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Nemaline myopathy

This is part of Rare diseases.

Diagnosis: Nemaline myopathy

Synonyms: --

Innehåll


Date of publication: 2014-03-24
Version: 2.0

ICD 10 code

G71.2

The disease

Nemaline myopathy is a congenital muscle disease, first described in 1963 by two independent research teams headed by G. M. Shy and P.E. Cohen, respectively. The condition belongs to a group of diseases known as congenital myopathies. “Nemaline” comes from the Greek word for thread, “nema”, and refers to the characteristic threadlike rods present in affected muscle fibres. The main symptoms of nemaline myopathy are to a large extent the same as those of other congenital myopathies, and include muscle weakness and low muscle tone (hypotonia). The severity of symptoms varies between individuals, ranging from neonates with severe muscle weakness and low muscle tone in large areas of the body, to individuals who develop mild symptoms in adulthood.

Occurrence

The number of people with the disease in Sweden is unknown. In Finland the estimated incidence rate is two per 100,000 live births, which, assuming the same rate applies to Sweden, indicates two new cases a year.

Cause

In nemaline myopathy, rod-like structures develop and accumulate in muscle fibres. Here they impair the action of contractile elements, called sarcomeres, in the muscle fibres. How and why these rod-like structures develop has not yet been fully explained, but it is known that genetic mutations which control the formation of proteins in the sarcomeres can cause the disease. In simple terms, sarcomeres consist of both thin and thick filaments which, when they slide past each other, cause the muscle to contract.

To date (2013), the mutations which have been identified are located on eight different genes. All of them control the formation of proteins which are components of sarcomeres. When their function is impaired, muscle contraction is disrupted, leading to muscle weakness.

Gene Protein Gene location Heredity
ACTA1 skeletal muscle α-actin 1q42.13 autosomal dominant or recessive
TPM2 β-tropomyosin 9p13.3 autosomal dominant
TPM3 α-tropomyosin slow 1q21.3 autosomal dominant or recessive
NEB nebulin 2q23.3 autosomal recessive
TNNT1 troponin 19q13.42 autosomal recessive
CFL2 cofilin 14q13.1 autosomal recessive
KBTBD13 Kelch repeat and BTB domain-containing protein 13 15q22.31 autosomal dominant
KLHL40 Kelch-like 40 3p.22.1 autosomal recessive

Table: Mutations causing nemaline myopathy.

Heredity

The inheritance pattern of nemaline myopathy can be either autosomal dominant or autosomal recessive. An autosomal dominant pattern of inheritance means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it down.

Figure: Autosomal dominant inheritance

An autosomal recessive inheritance pattern means that both parents are healthy carriers of a mutated gene. In each pregnancy with the same parents there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent). In this case the child will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

Symptoms

The primary symptoms are muscle weakness and low muscle tone. The severity of the disease varies significantly between individuals, even if they are members of the same family. It is mainly the muscles in the face, the neck, the upper arms, the thighs, the shoulders and pelvic girdle (the proximal musculature) which are affected. In some individuals, the lower legs and forearms (distal muscles) are also involved, especially in the later stages of the disease. The muscles governing respiration (the muscles of the diaphragm and rib cage) are often weak, while muscles which control the movements of the eyes and eyelids are not affected. The level of muscle weakness usually remains stable, or its progression is very slow. The disease is currently divided into six groups, categorized according to severity and age of onset:

The most severe forms (types 1 to 3) are present at birth or in the foetal stage. Children’s symptoms include very severe, generalized muscle weakness and low muscle tone so they may not be able to move their arms and legs, or may be able to perform only minimal spontaneous movements. Breathing difficulties are common and a ventilator is usually needed, at least in the short term. Muscle weakness also causes sucking and swallowing difficulties, and a nasal feeding tube is often necessary. The mother may have noticed a lack of foetal activity during pregnancy and excessive amounts of amniotic fluid may have caused pregnancy complications. The most severe forms of the disease often cause death in early infancy but some children live longer, although their respiration and/or ability to walk are impaired.

Typical congenital form (type 4) is the most common variant and symptoms include muscle weakness, low muscle tone, and sucking and swallowing difficulties, which are usually evident at birth or develop during the first year of life. Breathing problems are less severe than in types 1 to 3. During their first few years of life, children with the typical form are often susceptible to respiratory tract and pulmonary infections.

