. Of importance, three out of seven mutated patients present with cHSP without TCC. Among the novel mutations identified, we characterised a large intragenic rearrangement deleting 2.6 kb of the SPG11 gene. The rearrangement is due to non-allelic homologous recombination between Alu sequences flanking the breakpoints. CONCLUSIONS: These findings expand the mutation spectrum of SPG11 and suggest that SPG11 mutations may occur more frequently in familial than sporadic forms of cHSP without TCC. This helps to define further clinical and molecular criteria for a correct diagnosis of the SPG11 related form of cHSP. In addition, the intragenic deletion detected here, and the mechanism involved, both provide clues to address the issue of SPG11 missing mutant alleles previously reported.

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BACKGROUND: McArdle disease (Glycogen Storage Disease type V) is caused by the absence of the glycolytic enzyme, muscle phosphorylase. People present with exercise-induced pain, cramps, fatigue, and myoglobinuria, which can result in acute renal failure if it is severe. OBJECTIVES: To systematically review the evidence from randomised controlled trials of pharmacological or nutritional treatments in improving exercise performance and quality of life in McArdle disease. SEARCH STRATEGY: We updated the review by searching the Cochrane Neuromuscular Disease Group Trials Register (November 2007), MEDLINE (January 1966 to November 2007) and EMBASE (January 1980 to November 2007) using the search terms 'McArdle disease' and its synonym 'Glycogen Storage Disease type V'. SELECTION CRITERIA: We included randomised controlled trials (including crossover studies) and quasi-randomised trials. Open trials and individual patient studies with no participant or observer blinding were included in the discussion. Types of interventions included any pharmacological agent or micronutrient or macronutrient supplementation. Primary outcome measures included any objective assessment of exercise endurance (for example aerobic capacity (VO(2)) max, walking speed, muscle force or power and improvement in fatiguability). Secondary outcome measures included metabolic changes (such as reduced plasma creatine kinase activity and a reduction in the frequency of myoglobinuria), subjective measures (including quality of life scores and indices of disability) and serious adverse events. DATA COLLECTION AND ANALYSIS: Three review authors checked the titles and abstracts identified by the search and reviewed the manuscripts. Two review authors (RQ and RB) independently assessed methodological quality of the full text of potentially relevant studies and extracted data onto a specially designed form. MAIN RESULTS: We reviewed 24 studies. Twelve trials fulfilled the criteria for inclusion, with two being first identified in this update. The 12 excluded trials are included in the discussion. The largest treatment trial included 19 cases. The other trials included fewer than 12 cases. As there were only single trials for a given intervention we were unable to undertake a meta-analysis. AUTHORS' CONCLUSIONS: There is no evidence of significant benefit from any specific nutritional or pharmacological treatment in McArdle disease. In one small trial low dose creatine produced slight benefit but high dose creatine caused myalgia. Ingestion of oral sucrose immediately before exercise reduced perceived ratings of exertion and heart rate and improved exercise tolerance. This treatment will not influence sustained or unexpected exercise and may cause significant weight gain. A carbohydrate rich diet did benefit patients. Because of the rarity of McArdle disease, there is a need to develop international multicentre collaboration and standardised assessment protocols for future treatment trials.

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Despite much evidence of cognitive and affective disorders in Friedreich's ataxia (FRDA), the nature of mental status in FRDA has received little systematic attention. It has been proposed that the cerebellum may interfere indirectly with cognition through the cerebello-cortical loops, whereas the role of pathological changes in different areas of the central nervous system is still undetermined. In the present study, 13 patients with molecularly determined FRDA and a group of matched controls were evaluated by a comprehensive battery of neuropsychological tests and the Minnesota Multiphasic Personality Inventory. A repetitive task of simple visual-reaction times was used to investigate implicit learning in all subjects. Pathological changes in cortical areas were explored comparing cerebral activations of patients and controls during finger movements (functional MRI). The intelligence profile of FRDA patients is characterized by concrete thinking, poor capacity in concept formation and visuospatial reasoning. FRDA patients show reduced speed of information processing. The learning effect seen in controls was notably absent in patients with FRDA. The patients' personality is characterized by some pathological aspects and reduced defensiveness. Patterns of cortical activation during finger movements are heterogeneous in patients compared to controls. Cognitive impairment, mood disorders and motor deficits in FRDA patients may be the result of the cumulative damage caused by frataxin deficiency not only in the cerebellum and spinal cord but also in other brain areas.

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BACKGROUND: Intraventricular haemorrhages (IVHs) caused by bleeding aneurysms are critical conditions that often carry a severe prognosis. Two main problems must be urgently dealt with: the secondary damage caused by intraventricular clotting and the risk of early rebleeding. A protocol of ultra-early endoscopic ventricular evacuation, after securing the aneurysm with coils, is proposed to solve this challenge in the acute phase and within a few hours of onset. METHODS: Ten consecutive patients presenting with haematocephalus from aneurysm rupture were treated in our institute with coiling and endoscopic clot aspiration extended to the whole ventricular system. The only inclusion criteria were the presence of a massive IVH and an aneurysm appropriate for coiling. Computed tomography scans obtained before (within 4 h of symptom onset in all patients) and immediately after surgery were compared for Graeb score and ventriculocranial ratio (VCR); the Glasgow Outcome Scale (GOS) was assessed at 1 year. RESULT: All patients were treated within 2 days of onset. The procedure resulted in a mean 58% removal of ventricular blood and decrease of hydrocephalus; the mean (standard deviation (SD)) Graeb score reduced from 11.5 (0.7) to 4.7 (2.2) (p<0.001) and mean ventriculocranial ratio from 0.26 (0.06) to 0.17 (0.05) (p<0.001). No rebleeding or delayed hydrocephalus needing shunt was observed. Mortality at 1 year was 30%; marked disability (GOS = 3) and good recovery (GOS = 5) were observed in 40% and 30% of patients, respectively. CONCLUSIONS: Early neuroendoscopic removal of blood casting from the lateral to the fourth ventricle after coiling of bleeding aneurysms is a feasible approach, allowing in most instances the rapid improvement of the IVH.

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Leber's hereditary optic neuropathy (LHON) is associated with mitochondrial DNA point mutations affecting different subunits of complex I. By replacing glucose with galactose in the medium, cybrids harboring each of the three LHON pathogenic mutations (11778/ND4, 3460/ND1, 14484/ND6) suffered a profound ATP depletion over a few hours and underwent apoptotic cell death, which was caspase-independent. Control cybrids were unaffected. In addition to cytochrome c, apoptosis inducing factor (AIF) and endonuclease G (EndoG) were also released from the mitochondria into the cytosol in LHON cybrids, but not in control cells. Exposure of isolated nuclei to cytosolic fractions from LHON cybrids maintained in galactose medium caused nuclear fragmentation, which was strongly reduced by immuno-depletion with anti-AIF and anti-EndoG antibodies. In conclusion, the caspase-independent death of LHON cybrids incubated in galactose medium is triggered by rapid ATP depletion and mediated by AIF and EndoG.

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