The clinical and molecular spectrum of autosomal dominant limb-girdle muscular dystrophies focusing on transportinopathy

ABSTRACT

Introduction: Limb-girdle muscular dystrophies (LGMD) are a clinical and genetically heterogeneous group of muscle diseases presenting with a phenotypic spectrum. Autosomal dominant LGMDs represent less than 10% of the group and are subdivided, according to the last classification, in five dominant LGMD forms (type D1-D5), in which mutations in various genes have been identified. Dominant LGMD might be due to a defect of DNAJB6 (LGMD D1), transportin-3 (LGMD D2, TNPO3-related), mutations in HNRNPDL gene (LGMD D3), in CAPN3 gene (LGMD D4) and in collagen 6 (LGMD D5, collagen 6-related).

Areas covered: We present the pathomechanism of dominant LGMDs and clinical management of respiratory and bulbar complications. We analyze the clinical presentation of cases affected by LGMD D2 in a large Italo-Spanish family. We consider two main phenotypic entities: the childhood form developing the clinical features in the first decade of life and the late-onset phenotype, that present distinct clinical, histopathological and MRI features. The main features in dominant LGMDs, such as LGMD D1, D3, D4, D5 are highlighted, including the differential ones with other dystrophies.

Expert opinion: Early diagnosis of LGMD, utilizing Next Generation Sequencing technique (NGS), is crucial for offering an accurate diagnosis. Muscle MRI imaging is emerging both for diagnosis and follow-up of disease progression.

KEYWORDS:

• Atrophy
• dominant LGMD
• LGMD treatment
• nucleus
• transportin-3

Article highlights

• Fewer than 10% of LGMD cases are dominant and have in general slow clinical course.

• The advent of new sequencing technologies has allowed to identify other families affected by dominant LGMD with new mutations.

• MRI imaging is a useful tool in follow-up and to diagnose pauciaffected carriers.

• Rehabilitative techniques aimed to reduce joint contractures are useful for treatment.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Association Conquistando Escalones and The French Muscular Dystrophy Association (AFM).