Guido Primiano

Peripheral neuropathy is a common manifestation of mitochondrial diseases: a single-centre experience

Peripheral neuropathy in mitochondrial diseases (MDs) may vary from a subclinical finding in a multisystem syndrome to a severe, even isolated, manifestation in some patients.

Myoclonus in mitochondrial disorders

Myoclonus is a possible manifestation of mitochondrial disorders, and its presence is considered, in association with epilepsy and the ragged red fibers, pivotal for the syndromic diagnosis of MERRF (myoclonic epilepsy with ragged red fibers). However, its prevalence in mitochondrial diseases is not known. The aims of this study are the evaluation of the prevalence of myoclonus in a big cohort of mitochondrial patients and the clinical characterization of these subjects. Based on the database of the “Nation‐wide Italian Collaborative Network of Mitochondrial Diseases,” we reviewed the clinical and molecular data of mitochondrial patients with myoclonus among their clinical features. Myoclonus is a rather uncommon clinical feature of mitochondrial diseases (3.6% of 1,086 patients registered in our database). It is not strictly linked to a specific genotype or phenotype, and only 1 of 3 patients with MERRF harbors the 8344A>G mutation (frequently labeled as “the MERRF mutation”). Finally, myoclonus is not inextricably linked to epilepsy in MERRF patients, but more to cerebellar ataxia. In a myoclonic patient, evidences of mitochondrial dysfunction must be investigated, even though myoclonus is not a common sign of mitochondriopathy. Clinical, histological, and biochemical data may predict the finding of a mitochondrial or nuclear DNA mutation. Finally, this study reinforces the notion that myoclonus is not inextricably linked to epilepsy in MERRF patients, and therefore the term “myoclonic epilepsy” seems inadequate and potentially misleading.

Copper deficiency myelopathy: A report of two cases

Abstract Context Copper deficiency myelopathy represents an often underdiagnosed, acquired neurological syndrome, clinically characterized by posterior column dysfunction. The main causes of copper deficiency are bariatric surgery, increased consumption of zinc, and malabsorption. However, even after a careful history taking and extensive laboratory researches, the etiology of copper deficiency remains undetermined in a significant percentage of cases. Patients affected by copper deficiency myelopathy usually present with sensory ataxia due to dorsal column dysfunction and sometimes with mild leg spasticity. In such patients, spinal cord magnetic resonance imaging (MRI) may show hyperintense lesions in T2-weighted sequences involving the posterior columns of cervical and thoracic cord. These MRI findings are not distinguishable from those of subacute combined degeneration associated with vitamin B12 deficiency. Findings Here, we describe two patients with gait ataxia and sensory symptoms in which a diagnosis of copper deficiency myelopathy was made. Both patients showed a significant clinical, neuroradiological, and neurophysiological improvement after proper supplementation therapy. Conclusion The patients herein described underline the importance to include serum copper and ceruloplasmin levels as part of the myelopathy diagnostic workup, especially in the cases of otherwise unexplained subacute myelopathy involving the posterior columns. Since copper deficiency myelopathy is a progressive syndrome, early diagnosis is mandatory in order to promptly provide a proper supplementation therapy and, thus, prevent an irreversible neurological damage.

Migraine in mitochondrial disorders: Prevalence and characteristics

Background Migraine is a well-known feature of mitochondrial disorders (MDs). However, no systematic epidemiological data are available in large populations of patients. Aims The aim of this cross-sectional cohort study was to describe the prevalence and migraine characteristics in a large cohort of patients with mitochondrial encephalomyopathies. Methods We studied 93 consecutive patients with characterised MDs referred to our Neuromuscular Unit during a 12-month period. All patients (age range = 16–78 years; 31 men; 58 progressive external ophthalmoplegia [PEO], 12 myoclonic epilepsy with ragged red fibres [MERRF], eight mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes [MELAS], two mitochondrial neurogastrointestinal encephalomyopathy [MNGIE] and 13 other MDs) underwent a structured diagnostic headache interview using an operational diagnostic tool following the IHS criteria. If they met the criteria for migraine, they were included in the ‘Migraine Group’. The other patients were counted in the ‘No Migraine Group’. Patient demographic and migraine characteristics were examined. Clinical, neuroradiological and neurophysiological data were compared between groups. Results Migraine was reported in 35.5% of patients. Migraine without aura was the most common headache (81.8%). The migraine group showed younger age (P < 0.01), increased prevalence of epilepsy (P = 0.01), myoclonus (P = 0.03), stroke-like episodes (P = 0.03) and decreased prevalence of muscle weakness (P < 0.01). Multivariate analysis showed that migraine was positively associated with absence of muscle weakness (P = 0.04) and presence of EEG abnormalities (P = 0.02). Conclusion Migraine has a higher prevalence in MDs compared with general population-based data, independently from genotype or phenotype. Migraine is not merely a phenotypic aspect of specific MDs but is rather the expression of vulnerability of the central nervous system, probably directly related with defects of the respiratory chain.

Acute refractory intestinal pseudo-obstruction in MELAS: Efficacy of prucalopride

In mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a multisystem mitochondrial disorder, gastrointestinal involvement is frequent with dysphagia, chronic diarrhea, anorexia, abdominal pain, delayed gastric emptying, and paralytic, often intractable, ileus.1 In this article, we report a patient with chronic gastrointestinal dysmotility and acute refractory intestinal pseudo-obstruction responsive to prucalopride.

