Hereditary myopathy with early respiratory failure (HMERF) is a rare myopathy resulting from a mutation on the TTN region of the titin gene. A case report and a thorough review of PubMed-reported cases were conducted. A 53-year-old man reported progressive lower extremity weakness and dyspnea. On examination, he had steppage gait and muscle strength was reduced in lower limb muscles. Electromyography showed myopathic findings in iliopsoas and gastrocnemius muscles. A lumbar magnetic resonance imaging demonstrated patchy fatty atrophy of iliopsoas and lumbar paraspinals muscles. Next-generation sequencing revealed a heterozygous titin gene (TTN) mutation c.95187 G > C (p.Trp31729Cys) consistent with the diagnosis of HMERF. Fifty-eight patients of HMERF (14-78 years old) were identified. The earlier age of onset was 14 years. Most patients presented with limb muscle weakness but 11 began with an initial respiratory complaint. On average, patients required noninvasive ventilation 5.5 years postsymptom onset. HMERF should be considered in the differential diagnosis of an adult with concomitant respiratory and limb muscle weakness.

Hereditary myopathy with early respiratory failure (HMERF) is a rare autosomal dominant disorder caused by TTN variants. COL4A5 mutations are linked to X-linked Alport syndrome. A 34-year-old male developed progressive lower limb weakness, gait disturbance, nocturnal hypoventilation, and calf hypertrophy. Family history revealed similar symptoms in his mother and sister. Examination showed absent reflexes; MRI demonstrated muscle atrophy and fatty replacement; needle electromyography (EMG) was performed and showed findings consistent with advanced myopathy; however, it was not used as a primary diagnostic tool. Whole-exome sequencing identified a pathogenic TTN variant (c.95126C > G, p.Pro31709Arg), confirming HMERF. A hemizygous COL4A5 variant (c.4891C > T, p.Arg1631Cys) was also detected but lacked clinical correlation. This case illustrates a classic HMERF phenotype confirmed genetically, with an incidental COL4A5 variant of uncertain significance. It underscores the importance of genomic testing in atypical neuromuscular presentations and the need for cautious interpretation of incidental findings.

Titin is critical for sarcomere structure and function, and mutations in this gene cause titinopathies, a group of neuromuscular disorders. Muscle MRI is a key tool for diagnosing and understanding these conditions. This study aims to compare the muscle involvement patterns in two autosomal dominant, adult-onset titinopathies: Tibial Muscular Dystrophy (TMD) and Hereditary Myopathy with Early Respiratory Failure (HMERF). In this multicenter, cross-sectional study, lower limb MRI scans were analyzed for 17 patients with TMD and 15 with HMERF. Clinical and demographic data were collected from medical records. Muscle fat replacement was assessed using a modified Mercuri score for 30 muscles per patient. Two independent evaluators reviewed the images. Heatmaps were used to visualize asymmetry and patterns of fat replacement. Statistical analysis included Cliff's delta and random forests to distinguish muscle involvement between TMD and HMERF, and Spearman's rho to explore correlations between fat replacement and disease duration. HMERF showed extensive, severe fat replacement, particularly in muscles like the semitendinosus, obturator externus, and gluteus minimus, with distinct intramuscular patterns. In contrast, TMD presented more localized fat replacement, primarily affecting the tibialis anterior and extensor digitorum longus. Both conditions exhibited mixed patterns of muscle replacement and preservation. Random forests confirmed differential muscle involvement, and fat replacement correlated with disease duration more strongly in HMERF than in TMD. This systematic MRI analysis reveals distinct muscle involvement patterns in TMD and HMERF, providing insights into the differential progression of these titinopathies.

Neuromuscular diseases can present with acute respiratory failure with no other symptoms. A 30-year-old woman presented with progressive dyspnoea, culminating in respiratory failure requiring critical care admission for non-invasive ventilation. On examination, she had proximal and distal muscle weakness with bilateral scapular winging. An MR scan of the muscle showed selective fatty replacement in the semitendinosus, tibialis anterior and peroneus longus muscles. Muscle biopsy identified rimmed vacuoles, core-like structures and desmin-positive aggregates. Genetic testing identified a novel heterozygous missense mutation (c.95350G>A, p.Ala31784Thr) in the fibronectin type-III 119 domain of the TTN gene, leading to the diagnosis of hereditary myopathy with early respiratory failure (HMERF). Her muscle weakness has since progressed over 3 years, and she still depends on non-invasive ventilation. Clinicians should consider HMERF in adults presenting with unexplained respiratory failure.

Titinopathies are heterogenous group of disorders affecting the skeletal and cardiac muscles variably and caused by Titin (TTN) gene mutations located in Chromosome 2. The manifestations extend from congenital to adult-onset myopathies. Here we describe the phenotype-genotype heterogeneity of patients with myopathy/muscular dystrophy associated with TTN variants in an Indian cohort. A retrospective descriptive study of 12 patients diagnosed with primary muscle disease evaluated between 2016 and 2023 harboring rare TTN variants. Eight patients were included (M:F ratio - 3:1). The median age at onset of entire cohort is 5 (range: birth- 33 years). The major clinical phenotypes were congenital myopathy [n = 3, 37.5%], juvenile onset myopathy [n = 3, 37.5%] and adult AD - Hereditary myopathy with early respiratory failure (HMERF) phenotype [n = 2, P6, P8; 25%]. Prominent / wide first interdigital space in feet in congenital and juvenile forms (c.38421_38437delinsC, c.106531 + 1G > A) was a novel feature. The variant c.95134T > C previously reported in HMERF in British population, was noted in two patients in our cohort and with GNE myopathy like phenotype in one. Muscle MRI done in congenital myopathy (c.26201-1G > A) showed fatty infiltration of anterior and posterior thigh with sparing of gracilis, adductor magnus and tibialis anterior. This is the first Indian study with a large cohort demonstrating many novel mutations and clinical heterogeneity expanding the spectrum of titinopathies. Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support about ten years after onset. The phenotype varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s. The diagnosis of HMERF is established in a proband with typical clinical findings and/or a heterozygous pathogenic variant in the region of TTN that encodes the 119th fibronectin-3 domain of titin on molecular genetic testing. Treatment of manifestations: Management is supportive. For distal leg weakness, use of ankle-foot orthoses can optimize independent ambulation early in the disease course; later in the disease course other mobility aids (canes, walkers, or wheelchairs) may be required. Noninvasive ventilation with bilevel positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP) may be indicated for nocturnal hypoventilation initially, followed by mechanical ventilatory support as needed. Influenza vaccination, occupational therapy, and social service support are important. Surveillance: Reassessment of muscle strength and clinical status annually by a neurologist; pulmonary function testing every six to 12 months, or guided by individual findings. Pregnancy management: Although the onset of symptoms usually occurs after the age of childbearing, a pregnant woman with early manifestations of HMERF or at risk for HMERF should be considered high-risk because of the associated respiratory muscle weakness and the increased physiologic demands of pregnancy. Consultation with a high-risk maternal-fetal medicine specialist is recommended when possible. HMERF is inherited in an autosomal dominant manner with variable expressivity. Most individuals diagnosed with HMERF have an affected parent; to date, de novo pathogenic variants have not been reported in any individuals with genetically confirmed HMERF. Each child of an individual with HMERF has a 50% chance of inheriting the pathogenic variant. If the pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.