Rare, congenital, slowly progressive inherited neuromuscular disease that usually is apparent at birth; characterized by extreme hypotonia. No evidence for susceptibility for malignant hyperpyrexia.
Affects females more than males; estimated incidence is 1/50,000 live births except for the Amish form (TNNT1), where the prevalence is 1/500.
Approximately two-thirds of nemaline rod myopathies are sporadic mutations. The most common genetic causes of nemaline myopathy are autosomal recessive mutations in NEB, which encodes nebulin (a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle) and de-novo autosomal dominant mutations in ACTA1, which encodes the skeletal muscle alpha-actin.
The 70th European Neuromuscular Centre (ENMC) International Consortium on Nemaline Myopathy defined six clinical subtypes:
Severe Congenital (Neonatal) Form: Characterized by severe muscle hypotonia with little spontaneous movements, severe dysphagia and absence of sucking ability, and respiratory problems that are considered life-threatening during the first week or month of life. A fetal form (“fetal akinesia sequence”) has been suggested, but is still considered part of this entity. It is associated with large quantity of amniotic fluid, abnormal muscle growth, and underdevelopment of the lungs. Genes affected: ACTA-1, NEB, KLHL 40, LMOD3.
Intermediate Congenital Form (Includes Amish Form): Hypotonia and generalized muscle weakness that appear after a few months of life; important developmental retardation: neither walking nor seating is acquired; scoliosis and muscle contracture with early respiratory failure. Genes affected: NEB, TNNT1.
Mild Congenital or “Typical” Form: Age at onset between birth and the first year of life. It is characterized by extreme muscle weakness, feeding difficulties, delayed motor development (eg, walking difficulties, speech abnormalities), and respiratory complications that are not considered as severe at the neonatal form. The evolution of the disease is often static or very slowly progressive. Most affected individuals can have an active life; others may experience deterioration during the period of rapid growth before puberty. Genes affected: NEB, TMP2, KLHL41.
Childhood-Onset Form: Age at onset between 10 and 20 years. The apparition of proximal muscle weakness is slowly progressive and allows motor development to be considered normal. The clinical symptoms typically progress during childhood, but exercises that increase muscle development and strength may offset the progression of the disease. Genes affected: TMP3.
Late-Onset or Adult-Onset Form: Characterized by the absence of family history or symptomatology before the apparition of the muscle weakness, which is mostly apparent in the extremities and the trunk.
Other Forms of Nemaline Rod Myopathy: These include a mostly cardiac form in cases related to a mutation the ACTA1 gene: dilated cardiomyopathy, congestive heart failure, ventricular rhythm disorders, and an asymptomatic form which is only found at muscle biopsy during familial screening.