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Transient neonatal myasthenia gravis, i.e., TNMG (also termed neonatal myasthenia gravis), is one of the various forms of myasthenia gravis, i.e., MG. MG is an autoimmune disease in which individuals develop or acquire antibodies in their circulating blood that cause easily fatigable (i.e., weakened after relatively little use) skeletal muscles. The antibodies interfere with acetylcholine-induced activation of the nicotinic acetylcholine receptors located on the skeletal muscles at the sites of their neuromuscular junctions. There are at least 4 types of antibodies that cause this interference. An bind to the acetylcholine receptor in most cases of MG or to the adjacent: a) MuSK protein in uncommon cases of MG, b) low-density lipoprotein receptor-related protein 4 (i.e., LRP4) in rare cases of MG, or c) agrin protein in very rare cases of MG. The binding of these antibodies to their targeted proteins is responsible for an autoimmune attack on the neuromuscular junction that reduces its neuromuscular transmission and thereby skeletal muscle's contractibility.

MG causes fatigable muscle weakness in different areas of the body: a) ocular myasthenia gravis skeletal muscle weakness in the eyes that cause ptosis (i.e., eye lid drooping), weak eye lid closure, ptosis, i.e. double vision, and/or strabismus, i.e., double vision; b) skeletal muscle weaknesses of the arms, legs, trunk, and/or head with cause symptoms of finger and wrist extensions, foot and hand dorsiflexions (backward bending or contracting of hand or foot), and difficulty in raising the arms above the head, getting up from low seats or toilets, walking for prolonged distances, and climbing stairs; and c) bulbar (i.e., involving nerves derived from the lower part of the brain stem termed the medulla oblongata) which cause symptoms such as slurred speech, dysphagia (i.e., difficulty in swallowing), dysphonia (i.e., hoarse voice), bilateral facial nerve weaknesses, jaw weakness, and respiratory muscle weakness that may lead to a myasthenia crisis, i.e., life-threatening respiratory arrest. MG, particularly in long-standing cases, may have two or all three ocular, arm/leg/trunk/head, or bulbar symptoms.

Cause

TNMG is due to the transfer of antibodies against the acetylcholine receptor, MuSK, LRP4, or agrin protein that is circulating in a pregnant mother's blood. This antibody passes through the placenta and into the fetus's circulation. TNMG affects about 1 in 8 children born to mothers who have been diagnosed with myasthenia gravis. In rare cases, a form of TNMG termed fetal acetylcholine receptor inactivation syndrome (also termed FARIS) develops in the fetus. It occurs when maternal antibodies to the acetylcholine receptor are directed at the fetal form of this receptor. The fetal and adult acetylcholine receptors consists of 4 major subunit proteins, (α2, β, γ, δ) and (α2, β, ε, δ), respectively, with the fetal form persisting until its γ subunit is replaced by the ε subunit to form the adult acetylcholine receptor; this occurs by about the 33rd week of gestation. Some publications have termed the more severe forms of FARIS as arthrogryposis multiplex congenita. i.e., AMC.

Symptoms

Prior to birth, a fetus with TNMG may exhibit akinesia, i.e., reductions in or absence of fetal movements. This finding, when present, is the first evidence suggesting that a fetus has TNMG. Otherwise, the onset of symptoms in the neonate is often delayed by 6 to 72 hours or in rare cases up to 4 days after birth. Following this delay, the neonates typically show skeletal muscle hypotonia (i.e., poor muscle tone and weaknesses that are most prominent in head and neck muscles and cause reduced control of swallowing; weak crying, sucking, and chewing; an inability to keep the jaw in place; feeding difficulties; and breathing difficulties which, while rare, can be severe, require mechanical ventilation and, if not treated quickly, be a potentially lethal event (i.e., myasthenia crisis.) However, in the majority of cases TNMG does not involve life-threatening dysfunctions and disappears after the maternal TNMG-causing antibody has dissipated, generally within 3 months of birth.

Fetal acetylcholine receptor inactivation syndrome

In a review of 46 FARIS cases (which included cases that would be classified as the more severe form of FARIS, i.e., AMC): a) half of the mothers had not previously been diagnoses as having MG; ; b) 7 of 46 pregnancies were terminated of pregnancies because of advanced, serious symptoms in the fetus and 4 of the 47 born infants died after birth due to respiratory failure; c) the surviving infants exhibited weakness in or contractures of the bulbar and respiratory skeletal muscles that were prominent early in life but improved over time; and d) 73.5% of facial muscle weaknesses, 43.8% of leg/arm muscle weakness, 75% of velopharyngeal insufficiency speech deficit cases, and 44.4% of feeding difficulty cases commonly after the long-term. Unexpectedly, hearing losses in 37.5% of cases, central nervous system involvement in 17.5% of cases (i.e., autism, language disorder, attention deficit hyperactivity disorder, and/or intellectual impairment), weakness of the diaphragm in 4.3% of cases, and pyloric stenosis in 8.1% of cases were also detected.<ref name="pmid37186601">

All 30 of the mothers acetylcholine receptor antibodies that were evaluated bound more strongly to the fetal than to the adult forms of the skeletal muscle nicotinic acetylcholine receptor;

lasts for about three months . However, in some cases, neonatal MG can lead to other health effects, such as arthrogryposis and even fetal death. These conditions are thought to be initiated when maternal AChR antibodies are directed to the fetal AChR and can last until the 33rd week of gestation, when the γ subunit of AChR is replaced by the ε subunit.

In the FARIS form of NNMG, the mother typically does not have symptoms of MG because her antibodies mainly or exclusively target the fetal acetylcholine receptor. The fetus, however may exhibit a severe form of TNMG with, for example, arthrogryposis, i.e., congenital joint contractures; esophageal atresia, i.e., the esophagus ending in a pouch rather then entering the stomach; polyhydramnios, i.e., excessive amniotic fluid in the amniotic sac; and fetal death.