Both hereditary sensorimotor neuropathy due to PMP22 duplication (CMT1A) and facioscapulohumeral muscular dystrophy (FSHD) due to a shortened fragment of the D4Z4 locus (19 kb) were identified in the described patient. To the best of our knowledge this is one of only three published cases describing coincidence of CMT1A and FSHD.
Recent epidemiological data suggest that the frequency of CMT1A is around 1:7,500 [4
] while the frequency of FSHD is estimated at 1:20,000 [7
]. Thus, the chance of being affected by both disorders is about 1:150,000,000.
In the patient’s family history his sister and her daughter were suggestive of CMT1A as well. However, since both parents have died and no DNA samples of further family members were available, segregation could not be proven. Our patient showed typical symptoms of this generalized, primarily demyelinating neuropathy with reduced nerve conduction velocities, distal hypoesthesia and distal muscle atrophy leading to steppage gait and foot deformities like pes cavus und claw toes [1
Since additional features like proximal muscle weakness of the shoulder girdle, myopathic changes in muscle biopsy specimen and EMG analysis were suggestive of additional primary involvement of the skeletal muscle genetic analyses were extended to include frequent forms of muscular dystrophies and myopathies. FSHD diagnosis was established by Southern blot analysis for the D4Z4 locus showing contraction of the repeat (19 kb) and a FSHD-related 4qA haplotype. It remains unclear if FSHD results from a de novo
mutation occurring in 10% to 30% of all cases [12
] or from familial inheritance as we cannot rule out the possibility of an undiagnosed mild presentation in other family members. Until now, the pathogenic relevance of the D4Z4 deletion has not been fully clarified and has been questioned in recent studies [13
]. However, in addition to the clinical findings, electromyography in our patient revealed mild myopathic changes in proximal muscles along with the myopathic changes in the muscle biopsy specimen. Along with shortening of the D4Z4 locus to 19 kb on EcoRI
double digestion, FSHD is likely to be causative for the additional myopathy.
The classical FSHD phenotype was described in 1884 by Landouzy and Dejerine with facial weakness, shoulder girdle and pectoral muscle weakness and atrophy, in some cases resulting in subsequent impairment of pelvic and lower leg muscles [14
]. But clinical variability has long been recognized in neuromuscular disorders. This has become most obvious with the advent of molecular genetic testing showing that identical molecular defects can result in diverse clinical presentations. This is especially true for FSHD where several unusual phenotypes and atypical morphological features ranging from hyperCKemia, severe muscle pain, facial-sparing, hypertrophic cardiomyopathy, camptocormia, distal and axial myopathy, along with atypical morphological changes such as vacuolar and/or inflammatory myopathy, nemaline rods, and deficiency of complex III of the mitochondrial respiratory chain were reported [15
]. Our patient provides further evidence for this variability by not fulfilling all four major diagnostic criteria for diagnosis of FSHD as described above [8
]. Autosomal dominant inheritance cannot be proven since the parents were not available for molecular testing, and facial weakness was not seen.
Interfamilial and intrafamilial clinical variability has also been observed in CMT [24
] including cases of demyelinating CMT with scapuloperoneal distribution of motor impairment reported in the 1980s [26
]. In contrast to our case, these cases were confined to clinical findings since molecular genetic testing was not yet available in the 1980s. Harding and Thomas described a constellation of clinical symptoms similar to our patient but with striking wasting of both deltoid muscles which is rather uncommon in FSHD so that we cannot exclude that this patient suffered from another scapuloperoneal myopathy.
In addition to stochastic effects, environmental influences, allelic variation, modifier genes, somatic mosaicism and complex genetic and environmental interactions [28
], some of this variability might be caused by concomitant mutations in other genes for neuromuscular conditions. In FSHD, such overlapping syndromes have been described several times in literature. Association with pathogenic mutations in other genes have been reported in cases of patients with mitochondrial myopathy/FSHD, Becker muscular dystrophy/FSHD, Duchenne muscular dystrophy/FSHD, Leber’s hereditary optic neuropathy/FSHD and caveolinopathy/FSHD determining overlapping phenotypes [15
]. For CMT1A, concomitant mutations in the PMP22
gene and the Connexin32 gene (causing CMTX), the DMPK1 gene (DM1 myotonic dystrophy) and the ABCD1 gene (adrenomyeloneuropathy) have been described to produce peculiar phenotypes [34
]. In addition, a combination of CMTX with Becker muscular dystrophy has been reported [35
], causing both, generalized weakness and CK elevation as typical phenotype for a muscular dystrophy as well as foot deformity, decreased tendon reflexes and sensory loss due to a mutation in the Connexin32 gene.
There is one further report similar to ours on one family suffering from CMT1A and FSHD [36
]. Auer-Grumbach et al. reported on this family affected by genetically confirmed CMT1A with scapuloperoneal motor deficit but conflicting data concerning the concomitant presence of FSHD. Co-segregation of FSHD in this family was unconvincing and haplotype analysis on chromosome 4q was not performed as it was not described in the paper. In contrast to our report, no muscle histology was performed and EMG revealed a mild chronic neurogenic pattern in proximal and distal muscles. However, our patient showed myopathic changes assessed by electromyography and muscle biopsy which further support the molecular diagnosis of FSHD.
In our patient a contracted fragment of 19 kb in the D4Z4 locus was detected. It is generally accepted that there is a correlation between clinical severity and size of the D4Z4 repeat: small repeats stand for early age at onset and severe clinical course, whereas larger repeats mean later age at onset and milder course [37
]. Although the patient reported here carries a repeat size usually expected to result in a moderately severe phenotype with onset in the 1st
decade, he showed only mild symptoms of shoulder girdle weakness developing in the second half of life without facial or proximal leg muscle impairment until now. There is no obvious explanation for the unexpectedly mild phenotype in our patient and in contrast, the association of FSHD with X-linked CMT and Duchenne muscular dystrophy leads to severe infantile phenotypes [31
]. Butefisch et al. described a further patient with the combination of CMT1A and FSHD in 1998 [39
]. This female patient inherited CMT1A from her father and FSHD from her mother and this comorbidity resulted in severe generalized weakness, respiratory insufficiency and early death. However, according to the information given in the paper, only the diagnosis of CMT1A was proven by molecular testing but not the FSHD, neither in the patient nor in relatives. Thus, we cannot exclude the possibility that another progressive muscular dystrophy might be causative for this devastating clinical course in this patient.
All in all, too few “double trouble” patients are known to draw significant conclusions on how concomitant genetic conditions modify each other’s severity and progression in these patients. Nevertheless, the number of cases with genetically proven double trouble is likely to increase with the availability of improved genetic testing and whole exome or genome sequencing methods. This will result in an even broader variety of atypical clinical pictures but may also help to understand interference at the phenotypic, genetic and epigenetic levels having a direct impact on medical care and genetic counseling.