Muscle weakness mainly affects facial, neck, shoulder and pelvic regions as well as the upper arms and thighs. Motor development is usually delayed, but most children learn to walk. Later in life, muscles in the underarms, lower legs, hands and feet may be affected. However, cardiac involvement is very rare. Joint hypermobility is common in early life, but later, limitations in joint mobility (contractures) may develop.

Children with types 1 to 4 have a characteristic appearance, with a long, thin face and a triangular-shaped mouth. Facial muscles may be affected, resulting in a receding lower jaw (mandibular retrognathy), causing swallowing and speech problems. The voice sometimes becomes nasal.

Muscle weakness is non-progressive or progresses very slowly. Many people with the typical form of the disease therefore live relatively normal, active lives. Some women with nemaline myopathy have undergone pregnancy and delivery without major complications.

There is another form of the disease, type 5, which presents in childhood, and is mainly characterized by muscle weakness in the hands and feet. More generalized muscle weakness may develop at a later stage of the disease.

Type 6 is an adult-onset form, usually presenting between the ages of 20 and 50. This variant is characterized by more rapid disease progression than the typical form, and its first symptom is sometimes heart failure, caused by damage to the muscles of the heart.

Diagnosis

If a muscle disease is suspected, a neurophysiological evaluation is performed including analyses of peripheral nerve conduction (NC), muscle function (EMG), and the blood concentration of creatine kinase (CK). In nemaline myopathy, peripheral nerve conduction is normal, but the EMG test reveals signs of muscle disease. Creatine kinase levels in the blood are often normal or only slightly elevated. MRI (magnetic resonance imaging) scans can show which muscle groups are affected by the disease. Certain types of nemaline myopathy are associated with damage to specific muscle groups, information which can be taken into account before a muscle biopsy.

The diagnosis is confirmed with a muscle biopsy, where a tissue sample is taken from an affected muscle, under local or general anaesthetic. Under a microscope it is possible to identify the rod-like structures, called the nemaline bodies, which characterize the condition. An electron microscope can be used to further magnify the sample, enabling a more detailed analysis.

As nemaline bodies may be present in some other muscle diseases, symptoms should always be considered in conjunction with test results before a diagnosis is made.

DNA-based diagnosis is often possible. In such cases it is possible to identify precisely which genetic mutation has caused the disease in an individual, and its pattern of inheritance. At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD) in association with IVF (in vitro fertilization), are available in families where the mutation is known.

Treatment/interventions

There is as yet no cure for nemaline myopathy, and efforts are directed at alleviating symptoms and compensating for disabilities as far as possible. At delivery, newborns with the most severe forms of the disease usually require immediate medical intervention. Initially a ventilator is used to help with breathing, and a feeding tube is often necessary. Breathing problems increase the risk of respiratory tract infections. Prophylactic care should include bacterial and viral pneumonia vaccinations. Any sign of pneumonia should be taken seriously and treated as promptly as possible.

While growing up, children with the disease require contact with various specialists including a paediatric neurologist and a paediatric orthopaedic surgeon. Treatment is then directed at supporting physical functions which are negatively affected by muscle weakness. Early contact should be established with a habilitation team, which includes professionals with special expertise in how disability affects everyday life, health and development. Help is available within the medical, educational, psychological, social and technical fields. Habilitation may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. It also includes information about support offered by public services as well as advice on the way accommodation and other environments can be adapted to the child’s needs. Parents and siblings and others close to the child may also receive support.

Many people with the condition have hypermobility of the joints early in life but later, joint mobility may be impaired causing contractures, joint deformities and pathological curvature of the spine (scoliosis). If people with nemaline myopathy are followed up carefully these abnormalities can be discovered early and further damage halted or slowed by the introduction of stretching exercises, braces (orthoses) and in some cases surgical procedures. The value of more active forms of physical therapy in building strength and endurance in people with muscle diseases is poorly documented, and is a much-debated issue. There is evidence that low-intensity exercise is not harmful and probably has positive effects on muscle function as well as on the prevention of contactures. However, weight training and highly intensive exercise resulting in fatigue should be avoided, as there is a risk that they may cause the disorder to progress more rapidly. Swimming (backstroke) and water exercise or play, are suitable forms of exercise.

Mobility aids may be necessary. For example, surgical braces (orthoses) can make it easier to walk. A manual wheelchair may be necessary or, in cases of more severe muscular weakness, an electric wheelchair. Occupational therapists, physiotherapists, and assistive technology consultants provide and try out assistive devices.

