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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.

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.

Dear Sirs, CANOMAD (chronic ataxic neuropathy, opthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies) is a rare variant of IgM paraproteinaemic neuropathy in which the paraprotein fraction contains antibodies against specific disialylated gangliosides, including GD1B, GD3, GT1B and GQ1B [1]. This disorder has so far not been reported in association with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here we describe a patient who developed SIADH during the first relapse of CANOMAD. A 57-year-old woman was admitted to our department because of the progressive development of gait unsteadiness and distal paresthesias over the past 2 years. Neurological examination showed a mild sensory ataxia (Table 1) and a stable exotropia with ambliopia in her left eye due to infantile strabismus; nerve conduction studies documented the absence of SAPs, consistent with a sensory neuropathy (Table 1). A diagnostic screening ruled out malignancies, malabsorption or systemic autoimmune disorders. Serum immuno-fixation electrophoresis revealed an IgM monoclonal gammopathy with k light chain component. Serum testing for anti-gangliosides antibodies [1] showed high titers of anti-GD1b, -GT1b, -GQ1b of IgM type ([1:12,500, n.v. IgM \ 1:500), while anti-MAG antibodies were negative. Serum test for cold agglutinins also resulted positive. One week later, she subacutely manifested a severe neurological deterioration (Table 1) and also developed a hypertensive state treated by calcium-antagonists and clonidine. Arterial blood gas analysis was normal. Routine blood studies documented severe hyponatremia (120 mEq/l) and hypokalemia (2.9 mEq/l), low levels of uric acid (1.3 mg/ dl) and urea nitrogen (7 mg/dl); urinary osmolality (570 mOsm/kg) was increased despite a low plasmatic osmolality (274 mOsm/kg) in clinical conditions of euvolemia, and natriuresis increased ([40 mmol/l) with unaltered dietary salt intake. These parameters indicated the occurrence of SIADH, which was successfully treated according to reported protocols [2]. In order to define the etiology of SIADH, brain and spinal cord MRI with i.v. gadolinium, thyroid and adrenal functions, serum AVP levels and urinary excretions of porphobilinogen and aminolevulinic acid were performed, all with normal results. A lumbar puncture documented a mild hyperproteinorrachia (59 mg/dl, n.v 20–40) with normal cell count; search for infections and oligoclonal bands were negative. Neurophysiologic studies suggested the development of proximal demyelination associated with axonal degeneration (Table 1): in fact, we documented a mild reduction of the CMAP amplitude of the axillary nerve, and the R. Iorio F. Capone E. Iannaccone A. Modoni P. A. Tonali G. Silvestri Department of Neurosciences, Institute of Neurology, Catholic University, Rome, Italy

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.

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.

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.

Background and purpose 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. Methods Evaluation of pelvic and lower limb MRI scans of 12 dystrophinopathy carriers was performed. Results We found a frequent involvement of the quadratus femoris, gluteus maximus and medius, biceps femoris long head, adductor magnus, vasti and paraspinal muscles, whilst the popliteus, iliopsoas, recti abdominis, sartorius, and gracilis were relatively spared. Asymmetry was a major feature on MRI; it could be detected significantly more often than with sole clinical examination and even in patients without weakness. Conclusions The pattern we describe here is similar to that reported in Duchenne and Becker muscular dystrophy, although asymmetry represents a major distinctive feature. Muscle MRI was more sensitive than clinical examination for detecting single muscle involvement and asymmetry. Further studies are needed to verify the consistency of this pattern in larger cohorts and to assess whether muscle MRI can improve diagnostic accuracy in carriers with normal dystrophin staining on muscle biopsy.

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.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies and is characterized by a non-conventional genetic mechanism activated by pathogenic D4Z4 repeat contractions. By muscle Magnetic Resonance Imaging (MRI) we observed that T2-short tau inversion recovery (T2-STIR) sequences identify two different conditions in which each muscle can be found before the irreversible dystrophic alteration, marked as T1-weighted sequence hyperintensity, takes place. We studied these conditions in order to obtain further information on the molecular mechanisms involved in the selective wasting of single muscles or muscle groups in this disease. Methods: Histopathology, gene expression profiling and real time PCR were performed on biopsies from FSHD muscles with different MRI pattern (T1-weighted normal/T2-STIR normal and T1-weighted normal/T2-STIR hyperintense). Data were compared with those from inflammatory myopathies, dysferlinopathies and normal controls. In order to validate obtained results, two additional FSHD samples with different MRI pattern were analyzed. Results: Myopathic and inflammatory changes characterized T2-STIR hyperintense FSHD muscles, at variance with T2-STIR normal muscles. These two states could be easily distinguished from each other by their transcriptional profile. The comparison between T2-STIR hyperintense FSHD muscles and inflammatory myopathy muscles showed peculiar changes, although many alterations were shared among these conditions. Conclusions: At the single muscle level, different stages of the disease correspond to the two MRI patterns. T2-STIR hyperintense FSHD muscles are more similar to inflammatory myopathies than to T2-STIR normal FSHD muscles or other muscular dystrophies, and share with them upregulation of genes involved in innate and adaptive immunity. Our data suggest that selective inflammation, together with perturbation in biological processes such as neoangiogenesis, lipid metabolism and adipokine production, may contribute to the sequential bursts of muscle degeneration that involve individual muscles in an asynchronous manner in this disease.

