Hereditary myopathy with early respiratory failure (HMERF).
The diagnosis was confirmed by gene analysis showing a heterozygous titin gene (TTN) mutation g.284701T > C (p.Cys31712Arg) in the FN3 119 domain in the A-band region (ENST00000589042).
HMERF is a hereditary myopathy caused by mutations in the A-band region of TTN.(1, 2) Since the causative gene was reported in 2012, an increasing number of patients with HMERF have been identified worldwide.(4)
HMERF is clinically characterized by adult-onset muscle weakness with respiratory insufficiency from an early, typically ambulant stage of the disease. A common initial symptom is gait disturbance because of distal (especially the anterior compartment) and/or proximal lower limb muscle weakness. Weakness of ankle dorsiflexion is prominent, leading to easy tripping and foot drop. There is no or minimal, if any, weakness in the upper limbs at disease onset. Respiratory insufficiency subsequently appears after a median of six years post-onset (range: 0 - 16 years)(4), although respiratory symptoms can be the initial manifestation in 24% - 36% of patients.(1, 4) Most patients are ambulant when they need nocturnal ventilation.(1) Till date, clinically evident primary cardiomyopathy has not been reported in patients with HMERF, although right heart failure secondary to severe respiratory failure is occasionally observed. Nevertheless, a recent study found cardiac conduction abnormalities in 32% (7/22) of patients with the p.Cys31712Arg mutation of TTN and imaging evidence of otherwise unexplained asymptomatic cardiomyopathy in 18% (4/22). (5)
Skeletal muscle imaging demonstrates that the semitendinosus muscles and the anterior compartment of the lower legs (preferentially, the peroneus longus muscles) are selectively involved in the early stage.(1, 2, 4) Indeed, the selective involvement of the semitendinosus muscles is often observed (93% - 100%) (2, 4). The pattern is a radiological clue for diagnosis of HMERF, although it can be observed in other muscle diseases, including desminopathy, alpha-B-crystallinopathy, and anoctaminopathy.(3)
The pathological hallmark of HMERF is necklace cytoplasmic bodies; at cross section, a number of cytoplasmic bodies are often circumferentially aligned in the subsarcolemmal region in muscle fibers, mimicking a necklace.(4) The finding of necklace cytoplasmic bodies is highly specific for HMERF (sensitivity: 82%, specificity: 99%).(4) Rimmed vacuoles are also sometimes observed but less specific.
Since TTN encodes the largest known protein consisting of 35,991 amino-acid polypeptides in 363 exons among those recognized so far, sequence analysis of all the exons requires considerable labor. Even if next generation sequencing is available for the genetic analysis, it would still be difficult to determine which variant is truly pathogenic because TTN is a highly polymorphic gene. Despite this, all HMERF patients reported so far carry a mutation in exon 343 encoding the FN3 119 domain in the A-band region (ENST00000589042). Therefore, exon 343 should be considered as the primary target for genetic diagnosis of HMERF.
When a patient shows the pathological finding of necklace cytoplasmic bodies, sequencing of exon 343 of TTN should be considered for definite diagnosis of HMERF, even though the patient does not exhibit respiratory problems at that time. If the patient has a mutation in exon 343 of TTN, the patient will eventually develop a severe respiratory insufficiency. Early diagnosis of the disease would enable earlier recognition of asymptomatic respiratory insufficiency and appropriate intervention without delay (e.g., nocturnal ventilation).
We thank Ms. Kaoru Tatezawa and Ms. Kanako Goto for their technical assistance. This study was supported partly by JSPS KAKENHI Grant Number of 24659437; partly by Research on Rare and Intractable Diseases, Comprehensive Research on Disability Health and Welfare and Applying Health Technology from the Ministry of Health, Labour and Welfare of Japan; and partly by Intramural Research Grant 23-5 and 26-8 for Neurological and Psychiatric Disorders of NCNP.
Contributed by Akinori Uruha, MD, PhD, Yukiko K. Hayashi, MD, PhD, Madoka Mori-Yoshimura, MD, PhD, Yasushi Oya, MD, Masahiro Kanai, MD, Miho Murata, MD, PhD, Ichizo Nishino, MD, PhD