The environment should be adapted to the needs of the individual, and an occupational therapist in collaboration with staff from the local public services can make necessary changes. Such collaboration can also be necessary in making adjustments to the school and, later, the work environments.

People with problems swallowing or speaking should be assessed and, if necessary, treated by a speech/language therapist.

Psychological support adapted to age and maturity should be available continuously while the child is growing up. Even small children need their questions answered.

Adults with nemaline myopathy should maintain regular contact with a neurologist, and a habilitation/rehabilitation team consisting of an occupational therapist, a physiotherapist, a psychologist, a social worker and a speech therapist. Lung function should be monitored and if there are signs that it is impaired, the use of a ventilator should be considered. Many patients benefit from home ventilator therapy using a night-time breathing mask, while others require round-the-clock help with respiration. Breathing exercises help clear secretions from the lungs, thereby reducing the risk of respiratory tract infections.

If swallowing problems are severe a gastric feeding tube, surgically inserted through the abdominal wall and into the stomach (percutaneous endoscopic gastrostomy, PEG) may be considered. In this way, nutrition or nutritional supplements can be given directly into the stomach. The heart is not usually affected but cardiac function should nevertheless be regularly checked.

Practical advice

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National and regional resources in Sweden

At Swedish university hospitals in Gothenburg, Linköping, Lund - Malmö, Stockholm, Umeå, Uppsala and Örebro there are specialist medical teams to assess and treat children with muscular diseases.

In Gothenburg, Linköping, Stockholm and Örebro there are specialist neuromuscular units for adults with muscular diseases.

Muscle teams for children and adolescents

The Muscle Team, Paediatric Community Habilitation Service in Central Östergötland, Torkelbergsgatan 14 D, SE-582 25 Linköping, Sweden. Tel: +46 10 103 70 07.

The Muscle Team, Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

The Muscle Team, Neuropaediatric Unit, Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 774 67.

The Muscle Team, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel:+46 18 66 30 00.

REMUS, the regional muscle team of the Skåne region paediatric habilitation services. Contact via the local habilitation services.

Muscle teams for adults

Neuromuscular Centre, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden. Tel: +46 31 342 10 00.

Neurology Clinic, Karolinska University Hospital, Solna, SE-171 77 Stockholm, Sweden. Tel: +46 8 517 700 10. Also Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

Neuromuscular Unit, Linköping University Hospital, SE-581 85 Linköping, Sweden. Tel: +46 10 103 00 00.

Muscle Centre, Örebro University Hospital, SE-701 85 Örebro, Sweden. Tel: +46 19 602 10 00.

Other points

Expertise in orofacial problems can be found at Mun-H-Center, Institute of Odontology, Medicinaregatan 12A, SE-413 90 Gothenburg, Sweden. Tel: +46 31 750 92 00, email: mun-h-center@vgregion.se, www.mun-h-center.se.

Resource personnel

Associate Professor Christopher Lindberg, Neuromuscular Centre, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden. Tel: +46 31 342 10 00, email: christopher.lindberg@vgregion.se.

Senior Physician Eva Kimber, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 23 03.

Professor Tomas Sejersen, Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 777 00.

Professor Már Tulinius, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Courses, exchanges of experience, recreation

Ågrenska is a national competence centre for rare diseases and its families’ programme arranges stays for children and young people with disabilities and their families. Ågrenska is open to families from the whole of Sweden and focuses particularly on the needs of children and young people with rare diseases. A number of programmes every year is also provided for adults with rare diseases. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Organizations for the disabled/patient associations etc.

RBU, The Swedish National Association for Disabled Children and Young People, St Eriksgatan 44, Box 8026, SE-104 20 Stockholm, Sweden. Tel: +46 8 677 73 00, fax: +46 8 677 73 09, email: info@riks.rbu.se, www.rbu.se. There is a group within RBU which focuses on muscular diseases. Contact RBU for further information.

Neuro Sweden, Box 49084, St Eriksgatan 44, SE-100 28 Stockholm, Sweden. Tel: +46 8 677 70 10, email: info@neuroforbundet.se, www.neuroforbundet.se. Neuro Sweden contains a diagnosis group focusing on neuromuscular diseases.

Courses, exchanges of experience for personnel

During the Ågrenska Family Program weeks, training days are organized for personnel working with the children and young people who are participating. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Research and development

Research into nemaline myopathy is under way in a number of research groups in Sweden, Finland and the rest of Europe, North America and Australia. The latest results are published in reports from the European Neuromuscular Centre (ENCM), which organizes workshops where researchers meet and exchange their findings.

