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Nemaline Myopathy

Klinische Symptomatik

Nemaline myopathy (NM) is one of the most common forms of congenital myopathy and is characterized by the presence of specific morphological structures in skeletal muscle fibers observed in muscle histology. The diagnostic hallmark of NM is the appearance of distinct rod-like inclusions (nemaline bodies) in the sarcoplasm of skeletal muscle fibers with Gomori trichrome staining. Although the number of rods appears to increase with age, no definitive correlation exists between the number of rods and the severity or age of onset of the myopathy.

NM is a genetically and clinically heterogeneous disorder, clinically manifesting with varying phenotypes, with onset in childhood or, rarely, in adulthood. To date, mutations in seven genes have been described, following different patterns of inheritance. Notably severe forms of NM often are simplex, resulting from de novo dominant mutations.

Clinical features:

Muscle weakness, usually slowly progressive, is most severe in proximal limb, facial, and respiratory muscles, often accompanied by ptosis. Many children with NM have hypermobility of joints in infancy and early childhood; contractures and deformities of the joints, including scoliosis, commonly develop in time. Dysarthria and dysphagia are common; deep tendon reflexes are depressed or absent. The congenital form of NM clinically manifests as “floppy infant syndrome” often accompanied by respiratory insufficiency and difficulties with sucking and swallowing. In congenital forms of NM, a long "myopathic" and expressionless face is usual with a tent-shaped mouth, a high, arched palate, and retrognathia. Due to multiple contractures, the phenotype of congenital forms of NM often overlap with arthrogryposis multiplex congenital (AMC). Gross motor milestones are delayed, but most affected individuals are otherwise developmentally normal. Serum creatine kinase levels are usually within the normal range but are sometimes mildly to moderately higher than normal.

The existing classification of NM into different forms is based on age of onset, severity, and the distribution of muscle weakness and respiratory involvement:

Severe congenital (neonatal) NM (15 % of all individuals with NM): This form of NM presents at birth with severe hypotonia and profound muscle weakness, little spontaneous movement and difficulties with sucking and swallowing. In retrospect, decreased fetal movements in utero are common. Many patients with severe NM die soon after birth because of respiratory insufficiency or aspiration pneumonia.

Amish NM (1 : 500 in the Amish community; c.538G>T; p.Glu180X in TNNT1) is also evident at birth with hypotonia, contractures and, remarkably, with tremors which typically subside within the first two to three months of life. Early mortality within the second year of life is common.

Intermediate congenital NM (20 % of all individuals with NM): Muscle weakness is evident at birth but, in contrast to the severe congenital form, patients show spontaneous movements. The early development of joint contractures is characteristic and patients are included in this subgroup if weakness prevents achievement of motor milestones or necessitates use of a wheelchair and/or ventilator support by age 11.

Typical congenital NM (45 % of all individuals with NM) is often evident at birth or during the first year of life with hypotonia, muscle weakness and feeding difficulties. Like patients with the intermediate form of NM spontaneous movements are present but no contractures or fractures. Patients often have an expressionless face and a nasal voice due to the affected facial and bulbar muscles. Respiratory involvement is less prominent but may be subclinical, manifesting as frequent lower respiratory tract infections. Muscle weakness is usually proximal and static or very slowly progressive. Most patients are able to live rather normal, independent, active lives. 

Childhood-onset NM (15 % of all individuals with NM): Patients with childhood-onset NM show normal early development. Later, during the first or early second decade they experience the onset of symmetric weakness of ankle dorsiflexion. Remarkably, they move in "slow motion" and are unable to jump or run. Muscle weakness is slowly progressive without facial, respiratory or cardiac involvement.

Adult-onset (late-onset) NM (5 % of all individuals with NM): These patients can display a variety of symptoms and varying disease progression. Most develop generalized muscle weakness between the ages of 20 and 50 without prior symptoms or family history, which may progress rapidly. A typical hallmark of this kind of NM may be myalgia. Respiratory and cardiac involvement is uncommon but, when present, often occurs in association with increasing weakness and physical disability.


To date, mutations in 8 genes (ACTA1, NEB, TPM3, TPM2, TNNT1, CFL2, KBTBD13, KLHL40) have been identified, all of which (with the exception of KBTBD13 and KLHL40) code for components of sarcomere filaments. Nemaline myopathy can follow an autosomal dominant or an autosomal recessive pattern of inheritance, depending on the causative gene and the particular mutation. In approximately half of all cases, the disease occurs sporadically (with no family history of the disease); these cases are often caused by autosomal dominant de novo mutations.

  • Mutations in ACTA1 and NEB are the most common cause of NM.
  • A total of approximately 15 to 25 % of all affected patients have a mutation in the gene ACTA1. Genetic mutations in this gene are especially common in the severe congenital forms of the disease and account for approximately 50 % of these cases. These cases are often caused by autosomal dominant de novo mutations. Both autosomal dominant and autosomal recessive patterns of inheritance have been described in familial cases, as has high phenotype variability (even within single families).
  • Mutations in the unusually large gene NEB are responsible for approximately 50 % of all cases of nemaline myopathy. Mutations in this gene follow an autosomal recessive pattern of inheritance.
  • Mutations in TPM3 are responsible for approx. 2-3 % of cases. Patients in which nemaline bodies are found in only slow type 1 muscle fibers or for whom fiber type disproportion is the only histological abnormality should be tested for mutations in this gene.
  • An analysis of TPM2 should be considered for mild, dominant cases of NM.
  • Mutations in the genes TNNT1 and CFL2 are rare. 
  • In terms of founder mutations in particular ethnic groups, a mutation in TNNT1 (c.538G>T; p.Glu180X) is found in patients of Amish decent (carrier frequency 1: 500); a 2502bp deletion of exon 55 in the gene NEB is found in patients of Ashkenazy Jewish decent (carrier frequency 1: 100).
  • Mutations in the gene KLHL40 have been described in cases of severe congenital NM with an autosomal recessive pattern of inheritance. Patients with prenatal symptoms and/or contractures should also be tested for mutations in this gene.

1 : 50 000

Methodik Next Generation Sequencing (NGS)

Parallele Sequenzierung mehrerer Gene

Material 2-4 ml EDTA-Blut
3-6 Wochen


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