What’s new in neuromuscular pathology 2022: myopathy updates and gene therapies

European Neuromuscular Centre (ENMC) clinico-sero-pathological classification divides IIM into 4 subclasses, which are associated with myositis specific antibodies (MSAs), as outlined in Table 1.

MSA testing is preferentially performed prior to immune suppression treatment but should also be performed in patients with suspected IIM or interstitial lung disease of unknown etiology without prior MSA testing.

Polymyositis no longer exists as an IIM subclass.

A classification of DM cannot be made in the absence of DM rash (Gottron’s sign, Gottron’s papules, heliotrope rash).

In the presence of DM-like rash, DM can be diagnosed if a DM-specific autoantibody is present, or if definitive DM muscle biopsy features are present and are combined with clinical signs of proximal muscle weakness or elevated muscle enzymes.

Defined by the presence of an antibody to aminoacyl tRNA synthetase (ARS), together with a single or combination of the following clinical manifestations:

ASyS patients with a DM-like rash are not classified as DM, but as “ASyS with a DM-like rash.”

Pathology is characterized by:

Anti-HMGCR and anti-SRP autoantibodies are considered specific for IMNM.

Patients with anti-HMGCR antibody and a DM-like rash will be classified as having “anti-HMGCR myopathy with a DM-like rash,” while patients with anti-SRP antibody and a DM-like rash will be classified as having “anti-SRP myopathy with a DM-like rash.”

Pathology requires diffusely scattered necrotic fibers at different stages of resolution and macrophage dominant, pauci-lymphocytic inflammation.

The pathologic criteria for sIBM include:

Anti-cN1A autoantibody is present in 30%–70% of sIBM patients but has also been found in DM and other systemic autoimmune diseases such as Sjögren’s and lupus.

Clinically, elderly patients with asymmetric muscle weakness and atrophy of proximal and distal muscle groups, with predilection for wrist and finger flexors and knee extensors.

Usually refractory to immunosuppressive therapies.

The definition and nomenclature of LGMD have been re-defined in the 2017 ENMC international workshop as a genetically inherited condition that primarily affects skeletal muscle leading to progressive, predominantly proximal muscle weakness at presentation caused by a loss of muscle fibers.

All LGMD subclasses must fulfill all of the following:

New nomenclature: change from the alphanumeric system to include the name of the affected protein and mode of inheritance (D for dominant, R for recessive, X for X-linked); examples listed in Table 2.

Some previous LGMD subclasses no longer fulfill the new LGMD definition (Table 3).

MFM is a group of disorders associated with myofibrillar degradation that begins in the Z disk.

Histologically characterized by sarcoplasmic pleomorphic amorphous, granular or hyaline protein aggregates on Gomori trichrome (Fig. 2), and positive for desmin immunostain.

Most contain mutations in Z disk associated protein coding genes: DES, CRYAB, MYOT, ZASP, FLNC, BAG3.

Patients with mutations in FHL1, DNAJB6, HSBP8, TTN, ACTA1, PLEC, and LMNA have also been associated with MFM phenotype.

Autosomal dominant multi-system diseases with the common features of myotonia and progressive muscle weakness. There are two main forms: DM1 and DM2.

DM1 is caused by CTG trinucleotide repeats in the 3′ untranslated region of DMPK. DM1 shows striking anticipation, with age at onset decreasing by 20–30 years per generation.

DM1 muscle pathology is characterized by markedly increased internalized nuclei, often in chains and ring fibers, in a background of chronic myopathy.

DM2 is caused by CCTG repeat expansion in intron 1 of CNBP (ZNF9). Additionally, CLCN1 and SCN4A are disease modifying genes whose mutations may exaggerate DM2 phenotype; they therefore should be included in DM2 genetic screening.

DM2 muscle pathology is characterized by type 2 atrophy and frequent internalized nuclei predominantly in type 2 fibers.

Adeno-associated virus (AAV) based gene delivery vectors can produce replacement proteins in patients with loss of function mutations, such as spinal muscular atrophy (SMA) or Duchenne’s muscular dystrophy. The vector does not integrate into the patient’s genome and has a low immunogenicity.

CRISPR-Cas9-mediated gene editing does incorporate into the patient’s genome and can permanently replace a deleterious mutation in patient with conditions such as hereditary transthyretin-mediated (hATTR) amyloidosis.

Both methods entail only a single intravenous injection and thus have a clear advantage over siRNA based and antisense oligonucleotide (ASO) based therapies, which require serial infusions.

Zolgensma (Novartis) is the first ever FDA approved (2019), intravenously delivered, AAV9 vector mediated SMN gene therapy for spinal muscular atrophy.

NTLA-2001 is a CRISPR-Cas9-mediated gene editing construct that targets hATTR amyloidosis in a phase II–III trial for adults with polyneuropathy or cardiomyopathy (NCT04601051).

SRP-9001 (Sarepta), SGT-001 (Solid Biosciences) and PF-06939926 (Pfizer) are AAV based micro-dystrophin constructs in phase III trials for DMD (NCT03375164, NCT03769116, NCT04281485).

SPK-3006 (Spark Therapeutics) is an AAV based human GAA gene construct in a phase I/II trial for adult onset Pompe disease (NCT04093349).