In two new (2013) published articles, during animal and human trials treatment involving supplements of L-tyrosine (an amino acid) was shown to have a positive effect on musculature. This applies to the forms of nemaline myopathy which are caused by mutations in ACTA1.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under, “Mer hos oss” in the column on the right-hand side.

Newsletter from Ågrenska on nemaline myopathy, nr 429 (2013). Newsletters are edited summaries of lectures delivered at family and adult visits to Ågrenska. They may be ordered from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. They are also available at www.agrenska.se.

Literature

Agrawal PB, Greenleaf RS,Tomczak KK, Lehtokari VL, Wallgren-Pettersson C, Wallefeld W et al. Nemaline myopathy with minicores caused by mutation of the CFL2 gene encoding the skeletal muscle actin-binding protein cofilin-2. Am J Hum Genet 2007; 80: 162-167.

Ilkovski B, Cooper ST, Nowak K, Ryan MM, Yang N, Schnell C et al. Nemaline myopathy caused by mutations in the muscle alfa-skeletal actin gene. Am J Hum Gen 2001; 68: 1333-1343.

Jungbluth H, Sewry CA, Counsell S, Allsop J, Chattopadhyay A, Mercuri E et al. Magnetic resonance imaging of muscle in nemaline myopathy. Neuromuscul Diord 2004; 14: 779-784.

Laing NG, Dye DE, Wallgren-Pettersson C, Richard G, Monnier N, Lillis S et al. Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1). Hum Mutat 2009; 30: 1267-1277.

Nguyen MA, Joya JE, Kee AJ, Domazetovska A, Yang N, Hook JW et al. Hypertrophy and dietary tyrosine ameliorate the phenotypes of a mouse model of severe nemaline myopathy. Brain 2011; 134: 3513-3526.

North KN, Laing NG, Wallgren-Pettersson C. The ENMC international consortium on nemaline myopathy. J Med Genet 1997; 34: 705-713.

North KN, Laing NG, Wallgren-Pettersson C. Nemaline myopathy: current concepts. J Med Gen 1997; 34: 705-713.

Ohlsson M, Tajsharghi H, Darin N, Kyllerman M, Oldfors A. Follow-up nemaline myopathy in two patients with novel mutations in the skeletal muscle alfa-actin gene (ACTA1). Neuromusc Disord 2004; 14: 471-475.

Pelin K, Donner K, Holmberg M, Jungbluth H, Muntoni F, Wallgren-Pettersson C. Nebulin mutations in autosomal recessive nemaline myopathy: an update. Neuromusc Disord 2002; 12: 680-686.

Ravenscroft G, Miyatake S, Lehtokari VL, Todd EJ, Vornanen P, Yau KS et al. Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy. Am J Hum Genet 2013; 93: 6-18.

Ryan MM, Schnell C, Strickland CD, Shield LK, Morgan G, Iannacone ST et al. Nemaline myopathy: a clinical study of 143 cases. Ann Neurol 2001; 50: 312-320.

Ryan MM, Sy C, Rudge S, Ellaway C, Ketteridge D, Roddick LG et al. Dietary L-tyrosine supplementation in nemaline myopathy. J Child Neurol. 2008; 23: 609-613.

Sambuughin N, Yau KS, Olivé M, Duff RM, Bayarsaikhan M, Lu S et al. Dominant mutations in KBTBD13, a member of the BTB/Kelch family casue nemaline myopathy with cores. Am J Hum Genet 2010; 87: 842-847.

Sparrow JC, Nowak KJ, Durling HJ, Beggs AH, Wallgren-Pettersson C, Romero N et al. Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1). Neuromuscul Disord 2003; 13: 519-531.

Wallgren-Pettersson, Laing NG. 138th ENMC International Workshop: Nemaline Myopathy, 20-22 May 2005, Naarden, The Netherlands. Neuromusc Disord 2006; 16: 54-60.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: nemaline myopathy

GeneReviews (University of Washington)
www.genetests.org (select GeneReviews, then Titles)
Search: nemaline myopathy

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Dr Monica Ohlsson, Sahlgrenska University Hospital in Gothenburg, Sweden.

Associate Professor Christopher Lindberg, Sahlgrenska University Hospital, has revised the material.

The relevant organizations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2014-03-24
Version: 2.0
Publication date of the Swedish version: 2013-12-10

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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