X-linked myotubular myopathy mimics hereditary spastic paraplegia in two female manifesting carriers of pathogenic MTM1 variant

Abstract

X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy caused by pathogenic variants in the myotubularin 1 (MTM1) gene. XLMTM leads to severe weakness in male infants and majority of them die in the early postnatal period due to respiratory failure. Disease manifestations in female carriers vary from asymptomatic to severe, generalized congenital weakness. The symptomatic female carriers typically have limb-girdle weakness, asymmetric muscle weakness and skeletal size, urinary incontinence, facial weakness, ptosis and ophthalmoplegia. Here we describe a Finnish family with two females with lower limb spasticity and hyperreflexia resembling spastic paraplegia, gait difficulties and asymmetric muscle weakness in the limbs. A whole exome sequencing identified a heterozygous pathogenic missense variant MTM1 c.1262G > A, p.(Arg421Gln) segregating in the family. The variant has previously been detected in male and female patients with XLMTM. Muscle biopsy of one of the females showed variation in the myofiber diameter, atrophic myofibers, central nuclei and necklace fibers consistent with a diagnosis of XLMTM. This report suggests association between spastic paraplegia and pathogenic MTM1 variants expanding the phenotypic spectrum potentially associated with XLMTM, but the possible association needs to be confirmed by additional cases.

Introduction

X-linked myotubular myopathy (XLMTM, OMIM #310400) is a rare congenital myopathy caused by pathogenic variants in the myotubularin 1 (MTM1) gene encoding the phosphatase enzyme myotubularin, required for removing phosphatase groups from phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-biphosphate within muscle cell membranes (Laporte et al., 2000, 1996). XLMTM leads to severe weakness in male infants and majority of them die in the early postnatal period due to respiratory failure (Amburgey et al., 2017; Annoussamy et al., 2019; Beggs et al., 2018). Disease manifestations in female carriers vary from asymptomatic to severe, generalized congenital weakness (Biancalana et al., 2017; Cocanougher et al., 2019; Kosma et al., 2019). The symptomatic female carriers typically have limb-girdle weakness, asymmetric muscle weakness and skeletal size, urinary incontinence, facial weakness, ptosis and ophthalmoplegia (Biancalana et al., 2017; Cocanougher et al., 2019; Kosma et al., 2019). The variation in the phenotypes of the female carriers is hypothesized to be caused by skewed X-inactivation pattern (Biancalana et al., 2017; Tanner et al., 1999). Typical histological findings of XLMTM include centralized nuclei, necklace fibers and general disorganization of the muscle structure, and thus XLMTM is grouped in the genetically heterogeneous family of centronuclear myopathies (CNMs) (Jungbluth and Gautel, 2014). The incidence of XLMTM is estimated to be 1:50 000 male births (Jungbluth et al., 2008).

Hereditary spastic paraplegias (HSPs) refer to a group of neurodegenerative disorders characterized by bilateral progressive spasticity and weakness in the lower limbs caused by degeneration of the longest corticospinal nerves (Hedera, 1993). HSPs are classified into uncomplicated and complex forms. In uncomplicated forms, the symptoms are restricted to lower limbs, while the complex forms include additional features such as ataxia, parkinsonism and extrapyramidal disturbances (Hedera, 1993). So far, more than eighty genes causing HSP have been identified (D'Amore et al., 2018).

Here, we describe a Finnish family with two affected females with a pathogenic variant in the MTM1 gene presenting with lower limb spasticity and hyperreflexia resembling spastic paraplegia, gait difficulties and asymmetric muscle weakness in the limbs.