Diagnosis Of Facioscapulohumeral Muscular Dystrophy Research Articles

Distinguishing the 4qA and 4qB variants is essential for the diagnosis of facioscapulohumeral muscular dystrophy in the Chinese population

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscular dystrophy with markedly clinical variability and complex genetic cause. Several reports pertaining to the Caucasian population have confirmed that there are 4qA and 4qB variants of the 4qter subtelomere, and FSHD is uniquely associated with the 4qA variant. However, few data relevant to the Chinese population have been published. In present paper, detailed clinical and genetic re-evaluations were performed in members of four special families who had been initially diagnosed as atypical or asymptomatic FSHD based only on the D4Z4 repeat length analysis. The FSHD-sized D4Z4 repeats in the probands from families 1, 2 and 3 were identified as 4qB variants. These patients were further confirmed as limb-girdle muscular dystrophy (LGMD2) or myotonic dystrophy (DM1) by molecular analyses. Specifically, we identified a 4qB variant on chromosome 10 in the healthy members of the fourth FSHD family with complex D4Z4 rearrangements of two exchanged repeat arrays. For the first time, we demonstrated in the Chinese population that D4Z4 contractions on the 4qB variant do not cause FSHD and 4qB variant on chromosome 10 might also represent intermediate structures in the transition from 4q to 10q. Furthermore, our results emphasize that D4Z4 repeat length analysis alone is not sufficient for the diagnosis of FSHD, especially when used as an exclusion criterion. This analysis should be accompanied by 4qA/4qB variant determination and integrated chromosome assignments, especially in patients with obscure and unclassified myopathies similar to atypical forms of FSHD.

New multiplex PCR-based protocol allowing indirect diagnosis of FSHD on single cells: can PGD be offered despite high risk of recombination?

Molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) involves the heterozygous contraction of the number of tandemly repeated D4Z4 units at chromosome 4q35.2. FSHD is associated with a range of 1-10 D4Z4 units instead of 11-150 in normal controls. Several factors complicate FSHD molecular diagnosis, especially the cis-segregation of D4Z4 contraction with a 4qA allele, whereas D4Z4 shortening is silent both on alleles 4qB and 10q. Discrimination of pathogenic 4q-D4Z4 alleles from highly homologous 10q-D4Z4 arrays requires the use of the conventional Southern blot, which is not suitable at the single-cell level. Preimplantation genetic diagnosis (PGD) is a frequent request from FSHD families with several affected relatives. We aimed to develop a rapid and sensitive PCR-based multiplex approach on single cells to perform an indirect familial segregation study of pathogenic alleles. Among several available polymorphic markers at 4q35.2, the four most proximal (D4S2390, D4S1652, D4S2930 and D4S1523, <1.23 Mb) showing the highest heterozygote frequencies (67-91%) were selected. Five recombination events in the D4S2390-D4S1523 interval were observed among 144 meioses. In the D4S2390-D4Z4 interval, no recombination event occurred among 28 FSHD meioses. Instead, a particular haplotype segregated with both clinical and molecular status, allowing the characterization of an at-risk allele in each tested FSHD family (maximal LOD score 2.98 for theta=0.0). This indirect protocol can easily complement conventional techniques in prenatal diagnosis. Although our multiplex PCR-based approach technically fulfils guidelines for single-cell analysis, the relatively high recombination risk hampers its application to PGD.

Beevor’s sign in facioscapulohumeral muscular dystrophy: an old sign with new implications

Beevor's sign, an upward deflection of the umbilicus on flexion of the neck, is the result of paralysis of the inferior portion of the rectus abdominis muscle, so that the upper fibers predominate, pulling the umbilicus upwards. The condition may be caused by spinal cord injury at or below the level of Th10. It has also been observed in patients with facioscapulohumeral muscular dystrophy (FSHD). Positive Beevor's sign has been described as a sign of more than 90% sensitivity and specificity with regard to diagnosis of FSHD. We investigated 28 patients with FSHD, proven by genetic analysis, and 65 non-FSHD patients with other neuromuscular diseases. In 13 patients classical FSHD phenotype was observed, in 15 patients phenotype was atypical. Beevor's sign was positive in 15 out of 28 FSHD patients as well as in two of the 65 non-FSHD patients. In patients with typical FSHD phenotype, Beevor's sign was positive in 11/13. Only 4/15 patients with atypical FSHD phenotype showed Beevor's sign. Beevor's sign is less frequent in patients with atypical phenotype. Although Beevor's sign is significantly more frequent in FSHD patients than in patients with other neuromuscular diseases, Beevor's sign is not as sensitive as previously reported. However, especially in atypical cases, Beevor's sign might help in the diagnosis of FSHD.

