What are the phenotypic spectrum and disease course of NEB-related nemaline myopathy?

NEB-Related Nemaline Myopathy: Phenotypic Spectrum and Disease Course

NEB-related nemaline myopathy presents across a broad clinical spectrum ranging from severe neonatal forms with life-threatening respiratory failure and early mortality to mild adult-onset forms with subtle proximal weakness, and the disease course is typically static or slowly progressive with respiratory and skeletal complications accumulating over time. 1

Phenotypic Spectrum by Severity

Severe Congenital/Neonatal Form

• Presents with life-threatening generalized weakness in the neonatal period, characterized by profound hypotonia, respiratory distress requiring immediate ventilatory support, and bulbar dysfunction 1, 2.
• Muscle biopsies in the first days of life show significant myofibrillar dissociation, smallness of muscle fibers, and scattered globular rods in approximately one-third of fibers without type 1 fiber predominance 3.
• This form typically results in early mortality due to severe respiratory and cardiac failure 2.
• Contractile performance studies reveal markedly low force generation, correlating with the degree of sarcomeric dissociation 3.

Intermediate Form

• Manifests in infancy with generalized hypotonia, weakness, delayed motor development, and bulbar and respiratory difficulties 4.
• Muscle pathology demonstrates milder sarcomeric dissociation, dispersed or clustered nemaline bodies, and type 1 fiber predominance or uniformity 3.
• Patients present with prominent facial weakness (which may include ptosis), reduced deep tendon reflexes, and diminished muscle bulk 1.
• Proximal muscle weakness is accompanied by impaired respiratory and bulbar muscle function 1.

Mild/Typical Form

• Presents later in childhood or adulthood with subtle proximal muscle weakness and may remain relatively stable for decades 1, 5.
• Muscle biopsies show well-delimited clusters of subsarcolemmal elongated rods and type 1 fiber uniformity without significant sarcomeric alterations 3.
• Some patients may remain asymptomatic or minimally symptomatic until adulthood, with only mild axial and proximal weakness 5.

Disease Course and Progression

General Trajectory

• The overall disease course is typically static or slowly progressive, distinguishing it from progressive muscular dystrophies 1.
• Cognitive function and sensory perception remain preserved throughout the disease course, which helps differentiate nemaline myopathy from congenital muscular dystrophies 1.

Age-Related Progression Patterns

• Motor and swallowing function tend to remain relatively stable across age groups, but respiratory dysfunction and skeletal deformities show clear progression with age 6.
• Proportionally, older patients develop more scoliosis and respiratory dysfunction compared to younger age groups, suggesting disease progression primarily affects these domains 6.
• A critical pitfall: even patients with mild, stable weakness for decades can develop life-threatening respiratory failure, as documented in a case of a 39-year-old woman who remained stable for 25 years before acute decompensation requiring nighttime ventilation 5.

Specific Complications Over Time

Respiratory Involvement:

• Approximately 55% of NEB-related nemaline myopathy patients require ventilatory support 6.
• Respiratory dysfunction progresses more significantly than motor weakness, making regular pulmonary function monitoring essential 6.
• Patients using ventilatory support more commonly have scoliosis and dysphagia compared to those not requiring ventilation 6.

Skeletal Deformities:

• Scoliosis is strongly associated with respiratory dysfunction and becomes more prevalent with age 6.
• The presence of scoliosis correlates with the need for ventilatory support 6.

Bulbar Dysfunction:

• Approximately 32% of patients require G-tube placement due to dysphagia 6.
• A novel finding is triple furrow tongue atrophy, present in approximately half of patients, which directly correlates with dysphagia severity 6.
• Dysphagia is more common among patients requiring ventilatory support 6.

Motor Function:

• Approximately 35% of patients are unable to walk without support 6.
• Impaired force generation and altered thin filament length contribute to progressive motor limitations 4.

Cardiac Considerations

Cardiac disease is uncommon but documented in nemaline myopathy and requires specific monitoring 1:

• In a cohort of 143 patients, six neonates experienced transient heart failure, and one infant developed left-ventricular dysfunction with congenital long-QT syndrome 1.
• Reported cardiac phenotypes include hypertrophic, dilated, and left-ventricular non-compaction cardiomyopathy 1.
• Sudden cardiac death has been reported, necessitating cardiac vigilance 1.
• Cardiac evaluation must be performed before any anesthesia or sedation; if cardiac symptoms are present, re-evaluation within 3–6 months of the procedure is required 1.

Genotype-Phenotype Correlation

• NEB mutations are the most common genetic cause of nemaline myopathy, with nebulin mutations accounting for approximately 50% of genetically diagnosed cases 3.
• The clinical variability with differing age of onset and severity makes diagnosis difficult during infancy 2.
• It is difficult to establish firm genotype-phenotype correlations in NEB-related nemaline myopathy, as phenotypic variability can occur even within family members sharing the same mutation 3.
• The degree of sarcomeric dissociation and contractility efficiency correlates directly with clinical severity, while the percentage of fibers occupied by rods and their subsarcolemmal position appears to inversely correlate with severity 3.

Critical Management Implications

• Neurologists should collaborate with cardiologists experienced in neuromuscular disorders (or at minimum an electrophysiologist or heart-failure specialist) 1.
• For pediatric-onset cases, referral to a pediatric heart-failure specialist is advisable 1.
• During major surgery, cardiac monitoring by an anesthesiologist familiar with neuromuscular disease should be provided at centers equipped with appropriate intensive-care facilities 1.
• The key pitfall is underestimating respiratory risk in seemingly stable patients—even mild phenotypes can develop acute respiratory decompensation after years of stability 5.