Targeted Treatments for Inherited Neuromuscular Diseases of Childhood

Alex J. Fay, MD, PhD; Renatta Knox, MD, PhD; Erin E. Neil, DO; Jonathan Strober, MD


Semin Neurol. 2020;40(3):335-341. 

In This Article

Congenital Myasthenic Syndromes, Congenital Myopathies, Congenital Muscular Dystrophies

Congenital myasthenic syndromes (CMS) are inherited disorders of the neuromuscular junction and include dominant and recessive disorders that affect both pre- and postsynaptic function.[52] Clinical manifestations can occur before birth in the most severe cases or cause neonatal or infantile-onset hypotonia, feeding difficulties, episodic apnea, ptosis, and even episodic stridor from vocal cord paresis. Most forms of CMS affect the neuromuscular junction exclusively, without an impact on the heart, including the most common forms resulting from mutations in the muscle acetylcholine receptor subunits. There are rare forms that affect more general synapse functioning (SNAP-25) or glycosylation (ALG2, ALG14, GFPT1) and may affect the CNS.

Small molecule modifiers of neuromuscular transmission, some of which have been employed in autoimmune myasthenia gravis or Lambert–Eaton myasthenic syndrome, often improve muscle fatigability in patients with CMS. These include acetylcholinesterase inhibitors such as pyridostigmine, adrenergic agonists such as albuterol and ephedrine, and the potassium channel inhibitor 3,4-diaminopyridine.[53] There are reports of worsening weakness in patients treated with pyridostigmine, particularly those with mutations in the postsynaptic protein DOK7, in the endplate cholinesterase-binding ColQ and slow channel syndrome. Patients with slow channel syndrome caused by dominant mutations in the acetylcholine receptor subunits that result in slowed inactivation kinetics may benefit from medications with sodium channel blocking activity, including fluoxetine. Pyridostigmine and 3,4-diaminopyridine typically show immediate effect in the first days of treatment, whereas albuterol and ephedrine may take weeks to months to show benefit.

Congenital myopathies and muscular dystrophies have been described as distinct pathological entities, though genetically and mechanistically there is some overlap. Broadly speaking, the dystrophies are progressive disorders that lead to cycles of degeneration and regeneration of muscle fibers, leading to infiltrating immune cells (primarily monocytes) that replace muscle fibers with fat and fibrotic tissue over time. They tend to be caused by mutations in extracellular matrix proteins such as LAMA2 and Col6, or in proteins that glycosylate other extracellular matrix and sarcolemmal proteins (the α-sarcoglycanopathies). These disorders may, in some cases, affect cardiac, brain, or eye function. By contrast, the congenital myopathies are generally caused by mutations in proteins that affect, directly or indirectly, excitation and contraction.[54] This results in small, weak muscle fibers that do not typically show the prominent dystrophic findings of fibrosis and fatty replacement; rather, there are distinct features such as central nuclei, nemaline rods, and central cores or multiminicores that identified these diseases long before the causative genes were identified. Most congenital myopathies are restricted to the skeletal muscles and do not affect the heart or CNS.

Congenital myopathies are an attractive therapeutic target, given that weakness can be relatively nonprogressive compared with the dystrophies. Thus, replacing the defective gene even at older ages might be able to restore significant function to muscle fibers. Preclinical data have been encouraging for X-linked centronuclear myopathy due to mutation of MTM1 in a canine model.[55] Based on these findings, a gene therapy trial is underway for boys with this form of congenital myopathy using an AAV vector. Gene therapy may be feasible for some of the congenital muscular dystrophies as well, such as those caused by mutations in enzymes that glycosylate α-dystroglycan. However, due to limitations in the size of genes that can be packaged into AAV vectors, dystrophies and myopathies caused by loss of function of large genes such as LAMA2, titin, and RYR1 are not currently promising targets for gene replacement. However, CRISPR/Cas9-based gene editing, or even exon skipping approaches with ASOs, offer some promise.[56]