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

doi:10.1016/j.nmd.2008.06.387

Neuromuscular Disorders

Volume 18, Issue 11, November 2008, Pages 881-885

https://doi.org/10.1016/j.nmd.2008.06.387 Get rights and content

Abstract

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.

Introduction

With increasing knowledge of gene defects in neuromuscular disorders, the phenotypic spectrum has broadened considerably. If a patient has an atypical phenotype but displays a distinct gene defect, one is tempted to attribute the clinical picture to the variable phenotype caused by this genetic entity. This applies in particular to facioscapulohumeral muscular dystrophy (FSHD) which is well-known for its atypical presentations [1], [2].

We report a 12-year-old patient with proximal and facial weakness along with very high creatine kinase (CK) activity which prompted us to search for more than one disease mechanism. Finally, the diagnosis of FSHD and Becker’s muscular dystrophy (BMD) was established. Our patient is an illustrative example of a rare combination of two independently inherited myopathies and emphasizes the diagnostic challenges in atypical phenotypes.

Section snippets

Case report

The boy was the only son of healthy parents, his family history was negative regarding neuromuscular disorders. The patient was under pediatric supervision from age 3 because of muscular hypotonia and delayed language development. He sat at 8 months, walked alone at 17 months and started to speak single words at 3–4 years. The patient received regular physiotherapy until 10–12 years, when the therapist noted increasing muscle weakness and atrophy. Psychological testing (HAWIK III) revealed a

Discussion

Our patient illustrates the diagnostic challenges in the muscular dystrophies. Molecular genetic analysis has become the most important diagnostic tool for FSHD and DMD/BMD and replaces invasive methods in the majority of cases. The diagnostic algorithm for BMD started with multiplex deletion screening in the dystrophin gene, now increasingly replaced by MLPA for deletion and duplication detection, was completed by a muscle biopsy and finally by sequencing of the dystrophin gene. FSHD diagnosis

References (16)

R.J. Lemmers et al.
Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy
Am J Hum Genet
(2007)
M.M.O. Tonini et al.
Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD)
Neuromuscul Disord
(2004)
K.J. Felice et al.
Unusual clinical presentations in patients harboring the facioscapulohumeral dystrophy 4q35 deletion
Muscle Nerve
(2001)
S. Sacconi et al.
Diagnostic challenges in facioscapulohumeral muscular dystrophy
Neurology
(2006)
R.J. Lemmers et al.
Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere
Nat Genet
(2002)
A. Aartsma-Rus et al.
Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule
Muscle Nerve
(2006)
A.J. van Essen et al.
The clinical and molecular genetic approach to Duchenne and Becker muscular dystrophy: an updated protocol
J Med Genet
(1997)
M. de Visser et al.
Becker muscular dystrophy

There are more references available in the full text version of this article.