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.

Predictive values of motor unit potential analysis in limb muscles

In interpretation of diagnostic findings the probability that an abnormal test accurately indicates pathology (i.e., the positive predictive value), and a normal test accurately excludes pathology (i.e., the negative predictive value) is the most important. For motor unit potential (MUP) analysis no such data has been published; hence this was the aim of this study. In 31 patients with facioscapulohumeral muscular dystrophy (FSHD) and 34 controls the biceps brachii and vastus lateralis muscles were examined by concentric needle electromyography (EMG), using template operated MUP analysis. These results were compared to non-parametric reference data obtained in another group of 34 (biceps brachii) and 46 (vastus lateralis) control subjects. For the biceps brachii muscles sensitivity was 59%, specificity 91%, the positive predictive value 85%, and negative predictive value 72% with at least two criteria (mean values or outliers for MUP thickness, amplitude and duration) below the reference intervals. In addition, all subjects with three abnormal EMG criteria were FSHD patients, and 90% of subjects with normal EMG were controls. Template operated MUP analysis demonstrated reasonable predictive value for diagnosis and exclusion of myopathy. Quantitative MUP analysis seems to be useful for the preliminary diagnosis of FSHD in patients with appropriate clinical picture.

Facioscapulohumeral Dystrophy: Case Report and Discussion

Facioscapulohumeral dystrophy (FSHD) is often cited as the third most common form of muscular dystrophy. Therefore, it should be considered in patients with complaints of progressive weakness. We present the case of a man with facial, truncal, and leg weakness that initially sought medical attention for lower back pain. Electrodiagnostic testing revealed findings in the trapezius, serratus anterior, biceps, triceps, pectoralis major, tibialis anterior, and gastrocnemius muscles consistent with a myopathic disorder. Subsequent genetic testing identified a FSHD allele size consistent with a FSHD deletion mutation. Therefore, confirming the diagnosis of FSHD. Unfortunately, no effective treatments currently exist for FSHD. However, supportive measures involving physical therapy and the use of orthotics may aid in improving function and mobility.

Becker’s muscular dystrophy aggravating facioscapulohumeral muscular dystrophy – double trouble as an explanation for an atypical phenotype

We report a 12-year-old patient with mental impairment and proximal muscle weakness who had marked involvement of the shoulder girdle and facial muscles. CK levels were above 7000 U/l, multiplex PCR dystrophin gene deletion screening was negative. Further molecular studies revealed shortened D4Z4 fragments in the patient and his asymptomatic father, establishing the diagnosis of facioscapulohumeral muscular dystrophy (FSHD). Under the assumption of a second disease mechanism, a muscle biopsy was performed which revealed marked dystrophin deficiency. Eventually, a donor splice site mutation (c.4071+1 G>T) was found by direct sequencing of the dystrophin gene in the patient and his mother and confirmed the diagnosis of Becker’s muscular dystrophy along with FSHD.

First International “Institute of Myology Workshop” on Facioscapulohumeral Muscular Dystrophy, Paris, May 22, 2007

This one-day workshop was organized by Thomas Voit and assembled 13 researchers from five countries (Belgium, The Netherlands, France, Italy, USA) in order to create a collaborative interface between several international groups who are actively investigating the molecular background of facioscapulohumeral muscular dystrophy (FSHD) as well as to give an update on therapeutic projects on FSHD at the preclinical and clinical level. Such a collective effort seemed particularly timely because there is still no unifying and generally accepted patho-physiological concept that could explain the muscle degeneration in FSHD or the less frequently associated symptoms of cochlear hearing loss, Coats’s syndrome or, in rare infantile cases, mental retardation. Furthermore, opinions diverge as to which genes are possibly directly or indirectly implicated, and no animal model exists that resumes all the particular aspects of FSHD.

