Congenital Myopathy as a Phenotypic Expression of CACNA1S Gene Mutation: Case Report and Systematic Review of the Literature

Abstract

Background: Congenital myopathies are a group of clinically, genetically, and histologically heterogeneous diseases caused by mutations in a large group of genes. One of these is CACNA1S, which is recognized as the cause of Dihydropyridine Receptor Congenital Myopathy.

Methods: To better characterize the phenotypic spectrum of CACNA1S myopathy, we conducted a systematic review of cases in the literature through three electronic databases following the PRISMA guidelines. We selected nine articles describing 23 patients with heterozygous, homozygous, or compound heterozygous mutations in CACNA1S and we added one patient with a compound heterozygous mutation in CACNA1S (c.1394-2A>G; c.1724T>C, p.L575P) followed at our Institute. We collected clinical and genetic data, muscle biopsies, and muscle MRIs when available.

Results: The phenotype of this myopathy is heterogeneous, ranging from more severe forms with a lethal early onset and mild-moderate forms with a better clinical course.

Conclusions: Our patient presented a phenotype compatible with the mild-moderate form, although she presented peculiar features such as a short stature, myopia, mild sensorineural hearing loss, psychiatric symptoms, and posterior-anterior impairment gradient on thigh muscle MRI.

Keywords: CACNA1S; CACNA1S myopathy; congenital myopathies; dihydropyridine receptor congenital myopathy.

Figure 1

PRISMA flowchart of review.

Figure 2

(A). The CACNA1S human gene extends over 73 kb and contains 44 exons (each vertical black line denotes one exon). The position of the start codon (ATG) is indicated. (B). The corresponding protein domains are represented according to the Protein Families (PFAM) database (C). Schematic view of the CACNA1S mutations of patients described in the present work with related grade (mild, moderate, and severe) of phenotype and position (transmembrane, extracellular, or cytoplasmatic) according to UNIPROT (https://www.uniprot.org/uniprotkb/Q13698/entry accessed on 7 June 2023) (D). Schematic view of the CACNA1S-encoded α 1 sub-unit of DHPR. The subunit has a total of four transmembrane domains (I–IV) composed by six segments (1–6) and three intracellular loop domains (loops I–II, loops II–III, and loops III–IV). Patient mutations are indicated with a cross and respective number.

Figure 3

Left biceps brachialis muscle biopsy revealed fiber size variability, occasional internal nuclei, and disorganization of intermyofibrillar network (Hematoxylin-Eosin (A), NADH (B), stainings: 200×).

Figure 4

Muscle MRI images of axial T1 (I) and Ideal FSE (II) sequences of pelvis (A), thighs (B), and legs (C). MRI images showed: hypotrophy of pelvis muscles with adipose infiltration of gluteus muscles (A.I—white arrows) and tensor fasciae latae muscles (A.I—white arrow heads); hypotrophy of thigh with major involvement of medio-posterior muscles and an adipose infiltration of semitendinosus (B.I and B.II—white arrow heads) and sartorius muscles (B.I and B.II—white arrows); and mild adipose infiltration of peroneus (C.I and C.II—white arrow) and postero tibialis muscles (C.I and C.II—white arrow heads) in legs.

Figure 5

Graphic representation of symptoms in all patients and in different phenotypic groups. Muscle weakness: “Mild” indicates proximal and axial muscle weakness while “Severe” indicates generalized muscle weakness. Ophalmoplegia, Scoliosis, ID (Intellectual Disability): “Mild” indicates presence.