Elsevier

Neuromuscular Disorders

Volume 31, Issue 2, February 2021, Pages 139-148
Neuromuscular Disorders

Novel ACTA1 mutation causes late-presenting nemaline myopathy with unusual dark cores

https://doi.org/10.1016/j.nmd.2020.11.012Get rights and content

Highlights

  • A novel dominant mutation (Gly50Ser) in ACTA1 causes mild late onset core-rod myopathy.

  • Peculiar areas of fuzzy-dark material deposition corresponded to unstructured cores.

  • Affected members showed mild weakness with high arched palate and sternocleidomastoideus atrophy.

  • Muscle MRI showed the same pattern of fibro-fatty replacement in all examined probands.

  • Fiber contractility essay demonstrates a higher calcium sensitivity of force in type i fibers.

Abstract

ACTA1 gene encodes the skeletal muscle alpha-actin, the core of thin filaments of the sarcomere. ACTA1 mutations are responsible of several muscle disorders including nemaline, cores, actin aggregate myopathies and fiber-type disproportion. We report clinical, muscle imaging, histopatological and genetic data of an Italian family carrying a novel ACTA1 mutation. All affected members showed a late-presenting, diffuse muscle weakness with sternocleidomastoideus and temporalis atrophy. Mild dysmorphic features were also detected. The most affected muscles by muscle MRI were rectus abdominis, gluteus minimus, vastus intermedius and both gastrocnemii. Muscle biopsy showed the presence of nemaline bodies with several unusual dark areas at Gomori Trichrome, corresponding to unstructured cores with abundant electrodense material by electron microscopy. The molecular analysis revealed missense variant c.148G>A; p.(Gly50Ser) in the exon 3 of ACTA1, segregating with affected members in the family. We performed a functional essay of fibre contractility showing a higher pCa50 (a measure of the calcium sensitivity of force) of type 1 fibers compared to control subjects’ type 1 muscle fibers. Our findings expand the clinico-pathological spectrum of ACTA1-related congenital myopathies and the genetic spectrum of core-rod myopathies.

Introduction

Actinopathies represent a specific subgroup of congenital myopathies with protein accumulation in muscle biopsy due to mutations in the skeletal muscle α-actin gene (ACTA1) [1,2]. Both dominant and recessive traits have been reported, resulting in variable protein expression [3], [4], [5], [6], [7], [8], [9] and dysfunctional sarcomere contractility [10,11]. The observation of sporadic patients with de novo dominant mutations suggests a high new mutation rate in ACTA1 [12,13]. The most common morphological findings are nemaline bodies - rod-like structures - which typically accumulates in subsarcolemmal areas [2,8,14,15]. Intranuclear rods have also been described [4,[16], [17], [18]]. Besides nemaline bodies, several histopathological findings have been reported in association to ACTA1 mutations including actin filament aggregates [9,19], cores [20], caps [21], fiber type disproportion [22], [23], [24] and zebra bodies [25]. ACTA1-related nemaline myopathies account for about 20% of all nemaline myopathies and 50% of the severe cases, representing the most common clinical presentation [6,9,14,26]. Clinical picture is characterized by marked hypotonia at birth, myopathic face, high arched palate, respiratory failure and feeding difficulties, with death occurring within the first year of life or severe muscular weakness requiring mechanical ventilation in those who survive [13,17,27,28]. However, a wide range of clinical presentations has been reported, ranging from fetal akinesia syndrome [29] to milder phenotypes with adult onset [8,30,31]. Infrequently, ACTA1-myopathies can manifest with atypical clinical and histopathological findings, as facioscapuloperoneal myopathy [30], congenital muscular dystrophy with rigid spine [7], muscular stiffness and hypertonia [32], distal weakness with rimmed vacuoles [33], myofibrillar aggregates [28] or cytoplasmic bodies without nemaline bodies [34].

Herein we describe an Italian family manifesting a late-presenting core-rod myopathy with peculiar morphological elements at muscle biopsy due to a novel ACTA1 mutation.

Section snippets

Patients

All patients underwent a complete clinical examination including extensive manual muscle test scored by Medical Research Council (MRC) and laboratory analysis including creatine kinase (CK). Proband and her sister (the most affected patients) also underwent a neurophysiological study including nerve conduction study (NCS) and electromyography (EMG), whole body muscle MRI including T1 and STIR sequences, open muscle biopsy and targeted-NGS panel for congenital myopathies. In order to confirm the

Clinical findings

Proband (PII.4) is a 53-year-old woman, with a negative medical history, referred to our neuromuscular centre at the age of 39 just because of occasional Creatin Kinase (CK) elevation (range 90–1500 U/l). Since her infancy, she was having some difficulties in physical activities and presented mild rhinolalia, which had never been considered pathological by the patient. Clinical examination at age of 39 revealed a mild myopathic face with high arched palate, atrophy of sternocleidomastoideus

Discussion

Late, adult-manifesting congenital myopathy represents the milder spectrum of ACTA1 myopathies and the minority of ACTA1 cases reported [8,15]. Most of these cases had mild facial involvement with proximal weakness of upper limbs and variable proximo-distal weakness in lower limbs, most frequently reported as facioscapuloperoneal presentation [3,30,30,44,45]. Accordingly, the few reports including a muscle MRI study showed diffuse fibro-fatty replacement in lower limbs predominant in the

Disclosures

All authors report no relevant disclosures and conflict of interest for this study.

All data of this study are available from the corresponding author, upon motivated request.

This study complies all the ethical and local standards.

Funding

This study did not receive any funding.

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