Narcolepsy is a common phenotype in HSAN IE and ADCA-DN

We report on the extensive phenotypic characterization of five Italian patients from four unrelated families carrying dominant heterozygous DNMT1 mutations linked to two distinct autosomal dominant diseases: hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE (HSAN IE) and autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Patients underwent genetic analysis of DNMT1 gene, neurophysiological tests investigating sleep, auditory functions and peripheral nervous system, ophthalmological studies including optical coherence tomography, lymphoscintigraphy, brain magnetic resonance and nuclear imaging, cerebrospinal fluid hypocretin-1, total tau, phosphorylated tau, amyloid-β1-42 and 14-3-3 proteins measurement, skin, muscular and sural nerve biopsies. Exome and direct sequencing studies disclosed two different point mutations affecting exon 21 of DNMT1 gene in patients with ADCA-DN, a novel heterozygous point mutation in exon 20 in two affected HSAN IE siblings, and a trinucleotide deletion in exon 20 in the latter patient with HSAN IE. Phenotypic characterization pinpoints that ADCA-DN and HSAN IE represent two discrete clinical entities belonging to the same disease spectrum, with variable degree of overlap. Remarkably, narcolepsy with or without cataplexy with low/intermediate or normal cerebrospinal fluid hypocretin-1 is present in both diseases. The human leukocyte antigen DQB1*06:02 was absent in all patients. Other common symptoms and features observed in our cases, involving the central and peripheral nervous system, include deafness, optic neuropathy-previously not reported in HSAN IE-large and small fibres polyneuropathy and lower limbs oedema. Overall, the two syndromes share more characteristics than previously recognized and narcolepsy is common to both. HSAN IE and ADCA-DN are two extreme phenotypic manifestations of a DNMT1 methylopathy

Complexity of motor sequences and cortical reorganization in Parkinson's disease: a functional MRI study.

Motor impairment is the most relevant clinical feature in Parkinson's disease (PD). Functional imaging studies on motor impairment in PD have revealed changes in the cortical motor circuits, with particular involvement of the fronto-striatal network. The aim of this study was to assess brain activations during the performance of three different motor exercises, characterized by progressive complexity, using a functional fMRI multiple block paradigm, in PD patients and matched control subjects. Unlike from single-task comparisons, multi-task comparisons between similar exercises allowed to analyse brain areas involved in motor complexity planning and execution. Our results showed that in the single-task comparisons the involvement of primary and secondary motor areas was observed, consistent with previous findings based on similar paradigms. Most notably, in the multi-task comparisons a greater activation of supplementary motor area and posterior parietal cortex in PD patients, compared with controls, was observed. Furthermore, PD patients, compared with controls, had a lower activation of the basal ganglia and limbic structures, presumably leading to the impairment in the higher levels of motor control, including complexity planning and execution. The findings suggest that in PD patients occur both compensatory mechanisms and loss of efficiency and provide further insight into the pathophysiological role of distinct cortical and subcortical areas in motor dysfunction

Single-task analysis Complex Scale, PD Patients > Controls.

<p>The over-activations of right putamen, right inferior temporal cortex (a), left primary motor area, right dorsolateral prefrontal cortex, left posterior parietal cortex and rostral supplementary motor area (b) observed in patients, compared to controls, for Complex Scale, are shown. Colours bar range for F-score: 2 to 9,47.</p

Multi-task analysis Simple Scale vs Finger.

<p>The over-activations of bilateral posterior parietal cortex (a), left primary motor area and left rostral supplementary motor area (b) observed in patients, compared to controls, for the second level analysis (Simple Scale vs Finger), are shown. Colours bar range for F-score: 2 to 27,55.</p

Single-task analysis Finger.

<p>The over-activations of bilateral insula (a), bilateral primary motor area and caudal supplementary motor area (b) observed in patients, compared to controls, for Finger, are shown. Colours bar range for F-score: 2 to 8.09.</p

Single-task analysis Complex Scale, Controls > PD Patients.

<p>The over-activation of right hippocampus observed in controls, compared to patients, for Complex Scale, is shown. Colours bar range for F-score: 2 to 9,47.</p

Clinical characteristics of patients and control subjects.

<p>Clinical characteristics of patients and control subjects.</p

Single-task analysis Simple Scale.

<p>The over-activations of right hippocampus (a) and right insula (b) observed in controls, compared to patients, and of right cerebellum (c), left primary motor area, right dorsolateral prefrontal cortex and rostral supplementary motor area (d) observed in patients, compared to controls, for Simple Scale, are shown. Colours bar range for F-score: 2 to 8,63.</p

Multi-task analysis results.

<p>Results of whole brain fMRI between group analysis are reported. For each region with significant differences Talairach coordinates and F-score of the local maxima are reported (<i>p</i><0.001). L:left; M1: primary motor area; PPC: posterior parietal cortex; PD: Parkinson's disease; R: right; rSMA: rostral supplementary motor area.</p

Multi-task analysis Complex Scale vs Simple Scale.

<p>The over-activations of right parahippocampal (a) cortex and caudate (b) observed in controls, compared to patients, for the second level analysis (Complex Scale vs Simple Scale), are shown. Colours bar range for F-score: 2 to 18,14.</p