Clinical and Genetic Analysis of Korean Patients with Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominantly inherited muscular disorder, which is characterized by weakness of facial, shoulder and hip girdle, humeral, and anterior distal leg muscles. The FSHD gene has been mapped to 4q35 and a deletion of integral copies of a 3.3-kb DNA repeat motif named D4Z4 was known to be the genetic background of the disorder. Although FSHD is the second most common muscular dystrophy in adulthood, there were few reports on the genetically confirmed patients in Korea. Recently, we experienced four Korean patients with clinical features resembling FSHD. In order to confirm the diagnosis, conventional Southern blot (SB) analysis by using double digestion with EcoRI and BlnI and hybridization with p13E-11 probe was performed in three patients and newly developed long polymerase chain reaction (PCR) method was used for one patient because genomic DNA was not enough for conventional SB for this patient. All patients were demonstrated to have shortened D4Z4 repeats that were consistent with FSHD. Therefore, we could confirm the diagnosis of FSHD in four Korean patients and appropriate genetic counseling was done for the patients and their families. It is of note that long-PCR method could be a good alternative for conventional SB when D4Z4 repeats were less than 5.

G.P.7.03 Facioscapulohumeral dystrophy presenting as axial myopathy

Introduction: Axial myopathy is a rare neuromuscular disorder characterized by selective involvement of the spinal muscles with a bent spine and/or drooping head and/or camptocormia as leading clinical features. The cause is still unclear and probably heterogenous. Facioscapulohumeral dystrophy (FSHD) is characterized by a pattern of muscle weakness involving the face, scapula, upper arm, lower leg, and hip girdle. Methods: We demonstrate three patients with predominant axial weakness. Diagnosis of FSHD was established in all three cases by genetic analysis at 4q35.

The Facioscapulohumeral muscular dystrophy region on 4qter and the homologous locus on 10qter evolved independently under different evolutionary pressure

BackgroundThe homologous 4q and 10q subtelomeric regions include two distinctive polymorphic arrays of 3.3 kb repeats, named D4Z4. An additional BlnI restriction site on the 10q-type sequence allows to distinguish the chromosomal origin of the repeats. Reduction in the number of D4Z4 repeats below a threshold of 10 at the 4q locus is tightly linked to Facioscapulohumeral Muscular Dystrophy (FSHD), while similar contractions at 10q locus, are not pathogenic. Sequence variations due to the presence of BlnI-sensitive repeats (10q-type) on chromosome 4 or viceversa of BlnI-resistant repeats (4q-type) on chromosome 10 are observed in both alleles.ResultsWe analysed DNA samples from 116 healthy subiects and 114 FSHD patients and determined the size distributions of polymorphic 4q and 10q alleles, the frequency and the D4Z4 repeat assortment of variant alleles, and finally the telomeric sequences both in standard and variant alleles.We observed the same frequency and types of variant alleles in FSHD patients and controls, but we found marked differences between the repeat arrays of the 4q and 10q chromosomes. In particular we detected 10q alleles completely replaced by the 4q subtelomeric region, consisting in the whole set of 4q-type repeats and the distal telomeric markers. However the reciprocal event, 10q-type subtelomeric region on chromosome 4, was never observed. At 4q locus we always identified hybrid alleles containing a mixture of 4q and 10q-type repeats.ConclusionThe different size distribution and different structure of 10q variant alleles as compared with 4q suggests that these loci evolved in a different manner, since the 4q locus is linked to FSHD, while no inheritable disease is associated with mutations in 10qter genomic region. Hybrid alleles on chromosome 4 always retain a minimum number of 4q type repeats, as they are probably essential for maintaining the structural and functional properties of this subtelomeric region.In addition we found: i) several instances of variant alleles that could be misinterpreted and interfere with a correct diagnosis of FSHD; ii) the presence of borderline alleles in the range of 30–40 kb that carried a qA type telomere and were not associated with the disease.

Isolated paraspinal myopathy: A distinct subtype of facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is inherited as an autosomal dominant trait and is characterised by facial and shoulder girdle weakness usually appearing in early adulthood. In milder cases, clinical signs may not become apparent before late adulthood. A scapuloperoneal subtype sparing the facial muscles has been reported. We present 2 cases of genetically confirmed FSHD with a distinct phenotype solely affecting the paraspinal muscles. In both patients, needle electromyography revealed pathological spontaneous activity in the paraspinal muscles. Laboratory examinations showed normal or slightly elevated CPK levels. The clinical diagnosis was confirmed by DNA testing which revealed restriction fragments consistent with a D4Z4 repeat contraction on chromosome 4q35. The following conclusions can be drawn: i) Patients with FSHD may present with a phenotype of isolated paraspinal myopathy. ii) Besides other underlying causes (spinal canal stenosis, osteoporosis, Parkinson disease, ankylosing spondylitis, dystonia), the diagnosis of FSHD should be considered in cases with camptocormia.

