Elisabetta Bucci

Peripheral nerve ultrasound changes in CIDP and correlations with nerve conduction velocity

Objective: To evaluate the ultrasound (US) characteristics of peripheral nerves in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and their correlations with electrodiagnostic (EDX) characteristics. Methods: Nineteen patients with CIDP and 19 healthy controls matched by age and body mass index were included in a blind case-control, observational study. All patients underwent a neurologic examination (including inflammatory neuropathy cause and treatment [INCAT] and Medical Research Council [MRC] sum score) and an EDX study. Each patient and each control underwent a US study of 14 nerve segments, yielding a total number of 266 segments scanned in each group. Results: US changes, characterized by an increased nerve cross-sectional area (NCSA), were detected in 53% of the 266 patient nerve segments. Mean NCSA was higher in nerve segments of patients than in those of controls (p < 0.001). Nerve segments with abnormal US belonged to patients with longer disease duration, lower MRC sum score, higher INCAT score, and progressive disease form (all p < 0.0001). All the aforementioned variables were independently associated with the occurrence of US changes. Motor nerve conduction was significantly lower in nerve segments with increased NCSA than in those with normal NCSA (p < 0.0001). NCSA in segments with prevalent myelin damage was higher than that in segments with prevalent axonal damage (p = 0.001) or in segments with normal EDX characteristics (p < 0.0001). NCSA and motor nerve conduction velocity were inversely correlated in nerve segments with EDX evidence of myelin damage (R = 0.599; p < 0.0001). Conduction blocks were associated with increased NCSA (p = 0.001). Conclusions: US may, similar to MRI, have a supporting role in the diagnosis of CIDP. US and EDX changes are correlated.

Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy has been genetically linked to reduced numbers (≤8) of D4Z4 repeats at 4q35 combined with 4A(159/161/168) DUX4 polyadenylation signal haplotype. However, we have recently reported that 1.3% of healthy individuals carry this molecular signature and 19% of subjects affected by facioscapulohumeral muscular dystrophy do not carry alleles with eight or fewer D4Z4 repeats. Therefore, prognosis for subjects carrying or at risk of carrying D4Z4 reduced alleles has become more complicated. To test for additional prognostic factors, we measured the degree of motor impairment in a large group of patients affected by facioscapulohumeral muscular dystrophy and their relatives who are carrying D4Z4 reduced alleles. The clinical expression of motor impairment was assessed in 530 subjects, 163 probands and 367 relatives, from 176 unrelated families according to a standardized clinical score. The associations between clinical severity and size of D4Z4 allele, degree of kinship, gender, age and 4q haplotype were evaluated. Overall, 32.2% of relatives did not display any muscle functional impairment. This phenotype was influenced by the degree of relation with proband, because 47.1% of second- through fifth-degree relatives were unaffected, whereas only 27.5% of first-degree family members did not show motor impairment. The estimated risk of developing motor impairment by age 50 for relatives carrying a D4Z4 reduced allele with 1–3 repeats or 4–8 repeats was 88.7% and 55%, respectively. Male relatives had a mean score significantly higher than females (5.4 versus 4.0, P = 0.003). No 4q haplotype was exclusively associated with the presence of disease. In 13% of families in which D4Z4 alleles with 4–8 repeats segregate, the diagnosis of facioscapulohumeral muscular dystrophy was reported only in one generation. In conclusion, this large-scale analysis provides further information that should be taken into account when counselling families in which a reduced allele with 4–8 D4Z4 repeats segregates. In addition, the reduced expression of disease observed in distant relatives suggests that a family’s genetic background plays a role in the occurrence of facioscapulohumeral muscular dystrophy. These results indicate that the identification of new susceptibility factors for this disease will require an accurate classification of families.

