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Introduction Both prevalence and clinical features of the various movement disorders in adults with primary mitochondrial diseases are unknown. Methods Based on the database of the “Nation-wide Italian Collaborative Network of Mitochondrial Diseases”, we reviewed the clinical, genetic, neuroimaging and neurophysiological data of adult patients with primary mitochondrial diseases (n = 764) where ataxia, myoclonus or other movement disorders were part of the clinical phenotype. Results Ataxia, myoclonus and movement disorders were present in 105/764 adults (13.7%), with the onset coinciding or preceding the diagnosis of the mitochondrial disease in 49/105 (46.7%). Ataxia and parkinsonism were the most represented, with an overall prevalence at last follow-up of 59.1% and 30.5%, respectively. Hyperkinetic movement disorders were reported in 15.3% at last follow-up, being the less common reported movement disorders. The pathogenic m.8344A > G and POLG variants were always associated with a movement disorder, while LHON variants and mtDNA single deletions were more commonly found in the subjects who did not present a movement disorder. The most common neuroimaging features were cortical and/or cerebellar atrophy, white matter hyperintensities, basal ganglia abnormalities and nigro-striatal degeneration. Almost 70% of patients with parkinsonism responded to dopaminergic therapy, mainly levodopa, and 50% with myoclonus were successfully treated with levetiracetam. Conclusion Movement disorders, mainly ataxia and parkinsonism, are important findings in adult primary mitochondrial diseases. This study underlies the importance of looking for a mitochondrial etiology in the diagnostic flowchart of a movement disorder and may help direct genetic screening in daily practice.

Mitochondrial medicine is a field that expanded exponentially in the last 30years. Individually rare, mitochondrial diseases as a whole are probably the most frequent genetic disorder in adults. The complexity of their genotype–phenotype correlation, in terms of penetrance and clinical expressivity, natural history and diagnostic algorithm derives from the dual genetic determination. In fact, in addition to the about 1.500 genes encoding mitochondrial proteins that reside in the nuclear genome (nDNA), we have the 13 proteins encoded by the mitochondrial genome (mtDNA), for which 22 specific tRNAs and 2 rRNAs are also needed. Thus, besides Mendelian genetics, we need to consider all peculiarities of how mtDNA is inherited, maintained and expressed to fully understand the pathogenic mechanisms of these disorders. Yet, from the initial restriction to the narrow field of oxidative phosphorylation dysfunction, the landscape of mitochondrial functions impinging on cellular homeostasis, driving life and death, is impressively enlarged. Finally, from the clinical standpoint, starting from the neuromuscular field, where brain and skeletal muscle were the primary targets of mitochondrial dysfunction as energy-dependent tissues, after three decades virtually any subspecialty of medicine is now involved. We will summarize the key clinical pictures and pathogenic mechanisms of mitochondrial diseases in adults.

Summary Leber's hereditary optic neuropathy (LHON) is a neurodegenerative disorder that selectively affects the retinal ganglion cells (RGCs), consequently leading to optic atrophy and loss of central vision. The primary cause is a metabolic dysfunction of mitochondria due to mitochondrial DNA mutations affecting the respiratory complex I. Despite the metabolic defect is systemic and measurable in post-mitotic tissues, the disease is usually limited to the RGCs and leads to profoundly impaired vision. However, adjunctive neurological features may be present in a subset of LHON patients defining the so-called “plus” variant phenotype. The most frequent neurological features may be a multiple-sclerosis-like disease, basal ganglia involvement with dystonia or spastic dystonia and bilateral striatal necrosis, myoclonus, parkinsonism, peripheral neuropathy, migraine and sensorineural hypoacusia. Neurological exam, brain MRI, MR-spectroscopy and other ancillary exams may be needed to well characterize the “plus” phenotype of LHON patients. The genetic bases of these LHON “plus” cases are currently unclear, but private mtDNA mutations and nuclear genetic variants may be relevant.

Background and purpose: Optic nerve involvement is frequent in mitochondrial disease, and retinal abnormalities are described in Parkinson’s disease (PD). Methods: We evaluated retinal nerve fiber layer (RNFL) thickness by optical coherence tomography in 43 patients with PD and in 86 age-matched controls. We considered separately the eyes ipsilateral and contralateral to the most affected body side in patients with PD. ancova analysis, Pearson test, and multiple regression analysis were used (P

BACKGROUND AND PURPOSE: Brain white matter is frequently affected in mitochondrial diseases; optic atrophy gene 1-autosomal dominant optic atrophy and Leber hereditary optic neuropathy are the most frequent mitochondrial monosymptomatic optic neuropathies. In this observational study, brain white matter microstructure was characterized by DTI in patients with optic atrophy gene 1-autosomal dominant optic atrophy and Leber hereditary optic neuropathy, in relation to clinical and genetic features. MATERIALS AND METHODS: Nineteen patients with optic atrophy gene 1-autosomal dominant optic atrophy and 17 with Leber hereditary optic neuropathy older than 18 years of age, all genetically diagnosed, and 19 healthy volunteers underwent DTI by using a 1.5T MR imaging scanner and neurologic and ophthalmologic assessments. Brain white matter DTI metrics were calculated for all participants, and, in patients, their correlations with genetics and clinical findings were calculated. RESULTS: Compared with controls, patients with optic atrophy gene 1-autosomal dominant optic atrophy had an increased mean diffusivity in 29.2% of voxels analyzed within major white matter tracts distributed throughout the brain, while fractional anisotropy was reduced in 30.3% of voxels. For patients with Leber hereditary optic neuropathy, the proportion of altered voxels was only 0.5% and 5.5%, respectively, of which half was found within the optic radiation and 3.5%, in the smaller acoustic radiation. In almost all regions, fractional anisotropy diminished with age in patients with optic atrophy gene 1-autosomal dominant optic atrophy and correlated with average retinal nerve fiber layer thickness in several areas. Mean diffusivity increased in those with a missense mutation. Patients with Leber hereditary optic neuropathy taking idebenone had slightly milder changes. CONCLUSIONS: Patients with Leber hereditary optic neuropathy had preferential involvement of the optic and acoustic radiations, consistent with trans-synaptic degeneration, whereas patients with optic atrophy gene 1-autosomal dominant optic atrophy presented with widespread involvement suggestive of a multisystemic, possibly a congenital/developmental, disorder. White matter changes in Leber hereditary optic neuropathy and optic atrophy gene 1-autosomal dominant optic atrophy may be exploitable as biomarkers. ABBREVIATIONS: DOA autosomal dominant optic atrophy; FA fractional anisotropy; LHON Leber hereditary optic neuropathy; MD mean diffusivity; OPA1 optic atrophy gene 1 ;O R optic radiation; RNFL retinal nerve fiber layer; TBSS tract-based spatial statistics