Hybridization analysis of D4Z4 repeat arrays linked to FSHD

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease involving shortening of D4Z4, an array of tandem 3.3-kb repeat units on chromosome 4. These arrays are in subtelomeric regions of 4q and 10q and have 1-100 units. FSHD is associated with an array of 1-10 units at 4q35. Unambiguous clinical diagnosis of FSHD depends on determining the array length at 4q35, usually with the array-adjacent p13E-11 probe after pulsed-field or linear gel electrophoresis. Complicating factors for molecular diagnosis of FSHD are the phenotypically neutral 10q D4Z4 arrays, cross-hybridizing sequences elsewhere in the genome, deletions including the genomic p13E-11 sequence and part of D4Z4, translocations between 4q and 10q D4Z4 arrays, and the extremely high G + C content of D4Z4 arrays (73%). In this study, we optimized conditions for molecular diagnosis of FSHD with a 1-kb D4Z4 subfragment probe after hybridization with p13E-11. We demonstrate that these hybridization conditions allow the identification of FSHD alleles with deletions of the genomic p13E-11 sequence and aid in determination of the nonpathogenic D4Z4 arrays at 10q. Furthermore, we show that the D4Z4-like sequences present elsewhere in the genome are not tandemly arranged, like those at 4q35 and 10q26.

Diagnostic challenges in facioscapulohumeral muscular dystrophy

The diagnosis of facioscapulohumeral muscular dystrophy (FSHD) can be difficult due to its clinical variability and complex genetic cause. We present three challenging cases: one misdiagnosis of FSHD, one patient with FSHD resembling mitochondrial myopathy, and one patient with combined FSHD and limb girdle muscular dystrophy 2A. Detailed clinical and genetic evaluation, including 4qA/4qB allele determination, may be needed for the diagnosis of FSHD.

Rapid and accurate diagnosis of facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a common muscular disorder, but clinical and genetic complications make its diagnosis difficult. Southern blot analysis detects a smaller sized EcoRI fragment on chromosome 4q35 in most facioscapulohumeral muscular dystrophy patients, that contains integral number of 3.3-kb tandem repeats known as D4Z4. The problems for the genetic diagnosis are that southern blotting for facioscapulohumeral muscular dystrophy is quite laborious and time-consuming, and the D4Z4 number is only estimated from the size of the fragment. We developed a more simplified diagnostic method using a long polymerase chain reaction (PCR) amplification technique. Successful amplification was achieved in all facioscapulohumeral muscular dystrophy patients with an EcoRI fragment size ranging from 10 to 25 kb, and each patient had a specific polymerase chain reaction product which corresponded to the size calculated from the number of D4Z4. Using southern blot analysis, more than 90% of facioscapulohumeral muscular dystrophy patients have a smaller EcoRI fragment than 26 kb in our series, and the number of D4Z4 repeats is precisely counted by this polymerase chain reaction method. We conclude that this long polymerase chain reaction method can be used as an accurate genetic screening technique for facioscapulohumeral muscular dystrophy patients.

Isolated paraspinal myopathy: a distinct subtype of facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is inherited as an autosomal dominant trait and is characterised by facial and shoulder girdle weakness usually appearing in early adulthood. In milder cases, clinical signs may not become apparent before late adulthood. A scapuloperoneal subtype sparing the facial muscles has been reported. We present 2 cases of genetically confirmed FSHD with a distinct phenotype solely affecting the paraspinal muscles. In both patients, needle electromyography revealed pathological spontaneous activity in the paraspinal muscles. Laboratory examinations showed normal or slightly elevated CPK levels. The clinical diagnosis was confirmed by DNA testing which revealed restriction fragments consistent with a D4Z4 repeat contraction on chromosome 4q35. The following conclusions can be drawn: i) Patients with FSHD may present with a phenotype of isolated paraspinal myopathy. ii) Besides other underlying causes (spinal canal stenosis, osteoporosis, Parkinson disease, ankylosing spondylitis, dystonia), the diagnosis of FSHD should be considered in cases with camptocormia.

Sensitivity of motor unit potential analysis in facioscapulohumeral muscular dystrophy

Template-operated motor unit potential (MUP) analysis has made quantitative electromyography (EMG) feasible, even in busy laboratories, but validation of this approach is still necessary. In the present study, the utility of multi-MUP analysis was assessed in patients with a molecular genetic diagnosis of facioscapulohumeral muscular dystrophy (FSHD). Manual assessment of muscle strength and concentric-needle EMG of the biceps brachii and vastus lateralis muscles were performed. The sensitivity for diagnosing myopathy (mean values and outliers) was tested for eight MUP parameters and four of their combinations. The group comprised 31 patients. Elbow flexion and knee extension strength was normal in 45% and 52% of patients, respectively. The most sensitive MUP parameter was thickness, followed by duration. A combination of three MUP parameters (thickness, amplitude, and duration/area) was needed for maximal sensitivity. The study demonstrated a high sensitivity of multi-MUP analysis in FSHD. Myopathic abnormalities were demonstrated in all weak biceps brachii muscles, and in 77% of biceps brachii muscles with normal strength.

