Facioscapulohumeral muscular dystrophy and Charcot-Marie-Tooth neuropathy 1A - evidence for “double trouble” overlapping syndromes

Abstract

BackgroundWe report on a patient with genetically confirmed overlapping diagnoses of CMT1A and FSHD. This case adds to the increasing number of unique patients presenting with atypical phenotypes, particularly in FSHD. Even if a mutation in one disease gene has been found, further genetic testing might be warranted in cases with unusual clinical presentation.Case presentationThe reported 53 years old male patient suffered from walking difficulties and foot deformities first noticed at age 20. Later on, he developed scapuloperoneal and truncal muscle weakness, along with atrophy of the intrinsic hand and foot muscles, pes cavus, claw toes and a distal symmetric hypoesthesia. Motor nerve conduction velocities were reduced to 20 m/s in the upper extremities, and not educible in the lower extremities, sensory nerve conduction velocities were not attainable. Electromyography showed both, myopathic and neurogenic changes. A muscle biopsy taken from the tibialis anterior muscle showed a mild myopathy with some neurogenic findings and hypertrophic type 1 fibers. Whole-body muscle MRI revealed severe changes in the lower leg muscles, tibialis anterior and gastrocnemius muscles were highly replaced by fatty tissue. Additionally, fatty degeneration of shoulder girdle and straight back muscles, and atrophy of dorsal upper leg muscles were seen. Taken together, the presenting features suggested both, a neuropathy and a myopathy. Patient’s family history suggested an autosomal dominant inheritance.Molecular testing revealed both, a hereditary motor and sensory neuropathy type 1A (HMSN1A, also called Charcot-Marie-Tooth neuropathy 1A, CMT1A) due to a PMP22 gene duplication and facioscapulohumeral muscular dystrophy (FSHD) due to a partial deletion of the D4Z4 locus (19 kb).ConclusionMolecular testing in hereditary neuromuscular disorders has led to the identification of an increasing number of atypical phenotypes. Nevertheless, finding the right diagnosis is crucial for the patient in order to obtain adequate medical care and appropriate genetic counseling, especially in the background of arising curative therapies.

Co-occurrence of Xp21 microduplication encompassing the DMD locus in conjunction with 17p12/PMP22 microduplication in a female with Charcot–Marie–Tooth disease type 1A

“…Motor milestones delayed at 6 months with later manifestations of bilateral pes cavus, absent deep tendon reflexes, and sensory loss are indicative of CMT1A. Upon review of literature, Charcot-Marie-Tooth neuropathies in association with various forms of muscular dystrophy have been reported in four cases [10][11][12][13]. Butefisch et al first reported on a 22-year-old female who inherited both facioscapulohumeral muscular dystrophy (FSHD) and CMT1A from each of her parents leading to shortened life span and early death [11].…”

“…Literature evidence shows alteration of disease course with worse prognosis in the presence of CharcotMarie-Tooth neuropathy and a muscular dystrophy [10,11,13]. Hence even if a mutation in a disease gene has been detected, further genetic testing may be warranted in unusual clinical presentations.…”

“…His clinical course was changed with severe proximal and distal muscle wasting and rapid progression of both the diseases. Recent publication by Schreiber et al [13] describes a 53-year-old male with both CMT1A and FSHD mutations presenting with an atypical phenotype. There is one further report similar to our case on Figure 1 The family pedigree.…”

Charcot–Marie–Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges

“…All had the core features of CMT4C, including demyelinating neuropathy with early‐onset scoliosis. There are reports of CMT4C patients presenting with side‐to‐side asymmetry, lack of scoliosis, and phenotypic variability despite identical genotypic mutations . Sleep apnea, respiratory failure, and cranial nerve involvement such as nystagmus and facial weakness have also been described in some patients …”

A new double-trouble phenotype: fascioscapulohumeral muscular dystrophy ameliorates hereditary spastic paraparesis due to spastin mutation

“…This is a further example of how a second mutation may modify the severity and presentation of genetic disorders within the same family and it stresses the importance to extend the genetic analysis on asymptomatic siblings. Other double-trouble phenotypes involving FSHD have been reported [4][5][6][7][8], but no one with motoneuron disease as second genetic disorder.…”