Variants Cause Spastic Paraplegia Associated with Cerebral Hypomyelination

Oculodentodigital dysplasia is an autosomal dominant disorder due to variants characterized by dysmorphic features. Neurologic symptoms have been described in some patients but without a clear neuroimaging pattern. To understand the pathophysiology underlying neurologic deficits in oculodentodigital dysplasia, we studied 8 consecutive patients presenting with hereditary spastic paraplegia due to variants. Clinical disease severity was highly variable. Cerebral MR imaging revealed variable white matter abnormalities, consistent with a hypomyelination pattern, and bilateral hypointense signal of the basal ganglia on T2-weighted images and/or magnetic susceptibility sequences, as seen in neurodegeneration with brain iron accumulation diseases. Patients with the more prominent basal ganglia abnormalities were the most disabled ones. This study suggests that -related hereditary spastic paraplegia is a complex neurodegenerative disease affecting both the myelin and the basal ganglia. variants should be considered in patients with hereditary spastic paraplegia presenting with brain hypomyelination, especially if associated with neurodegeneration and a brain iron accumulation pattern

No excess of mitochondrial DNA deletions within muscle in progressive multiple sclerosis

BACKGROUND: Mitochondrial dysfunction is an established feature of multiple sclerosis (MS). We recently described high levels of mitochondrial DNA (mtDNA) deletions within respiratory enzyme-deficient (lacking mitochondrial respiratory chain complex IV with intact complex II) neurons and choroid plexus epithelial cells in progressive MS. OBJECTIVES: The objective of this paper is to determine whether respiratory enzyme deficiency and mtDNA deletions in MS were in excess of age-related changes within muscle, which, like neurons, are post-mitotic cells that frequently harbour mtDNA deletions with ageing and in disease. METHODS: In progressive MS cases (n=17), known to harbour an excess of mtDNA deletions in the central nervous system (CNS), and controls (n=15), we studied muscle (paraspinal) and explored mitochondria in single fibres. Histochemistry, immunohistochemistry, laser microdissection, real-time polymerase chain reaction (PCR), long-range PCR and sequencing were used to resolve the single muscle fibres. RESULTS: The percentage of respiratory enzyme-deficient muscle fibres, mtDNA deletion level and percentage of muscle fibres harbouring high levels of mtDNA deletions were not significantly different in MS compared with controls. CONCLUSION: Our findings do not provide support to the existence of a diffuse mitochondrial abnormality involving multiple systems in MS. Understanding the cause(s) of the CNS mitochondrial dysfunction in progressive MS remains a research priority

Les atrophies optiques héréditaires

IntroductionLes atrophies optiques héréditaires forment un groupe hétérogène de maladies responsables d’une dégénérescence des cellules ganglionnaires de la rétine avec une expression phénotypique variable, allant de formes asymptomatiques jusqu’à des formes sévères avec cécité. État des connaissances Les deux phénotypes les plus fréquents sont la maladie de Kjer, de transmission autosomique dominante provoquée par des mutations du gène OPA1 et la neuropathie optique héréditaire de Leber, causée par des mutations de l’ADN mitochondrial, de transmission maternelle. Perspectives et conclusion Ces deux neuropathies optiques habituellement isolées sont parfois associées à des signes extraoculaires essentiellement neurologiques centraux qui justifient un avis neurologique systématique ainsi qu’une imagerie cérébrale

Clinical and genetic characteristics of late-onset Huntington's disease

BACKGROUND: The frequency of late-onset Huntington\u27s disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. OBJECTIVE: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. METHODS: Participants with late- and common-onset (30-50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. RESULTS: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P < .001). Overall motor and cognitive performance (P < .001) were worse, however only disease motor progression was slower (coefficient, -0.58; SE 0.16; P < .001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P < .001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P < .001). CONCLUSIONS: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients

Disease Severity and Progression in Progressive Supranuclear Palsy and Multiple System Atrophy: Validation of the NNIPPS – PARKINSON PLUS SCALE