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Facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy: "double trouble" overlapping syndrome?
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The FSHD2 gene SMCHD1 Is a modifier of disease severity in families affected by FSHD1
2013, American Journal of Human Genetics
Citation Excerpt :
In this context, the identification of three unrelated individuals with unusually severe clinical phenotypes associated with a borderline FSHD1 allele, and the presence of marked intrafamilial variability of disease severity in some familial carriers of the FSHD1 allele prompted us to consider the possibility that additional genetic defects may segregate in these families acting as disease modifiers. “Double trouble” in FSHD has been reported previously in isolated cases.46–48 In these cases, however, it was the result of concomitant mutations in other dystrophy genes and resulted in atypical FSHD phenotypes, suggesting synergistic effects of the two genetic lesions, rather than a genetic modifier acting on the D4Z4 locus itself.
Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array on chromosome 4 to a size of 1–10 units. The residual number of D4Z4 units inversely correlates with clinical severity, but significant clinical variability exists. Each unit contains a copy of the DUX4 retrogene. Repeat contractions are associated with changes in D4Z4 chromatin structure that increase the likelihood of DUX4 expression in skeletal muscle, but only when the repeat resides in a genetic background that contains a DUX4 polyadenylation signal. Mutations in the structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) gene, encoding a chromatin modifier of D4Z4, also result in the increased likelihood of DUX4 expression in individuals with a rare form of FSHD (FSHD2). Because SMCHD1 directly binds to D4Z4 and suppresses somatic expression of DUX4, we hypothesized that SMCHD1 may act as a genetic modifier in FSHD1. We describe three unrelated individuals with FSHD1 presenting an unusual high clinical severity based on their upper-sized FSHD1 repeat array of nine units. Each of these individuals also carries a mutation in the SMCHD1 gene. Familial carriers of the FSHD1 allele without the SMCHD1 mutation were only mildly affected, suggesting a modifier effect of the SMCHD1 mutation. Knocking down SMCHD1 in FSHD1 myotubes increased DUX4 expression, lending molecular support to a modifier role for SMCHD1 in FSHD1. We conclude that FSHD1 and FSHD2 share a common pathophysiological pathway in which the FSHD2 gene can act as modifier for disease severity in families affected by FSHD1.
Rippling muscle disease and facioscapulohumeral dystrophy-like phenotype in a patient carrying a heterozygous CAV3 T78M mutation and a D4Z4 partial deletion: Further evidence for "double trouble" overlapping syndromes
2012, Neuromuscular Disorders
Citation Excerpt :
This is particularly true for FSHD, in which various clinical features have been found in subjects carrying FSHD-sized D4Z4 alleles, including a facial-sparing form of FSHD (SHD) [42], limb-girdle muscular dystrophy [43], distal myopathy [44], asymmetric brachial weakness [43], chronic progressive external ophthalmoplegia [45], asymptomatic hyperCKemia [46], hypertrophic cardiomyopathy [47], adult-onset distal myopathies with rimmed vacuoles [48], isolated axial myopathy with camptocormia and bent spine syndrome [49,50]. In addition, overlapping FSHD phenotypes in which 4q35 deleted D4Z4 mutation is associated with other pathogenic mutations in other genes, have been reported in cases of patients with mitochondrial myopathy/FSHD [51], Becker dystrophy/FSHD [52], Duchenne dystrophy/FSHD [53,54], Leber’s hereditary optic neuropathy/FSHD [55], suggesting a synergistic effect of those simultaneous mutations in reaching disease threshold and determining overlapping phenotypes. In conclusion, our case may represent a further example of such atypical phenotypes in which D4Z4 deletion contributes to pathogenicity of heterozygous CAV3 T78M mutation for the observed myopathic phenotype, resulting in an overlapping syndrome.
We report the first case of a heterozygous T78M mutation in the caveolin-3 gene (CAV3) associated with rippling muscle disease and proximal myopathy. The patient displayed also bilateral winged scapula with limited abduction of upper arms and marked asymmetric atrophy of leg muscles shown by magnetic resonance imaging. Immunohistochemistry on the patient’s muscle biopsy demonstrated a reduction of caveolin-3 staining, compatible with the diagnosis of caveolinopathy. Interestingly, consistent with the possible diagnosis of FSHD, the patient carried a 35 kb D4Z4 allele on chromosome 4q35. We discuss the hypothesis that the two genetic mutations may exert a synergistic effect in determining the phenotype observed in this patient.
Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy
2012, American Journal of Human Genetics
Citation Excerpt :
In some rare cases, that could be by becoming homozygous20 and doubling the dose of a dominant factor such as DUX4. In others, it might be by the simultaneous heterozygosity for a different and recessive myopathy, as suggested by many reports in which the FSHD contractions are found in association with a second molecular defect.31–44 This possibility is also consistent with previous reports of expression changes of candidate proteins such as CRYM that were associated with FSHD in some families but that were unchanged when other families were examined.
Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary myopathy causally linked to reduced numbers (≤8) of 3.3 kilobase D4Z4 tandem repeats at 4q35. However, because individuals carrying D4Z4-reduced alleles and no FSHD and patients with FSHD and no short allele have been observed, additional markers have been proposed to support an FSHD molecular diagnosis. In particular a reduction in the number of D4Z4 elements combined with the 4A(159/161/168)PAS haplotype (which provides the possibility of expressing DUX4) is currently used as the genetic signature uniquely associated with FSHD. Here, we analyzed these DNA elements in more than 800 Italian and Brazilian samples of normal individuals unrelated to any FSHD patients. We find that 3% of healthy subjects carry alleles with a reduced number (4–8) of D4Z4 repeats on chromosome 4q and that one-third of these alleles, 1.3%, occur in combination with the 4A161PAS haplotype. We also systematically characterized the 4q35 haplotype in 253 unrelated FSHD patients. We find that only 127 of them (50.1%) carry alleles with 1–8 D4Z4 repeats associated with 4A161PAS, whereas the remaining FSHD probands carry different haplotypes or alleles with a greater number of D4Z4 repeats. The present study shows that the current genetic signature of FSHD is a common polymorphism and that only half of FSHD probands carry this molecular signature. Our results suggest that the genetic basis of FSHD, which is remarkably heterogeneous, should be revisited, because this has important implications for genetic counseling and prenatal diagnosis of at-risk families.
Step-by-Step Double-Trouble OBAIRH and DMD Diagnosis in a One-Year-Old Boy
2023, International Journal of Molecular Sciences
Becker muscular dystrophy: case report, review of the literature, and analysis of differentially expressed hub genes
2022, Neurological Sciences

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

Abstract

Introduction

Section snippets

Case report

Discussion

Am J Hum Genet

Neuromuscul Disord

Unusual clinical presentations in patients harboring the facioscapulohumeral dystrophy 4q35 deletion

Muscle Nerve

Diagnostic challenges in facioscapulohumeral muscular dystrophy

Neurology

Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere

Nat Genet

Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule

Muscle Nerve

The clinical and molecular genetic approach to Duchenne and Becker muscular dystrophy: an updated protocol

J Med Genet

Becker muscular dystrophy

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