Rocco Liguori

Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy

The mechanisms of incomplete penetrance in Leber’s hereditary optic neuropathy are elusive. Giordano et al. show that mitochondrial DNA content and mitochondrial mass are both increased in tissues and cells from unaffected mutation carriers relative to affected relatives and control individuals. Upregulation of mitochondrial biogenesis may represent a therapeutic target.

Syndromic parkinsonism and dementia associated with OPA1 missense mutations.

Mounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.

Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder

Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.

Skin nerve misfolded α-synuclein in pure autonomic failure and Parkinson disease

To characterize the expression in skin nerves of native (n‐syn) and misfolded phosphorylated (p‐syn) α‐synucleins in pure autonomic failure (PAF) and idiopathic Parkinson disease (IPD). The specific aims were to (1) define the importance of n‐syn and p‐syn as disease biomarkers and (2) ascertain differences in abnormal synuclein skin nerve deposits.

Iodine-123 metaiodobenzylguanidine scintigraphy and iodine-123 ioflupane single photon emission computed tomography in lewy body diseases: Complementary or alternative techniques?

To compare myocardial sympathetic imaging using 123I‐Metaiodobenzylguanidine (MIBG) scintigraphy and striatal dopaminergic imaging using 123I‐Ioflupane (FP‐CIT) single photon emission computed tomography (SPECT) in patients with suspected Lewy body diseases (LBD).

A multi-center, multinational age- and gender-adjusted normative dataset for immunofluorescent intraepidermal nerve fiber density at the distal leg

Quantification of intraepidermal nerve fibers (IENFs) in skin biopsies is now the tool of choice to diagnose small fiber neuropathies. An adequate normative dataset, necessary to assess normality cutoffs, is available for brightfield microscopy but not for immunofluorescence.

LOPED study: looking for an early diagnosis in a late-onset Pompe disease high-risk population

Objective A multicentre observational study was aimed to assess the prevalence of late-onset Pompe disease (LOPD) in a large high-risk population, using the dried blood spot (DBS) as a main screening tool. Design/methods 17 Italian neuromuscular centres were involved in the late-onset Pompe early diagnosis (LOPED) study. Inclusion criteria were: (1) age ≥5u2005years, (2) persistent hyperCKaemia and (3) muscle weakness at upper and/or lower limbs (limb-girdle muscle weakness, LGMW). Acid α-glucosidase (GAA) activity was measured separately on DBS by fluorometric as well as tandem mass spectrometry methods. A DBS retest was performed in patients resulted positive at first assay. For the final diagnosis, GAA deficiency was confirmed by a biochemical assay in skeletal muscle, whereas genotype was assessed by GAA molecular analysis. Results In a 14-month period, we studied 1051 cases: 30 positive samples (2.9%) were detected by first DBS screening, whereas, after retesting, 21 samples were still positive. Biochemical and molecular genetic studies finally confirmed LOPD diagnosis in 17 cases (1.6%). The median time from the onset of symptoms/signs to diagnosis was 5u2005years. Among those patients, 35% showed presymptomatic hyperCKaemia and 59% showed hyperCKaemia+LGMW, whereas 6% manifested with LGMW. Conclusions LOPED study suggests that GAA activity should be accurately screened by DBS in all patients referring for isolated hyperCKaemia and/or LGMW. A timely diagnosis was performed in five patients with presymptomatic hyperCKaemia, but two had already manifested with relevant changes on muscle morphology and MRI. Consequently, enzyme replacement therapy was started in 14/17 patients, including the 2 patients still clinically presymptomatic but with a laboratory evidence of disease progression.

Neurophysiological correlates of abnormal somatosensory temporal discrimination in dystonia

Somatosensory temporal discrimination threshold is often prolonged in patients with dystonia. Previous evidence suggested that this might be caused by impaired somatosensory processing in the time domain. Here, we tested if other markers of reduced inhibition in the somatosensory system might also contribute to abnormal somatosensory temporal discrimination in dystonia.

OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation

Santarelli et al. reveal that hearing impairments in patients carrying OPA1 missense mutations are the result of disordered synchrony in auditory nerve fibre activity owing to degeneration of terminal dendrites. Cochlear implantation improves speech perception and synchronous activation of auditory pathways in these patients by bypassing the lesion site.

Epidemiology of amyotrophic lateral sclerosis in Emilia Romagna Region (Italy): A population based study

Abstract Our objective was to describe incidence and clinical features of ALS from a prospective population-based study in Emilia Romagna Region (ERR). From 2009 onwards, a prospective registry recorded all incident cases of ALS among residents in the ERR (population, 4.4 million inhabitants), involving 17 neurological departments. For each patient, detailed demographic and clinical information was collected by caring physicians. Results showed that from 1 January 2009 to 31 December 2011, 347 patients received a new diagnosis of ALS with a crude incidence rate of 2.63/100,000/year. There was micro-geographic heterogeneity throughout ERR, with higher incidence rates in the low density population (3.27/100,000) (p < 0.01). ALS patients have been more frequently employed in agriculture than the general ERR population (8.64% vs. 4.6%, p < 0.01). Clinical features were similar to those described in previous population based studies. In conclusion, we report incidence rates similar to those reported by European registries, reflecting good accuracy of our prospective study. We confirmed previous studies reporting higher incidence rates in rural areas and among agricultural workers. Although genetics has been gaining increasing importance in ALS aetiology, some epidemiological data are still unexplained. Identifying geographical areas or populations with high incidence rates can be a starting point for identifying environmental risk factors. Further studies having this specific aim can shed light on these topics.