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

SPG4 or SPAST-associated hereditary spastic paraplegia (HSP) is an autosomal dominant (AD) disorder characterized by corticospinal tract degeneration causing lower limb weakness and spasticity [1]. Facioscapulohumeral muscular dystrophy (FSHD) is an AD muscular dystrophy characterized by progressive atrophy and weakness of facial, shoulder limb girdle, abdominal and anterior leg muscles [2]. We describe a family with genetically confirmed overlapping diagnoses of those two diseases. The proband, now 56-year-old woman (III:7), complained of a progressive spastic gait that started in her late 20s. Later on her gait became waddling with bilateral foot drop but less spastic. Moreover, a mild orbicular, scapuloperoneal and axial muscle weakness with a limited arm abduction and scapular winging were present. EMG showed myopathic changes, whole body muscle MRI revealed asymmetric fatty replacement muscles (Fig. 1). The spastic gait was present in other family members and inherited as AD trait (Fig. 1). Mutation analysis of the SPAST gene showed the novel c.910_914delinsTAGG structural variant, leading to the formation of a premature stop codon (p.Pro304*). When the 24-year-old nephew (IV:8) was diagnosed as having FSHD based on clinical phenotype, MRI studies (Fig. 1) and the presence of a 25-kb deletion in the D4Z4 locus, the molecular analysis for both genes was extended to other family members. The coexistence of the two mutations was then confirmed in our proband and in two siblings, a 50-year-old man and a 48-year-old woman. We also speculated that the father was affected by both diseases based on the referred wasting of the upper girdle muscles, shoulder antiversion and a spastic gait. During the proband clinical follow-up, we observed FSHD features overcoming those associated with SPAST mutation, as she is now wheel chair bound, presenting lumbar hyperlordosis, bilateral foot drop and proximal muscle weakness without spasticity. The two affected brothers have a much milder phenotype. The male has shoulder muscle wasting and scapular winging with preserved arm abduction, wasting of tibialis and peroneous muscles and pes cavus. He is still able to walk on heels and toes and does not present clinical evidence of spasticity, except for Babinski sign and brisk reflexes. The sister has no limitation in her every day activities. All the other family members carrying only one of the other gene mutations have HSP or FSHD features at different degree (Table 1). The two genes are localized on different chromosomes, respectively, 4q35 for FSHD and 2p22-p21 for SPG4, thus M. Scarlato (&) A. Nuara S. C. Previtali Department of Neurology, INSPE and Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy e-mail: scarlato.marina@hsr.it