Increased temporal dispersion of myocardial repolarization in myotonic dystrophy Type 1: Beyond the cardiac conduction system

BACKGROUND AND OBJECTIVES The most frequently mechanism underlying sudden cardiac death in myotonic dystrophy type 1 (DM1) is bradyarrhythmias due to cardiac conduction abnormalities. However the risk of ventricular tachyarrhythmias remains a concern in clinical management as well as in its determinant. We therefore assessed autonomic nervous system activity aiming to disclose differences in the QT variability index (QTVI)-a marker of temporal myocardial repolarization lability-between DM1 patients and healthy controls. We also investigated the possible differences within DM1 patients by subdividing them according either to the presence of first degree atrioventricular block (1st AVB) or to the cytosine-thymine-guanine (CTG) repeat expansion size. METHODS Sixty-two DM1 patients and 20 healthy subjects underwent neurological and cardiological examinations, the latter including ECG, echocardiography and 24-hour Holter monitoring. All underwent a 5-minute ECG recording to assess heart rate variability power spectral components, and the QTVI values. RESULTS Power spectral data, namely total power, low frequency power and high frequency power, were lower, whereas QTVI values were higher in DM1 patients than in controls (p<.0001). Higher QTVI values were found in DM1 subgroups with 1st AVB (p=.009) and more than 500 CTG repeat (p=.014) with respect to DM1 patients without 1st AVB and CTG<500. Spectral data did not significantly differ. At multivariable analysis, QTVI and age were independently associated with PR interval and CTG repeat. CONCLUSIONS The increased values of QTVI argue in favour of an important heart involvement extending beyond the conduction system. Whether QTVI could be useful in predicting clinical course of DM1 clearly requires larger prospective studies.

Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles: Experience of the FSHD Italian National Registry

Objectives Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (≤8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1–3 repeats (1–3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1–3 DRA. Setting Italy. Participants 66 index cases and 33 relatives carrying 1–3 DRA. Outcomes The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk. Results No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1–3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment. Conclusions The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high degree of clinical variability suggests that additional factors contribute to the phenotype complexity.

Functional MRI changes in the central motor system in myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is a multisystemic disease involving multiple organ systems including central nervous system (CNS) and muscles. Few studies have focused on the central motor system in DM1, pointing to a subclinical abnormality in the CNS. The aim of our study was to investigate patterns of cerebral activation in DM1 during a motor task using functional MRI (fMRI). Fifteen DM1 patients, aged 20 to 59 years, and 15 controls of comparable age were scanned during a self-paced sequential finger-to-thumb opposition task of their dominant right hand. Functional MRI images were analyzed using SPM99. Patients underwent clinical and genetic assessment; all subjects underwent a conventional MR study. Myotonic dystrophy type 1 patients showed greater activation than controls in bilateral sensorimotor areas and inferior parietal lobules, basal ganglia and thalami, in the ipsilateral premotor area, insula and supplementary motor area (corrected P<.05). Analysis of the interaction between disease and age showed that correlation with age was significantly greater in patients than in controls in bilateral sensorimotor areas and in contralateral parietal areas. Other clinical and MR characteristics did not correlate with fMRI. Functional changes in DM1 may represent compensatory mechanisms such as reorganization and redistribution of functional networks to compensate for ultrastructural and neurochemical changes occurring as part of the accelerated aging process.

I know that you know that I know: neural substrates associated with social cognition deficits in DM1 patients

Myotonic dystrophy type-1 (DM1) is a genetic multi-systemic disorder involving several organs including the brain. Despite the heterogeneity of this condition, some patients with non-congenital DM1 can present with minimal cognitive impairment on formal testing but with severe difficulties in daily-living activities including social interactions. One explanation for this paradoxical mismatch can be found in patients’ dysfunctional social cognition, which can be assessed in the framework of the Theory of Mind (ToM). We hypothesize here that specific disease driven abnormalities in DM1 brains may result in ToM impairments. We recruited 20 DM1 patients who underwent the “Reading the Mind in the Eyes” and the ToM-story tests. These patients, together with 18 healthy controls, also underwent resting-state functional MRI. A composite Theory of Mind score was computed for all recruited patients and correlated with their brain functional connectivity. This analysis provided the patients’ “Theory of Mind-network”, which was compared, for its topological properties, with that of healthy controls. We found that DM1 patients showed deficits in both tests assessing ToM. These deficits were associated with specific patterns of abnormal connectivity between the left inferior temporal and fronto-cerebellar nodes in DM1 brains. The results confirm the previous suggestions of ToM dysfunctions in patients with DM1 and support the hypothesis that difficulties in social interactions and personal relationships are a direct consequence of brain abnormalities, and not a reaction symptom. This is relevant not only for a better pathophysiological comprehension of DM1, but also for non-pharmacological interventions to improve clinical aspects and impact on patients’ success in life.