Genetic confirmation of facioscapulohumeral muscular dystrophy in a case with complex D4Z4 rearrangments

Facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of the D4Z4 repeat on chromosome 4q. Genetic confirmation of the clinical diagnosis of FSHD is complicated by the presence of a homologous repeat on chromosome 10q and the frequent repeat exchanges between both chromosomes. Here, we describe the genetic evaluation of an FSHD patient with a complex D4Z4 allele constitution in which the potentially pathogenic allele seemingly resides on chromosome 10, despite FSHD being exclusively linked to chromosome 4. Complementary allele typing and segregation analysis confirmed the clinical diagnosis of FSHD by revealing the chromosome 4 origin of the pathogenic allele in the presence of two exchanged repeat arrays, one on chromosome 4 and one on chromosome 10, an allele constitution that cannot be identified by conventional DNA diagnosis.

Drug treatment for facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy is a progressive muscle disease which has no agreed treatment. Early suggestions that corticosteroids might be helpful were not supported by a subsequent open label study. The beta 2 adrenergic agonist albuterol, also known as salbutamol, is known to have anabolic effects which might be beneficial for facioscapulohumeral muscular dystrophy. Creatine has been used as a muscle performance enhancer by athletes and it might be helpful in muscular dystrophies including facioscapulohumeral muscular dystrophy. The objective of the review was to determine whether there is any drug treatment which alters the progression of facioscapulohumeral muscular dystrophy. We searched the Cochrane Neuromuscular Disease Group specialised register (searched August 2003), MEDLINE (January 1966 to August 2003) and EMBASE (January 1980 to August 2003) for any references to facioscapulohumeral muscular dystrophy. Abstracts from the major neurological meetings and trial bibliographies were also searched for further references to trials. Experts were contacted for information regarding unpublished trials or trials in progress. We included all randomised or quasi-randomised trials of any drug treatment for facioscapulohumeral muscular dystrophy, in adults with a recognised diagnosis of facioscapulohumeral muscular dystrophy. Trials had to include an assessment of muscle strength at one year. All identified trials were independently assessed by both reviewers to ensure that they fulfilled the selection criteria and were then rated for their quality. Trial data were extracted and entered by one reviewer and checked by the other. If appropriate data existed a weighted treatment effect was to be calculated across trials using the Cochrane statistical package, Review Manager. The results were to have been expressed as relative risks and 95% confidence intervals and risk differences and 95% confidence intervals for dichotomous outcomes, and weighted mean differences and 95% confidence intervals for continuous outcomes. Two published high quality randomised controlled trials fulfilled the selection criteria. One compared creatine supplementation with placebo and the other compared high and low-dose albuterol with placebo. A further unpublished randomised controlled trial of albuterol in facioscapulohumeral muscular dystrophy was identified. The creatine trial showed a non-significant difference in favour of creatine. The albuterol trial showed no significant difference in muscle strength at one year but some secondary measures such as lean body mass and handgrip strength did improve. There is no evidence from randomised controlled trials to support any drug treatment for facioscapulohumeral muscular dystrophy but only two randomised controlled trials have been published.

FSHD-like patients without 4q35 deletion

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive weakness and wasting of facial, shoulder-girdle and upper arm muscles. Despite of the characteristic clinical features, the diagnosis of FSHD is sometimes difficult because clinical symptoms are extremely variable including facial sparing type, limb-girdle type, and distal myopathy type. Most of the FSHD patients have a deletion in the subtelomeric region of chromosome 4q35 (FSHMD1A), however the linkage analysis in some families suggested genetic heterogeneity. In the present study, we identified 40 patients without a deletion in the 4q35 region (non-4q35del) among 200 Japanese patients who were clinically suspected to have FHSD. All non-4q35del patients had shoulder-girdle weakness and 75% also had facial weakness. Eight patients showed clinical features that were indistinguishable from FSHD, but two of them had Becker muscular dystrophy. FSHD is clinically, and most likely genetically, as well, variable. Other forms of muscular dystrophy can also mimic FSHD.