Nemaline myopathy (NEM, NM) is one of the most common congenital myopathies characterized by hypotonia, weakness and absent deep tendon reflexes. NEM is classified into six forms based on onset and severity of motor and respiratory involvement To date, 10 genes involved in muscle thin filament structure and function, have been linked to NEM: ACTA1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3, NEB, TNNT1, TPM2, TPM3 (Table 1)1.
Autosomal dominant, autosomal recessive
1/50,000 live births1, 9; 1/500 in the Amish community1, 10, 11.
Major clinical symptoms for NEM include the following1:
- Muscle weakness of face, neck and trunk and upper arms and legs (proximal muscle weakness)
- Decreased or absent deep tendon reflexes
- Feeding and swallowing difficulties
- Breathing difficulties and recurrent respiratory infections due to respiratory muscles weakness
- Joint contractures
- Diagnosis of NEM is based on clinical findings and the observation of characteristic rod-shaped structures (nemaline bodies) on muscle biopsy.
- Diagnosis is confirmed by identification of a pathogenic variant in one of the following genes: ACTA1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3, NEB, TNNT1, TPM2, TPM3.
There is no cure for NEM to date, but a number of procedurescould significantly improve the quality of life 1, 15:
- Treatment of lower respiratory tract infections
- Ventilator use for nocturnal hypoxia
- Special feeding techniques
- Physical therapy to help prevent joint contractures
- Speech therapy
- Congenital myasthenic syndromes
- Mitochondrial myopathies
- Prader-Willi syndrome
- Metabolic myopathies (Pompe disease)
- Spinal muscular atrophy
- Seconardy nemaline myopathies, including mitochondrtial myopathy, dermatomyositis, myotonic dystrophy type 1, and Hodgkin’s disease, and in normal human extraocular muscle
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for nemaline myopathy using NGS Panel Genomic:
Step 1: Whole genome sequencing from a single filter card (drop of blood), covering the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the nemaline myopathy . Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no pathogenic variant is identified in Step1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.
- Individuals with a positive family history of nemaline myopathy.
- Individuals with most common symptoms of nemaline myopathy (regardless of family history).
Confirmation of a clinical diagnosis through genetic testing of nemaline myopathy can allow for genetic counseling and may direct medical management.
Overview of the genes in CENTOGENE´s Nemaline myopathy panel
|Protein||% of mutations||Associated and allelic disorders|
|Actin a1 sceletal muscle protein||15%-25% 1, 2, 3 >50% of severe lethal congenital NM 1, 4||Nemaline myopathy 3; Scapulohumeroperoneal myopathy; Actin congenital myopathy; Congenital myopathy with fiber-type disproportion 1|
|Cofilin 2||3 families 1, 5, 6||Nemaline myopathy 7 autosomal recessive|
|Myotubularin||Rare, 5/504 7||Myotubular myopathy X-linked, Centonuclear myopathy X-linked|
|Nebulin||Up to 50% 1, 8 |
Hot spot 2502-bp del (exon 55) in Ashkenazi Jewish 9
|Nemaline myopathy 2, autosomal recessive|
|Troponin T1||Only in Old Amish 1, 10 common Amish nonsense mutation p.Glu180Ter 11||Nemaline myopathy 5 Amish type; Amish Nemaline Myopath|
|Tropomyosin 2||2/54 families (<1%) 1, 12||Nemaline myopathy 4 autosomal dominant; CAP myopathy 2; Arthrogryposis multiplex congenita, distal type 1; Arthrogryposis distal type 2B|
|Tropomyosin 3||3/117 (2%-3%) 1, 13, 14||Nemaline myopathy 1; CAP myopathy 1; Congenital myopathy with fiber-type disproportion|