H. Lewis

Nemaline myopathy

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Keywords ICD 10: G71.2; OMIM: 161 800, 256 030, 605 355; Synonyms: NM, rod myopathy, congenital rod disease, nemaline rod myopathy
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Nemaline myopathy (NM) is a rare congenital myopathy that affects males and females. The incidence is estimated at 1 in 50,000 live births.

NM is a genetic disorder (with the exception of sporadic late onset NM, which is an autoimmune disorder) with pathogenic variants that are either sporadic de-novo or else inherited in either an autosomal recessive or dominant fashion. Pathogenic variants in 11 genes have been identified, accounting for approximately 75% of the total genetic burden of the disease (see table). Recessive variants in the nebulin (NEB) gene are the most common cause and account for 50 % of the cases, while ACTA1 variants are the common dominant/de-novo cause (15–25 %). Muscle biopsy shows the presence of ‘nemaline bodies’, or rod-like structures. Nemaline bodies are extensions of the Z disc and may include aggregates of proteins such as alpha-actinin and actin. The cause of weakness in the majority of NM cases is abnormal thin filament function, including reduced thin filament length and impaired actin-myosin cross bridging. Of note, NM likely exists on a pathological spectrum and some patients with mutations in NM associated genes may have biopsies that, instead, show a congenital fibre-type disproportion or a mixed pattern with cores and rods.

The disease is clinically heterogeneous and can be divided into six clinical subtypes based on age of onset and severity. These subtypes are: severe congenital, Amish type, intermediate congenital, typical congenital, childhood-onset and adult-onset. The severe congenital and Amish type are life limiting and affected individuals typically do not survive beyond early childhood due to respiratory failure. The typical congenital type is the most common. It is mild and non-progressive, presenting with hypotonia, extremity weakness, and feeding difficulties in infancy. The childhood-onset and adult-onset are mild and present later. There are some genotype-phenotype correlations, with LMOD3, KLHL40, and KLHL41 related NM associated with the severe congenital subtype. NEB related NM can present with a range of severity, though most commonly it is associated with typical congenital NM. ACTA1 NM exhibits the most extreme variability, with individual presentations ranging from foetal akinesia and severe congenital to mild adolescent or adult onset. Important: with ACTA1, there can be variable expressivity even within families.

About 50 % of the adult forms are acquired and associated with the presence of a benign monoclonal gammopathy of undetermined significance (MGUS): they show good therapeutic response to corticotherapy with or without azathioprine or a bone marrow graft.

Clinical manifestations include craniofacial (high-arched palate, micrognathia, retrognathia, dental malocclusion and cleft palate) and musculoskeletal (kyphosis, scoliosis, talipes, pectus excavatum and pes cavus) abnormalities. Rarely it is associated with cardiac lesions; either congenital (atrial septal and/or ventricular septal defect, patent ductus arteriosus, aortic regurgitation or infundibular pulmonary stenosis) or direct involvement of the cardiac muscle leading to cardiomyopathy. Cardiac disease has been described in only certain genotypes, such as NEB11 (due to myopalladin mutation) and a small subset of ACTA1 patients. 

Anaesthetic considerations are a potentially difficult airway (bag-mask ventilation and intubation), difficult intravenous access (due to contractures), poor respiratory reserve, potentially underappreciated chronic hypercapnia, risk of aspiration (potentially leading to pulmonary infection) and cardiac dysfunction. There is no convincing evidence of an association between NM and malignant hyperthermia. While no specific concerns have been noted in NM, neuromuscular blocking agents are best avoided (given the potential risk of exacerbating respiratory muscle weakness). In genetically undefined cases, particularly if there is biopsy evidence of cores with rods, MH precautions are logical. This is because pathogenic variants in RYR1 have been described in a small number of cases of core-rod myopathy or pure NM, and RYR1 variants are also a common cause of congenital fibre-type disproportion. However, if RYR1 variants have been excluded, there is no evidence to support MH risk associated with the other 11 known NM genetic subtypes.