A 21-year-old woman with acute lymphoblastic leukemia underwent bone marrow transplantation (BMT). The conditioning regimen consisted of an association of busulfan (BU) and cyclophosphamide (Cy). The day after starting BU, she suffered a generalized tonic-clonic seizure. Electroencephalography (EEG) performed the day after the seizure showed diffuse polyspikes and spike-and-wave discharges. EEG on the following days showed persistent abnormalities (slowing of background activity intermixed with diffuse slow waves and isolated delta and theta bursts). These abnormalities persisted for about 20 days with complete normalization one month after the seizure. We suggest that BU is implicated in these abnormalities and emphasize the importance of EEG recording before and after bone marrow transplantation to disclose BU neurotoxicity.

Results Among the 23 consecutive patients enrolled, 19 (13 F, 6 M; mean age 47.9 ± 12.3; mean BMI 26.1± 4.8) completed the study, 4 female patients dropped out. None of the 19 patients had papilledema. We found a TSS in 11 of 19 cases (58%): bilateral in 3 patients and unilateral in 8 cases. All of 19 cases displayed OP lower than 250 mmH2O (range 102-245) and normal CSF composition. We found a OP greater than 200 mmH2O only in four patients (1M, 3 F) (17%): two of them achieved an improvement of headache intensity and frequency after 12-18 ml CSF withdrawal; one of them had bilateral TSS.

Objective: To investigate the mechanisms underlying myoclonus in Leber hereditary optic neuropathy (LHON). Methods: Five patients and one unaffected carrier from two Italian families bearing the homoplasmic 11778/ND4 and 3460/ND1 mutations underwent a uniform investigation including neurophysiologic studies, muscle biopsy, serum lactic acid after exercise, and muscle ( 31 P) and cerebral ( 1 H) magnetic resonance spectroscopy (MRS). Biochemical investigations on fibroblasts and complete mitochondrial DNA (mtDNA) sequences of both families were also performed. Results: All six individuals had myoclonus. In spite of a normal EEG background and the absence of giant SEPs and C reflex, EEG-EMG back-averaging showed a preceding jerk-locked EEG potential, consistent with a cortical generator of the myoclonus. Specific comorbidities in the 11778/ND4 family included muscular cramps and psychiatric disorders, whereas features common to both families were migraine and cardiologic abnormalities. Signs of mitochondrial proliferation were seen in muscle biopsies and lactic acid elevation was observed in four of six patients. 31 P-MRS was abnormal in five of six patients and 1 H-MRS showed ventricular accumulation of lactic acid in three of six patients. Fibroblast ATP depletion was evident at 48 hours incubation with galactose in LHON/myoclonus patients. Sequence analysis revealed haplogroup T2 (11778/ND4 family) and U4a (3460/ND1 family) mtDNAs. A functional role for the non-synonymous 4136A>G/ND1, 9139G>A/ATPase6, and 15773G>A/ cyt b variants was supported by amino acid conservation analysis. Conclusions: Myoclonus and other comorbidities characterized our Leber hereditary optic neuropathy (LHON) families. Functional investigations disclosed a bioenergetic impairment in all individuals. Our sequence analysis suggests that the LHON plus phenotype in our cases may relate to the synergic role of mtDNA variants.

Background: An increasing number of mitochondrial DNA (mtDNA) mutations, mainly in complex I genes, have\ud been associated with variably overlapping phenotypes of Leber’s hereditary optic neuropathy (LHON),\ud mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and Leigh syndrome (LS). We here describe\ud the first case in which the m.4171C>A/MT-ND1 mutation, previously reported only in association with LHON, leads\ud also to a Leigh-like phenotype.\ud Case presentation: A 16-year-old male suffered subacute visual loss and recurrent vomiting and vertigo associated\ud with bilateral brainstem lesions affecting the vestibular nuclei. His mother and one sister also presented subacute\ud visual loss compatible with LHON. Sequencing of the entire mtDNA revealed the homoplasmic m.4171C>A/MT-ND1\ud mutation, previously associated with pure LHON, on a haplogroup H background. Three additional non-synonymous\ud homoplasmic transitions affecting ND2 (m.4705T>C/MT-ND2 and m.5263C>T/MT-ND2) and ND6 (m.14180T>C/MT-ND6)\ud subunits, well recognized as polymorphisms in other mtDNA haplogroups but never found on the haplogroup H\ud background, were also present.\ud Conclusion: This case widens the phenotypic expression of the rare m.4171C>A/MT-ND1 LHON mutation, which\ud may also lead to Leigh-like brainstem lesions, and indicates that the co-occurrence of other ND non-synonymous\ud variants, found outside of their usual mtDNA backgrounds, may have increased the pathogenic potential of the\ud primary LHON mutation.