The emerging spectrum of fetal acetylcholine receptor antibody-related disorders (FARAD)

Figures

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  Figure 1. Clinical features in offspring with fetal acetylcholine receptor antibody-related disorders (FARAD) at different time points. The offspring of myasthenic mothers with antibodies to the (fetal) acetylcholine receptor has a wide spectrum of features, ranging from lethal arthrogryposis multiplex congenita (AMC) (A–D) to less severe contracture phenotypes (F and H–J). Congenital hypotonia and facial weakness (E) are common. Respiratory impairment requiring (non-invasive) ventilation (G) and bulbar involvement requiring nasogastric tube feeds (F, G and L–N) are common. Less common features include diaphragmatic paresis (K) and extraocular muscle involvement (L). Later in life, persistent facial weakness with a myopathic facial appearance (O, P and T–V, and X), incomplete eye closure and an inverted V-shaped mouth are common. Facial weakness may at least be partially responsive to treatment with oral salbutamol (W). Significant jaw contractures (Q and R, 3D CT reconstruction) in more severely affected patients, and scoliosis (Y and Z, 3D CT reconstruction) can occur. A small proportion of children may have a longer ventilatory and enteral feeding requirement (N).

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  Figure 2. Maternal acetylcholine receptor antibody results. Fetal (f) and adult (ad) acetylcholine receptor (AChR) antibody titres varied considerably. The figure shows representative cell-based assays (CBAs) from two mothers with (A, Case 2.1) very high fAChR binding scoring 3 even at 1:1600 dilution compared with almost undetectable binding to adAChR at 1:50 dilution; the mother shown in B (Case 9) had less fAChR antibodies but more adAChR antibodies than the mother in A. Titres of all sera binding to fetal (red) and adult (black) AChRs, tested by CBAs, are shown in C, with the ratio of fetal to adult titres illustrating the variability.

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  Figure 3. Correlation between maternal immunotherapy during pregnancy and outcome in offspring. (A) Comparison of overall rate (%) and reduction of major clinical features (complications) in the maternally-administered immunotherapy during pregnancy (pIMT) group compared to those with no pIMT (*P < 0.05). (B) Devised score to reflect the mode and timing of treatment during pregnancy (Supplementary Table 3) showing the relative proportion of deaths decreased with the intensity of treatment (P < 0.05), and (C) no deaths observed with a treatment score above 15. Similar trends were seen for other major features (Table 3 and Supplementary Tables 2 and 5).

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  Figure 4. Illustrative case scenarios showing effect of pregnancy immunotherapy on outcome. The main determinants of outcome are the mode and timing of immunotherapy during pregnancy, with plasmapheresis (PLEX) and intravenous immunoglobulin (IVIG), alone or in combination with moderate-high dose steroids, early in the pregnancy most effective. Poor outcomes/death seen with less effective (or ineffective) interventions; intermediate outcomes are highlighted in orange; good outcomes are clear. (A) Family 41(H) illustrates poor outcome [severe arthrogryposis multiplex congenita (AMC) and death] in two untreated pregnancies, but good outcome in the third pregnancy treated with combination of high dose prednisolone and PLEX in early gestation (aTNMG-like but details of longer follow-up not available). (B) Family 23(F) illustrates better outcome in the second (orange) and good outcome in the third pregnancies treated with IVIG and PLEX from Trimester 1 onward respectively, compared to the first pregnancy with poor outcome, where similar treatments were administered only from Trimester 3 onwards. (C) Family 11 illustrates that the outcome may not be invariably severe even in untreated…