HNRNPDL-related muscular dystrophy: expanding the clinical, morphological and MRI phenotypes

Abstract

Autosomal dominant limb girdle muscular dystrophy D3 HNRNPDL-related is a rare dominant myopathy caused by mutations in HNRNPDL. Only three unrelated families have been described worldwide, a Brazilian and a Chinese carrying the mutation c.1132G>A p.(Asp378Asn), and one Uruguayan with the mutation c.1132G>C p. (Asp378His), both mutations occurring in the same codon. The present study enlarges the clinical, morphological and muscle MRI spectrum of AD-HNRNPDL-related myopathies demonstrating the significant particularities of the disease. We describe two new unrelated Argentinean families, carrying the previously reported c.1132G>C p.(Asp378His) HNRNPDL mutation. There was a wide phenotypic spectrum including oligo-symptomatic cases, pure limb girdle muscle involvement or distal lower limb muscle weakness. Scapular winging was the most common finding, observed in all patients. Muscle MRIs of the thigh, at different stages of the disease, showed particular involvement of adductor magnus and vastus besides a constant preservation of the rectus femoris and the adductor longus muscles, defining a novel MRI pattern. Muscle biopsy findings were characterized by the presence of numerous rimmed vacuoles, cytoplasmic bodies, and abundant autophagic material at the histochemistry and ultrastructural levels. HNRNPDL-related LGMD D3 results in a wide range of clinical phenotypes from the classic proximal form of LGMD to a more distal phenotype. Thigh MRI suggests a specific pattern. Codon 378 of HNRNPDL gene can be considered a mutation hotspot for HNRNPDL-related myopathy. Pathologically, the disease can be classified among the autophagic rimmed vacuolar myopathies as with the other multisystem proteinopathies.

hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its Aggregation

“…The conserved Asp is involved in destabilizing electrostatic interactions and the removal of repulsion by mutation seems to be responsible for the increased propensity of the mutated PrLDs to self-associate and aggregate. Mutation of Asp378 of hnRNPDL to either Asn or His has been associated with LGMD1G (Berardo et al, 2019;Sun et al, 2019;Vieira et al, 2014). As in the case of hnRNPA1 and hnRNPA2, this Asp maps at the PrLD of hnRNPDL (Figure 6A; Navarro et al, 2015) and it is strictly conserved in vertebrates (Figure S7).…”

“…Moreover, hnRNPDL expression is upregulated in different types of cancers, such as prostate cancer, chronic myeloid leukemia, colon cancer, and hepatocellular carcinoma (Zhou et al, 2014;Liu et al, 2007;Wu et al, 2008;Zhang et al, 2018). Finally, genome sequencing of Brazilian, Chinese, Uruguayan, and Argentinian families affected by limb-girdle muscular dystrophy 1G (LGMD1G, or LGMDD3 in the new nomenclature; Straub et al, 2018) detected D378N and D378H point substitutions in HNRNPDL, indicating a mutation hotspot for this disease (Berardo et al, 2019;Sun et al, 2019;Vieira et al, 2014).…”

Differential diagnosis of vacuolar myopathies in the NGS era

“…Sixteen patients showed moderate (affecting <10%), 10 marked (10%–50%) and six severe (>50% of the muscle fibers in the sections examined) myopathic changes including myofibrillar disintegration, non‐subsarcolemmal nuclei, atrophy, basophilia and necrosis. By light microscopy, 16 biopsies exhibited numerous (>10) (rimmed) vacuoles, 10 biopsies had light (1–3) to moderate (3–10) vacuolar defects in the sections examined; in six patients a considerable vacuolar myopathy characterized by large abnormal autophagic vacuoles was evident on the ultrastructural level only (Table 3). In 18 cases, there was additional neurogenic muscle fiber atrophy.…”

Comparison of multifidus degeneration between scoliosis and lumbar disc herniation

“…According to the past literature, the rimmed vacuoles were mostly associated with congenital myogenic diseases, but there were no reports on the high proportion of rimmed vacuoles in LDH and degenerative scoliosis. The rimmed vacuoles are composed of autophagic vacuoles and myeloid bodies [ 22 ], indicating that autophagy occurs in muscle fibers, which is the main cellular pathway for degradation of expired proteins and organelles in eukaryotic cells and the formation of autophagic vacuoles in myopathy is considered to be a secondary reaction due to abnormal lysosomal function [ 23 , 24 ]. There are several conjectures about the formation of rimmed vacuoles, such as oxidative stress response, excess of substrate in normal lysosomes and secondary response to endoplasmic reticulum stress [ 25 ].…”