Dermatomyositis (DM)

• A classication 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-specic autoantibody is

present, or if denitive DM muscle biopsy

features are present and are combined with

clinical signs of proximal muscle weakness or

elevated muscle enzymes.

- Denitive DM muscle biopsy ndings: perifas-

cicular atrophy and/or perifascicular MxA

overexpression (Fig. 1) with rare or absent peri-

fascicular necrosis.

- Suggestive DM muscle biopsy ndings:

lymphocytic inltrates (often perivascular), evi-

dence of perifascicular disease (perifascicular

predominant bers that are pale on COX

staining and/or positive on NCAM staining).

- DM specic autoantibodies: Mi2, NXP2,

TIF1

, MDA5, SAE. Patients are subclassied

according to that autoantibody (e.g., anti-

TIF1

DM, anti-NXP2 DM). Patients who

have DM without a DM-specic autoantibody

are subclassied as having “autoantibody

negative DM.”

Antisynthetase syndrome (ASyS)

Issue 21 || December 2022

WHAT’S NEW IN

NEUROMUSCULAR

PATHOLOGY 2022:

MYOPATHY UPDATES

AND GENE THERAPIES

Chunyu Cai

Department of Pathology, University of Texas

Southwestern Medical Center, Dallas, TX, USA

Corresponding Author: Chunyu Cai, MD, PhD

Department of Pathology, University of Texas

Southwestern Medical Center, Dallas, Texas, USA

E-mail: Chunyu.Cai@utsouthwestern.edu

ORCID

Chunyu Cai

https://orcid.org/0000-0001-8808-4779

Abstract

This compilation of new changes in the diagnosis

and treatment of muscle and nerve disease is

extracted from the latest publications from the

European Neuromuscular Centre International

workshops, FDA.gov and clinicaltrials.gov.

MYOPATHY UPDATES

Classiﬁcation of idiopathic

inﬂammatory myopathies (IIM)

• European Neuromuscular Centre (ENMC)

clinico-sero-pathological classication divides

IIM into 4 subclasses, which are associated with

myositis specic 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.

• Dened by the presence of an antibody to

aminoacyl tRNA synthetase (ARS), together

with a single or combination of the following

clinical manifestations:

- Myositis

- Polyarthritis

- Interstitial lung disease

- Mechanic hands

- Raynaud phenomenon

• ASyS patients with a DM-like rash are not

classied as DM, but as “ASyS with a DM-like

rash.”

• Pathology is characterized by:

- Perifascicular pathology with necrotic myo-

bers and nonnecrotic bers with sarcolemmal

C5b-9 (MAC) expression

- Perimysial connective tissue with substantial

edema, fragmentation, and mixed mononucle-

ar inammation

- MHC1 sarcoplasmic expression and nuclear

actin inclusions in myobers

Immune mediated necrotizing

myopathies (IMNM)

• Anti-HMGCR and anti-SRP autoantibodies

are considered specic for IMNM.

• Patients with anti-HMGCR antibody and a

DM-like rash will be classied as having

“anti-HMGCR myopathy with a DM-like

rash,” while patients with anti-SRP antibody

and a DM-like rash will be classied as having

“anti-SRP myopathy with a DM-like rash.”

• Pathology requires diffusely scattered necrotic

bers at different stages of resolution and

macrophage dominant, pauci-lymphocytic

inammation.

Sporadic inclusion body myositis

(sIBM)

• The pathologic criteria for sIBM include:

- Endomysial T cell inammation with invasion

of non-necrotic bers

- Rimmed vacuoles

PathologyOutlines.com

WHAT’S NEW

IN PATHOLOGY?

Sponsored by an unrestricted grant from Roche

Fig. 1. Sarcoplasmic MxA expression is considered a

sensitive and speciﬁc marker for dermatomyositis.

