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