The patient was a 37-year-old woman with Fabry disease (GLA p.R112H) with a medical history of recurrent headache, nausea, vomiting, vertigo, and tobacco use (20 cigarettes/day). Fabry disease was diagnosed in 2005 when she experienced proteinuria, preeclampsia, and hypertension (201/130 mm Hg) during pregnancy (delivered 50 cm, 3.4 kg healthy boy; GLA wild type [WT]). Enzyme replacement therapy was initiated in 2009. The patient enrolled in the phase 3 ATTRACT trial and started migalastat in May 2012 while taking hormonal contraceptives. Two years after initiating migalastat, the patient had proteinuria (2166 mg/24 h) without hypertension (131/68 mm Hg), which persisted (788 mg/24 h a month later). Kidney biopsy results were consistent with existing Fabry disease. A serum pregnancy test and ultrasound confirmed pregnancy (18 weeks' gestation). Migalastat and hormonal contraceptives were stopped; the patient continued to smoke. Fetal MRI was normal at ~29 weeks' gestation. In October 2014, at 37+ weeks' gestation, the patient delivered a 45-cm, 2.29-kg healthy girl (GLA WT). Excepting low birth weight, which may be related to the patient's smoking, pregnancy outcome was normal despite exposure to migalastat for 18 weeks. Migalastat therapy during pregnancy is not advised.
2.1. Study Background
ATTRACT was a phase 3, randomized, open-label, active-controlled study designed to evaluate the efficacy and safety of migalastat HCl (150 mg every other day [QOD]) and ERT in patients with Fabry disease who were receiving ERT and who had an amenable GLA variant. Full methodology is described in Hughes et al. Briefly, eligible patients were randomly assigned to either continue ERT or switch to migalastat HCl (150 mg QOD) for 18 months. After completing the randomized treatment period, patients could participate in a 12-month open-label extension of migalastat HCl (150 mg QOD). Patients of reproductive potential agreed to use medically accepted methods of contraception throughout the duration of the study and for up to 30 days after the last dose of migalastat.
Written informed consent was obtained from all study participants before initiating any study-related procedures. The appropriate ethics committee approved the clinical study protocol at each site and the trial was conducted in accordance with the Declaration of Helsinski.
All clinical chemistry analyses were performed in an International Standardization Organization (ISO) 15189 accredited clinical laboratory at the Department of Laboratory Medicine, Medical University of Vienna. Glomerular filtration rate was estimated (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Analyses of complement-related proteins was performed at the third Department of Internal Medicine, Semmelweis University, Budapest, Hungary. Genetic testing for rare variants in GLA and complement-related genes was performed as previously described.
2.2. Patient History
The patient is a white woman who was diagnosed with Fabry disease in 2005 at 28 years of age.Her father had Fabry disease (generation II), and all 3 surviving siblings (all females) also had Fabry disease (generation III). The patient's medical history prior to migalastat treatment was significant for headache (beginning at 12 years of age ), psoriasis (beginning at 17 years of age), and nausea, vomiting, and vertigo (beginning at 18 years of age). The patient had a history of smoking (since the age of 14) and smoked 20 cigarettes per day. Her first pregnancy, which occurred in 2002 at the age of 25, resulted in a miscarriage during the fifth month (18 weeks' gestation) after having a traffic accident. At 26 years of age, the patient was hospitalized for strong headache and neck pain. At 27, the patient had a second pregnancy. An emergency cesarean delivery was performed at 38+ weeks of gestation due to preeclampsia (blood pressure ≥140/90 mm Hg), proteinuria (urine test for proteinuria was positive), and pelvic abnormalities, which resulted in delivery of a healthy male infant (50 cm, 3.4 kg, GLA WT).
Twenty days postpartum, an increase in 24-hour urine protein (935.9 mg/24 h) was recorded. Then, 1-month postpartum, an increase in 24-hour urine protein, hypertension (210/130 mm Hg), severe neck pain, headache, and edema resulted in a 7-day hospital stay and consultation with a nephrologist. During this time, Fabry disease was diagnosed based on kidney biopsy results and mutational analysis (GLA p.R1112H). For the next 4 years, the patient received no specific Fabry disease treatment, and experienced the occasional occurrence of leg edema and moderate swelling. In March 2009, at the age of 31, the patient experienced a mild increase of proteinuria (from 59 mg/g in September 2007 to 132 mg/g in March 2009) and headaches and was diagnosed with depression.
The patient began treatment with agalsidase alfa via infusion; during therapy, there was no progression of renal, cardiac, or neurological symptoms. Two years later, in 2011, the patient experienced new symptoms of chronic pharyngitis (secondary to tobacco use) and euthyroid goiter (thyroid volume, 31.8 mL). Ongoing psoriasis was treated with psoralen and long-wave ultraviolet radiation (PUVA) phototherapy.
Pedigree analysis. The patient is indicated by the arrow. Black boxes represent males with Fabry disease; circles with black dots represent females with Fabry disease. Slash indicates deceased.
Time course of (a) proteinuria and albuminuria, (b) creatinine, and (c) eGFRCKD-EPI. ACR, albumin-to-creatinine ratio; eGFRCKD-EPI, estimated glomerular filtration rate chronic kidney disease epidemiology collaboration; PCR, protein-to-creatinine ratio.
2.3. Migalastat Treatment and Pregnancy
In May 2012, the patient enrolled in the ATTRACT trial and was randomly assigned to migalastat HCl (150 mg QOD). At enrollment, 24-h urine protein was 83 mg/24 h. In accordance with the study protocol, the patient agreed to use hormonal contraceptives (Diane mite; ovulation inhibitor) for the duration of the study. While enrolled in the study, renal, cardiac, and neurologic assessments conducted through February 2014 showed no evidence of disease progression. In May 2014, after 2 years of migalastat treatment, proteinuria increased sharply from 78 mg/24 h (in February 2014) to 2166 mg/24 h, without hypertension (131/68 mm Hg). A urine pregnancy test was negative. The following month, ongoing proteinuria prompted kidney biopsy, which showed cellular characteristics consistent with existing Fabry disease. A serum pregnancy test result was positive, and pregnancy was confirmed via ultrasound examination (18 + 0 weeks gestation). Migalastat therapy and hormonal contraceptives were stopped; the patient continued to smoke during her pregnancy (20 cigarettes/day).
At 29 weeks' gestation, magnetic resonance imaging indicated normal fetal development. The pregnancy was uneventful, and a healthy female infant was delivered via cesarean section at 37+ weeks of gestation. After delivery, ERT therapy (agalsidase alfa, home infusion) was restarted and is currently ongoing.
Fetal MRI (coronal plane) during pregnancy at 29 weeks' gestation. MRI, magnetic resonance imaging. Images presented with patient permission.
Because the patient had complement C3 staining in her kidney biopsy specimens, serologic and genetic complement analyses were performed. The complement system is an important mediator of kidney injury, and complement activation is associated with a wide variety of kidney diseases. Results showed that the patient had a normal complement profile, was anti-C1q, anti-FH, and C3Nef negative, and had no signs of complement activation or consumption. DNA sequencing revealed no mutations in CFH, CFI, CD62, C3, CFB, THBD, CFHR5, and ADAMTS13; MLPA results showed no disease-causing deletions or duplications of CFH, CFHR1, CFHR2, CFHR3, and CFHR5.