Satellite potentials on EMG: neurophysiologic evidence of axonal transection in MS?

To detect signs of axonal damage in MS, the authors investigated the occurrence in EMG of motor unit action potentials with satellite potentials (SP-MUAP) in the upper limb muscles in 10 consecutive patients with MS with cervical spinal cord demyelinating lesions and 10 control subjects. Subjects’ SP-MUAP rate was 0 to 2.5% (median 0%) in the control group, and 0 to 17.5% (median 7.5%) in the MS group (p < 0.01). Motor unit remodeling secondary to axonal transection of spinal motor neurons traversing cervical demyelinating lesions may be hypothesized.

Dropped-head in recessive oculopharyngeal muscular dystrophy

A 69-year-old woman presented a dropped head, caused by severe neck extensor weakness that had started two years before. She had also developed a mild degree of dysphagia, rhinolalia, eyelid ptosis and proximal limb weakness during the last months. EMG revealed myopathic changes. Muscle MRI detected fatty infiltration in the posterior neck muscles and tongue. Muscle biopsy revealed fiber size variations, sporadic rimmed vacuoles, small scattered angulated fibers and a patchy myofibrillar network. Genetic analysis revealed homozygous (GCN)11 expansions in the PABPN1 gene that were consistent with recessive oculopharyngeal muscular dystrophy (OPMD). There are a few reports of the recessive form, which has a later disease onset with milder symptoms and higher clinical variability than the typical dominantly inherited form. This patient, who is the first Italian and the eighth worldwide reported case of recessive OPMD, is also the first case of OPMD with dropped-head syndrome, which thus expands the clinical phenotype of recessive OPMD.

Erectile dysfunction in myotonic dystrophy type 1 (DM1)

JO N 2912 and personal life of these patients. Hypothesizing that impotence may be an intrinsic characteristic in DM1, we performed a study to assess its frequency and characteristics. The complete series of male patients (aged 18-60 years) with genetically-confirmed DM1, under clinical surveillance in our Neuromuscular Unit in January 2005, was clinically evaluated for any disease or medication and tested with both the Mini-Mental State Examination and Hamilton Depression Rating Scale. Subjects with physical or mental diseases known to interfere with sexual activity [4] and those with congenital DM1, or cognitive dysfunction or HAM-D “severe” or “very severe” scores, were excluded. Patients are shown in Fig. 1. A total of 31 patients and 31 age-matched healthy controls filled out the questionnaire of the Internationally Validated Index of ErecGiovanni Antonini Alessandro Clemenzi Elisabetta Bucci Stefania Morino Matteo Garibaldi Micaela Sepe-Monti Franco Giubilei Giuseppe Novelli

Erratum to: Increased risk of tumor in DM1 is not related to exposure to common lifestyle risk factors.

Recent studies documented an increased risk of neoplasm in patients with myotonic dystrophies (DM). Yet, none of these studies evaluated the contribution of common cancer risk factors in such observation. In this study, we included a cohort of patients (n = 255) with an established molecular diagnosis of DM type 1 (DM1), and who receives their treatment in one of the four centers with recognized expertise in neuromuscular disorders in Rome. We estimated the prevalence of benign and malignant tumors, and assessed if lifestyle factors and/or specific disease features would be associated to their occurrence. Overall, 59 benign tumors in 54 patients and 19 malignant tumors in 17 patients were diagnosed. The most common malignant neoplasms were cancers of the skin (31.6 %), thyroid (21.0 %), ovary (10.5 %), and breast (10.5 %). Uterine fibroid was the most common benign tumor (37.6 %) in women, while pilomatricoma was the most common in men (28.6 %). Age at enrollment (OR = 1.02, 95 % CI 1.00–1.05), and female gender (OR = 5.71, 95 % CI 2.90–11.22) were associated with tumor development in DM1 patients, while thyroid disorders was associated with malignant tumors only in women (OR = 5.12, 95 % CI 1.35–19.37). There was no association between tumor development and evaluated lifestyle factors. In conclusion, the lack of association between common cancer risk factors and tumor development in DM1 support a pathogenic link between tumors and DM1 itself, emphasizing the need for a systematic surveillance. Our observation of an association between thyroid diseases in women and cancer development needs confirmation.