Mild phenotype of CHAT-associated congenital myasthenic syndrome: case series.

Congenital myasthenic syndrome with episodic apnea is associated with pathogenic variants in the CHAT gene. While respiratory disorders and oculomotor findings are commonly reported in affected individuals, a subset of patients only present with muscle weakness and/or ptosis but not apneic crises. In this case series, we describe five individuals with exercise intolerance caused by single nucleotide variants in the CHAT gene. The age of onset ranged from 1 to 2.5 years, and all patients exhibited a fluctuating course of congenital myasthenic syndrome without disease progression over several years. Notably, these patients maintained a normal neurological status, except for the presence of abnormal fatigability in their leg muscles following prolonged physical activity. We conducted a modified protocol of repetitive nerve stimulation on the peroneal nerve, revealing an increased decrement in amplitude and area of compound muscle action potentials of the tibialis anterior muscle after 15-20 min of exercise. Treatment with 3,4-diaminopyridine showed clear improvement in two children, while one patient experienced severe adverse effects and is currently receiving a combination of Salbutamol Syrup and pyridostigmine with slight positive effects. Based on our findings and previous cases of early childhood onset with muscle fatigability as the sole manifestation, we propose the existence of a mild phenotype characterized by the absence of apneic episodes.

X-Linked Myotubular Myopathy in a Female Patient with a Pathogenic Variant in the MTM1 Gene.

X-linked centronuclear myopathy is caused by pathogenic variants in the MTM1 gene, which encodes myotubularin, a phosphatidylinositol 3-phosphate (PI3P) phosphatase. This form of congenital myopathy predominantly affects males. This study presents a case of X-linked myotubular myopathy in a female carrier of a pathogenic c.1261-10A>G variant in the MTM1 gene.

Expanding the Phenotype of Hereditary Congenital Facial Paresis Type 3.

The HOXB1 gene encodes a homeobox transcription factor pivotal in the development of rhombomere 4. Biallelic pathogenic variants in this gene are associated with congenital facial paresis type 3 (HCFP3). Only seven single nucleotide variants have been reported in the literature to date. Here, we report a 27-year-old female with a unique presentation of HCFP3 with two novel compound-heterozygous missense variants: c.763C>G, p.(Arg255Gly), which arose de novo and an inherited c.781C>T, p.(Arg261Cys) variant. The patient exhibited HCFP3 symptoms with mild upward esodeviation and lacked the documented ear malformations common in HCFP. For many years, she was misdiagnosed with facio-scapulo-humeral muscular dystrophy, due to complaints of shoulder girdle and neck muscle weakness. No alternative genetic or acquired causes of neck and shoulder girdle weakness were found, suggesting its potential inclusion in the phenotypic spectrum.

Genetic and Clinical Spectrum of GNE Myopathy in Russia.

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.

The Presentation of Two Unrelated Clinical Cases from the Republic of North Ossetia-Alania with the Same Previously Undescribed Variant in the COL6A2 Gene.

Here, we described three affected boys from two unrelated families of Ossetian-Digor origin from the Republic of North Ossetia-Alania who were admitted to the Research Centre for Medical Genetics with unspecified muscular dystrophy. High-throughput sequencing was performed and revealed two novel frameshift variants in the COL6A2 gene (NM_001849.3) in a heterozygous state each in both cases: c.508_535delinsCTGTGG and c.1659_1660del (case 1) and c.1689del and c.1659_1660del (case 2). In two cases, the same nucleotide variant in the COL6A2 gene (c.1659_1660del) was observed. We have suggested that the variant c.1659_1660del may be common in the Ossetian-Digor population because two analyzed families have the same ancestry from the same subethnic group of Ossetians). The screening for an asymptomatic carriage of the nucleotide variant c.1659_1660del in 54 healthy donors from Ossetian-Digor population revealed that the estimated carrier frequency is 0.0093 (CI: 0.0002-0.0505), which is high for healthy carriers of the pathogenic variant. Molecular genetic, anamnestic data and clinical examination results allowed us to diagnose Ullrich muscular dystrophy in those affected boys. Genetic heterogeneity and phenotypic diversity of muscular dystrophies complicate diagnosis. It is important to make a differential diagnosis of such conditions and use HTS methods to determine the most accurate diagnosis.

Congenital myopathy as a new phenotype caused by two undescribed variants in ASCC1 gene.

We present a patient with congenital myopathy and an inborn epiphysiolysis of the ulna. Whole-exome sequencing analysis revealed two novel mutations in Activation Signal Cointegrator Complex 1 (ASCC1) gene in a compound heterozygous state-a splicing variant c.395-2A>G and a deletion of the first two coding exons. Homozygous and compound heterozygous LoF variants in ASCC1 gene lead to a severe phenotype of spinal muscular atrophy with congenital bone fractures 2 (SMABF2). All patients described to date presented with a severe muscular hypotony, inborn fractures, and passed away shortly after birth while our proband had moderate hypotony, no fractures, but epiphysiolysis and he was 3.5 years old at the time of examination. To explain the phenotype of our patient, we performed an RNA analysis of all family members. We discovered that the c.395-2A>G variant results in two aberrant mRNA isoforms. We also validated the deletion of two exons in ASCC1 gene that lead to the increased expression of this truncated transcript by 1.8 times. To investigate the possible impact of this deletion on the phenotype we predicted a new Kozak sequence in exon 4 that could lead to the formation of a truncated protein with shortened KH domain and a full RNA ligase-like domain. We suggest that this unexpectedly different phenotype of the proband with ASCC1-related disorder could be explained by the presence of the truncated protein with an increased expression.

The First Russian Patient with Native American Myopathy.

Congenital myopathy associated with pathogenic variants in the STAC3 gene has long been considered native American myopathy (NAM). In 2017, the first case of a non-Amerindian patient with this myopathy was described. Here, we report the first Russian patient with NAM. The patient is a 17-year-old female with compound-heterozygous single nucleotide variants in the STAC3 gene: c.862A>T, p.(Lys288Ter) and c.93del, p.(Lys32ArgfsTer78). She has a milder phenotype than the earlier described patients. To our knowledge, this is the first case of a patient who had both nonsense and frameshift variants. It is assumed that the frameshift variant with premature stop codon lead to nonsense-mediated RNA decay. However, there are two additional coding isoforms of the STAC3 gene, which are not affected by this frameshift variant. We can speculate that these isoforms may partially carry out the function, and possibly explain the milder phenotype of our patient.