Elisabetta Iannaccone

CD8+ T Cells in Facioscapulohumeral Muscular Dystrophy Patients with Inflammatory Features at Muscle MRI

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited disease, and although strongly suggested, a contribution of inflammation to its pathogenesis has never been demonstrated. In FSHD patients, we found by immunohistochemistry inflammatory infiltrates mainly composed by CD8+ T cells in muscles showing hyperintensity features on T2-weighted short tau inversion recovery magnetic resonance imaging (T2-STIR-MRI) sequences. Therefore, we evaluated the presence of circulating activated immune cells and the production of cytokines in patients with or without muscles showing hyperintensity features on T2-STIR-MRI sequences and from controls. FSHD patients displaying hyperintensity features in one or more muscles showed higher CD8+pSTAT1+, CD8+T-bet+ T cells and CD14+pSTAT1+, CD14+T-bet+ cells percentages and IL12p40, IFNγ and TNFα levels than patients without muscles displaying hyperintense features and controls. Moreover, the percentages of CD8+pSTAT1+, CD8+T-bet+ and CD14+pSTAT1+ cells correlated with the proportion of muscles displaying hyperintensity features at T2-STIR sequences. These data indicate that circulating activated immune cells, mainly CD8+ T cells, may favour FSHD progression by promoting active phases of muscle inflammation.

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.

QUALITY OF LIFE AND PAIN IN PATIENTS WITH FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY

The aim of this study was to assess quality of life (QoL) and evaluate the occurrence and characteristics of pain in facioscapulohumeral muscular dystrophy (FSHD) patients. No study has yet assessed QoL in a large group of FSHD patients and, overall, few studies have assessed pain in neuromuscular diseases. We performed a prospective study using a multidimensional protocol including: clinical (according to the Clinical Severity Scale Rev1); genetic (p13E‐11 EcoRI fragments Rev1); QoL (Short Form‐36); pain (Visual Analog Scale and Portenoy‐6 questions); and depression (Beck Depression Inventory) assessment. QoL measures of FSHD were compared with those of Italian norms. Moreover, we correlated QoL and pain measurements with clinical findings. Sixty‐five patients were enrolled in the study. QoL was statistically significantly reduced with respect to the Italian normative sample, mainly in physical domains. Our study demonstrated that pain is frequent in FSHD patients. More than half of the patients complained of at least moderate pain. Women complained of slightly higher levels of deterioration in the emotional aspects of QoL than men. Clinical pattern (as assessed by Clinical Severity Scale) was closely related to physical QoL domains: the higher the clinical involvement, the more severe the QoL deterioration. This study provided information that may be crucial in clinical practice: pain may be a relevant aspect in FSHD patients, and prevention strategies or relevant therapies should be considered as appropriate. Moreover, we must pay more attention to gender differences: women can suffer far greater deterioration in the emotional aspects of QoL. Further multidimensional observations are needed. Muscle Nerve 40: 200–205, 2009

Muscle MRI in Becker muscular dystrophy

The aim of this study was to evaluate pelvis and lower limb muscle MRI scans of 46 patients affected by Becker muscular dystrophy (BMD), subdivided according to disease severity, ranging from clinically asymptomatic patients to patients who had lost ambulation. We found a distinct pattern on muscle imaging characterized by prominent involvement of the gluteus maximus and medius, adductor magnus, biceps femoris long head, semimembranosus and vasti. This pattern was consistent in all the 25 symptomatic patients. Milder changes in the same muscles were found in 13 of the 21 asymptomatic cases. The other 8 asymptomatic patients had a normal scan. The severity of muscle involvement was significantly correlated with age. Our results suggest that a distinct pattern of muscle involvement can be detected in BMD. The early identification of muscle changes in a proportion of asymptomatic patients may be useful as an additional tool in the diagnostic workup.

Muscle imaging findings in GNE myopathy

GNE myopathy (MIM 600737) is an autosomal recessive muscle disease caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. Besides the typical phenotype, characterized by the initial involvement of the distal leg muscles that eventually spreads proximally with sparing of the quadriceps, uncommon presentations with a non-canonical clinical phenotype, unusual muscle biopsy findings or both are increasingly recognized. The aim of our study was to characterize the imaging pattern of pelvic and lower limb muscles in GNE myopathy, thus providing additional diagnostic clues useful in the identification of patients with atypical features. We retrospectively evaluated muscle MRI and CT scans of a cohort of 13 patients heterogeneous for GNE mutations and degree of clinical severity. We found that severe involvement of the biceps femoris short head and, to a lesser extent, of the gluteus minimus, tibialis anterior, extensor hallucis and digitorum longus, soleus and gastrocnemius medialis was consistently present even in patients with early or atypical disease. The vastus lateralis, not the entire quadriceps, was the only muscle spared in advanced stages, while the rectus femoris, vastus intermedius and medialis showed variable signs of fatty replacement. Younger patients showed hyperintensities on T2-weighted sequences in muscles with a normal or, more often, abnormal T1-weighted signal. Our results define a pattern of muscle involvement that appears peculiar to GNE myopathy. Although these findings need to be further validated in a larger cohort, we believe that the recognition of this pattern may be instrumental in the initial clinical assessment of patients with possible GNE myopathy.

