Donato Sauchelli

Phenotypic heterogeneity of the 8344A.G mtDNA "MERRF" mutation

Objectives: Myoclonic epilepsy with ragged-red fibers (MERRF) is a rare mitochondrial syndrome, mostly caused by the 8344A>G mitochondrial DNA mutation. Most of the previous studies have been based on single case/family reports or series with few patients. The primary aim of this study was the characterization of a large cohort of patients with the 8344A>G mutation. The secondary aim was revision of the previously published data. Methods: Retrospective, database-based study (Nation-wide Italian Collaborative Network of Mitochondrial Diseases) and systematic revision. Results: Forty-two patients carrying the mutation were identified. The great majority did not have full-blown MERRF syndrome. Myoclonus was present in 1 of 5 patients, whereas myopathic signs and symptoms, generalized seizures, hearing loss, eyelid ptosis, and multiple lipomatosis represented the most common clinical features. Some asymptomatic mutation carriers have also been observed. Myoclonus was more strictly associated with ataxia than generalized seizures in adult 8344A>G subjects. Considering all of the 321 patients so far available, including our dataset and previously published cases, at the mean age of approximately 35 years, the clinical picture was characterized by the following signs/symptoms, in descending order: myoclonus, muscle weakness, ataxia (35%–45% of patients); generalized seizures, hearing loss (25%–34.9%); cognitive impairment, multiple lipomatosis, neuropathy, exercise intolerance (15%–24.9%); and increased creatine kinase levels, ptosis/ophthalmoparesis, optic atrophy, cardiomyopathy, muscle wasting, respiratory impairment, diabetes, muscle pain, tremor, migraine (5%–14.9%). Conclusions: Our results showed higher clinical heterogeneity than commonly thought. Moreover, MERRF could be better defined as a myoclonic ataxia rather than a myoclonic epilepsy.

The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender?

Abstract The m.3243A>G “MELAS” (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) mutation is one of the most common point mutations of the mitochondrial DNA, but its phenotypic variability is incompletely understood. The aim of this study was to revise the phenotypic spectrum associated with the mitochondrial m.3243A>G mutation in 126 Italian carriers of the mutation, by a retrospective, database-based study (“Nation-wide Italian Collaborative Network of Mitochondrial Diseases”). Our results confirmed the high clinical heterogeneity of the m.3243A>G mutation. Hearing loss and diabetes were the most frequent clinical features, followed by stroke-like episodes. “MIDD” (maternally-inherited diabetes and deafness) and “PEO” (progressive external ophthalmoplegia) are nosographic terms without any real prognostic value, because these patients may be even more prone to the development of multisystem complications such as stroke-like episodes and heart involvement. The “MELAS” acronym is convincing and useful to denote patients with histological, biochemical and/or molecular evidence of mitochondrial disease who experience stroke-like episodes. Of note, we observed for the first time that male gender could represent a risk factor for the development of stroke-like episodes in Italian m.3243A>G carriers. Gender effect is not a new concept in mitochondrial medicine, but it has never been observed in MELAS. A better elucidation of the complex network linking mitochondrial dysfunction, apoptosis, estrogen effects and stroke-like episodes may hold therapeutic promises.

Rippling muscle disease and cardiomyopathy associated with a mutation in the CAV3 gene

Caveolin-3, the myocyte-specific isoform of caveolins, is preferentially expressed in skeletal, cardiac and smooth muscles. Mutations in the CAV3 gene cause clinically heterogeneous neuromuscular disorders, including rippling muscle disease, or cardiopathies. The same mutation may lead to different phenotypes, but cardiac and muscle involvement rarely coexists suggesting that the molecular network acting with caveolin-3 in skeletal muscle and heart may differ. Here we describe an Italian family (a father and his two sons) with clinical and neurophysiological features of rippling muscle disease and heart involvement characterized by atrio-ventricular conduction defects and dilated cardiomyopathy. Muscle biopsy showed loss of caveolin-3 immunosignal. Molecular studies identified the p.A46V mutation in CAV3 previously reported in a German family with autosomal dominant rippling muscle disease and sudden death in few individuals. We suggest that cardiac dysfunction in myopathic patients with CAV3 mutations may be underestimated and recommend a more thorough evaluation for the presence of cardiomyopathy and potentially lethal arrhythmias.

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.

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.

R208H-129VV haplotype in the prion protein gene: phenotype and neuroimaging of a patient with genetic Creutzfeldt-Jakob disease.