BACKGROUND The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. METHODS AND FINDINGS Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α ≥ 0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80-0.93), and moderate (Intra-class coefficient = 0.54-0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho ≥ 0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar. CONCLUSIONS The NNIPPS-PPS has suitable validity, is reliable and sensitive, and therefore is appropriate for use in clinical studies with PSP or MSA. TRIAL REGISTRATION ClinicalTrials.gov NCT00211224

Adenine nucleotide translocase is involved in a mitochondrial coupling defect in MFN2-related Charcot–Marie–Tooth type 2A disease

Charcot–Marie–Tooth type 2A disease (CMT2A), a dominantly inherited peripheral neuropathy, is caused by mutations in MFN2, a mitochondrial fusion protein. Having previously demonstrated a mitochondrial coupling defect in CMT2A patients’ fibroblasts, we here investigate mitochondrial oxygen consumption and the expression of adenine nucleotide translocase (ANT) and uncoupling proteins from eight other patients with the disease. The mitochondrial uncoupling was associated with a higher respiratory rate, essentially involving complex II proteins. Furthermore, a twofold increase in the expression of ANT led to the reduced efficiency of oxidative phosphorylation in CMT2A cells, suggesting that MFN2 plays a role in controlling ATP/ADP exchanges

OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes

Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations in the OPA1 gene can also be responsible for a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia and mitochondrial myopathy with cytochrome c oxidase negative and Ragged Red Fibres. Most remarkably, we demonstrate that these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle, thus revealing an unrecognized role of the OPA1 protein in mtDNA stability. The five OPA1 mutations associated with these DOA ‘plus’ phenotypes were all mis-sense point mutations affecting highly conserved amino acid positions and the nuclear genes previously known to induce mtDNA multiple deletions such as POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1) were ruled out. Our results show that certain OPA1 mutations exert a dominant negative effect responsible for multi-systemic disease, closely related to classical mitochondrial cytopathies, by a mechanism involving mtDNA instability

Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation

Hereditary spastic paraplegia refers to a genetically heterogeneous syndrome. We identified five members of a family suffering from a late-onset spastic paraplegia-like disorder, carrying the homoplasmic m.9176 T&gt;C mutation in the mitochondrial ATP6 gene. The clinical severity of the disease observed in the family was correlated with the biochemical and assembly defects of the ATP synthase. The m.9176 T&gt;C mutation has been previously associated to Leigh syndrome or familial bilateral striatal necrosis. Other factors such as modifying genes may be involved in the phenotypic expression of the disease. The family belongs to the mitochondrial haplogroup J, previously shown to play a role in modulating the phenotype of mitochondrial diseases and be associated with longevity. Moreover other nuclear modifying genes or environmental factors may contribute to the disease phenotype. This finding extends the genetic heterogeneity of the hereditary spastic paraplegia together with the clinical spectrum of mutations of the ATP6 gene

OPA1-associated disorders: Phenotypes and pathophysiology

The OPA1 gene, encoding a dynamin-like mitochondrial GTPase, is involved in autosomal dominant optic atrophy (ADOA, OMIM #165500). ADOA, also known as Kjer\u27s optic atrophy, affects retinal ganglion cells and the axons forming the optic nerve, leading to progressive visual loss. OPA1 gene sequencing in patients with hereditary optic neuropathies indicates that the clinical spectrum of ADOA is larger than previously thought. Specific OPA1 mutations are responsible for several distinct clinical presentations, such as ADOA with deafness (ADOAD), and severe multi-systemic syndromes, the so-called “ADOA plus” disorders, which involve neurological and neuromuscular symptoms similar to those due to mitochondrial oxidative phosphorylation defects or mitochondrial DNA instability. The study of the various clinical presentations of ADOA in conjunction with the investigation of OPA1 mutations in fibroblasts from patients with optic atrophy provides new insights into the pathophysiological mechanisms of the disease while underscoring the multiple physiological roles played by OPA1 in energetic metabolism, mitochondrial structure and maintenance, and cell death. Finally, OPA1 represents an important new paradigm for emerging neurodegenerative diseases affecting mitochondrial structure, plasticity and functions