Sleep disordered breathing in facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent forms of muscular dystrophy. The aims of this study were: 1) to evaluate the prevalence of sleep disordered breathing (SDB) in patients with FSHD; 2) to define the sleep-related respiratory patterns in FSHD patients with SDB; and 3) to find the clinical predictors of SDB. Fifty-one consecutive FSHD patients were enrolled, 23 women, mean age 45.7+/-12.3 years (range: 26-72). The diagnosis of FSHD was confirmed by genetic tests. All patients underwent medical and neurological evaluations, subjective evaluation of sleep and full-night laboratory-based polysomnography. Twenty patients presented SDB: 13 presented obstructive apneas, four presented REM related oxygen desaturations and three showed a mixed pattern. Three patients needed positive airways pressure. SDB was not related to the severity of the disease. Body mass index, neck circumference and daytime sleepiness did not allow prediction of SDB. In conclusion, the results suggest a high prevalence of SDB in patients with FSHD. The presence of SDB does not depend on the clinical severity of the disease. SDB is often asymptomatic, and no clinical or physical measure can reliably predict its occurrence. A screening of SDB should be included in the clinical assessment of FSHD.

Muscle MRI in female carriers of dystrophinopathy

Duchenne muscular dystrophy carriers represent a rare condition that needs to be recognized because of the possible implications for prenatal diagnosis. Muscle biopsy is currently the diagnostic instrument of choice in sporadic patients. We wanted to verify whether muscle magnetic resonance imaging (MRI) could identify a pattern of involvement suggestive of this condition and whether it was similar to that reported in Duchenne and Becker muscular dystrophy.

Pain and the Alpha‐Sleep Anomaly: A Mechanism of Sleep Disruption in Facioscapulohumeral Muscular Dystrophy

OBJECTIVE To measure the presence of the alpha-sleep anomaly in facioscapulohumeral muscular dystrophy (FSHD) and to evaluate the association between the sleep electroencephalogram (EEG) pattern and the presence of musculoskeletal pain. DESIGN Cross-sectional study. SETTING Sleep laboratory. SUBJECTS Fifty-five consecutive adult FSHD patients, 26 women and 29 men, age 49.6 ± 15.1 years (range 18-76). INTERVENTIONS Questionnaires and polysomnography. OUTCOME MEASURES Patients were asked to indicate if in the 3 months before the sleep study they presented persisting or recurring musculoskeletal pain. Patients who reported pain were asked to fill in the Italian version of the Brief Pain Inventory and the McGill Pain questionnaire, and a 101-point visual analog scale (VAS) for pain intensity. Polysomnographic recordings were performed. EEG was analyzed by means of Fast Fourier Transform. Four power spectra bands (δ 0-4 Hz, θ 4-8 Hz, α 8-14 Hz, β 14-32 Hz) were computed. Sleep macrostructure parameters and alpha/delta EEG power ratio during non rapid eye movement (NREM) sleep were compared between patients with and without pain. RESULTS Forty-two patients in our sample reported chronic pain. VAS mean score was 55.2 ± 23.8 (range 10-100), pain rating index score was 13.8 ± 10.2, and present pain intensity was 2.5 ± 0.8. The statistical analysis documented an increased occurrence of the alpha and beta rhythms during NREM sleep in FSHD patients with pain. Significant correlations were observed between the alpha/delta power ratio during NREM sleep and pain measures. CONCLUSIONS Chronic musculoskeletal pain is frequent in FSHD patients, and it represents a major mechanism of sleep disruption.

Myotonic dystrophy type 1 and de novo FSHD mutation double trouble: A clinical and muscle MRI study

Here we describe the first case of myotonic dystrophy type 1 (DM1) associated with facio-scapulo-humeral dystrophy (FSHD). From a clinical point of view, the patient displayed a pattern of muscle involvement reminiscent of both disorders, including hand-grip myotonia, facial, axial and distal limbs muscle weakness as well as a bilateral winged scapula associated with atrophy of the pectoralis major muscle and lumbar lordosis; pelvic muscles were mostly spared. An extensive muscle MRI assessment including neck, shoulder, abdominal, pelvic and lower limb muscles documented radiological features typical of DM1 and FSDH. Molecular genetic studies confirmed that the proband carried both a pathologically expanded DMPK allele, inherited from his father, and a de novo shortened D4Z4 repeat fragment at 4q35 locus.

An atypical phenotype of CJD associated with the E200K mutation in the prion protein gene

E200K mutation of the prion protein gene (PRNP) presented with a variety of phenotypes. A 55-year-old woman complaining of slowly progressive walking difficulties came to our observation. She showed a severe progressive ataxo-spastic syndrome but a mild cognitive impairment only. Repeated EEGs showed a diffuse slowing of the rhythm without specificity. Brain MRI revealed by FLAIR showed widespread multiple hyperintensities in the whole cerebral cortex, caudate and putamen nuclei, and in the pulvinar and medial thalamus bilaterally. These signal abnormalities were best detected by DWI with restricted diffusion on ADC map. The clinical diagnosis of possible genetic Creutzfeldt-Jakob disease (CJD) has been confirmed by PRNP gene analysis which revealed the presence of a E200K mutation. This report confirms the heterogeneity of phenotypes in E200K mutated familial CJD with the occurrence of a new phenotype not previously described.