Oculopharyngeal muscular dystrophy: Clinical and neurophysiological features

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Mitochondrial neuropathy: considerations on pathogenesis

Inspired by the letter of Finsterer & Frank [1] we further analysed our cohort of patients with mitochondrial diseases (MDs), providing additional data. Nerve conduction studies revealed a neuropathy in 40 patients without symptoms or signs (9 mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS), 10 myoclonic epilepsy with ragged-red fibers (MERRF), 4 mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), 13 progressive external ophthalmoplegia (PEO) and 4 other MDs). These data confirm the importance of always screening patients with MD for neuropathy. Neuropathy was defined as indicated in Luigetti et al. [2] and we used normative data from our laboratory obtained with the same electromyography (EMG) apparatus (Dantec Keypoint). Conversely, in 12 patients (two MERRF, nine PEO and one other MD) with neuropathic symptoms or signs (absence or reduction of distal tendon reflexes that are normally spared in myopathies), nerve conduction studies proved normal. Longitudinal neurophysiological followup will elucidate whether nerve involvement will occur also in these cases. As in our previous article [2], diabetes was reported in 15 cases, seven with neuropathy and eight without. All patients with diabetes were in treatment and the mean HbA1c value was 57.67 mmol/mol (range 46.0–85.0; normal value < 42.0), again excluding any correlation of diabetes or treatment with the presence of neuropathy. Other conditions predisposing to a neuropathy occurred in six patients (two hepatitis C virus (HCV), one hepatitis B virus (HBV), one with rheumatoid arthritis, one with chronic renal failure and one with previous assumption of chemotherapies). Neuropathy occurred only in half of those (one PEO with HCV, one MELAS with HBV and one MELAS with chronic renal failure). Furthermore, seven patients (one MELAS, one MERRF, four PEO and one other MD) suffered from hypothyroidism and all disclosed a polyneuropathy. All of these patients were in longlasting substitutive therapy with normal values of circulating hormones and therefore we do not believe that this condition could have influenced the neuropathy onset. In fact, neuropathy is a rare event in hypothyroidism and has been reported only in severely affected and untreated patients [3]. No patients suffered from parathyroid dysfunction. Hearing impairment, as we indicated previously [2], was reported in 84 patients (12 MELAS, 14 MERRF, one MNGIE, 50 PEO and seven other MDs) but none reported dizziness or other symptoms suggesting involvement of vestibular nerve. No patients suffered from autonomic system dysfunction. The mutation load in PEO associated with mitochondrial DNA (mtDNA) single deletion was available in muscle for 40 patients (from 20% to 91%). Heteroplasmy levels of the A8344G mutation were available in muscle for 12 patients (mutation load from 10% to 88%) and in blood for seven patients (mutation load from 0% to 76%). The mutation load for A3243G was available in muscle for four patients (from 50% to 80%) and in blood for six patients (from 14% to 67%). No clear relationship was observed between the mutation load and the presence of neuropathy. In summary, we believe that these new data strengthen and confirm the conclusion of our previous work that neuropathy is a common feature of mitochondrial disorders specifically related to the MD [2].

Systematic assessment and characterization of chronic pain in multiple sclerosis patients

Pain is one of the most disabling clinical symptoms in patients with multiple sclerosis (MS). Several studies have already assessed the prevalence of pain in MS patients, reporting variable results, probably due to methodological differences. The aim of this single-centre cross-sectional study was to define the prevalence and characteristics of chronic pain in a population of MS patients using validated tools, and to analyse these data in relation to demographic and clinical features, including disease duration and disability (EDSS and its single functional system scores). Of 397 enrolled patients, 23 were excluded due to a Beck’s Depression Inventory Score > 19. In the remaining 374 patients, the overall prevalence of chronic pain was 52.1%, most frequently affecting the lower limbs (36.9%). Neuropathic pain was the most frequent type of chronic pain (89 patients, overall prevalence of 23.7%) and was associated with a sensory functional system involvement. Pain intensity was significantly higher in patients with neuropathic pain as opposed to patients with non-neuropathic pain. Patients with chronic pain and, in particular, patients with neuropathic pain had significantly higher EDSS scores than those without pain. Only 24% of patients with chronic pain and 33% of patients with neuropathic pain were on a specific long-lasting treatment for pain. The present study supports the routine assessment of neuropathic pain in MS patients, especially in those with a sensory functional system involvement, in order to avoid underdiagnosing and undertreating a potentially disabling condition.

Resolution of Muscle Inflammation After Tumor Removal in a Woman with Paraneoplastic Dermatomyositis

The paraneoplastic association of dermatomyositis (DM) and underlying breast cancer is well established1,2. This report confirms the diagnostic and therapeutic value of searching for malignancy in patients with DM3,4. A 33-year-old woman developed subacute severe proximal muscle weakness, dysphagia, respiratory failure, skin lesions on the forehead, and purplish discoloration around the upper eyelid, with ulcerating nodules in …

Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration

Objective To characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families. Methods We used whole-exome sequencing (WES) (families 1 and 2) and a combined approach based on homozygosity mapping and WES (family 3). We performed in vitro studies to explore the effect of the nontruncating SQSTM1 mutation on protein function and the effect of impaired SQSTM1 function on autophagy. We analyzed the consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in vivo using zebrafish as a model. Results We identified 3 homozygous inactivating variants, including a splice site substitution (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a resulting protein lacking exon 2, as well as 2 truncating changes (c.875_876insT and c.934_936delinsTGA). We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress and decelerated autophagic flux. The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy. We provide a detailed clinical characterization of the disorder; the natural history is reported for 2 siblings who have been followed up for >20 years. Conclusions This study offers an accurate clinical characterization of this recently recognized neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy.