Transient neonatal myasthenia gravis information

Transient neonatal myasthenia gravis, i.e., TNMG (also termed neonatal myasthenia gravis^[1]), and its more severe form, fetal acetylcholine receptor inactivation syndrome (i.e., FARIS), is one of the various types of myasthenia gravis (i.e., MG).^[2] MG is an autoimmune disease in which individuals form antibodies that circulate in their blood, enter tissues, bind to certain proteins in the neuromuscular junctions of skeletal muscles, and thereby reduce the number or ability of these skeletal muscles to contract when appropriately stimulated by acetylcholine. The affected skeletal muscles are easily fatigable, i.e., weakened after relatively little use. There are 3 types of antibodies that are known to cause TNMG/FARIS: antibodies binding to the adult form of the nicotinic acetylcholine receptor, i.e., adult nAChR, are responsible for most cases of TNMG while antibodies binding to two proteins near these nAChRs, i.e., the MuSK protein and low-density lipoprotein receptor-related protein 4 (i.e., LRP4) are responsible for many of the remaining cases of TNMG.^[3][4][5] Antibodies directed at the fetal form of nAChRs are responsible for all cases of FARIS.^[1][4][5]

MG may present as muscle weakness in different areas of the body: a) ocular MG is skeletal muscle weakness in the eyes that causes ptosis (i.e., eyelid drooping), weak eyelid closure, strabismus (i.e., one eye turned in a direction different from the other eye), diplopia (i.e., double vision), and/or complex ophthalmoplegias (e.g., weakness or paralysis of one or more extraocular muscles responsible for eye movements);^[6][7][8] b) limb/axial MG is skeletal muscle weakness of the arms, legs, trunk, and/or head that causes weak finger extension, wrist drop, foot and hand dorsiflexions (backward bending or contraction of the foot or hand), difficulty in raising the arms above the head, getting up from low seats or toilets, walking long distances, and climbing stairs, and head drop (i.e., relaxing of the neck muscles);^[9][10] and c) bulbar MG is weakness of the skeletal muscles activated by nerves from the lower part of the brain stem termed the medulla oblongata that causes slurred speech, dysphagia (i.e., difficulty in swallowing), dysphonia (i.e., hoarse voice), bilateral facial nerve weakness, jaw weakness, and weaknesses of the respiratory muscles that may lead to a myasthenic crisis, i.e., life-threatening respiratory arrest.^[9][11] MG, particularly in long-standing cases, may have two or all three ocular, limb/axial, or bulbar symptoms.^[9][10][11] MG has also been separated into only two types: ocular MG and generalized MG, i.e., all other types of MG.^[12] MG is caused by antibodies directed at adult nAChR (70-85% of cases), the MUSK protein (1-10 % of cases), or the LRP4 protein (1% to 5% of cases).^[13][14] Uncommonly, individuals present with the symptoms of MG but test negative for antibodies to the nAChR, MuSK, and LRP4 protein, i.e., they have triple seronegative MG. This may be due to laboratory test inaccuracies, decreased antibody production, immunosenescence, previous immunosuppressive therapies, acquired immunodeficiencies, depletion of the antigen attacked by the MG-causing antibody, or other diseases that mimic MG.^[15] It is also possible that other proteins found to be elevated in some cases of MG (i.e., the agrin protein) or some as yet unidentified protein will be found to cause MG.^[14]

TNMG is one form of pediatric myasthenia gravis. Pediatric myasthenia gravis has two other forms which should not be confused with TNMG. Juvenile myasthenia gravis (i.e., JMG) refers to cases of MG that occur in children before the age of 19. It has been diagnosed in children as young as 8 months of age but, unlike TNMG, has not been diagnosed in fetuses (i.e., 9 weeks or older unborn offspring) or newborns.^[12] JMG accounts for about 10–15% of all MG cases and appears to be more prevalent in Asian than white populations, i.e., it represents up to 50% of all TNMG in Asians. Unlike TNMG but similar to MG, JMG is caused by the afflicted individuals production of antibodies directed at adult nAChRs, MuSK, or LRP4. (Individuals with JMG have an increased rate of also having Hashimoto disease, polymyositis, and other autoimmune diseases.^[12][16]) The other form of pediatric myasthenia gravis is termed the congenital myasthenic syndrome, i.e., CMGS. CMGS is not an autoimmune disease. It is a group of rare hereditary disorders in which the neuromuscular transmission in their skeletal muscles is dysfunctional due to the inheritance of defective genes.^[17] The defective genes code for proteins in the neuromuscular junctions that, due to their defects, reduce the number of nAChRs that are functional.^[5] One study reviewed the mutations in 32 genes that were responsible for causing CMGS. These genes' protein products function as ion-channels, enzymes, or structural, signaling, sensor, or transporter proteins in the neuromuscular junctions. The skeletal muscles of individuals with one of these mutations exhibited easy fatigability, hypotonia (i.e., poor muscle tone), weakness, and/or delayed development of facial, bulbar, limb, respiratory, head, and/or back skeletal muscles.^[18] Mutations in the COLQ, CHRNE, RAPSN, Dok-7, and CHAT genes were the most common mutations causing CMGS. None of the reported mutations caused pure ocular myasthenia, i.e., skeletal muscles weaknesses in the eye but not other areas.^[18]