Genetic and Clinical Spectrum of GNE Myopathy in Russia

Abstract

GNE myopathy (GNEM) is a rare hereditary disease, but at the same time, it is the most common distal myopathy in several countries due to a founder effect of some pathogenic variants in the GNE gene. We collected the largest cohort of patients with GNEM from Russia and analyzed their mutational spectrum and clinical data. In our cohort, 10 novel variants were found, including 2 frameshift variants and 2 large deletions. One novel missense variant c.169_170delGCinsTT (p.(Ala57Phe)) was detected in 4 families in a homozygous state and in 3 unrelated patients in a compound heterozygous state. It was the second most frequent variant in our cohort. All families with this novel frequent variant were non-consanguineous and originated from the 3 neighboring areas in the European part of Russia. The clinical picture of the patients carrying this novel variant was typical, but the severity of clinical manifestation differed significantly. In our study, we reported two atypical cases expanding the phenotypic spectrum of GNEM. One female patient had severe quadriceps atrophy, hand joint contractures, keloid scars, and non-classical pattern on leg muscle magnetic resonance imaging, which was more similar to atypical collagenopathy rather than GNEM. Another patient initially had been observed with spinal muscular atrophy due to asymmetric atrophy of hand muscles and results of electromyography. The peculiar pattern of muscle involvement on magnetic resonance imaging consisted of pronounced changes in the posterior thigh muscle group with relatively spared muscles of the lower legs, apart from the soleus muscles. Different variants in the GNE gene were found in both atypical cases. Thus, our data expand the mutational and clinical spectrum of GNEM.

Keywords: GNE myopathy; Nonaka myopathy; atypical cases; hereditary inclusion body myopathy.

Figure 1

Mutational spectrum of GNEM in Russia. (a) Distribution of all detected variants; (b) Distribution of novel causative variants on the scheme of the GNE gene, and (c) Place of birth of 26 out of 27 unrelated patients with variants in the GNE gene are presented on the map of the Russian Federation. One patient was from Kazakhstan, but she identified her ancestry as Russian. Three variants were detected in a homozygous state (those families are identified as full-colored signs). Other variants were revealed only in a compound heterozygous state (those families are identified as half-colored signs). Only one variant, p.Ala57Phe, is clustered in neighboring regions of Russia.

Figure 2

Hands of GNEM patients. Prominent atrophy of hand muscles, especially first dorsal interosseus, are noted with arrows.

Figure 3

Muscle MRI data in the cohort of GNEM patients. The scores and colors represent the severity of fat infiltration of skeletal muscle according to the scale published by Mercuri et al. [23] Gl Max—gluteus maximus; Gl Med—gluteus medius; Gl Min—gluteus minimus; VL—vastus lateralis; VI—vastus intermedius; RF—rectus femoris; VM—vastus medialis; Sa—sartorius; Gr—gracilis; AL—adductor longus; AM—adductor magnus; ST—semitendinosus; SM—semimembranosus; BFL—biceps femoris caput longum; TA—tibialis anterior; TP—tibialis posterior; PL—peroneus longus; GC—gastrocnemius; So—soleus; n/a— not applicable.

Figure 4

The patient No. 8.1. with atypical GNEM. (a) Genealogy; (b) Hand muscle atrophy and hand joint contractures; (c) Lower limb muscle atrophy; (d) Keloid scars on the left thigh and left arm; (e) T1-weighted and T2-STIR muscle MR-images of the lower limbs.

Figure 5

The patient No. 18.1. with atypical GNEM. (a) Genealogy; (b) Hands and left lower arm muscles’ atrophy, asymmetrical atrophy of lower leg muscles; (c) T1-weighted muscle MR-images of the pelvic girdle and lower limbs.