The R208H substitution of the prion protein gene (PRNP) was first reported in 1996 in a subject with pathologically confirmed Creutzfeldt-Jakob disease (CJD) [1] and subsequently described in only five other patients [2–6]. Now we report a case with CJD and the rarely reported haplotype R208H-129VV, showing some distinctive clinical features and expanding the spectrum of phenotypes associated with R208H mutation. A 63-year-old woman with a left lower limb paresis because of poliomyelitis in her first year of life, subacutely developed akinesia, postural instability, depression, paranoid delusions and then, in a few weeks, an apathic–inertial syndrome. Six months after the onset she was partially oriented, showed poor verbal initiative, was unable to walk, had marked akinesia, hypomimia, limb rigidity, postural and kinetic tremor of upper limbs, startle reactions to acoustic stimuli, and left-sided ideomotor apraxia. She did not have myoclonus, dysarthria, dysmetria, gaze palsy, nystagmus or hallucinations. Mini Mental State Examination was 13/30; the inertia did not allow an extensive neuropsychological examination. Electroencephalogram (EEG) showed alpha rhythm reacting to eyes opening, diffuse theta activity with the slowest elements prevailing on right frontal regions, rare triphasic waves on anterior regions. In the subsequent 2 months, sporadic myoclonic jerks appeared. Magnetic resonance (MRI) showed hyperintensity of caudate and putamen on T2-weighted FLAIR and DWI images, and DWI hyperintensity of right frontal, temporal, parietal and insular cortices (Fig. 1a–c). Hyperintensities in deep white matter was also seen on T2 and FLAIR. Single voxel MRI spectroscopy (TE 144) of temporal cortex demonstrated reduced N-acetylaspartate/creatine ratio. Single photon emission computed tomography (SPECT) with Tc-ethyl-cysteinate-dimer demonstrated hypoperfusion in right frontal, temporal and parietal cortex (Fig. 1d). SPECT with radioligand for dopamine transporter (I-N-x-fluoropropyl-2b-carbomethoxy-3b-(4iodophenyl)nortropane, I-FP-CIT) did not reveal alterations of presynaptic nigro-striatal pathway (Fig. 1e). Six months after onset, cerebrospinal fluid examination for protein 14-3-3 (SDS-PAGE, immunoblotting) was negative, whereas total-tau values (ELISA) were increased (1,149 pg/ml). Restriction enzyme analysis showed homozygosity for valine (VV) at codon 129 of PRNP, while gene sequencing revealed the R208H mutation on one allele. Nine months after onset the patient was discharged from our clinic. This patient constitutes the seventh reported CJD case with R208H substitution, the third with VV at codon 129 (Table 1). The phenotype of the first reported subject carrying this haplotype was characterized by behavioral changes followed by ataxia, pyramidal signs, M. G. Vita D. Sauchelli P. E. Alboini A. Bizzarro E. Scaricamazza C. Masullo (&) Dipartimento di Gerontologia, Neuroscienze ed Ortopedia, Istituto di Neurologia, Università Cattolica del Sacro Cuore, Policlinico A.Gemelli, Largo A. Gemelli 8, 00168 Rome, Italy e-mail: cmasullo@rm.unicatt.it

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].

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 …

Neurological involvement during legionellosis, look beyond the lung

Legionella represents the etiologic agent of a relevant number of cases of pneumonia in patients admitted to the Emergency Department and is still associated with a remarkable mortality rate. Among extrapulmonary legionellosis manifestations, central nervous system (CNS) involvement has been frequently documented. Main symptoms are confusion, obtundation, stupor, headache, and behavioral abnormalities; cerebellar dysfunction may rarely occur. Encephalopathic manifestations are frequently reversible within weeks or months, although ataxia and dysarthria may persist after years. Since the mechanisms of extrapulmonary manifestations, including neurological ones, still need to be clarified, no specific therapeutic strategies have been proposed to treat complicated patients so far [1–3]. A 36-year-old Caucasian man without any significant medical comorbidities was admitted to our hospital with fever and tachypnea. In the last 3 days he had presented fever, malaise, progressive dyspnea, abdominal pain and confusion. Chest X-ray showed a left median-inferior consolidation with consensual pleural effusion. The urinary antigen test for Legionella pneumophila serogroup one was positive. Lumbar puncture revealed normal protein and glucose levels, and 12 lymphocytes/mm; cerebrospinal fluid (CSF) bacterial cultures were negative. Antimicrobial therapy with intravenous levofloxacin and azitromicin was started. Within a few days, fever and respiratory distress progressively disappeared. However, on day 3 after admission, neurological examination showed severe dysarthria, limb and trunk ataxia, impaired finger-to-nose and heel-to-shin movement, nystagmus, and slight intentional tremor. Brain magnetic resonance imaging (MRI) showed a strongly increased signal of 12 mm in the splenium of the corpus callosum (SCC) on T2and diffusion-weighted

Hypoglossal palsy and coeliac disease: An uncommon presentation for a common disease?

Twelfth-nerve palsy, associated with other cranial neuopathies, is relatively common in clinical practice and is often an minous sign of malignant disease [1]. Isolated hypoglossal palsy IHP), rather, is rare. Tongue weakness and atrophy, sometimes ssociated with dysarthria, dysphagia and headache, are the only eatures of the clinical picture. Many disorders can be responsible for IHP. Neoplasia, once gain, is the most frequent cause but trauma, malformations, vasular, infectious and autoimmune diseases have been reported as ell. Searching for the correct etiological diagnosis requires the ystematic use of many radiological and laboratory investigations nd, above all, careful and prolonged follow-up. In spite of these easures, very rarely, the cause is not found and this condition is nown as idiopathic IHP. Coeliac disease (CD) is a chronic disorder caused by immune esponse to gluten, a protein present in wheat, rye and barley. This ondition produces inflammation, villous atrophy and crypt hyperlasia in the proximal part of the intestine. Clinically, the typical icture of CD as pediatric gastrointestinal disorder is now out of ate. The diagnosis is, in fact, often made in adults with extrainestinal symptoms.