Hereditary proximal myopathy with early respiratory failure

Alternate names

ADMERF; Edström Myopathy; Hereditary inclusion body myopathy with early respiratory failure; HMERF; HMERF-ERF; Myofibrillar myopathy with early respiratory failure; Myopathy, proximal, with early respiratory muscle involvement; HIBM-ERF; Hereditary myopathy with early respiratory failure; MFM-titinopathy; Myofibrillar myopathy-titinopathy

Definition

Hereditary myopathy with early respiratory failure (HMERF) is an inherited disease that affects skeletal muscles and muscles that are needed for breathing (respiratory muscles).

Cause

• HMERF is caused by mutations in the TTN gene.
• This gene provides instructions for making a protein called titin.
• Titin plays an important role in muscles the body uses for movement (skeletal muscles) and in heart (cardiac) muscle.
• Within muscle cells, titin is an essential component of structures called sarcomeres.
• Sarcomeres are the basic units of muscle contraction; they are made of proteins that generate the mechanical force needed for muscles to contract.
• Titin has several functions within sarcomeres.
• One of its most important jobs is to act as a backbone in these structures, providing structure, flexibility, and stability.
• Titin also plays a role in chemical signaling and in assembling new sarcomeres.

Gene mutations

• The TTN gene mutations responsible for HMERF lead to the production of an altered version of the titin protein
• It cannot fold into its normal 3-dimensional shape.
• It is unclear why these effects are usually limited to skeletal muscles and respiratory muscles, and do not involve cardiac muscle.
• Rarely, people with the characteristic features of HMERF do not have identified mutations in the TTN gene.
• In these cases, the genetic cause of the condition is unknown.

Inheritance

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Autosomal dominant pattern, a 50/50 chance.

HMERF is typically inherited in an autosomal dominant pattern.

Signs and symptoms

The usual symptoms 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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

30%-79% of people have these symptoms

• Elevated serum creatine kinase(Elevated blood creatine phosphokinase)
• EMG: myopathic abnormalities
• Foot dorsiflexor weakness(Foot drop)
• Increased variability in muscle fiber diameter
• Internally nucleated skeletal muscle fibers
• Limited hip movement
• Muscle fiber splitting
• Neck flexor weakness(Neck flexion weakness)
• Necrotizing myopathy
• Orthopnea
• Reduced vital capacity
• Respiratory insufficiency due to muscle weakness(Decreased lung function due to weak breathing muscles)
• Restrictive ventilatory defect(Stiff lung or chest wall causing decreased lung volume)
• Rimmed vacuoles
• Skeletal muscle atrophy(Muscle degeneration)
• Type 1 muscle fiber predominance

5%-29% of people have these symptoms

• Calf muscle hypertrophy(Increased size of calf muscles)
• Muscle fiber hypertrophy
• Proximal muscle weakness(Weakness in muscles of upper arms and upper legs)
• Tibialis muscle weakness

1%-4% of people have these symptoms

• Achilles tendon contracture(Shortening of the achilles tendon)
• Adult onset(Symptoms begin in adulthood)
• Falls
• Nocturnal hypoventilation
• Scapular winging(Winged shoulder blade)

Diagnosis

The diagnosis of HMERF is established by clinical findings and/or a heterozygous pathogenic variant of TTN gene that encodes the 119th fibronectin-3 domain of titin by molecular genetic testing.<ref>Pfeffer G, Chinnery PF. Hereditary Myopathy with Early Respiratory Failure. 2014 Feb 27 [Updated 2020 Mar 19]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK185330/</ref>

Treatment

• 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.<ref>Pfeffer G, Chinnery PF. Hereditary Myopathy with Early Respiratory Failure. 2014 Feb 27 [Updated 2020 Mar 19]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK185330/</ref>[1].

References

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NIH genetic and rare disease info

• NIH info on Hereditary proximal myopathy with early respiratory failure

Hereditary proximal myopathy with early respiratory failure is a rare disease.

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