Table 1. IIM subtypes and their associated autoantibodies

Dermatomyositis (DM) Mi2, NXP2, TIF1

, MDA5, SAE

Inclusion body myositis (IBM) cN1A*

Immune mediated necrotizing myopathy (IMNM) SRP, HMGCR

Anti-synthetase syndrome (ASys) Jo-1, PL7, PL12, EJ, OJ, KS, Zo, Ha

*MSAs are usually mutually exclusive and speciﬁc for IIM subclasses, with the exception of cN1A

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 pheno-

type.

Myotonic dystrophy (DM1/DM2)

• 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 bers, 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

Fig. 2. Myofibrillar myopathy on Gomori trichrome

stain.

- P62 or TDP-43 positive protein aggregates or

15-18 nm laments (tubulolamentous

inclusions) on electron microscopy

• 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 nger exors and knee extensors.

• Usually refractory to immunosuppressive

therapies.

Limb girdle muscular dystrophies

(LGMD)

• The denition and nomenclature of LGMD

have been re-dened in the 2017 ENMC

international workshop as a genetically inher-

ited condition that primarily affects skeletal

muscle leading to progressive, predominantly

proximal muscle weakness at presentation

caused by a loss of muscle bers.

• All LGMD subclasses must fulll all of the

following:

- Described in at least two unrelated families

- Patients have achieved independent walking (to

differentiate from congenital muscular

dystrophies)

- Elevated serum creatine kinase

- Degenerative changes on muscle imaging over

the course of disease

- Dystrophic changes on muscle histology,

ultimately leading to end-stage pathology

• New nomenclature: change from the alphanu-

meric 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

fulll the new LGMD denition (Table 3).

Myoﬁbrillar myopathies (MFM)

• MFM is a group of disorders associated with

myobrillar degradation that begins in the Z

Dr. Chunyu Cai has been part of the

PathologyOutlines.com editorial board and

the Deputy Editor in Chief for Neuropathology

since 2020. He is a pathologist and an

Associate Professor at University of Texas

Southwestern Medical Center. His research

focuses on neuromuscular diseases and brain

tumors.

Meet the Author

in DM2 genetic screening.

• DM2 muscle pathology is characterized by type

2 atrophy and frequent internalized nuclei

predominantly in type 2 bers.

GENE THERAPIES

Gene replacement therapies for

hereditary neuromuscular diseases

• Adeno-associated virus (AAV) based gene deliv-

ery vectors can produce replacement proteins in

patients with loss of function mutations, such

as spinal muscular atrophy (SMA) or Duch-

enne’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.

FDA approved gene therapy for

neuromuscular diseases

• Zolgensma (Novartis) is the rst ever FDA

approved (2019), intravenously delivered,

AAV9 vector mediated SMN gene therapy for

spinal muscular atrophy.

New gene therapies currently in clinical

trials

• NTLA-2001 is a CRISPR-Cas9-mediated gene

editing construct that targets hATTR amyloi-

dosis in a phase II-III trial for adults with

polyneuropathy or cardiomyopathy

(NCT04601051).

• SRP-9001 (Sarepta), SGT-001 (Solid Biosci-

ences) and PF-06939926 (Pzer) 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).

Table 2. Old vs new LGMD nomenclature

Previous name Gene New name

LGMD 1D DNAJB6 LGMD D1 DNAJB6-related

LGMD 1I CAPN LGMD D4 Calpain3-related

LGMD 2A CAPN LGMD R1 Calpain3-related

LGMD 2B DYSF LGMD R2 Dysferlin-related

Table 3. Previous LGMD subtypes that are no longer considered LGMD

Previous name Gene New name

LGMD 1A MYOT Myoﬁbrillar myopathy

LGMD 1B LMNA Emery–Dreifuss muscular dystrophy

LGMD 1C CAV3 Rippling muscle disease

LGMD 1E and 2R DES Myoﬁbrillar myopathy

LGMD 1H unknown n/a

LGMD 2V GAA Pompe disease/acid maltase deﬁciency

n/a, not available