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.

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.

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.

The purposes of the study are: (1) to establish if cephalometry and upper airway examination may provide tools for detecting facioscapulohumeral (FSHD) patients at risk for obstructive sleep apnea syndrome (OSAS); and (2) to correlate cephalometry and otorhinolaryngologic evaluation with clinical and polysomnographic features of FHSD patients with OSAS.Patients were 13 adults affected by genetically confirmed FSHD and OSAS, 11 men, with mean age 47.1 ± 12.8 years (range, 33-72 years). All underwent clinical evaluation, Manual Muscle Test, Clinical Severity Scale for FSHD, Epworth Sleepiness Scale, polysomnography, otorhinolaryngologic evaluation, and cephalometry.Cephalometric evidence of pharyngeal narrowing [posterior airways space (PAS) 10 mm] was present in only one patient. The mandibular planus and hyoid (MP-H) distance ranged from 6.5 to 33.1 mm (mean, 17.5 ± 7.8 mm). The mean length of soft palate (PNS-P) was 31.9 ± 4.8 mm (range, 22.2 to 39.7 mm). No patient presented an ANB angle 7°. There was no significant correlation between cephalometric measures, clinical scores, and PSG indexes. PAS and MP-H were not related to the severity of the disease.Upper airway morphological evaluation is of poor utility in the clinical assessment of FSHD patients and do not allow to predict the occurrence of sleep-related upper airway obstruction. This suggests that the pathogenesis of OSAS in FSHD is dependent on the muscular impairment, rather than to the anatomy of upper airways.

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.

To assess the pattern and degree of involvement of scapular girdle muscles in Facioscapulohumeral muscular dystrophy (FSHD). We standardized an MRI protocol that allowed the identification and evaluation of 14 muscle groups of the neck and upper girdle. 108 FSHD patients were included in the study. The involvement in FSHD was compared with that of limb girdle muscular dystrophies and other myopathies with upper girdle weakness. We were able to identify the most affected and spared muscles in FSHD. Asymmetry was a consistent feature, similarly to what is found in lower limb muscles, and T2-STIR hyperintensities could be detected as well. The pattern of involvement significantly differed from that encountered in other myopathies. Upper girdle imaging is a helpful tool in guiding the clinical diagnosis of FSHD. Moreover, the detailed knowledge of single muscle involvement provides information useful for understanding and following the natural history of the disease and developing rehabilitation protocols.

Scapular winging (SW) is a common sign in neuromuscular disorders. Besides “pure” phenotypes due to single muscle weakness often secondary to nerve injuries or dysfunctions,1,2 the phenotype can be complicated when a combination of different scapular fixators is involved by a myopathy. We show an example of 2 sisters with facioscapulohumeral muscular dystrophy (video 1 on the Neurology ® Web site at [www.neurology.org][1]). In patient 1, the SW is caused by an isolated trapezius weakness. Conversely, in patient 2, the left SW can be attributed on clinical grounds to a combined serratus anterior and trapezius weakness. Both hypotheses are confirmed by muscle MRI (figure 1). [1]: http://www.neurology.org/

Reduced mobility during sleep characterizes a variety of movement disorders and neuromuscular diseases. Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of muscular dystrophy in the general population, and people with FSHD have poor sleep quality. The aims of the present study were to evaluate nocturnal motor activity in patients with FSHD by means of videopolysomnography and to verify whether activity was associated with modifications in sleep structure.We enrolled 32 adult patients affected by genetically confirmed FSHD (18 women and 14 men, mean age 45.1 +/- 13.4 years) and 32 matched control subjects, (18 women and 14 men, mean age 45.5 +/- 11.4 years). Major body movements (MBM) were scored in videopolygraphic recordings in accordance with established criteria. An MBM index was calculated (number of MBM per hour of sleep).The FSHD group showed a decrease in the MBM index (FSHD: 1.2 +/- 1.1; control subjects: 2.3 +/- 1.2, analysis of variance F = 13.672; p = 0.008). The sleep pattern of patients with FSHD, as compared with that of controls, was characterized by longer sleep latencies, shorter sleep durations, an increased percentage of wake during sleep, and a decreased percentage of rapid eye movement sleep. In the patient group, the MBM index was inversely correlated with severity of disease (Spearman test: r30 = -0.387; p0.05).The present findings suggest that patients with FSHD have a reduced number of nocturnal movements, which is related to disease severity. Reduced movement in bed may contribute to the sleep modifications observed in these patients.