TTN – Hereditary Myopathy with Early Respiratory Failure

Titin, encoded by TTN (HGNC:12403), is a giant sarcomeric protein critical for muscle elasticity and structural integrity. Hereditary myopathy with early respiratory failure (HMERF) is an autosomal dominant disorder characterized by adult‐onset muscle weakness, severe respiratory compromise, and distinct myofibrillar inclusions in skeletal muscle biopsies (PMID:20708934).

Multiple unrelated kindreds demonstrate segregation of heterozygous A-band TTN variants with disease. In a large U.S. family, the p.Gly31791Asp mutation co-segregated in 7 affected relatives (PMID:23514108). The recurrent p.Cys31712Arg variant was found in three British pedigrees sharing a common haplotype (PMID:22577218), and an international study described pathogenic TTN mutations in 12 families (19 affected individuals) (PMID:23606733). These data confirm autosomal dominant inheritance with high penetrance.

Genetic analyses reveal a hotspot in the fibronectin III 119 (FN3 119) domain of the A-band. The recurrent c.95134T>C (p.Cys31712Arg) variant has been identified in over 60 probands across diverse populations (PMID:23514108; PMID:30666435). Other reported variants include c.90263G>T (p.Ala18983Thr) and c.107889del (p.Lys35963fs), highlighting allelic heterogeneity (PMID:23446887).

Biophysical studies demonstrate that FN3 119 domain mutations impair proper folding and solubility. Five disease-causing substitutions, including p.Cys31712Arg, reduce domain stability and promote aggregation (PMID:24636144). The mdm mouse, harboring a Ttn rearrangement, exhibits secondary calpain 3 deficiency and progressive muscle degeneration, mirroring human pathology (PMID:11829483).

Muscle pathology is marked by necklace-like subsarcolemmal cytoplasmic bodies, a diagnostic marker with 82% sensitivity and 99% specificity for HMERF among myofibrillar myopathies (PMID:25253871). These inclusions stain for myofibrillar proteins and distinguish HMERF from other myopathies.

Clinically, HMERF presents in mid‐adulthood (mean age ~32 years) often with hypercapnic coma at onset (PMID:20708934). Proximal and distal weakness progresses alongside respiratory insufficiency; up to 32% of p.Cys31712Arg carriers exhibit cardiac conduction abnormalities or cardiomyopathy (PMID:27511179). This spectrum mandates multidisciplinary care including ventilatory support and cardiac surveillance.

In summary, strong genetic and functional evidence defines HMERF as an autosomal dominant titinopathy caused by A-band FN3 119 domain variants. Targeted TTN sequencing, particularly of exons 343/344, is essential for diagnosis. Biochemical and histopathological assays provide confirmatory evidence. Key take-home: genetic testing for TTN enables early detection, informs prognosis, and guides multidisciplinary management of HMERF.

References

• Neuromuscular disorders • 2010 • An Italian case of hereditary myopathy with early respiratory failure (HMERF) not associated with the titin kinase domain R279W mutation. PMID:20708934
• BMC Neurology • 2013 • Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins. PMID:23514108
• Brain • 2012 • Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin. PMID:22577218
• Journal of Neurology, Neurosurgery & Psychiatry • 2014 • Hereditary myopathy with early respiratory failure: occurrence in various populations. PMID:23606733
• Journal of Human Genetics • 2013 • Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure. PMID:23446887
• Neuromuscular Disorders • 2014 • Hereditary myopathy with early respiratory failure is associated with misfolding of the titin fibronectin III 119 subdomain. PMID:24636144
• Genomics • 2002 • The muscular dystrophy with myositis (mdm) mouse mutation disrupts a skeletal muscle-specific domain of titin. PMID:11829483
• Journal of Neurology, Neurosurgery & Psychiatry • 2015 • Necklace cytoplasmic bodies in hereditary myopathy with early respiratory failure. PMID:25253871
• Neurology • 2016 • Cardiac involvement in hereditary myopathy with early respiratory failure: A cohort study. PMID:27511179
• Journal of Neurology • 2019 • Expanding the importance of HMERF titinopathy: new mutations and clinical aspects. PMID:30666435

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