IREB2-associated neurodegeneration.

Abstract

Sir, We read with great interest the report of ‘Absence of iron-responsive element binding protein 2 causes novel degeneration syndrome’ describing a single patient with an apparently new subclass of neurodegenerative disease caused by biallelic variants in iron-responsive element-binding protein 2 (IREB2) (Costain et al., 2019). We also recently identified a patient with bi-allelic variants in IREB2. The male patient died in January 2019 at age 10 years, as a result of progressive neurological disease. The parents provided informed consent to participate in this study, including publication of photographs and videos. Our patient was born at 38 weeks gestation to non-consanguineous parents, weighing 2.9 kg, and with a head circumference of 34 cm. He had conductive and sensorineural hearing loss and a small patent ductus arteriosus. Poor visual fixation, feeding problems, plagiocephaly and hypotonia were noted in the first 3 months. He demonstrated profound developmental delay and was diagnosed with cerebral palsy Gross Motor Function Classification System level IV; he was hypotonic and hyper-reflexic. He was non-verbal but had good facial recognition, a responsive smile, and brief facial expressions. He could reach for toys and scribble on a tablet computer. At his best motor function he mobilized in a supported walker but lost this ability over the final years of his life as he developed mild dystonia and athetosis (Supplementary Video 1). The MRI at 5 months of age showed a thickened corpus callosum. By 24 months of age progressive volume loss was evident, particularly in the frontal lobes (Fig. 1). He had no clinical seizures but an EEG was mildly abnormal, with a slow background and some unusual focal sharp waves over the vertex region that were seen with photic stimulation. Ophthalmological examination showed an alternating exotropia with horizontal nystagmus and slightly pale optic discs. Clinical photograph and selected brain imaging of the patient with biallelic variants IREB2. (A) Facial photograph taken at age 10 years showing mild non-specific dysmorphism including short filtrum, anteverted ears and thick wiry hair. (B) Sagittal T1 MRI at 5 months of age showing plagiocephaly, with no major abnormality, though the corpus callosum is thickened. (C) Sagittal T1 MRI at 24 months of age showing the corpus callosum diffusely thickened and prominent extra-axial spaces. (D) Axial T2-weighted image demonstrating prominent extra-axial spaces suggestive of volume loss, particularly in the frontal lobes. (E) Axial T2-weighted image demonstrating prominent axial spaces suggestive of volume loss, particularly in the frontal lobes, which has progressed from the previous image. Our patient had episodes of neutropenia that were associated with a normal bone marrow aspirate and were responsive to granulocyte-colony stimulating factor. He had recurrent viral infections with gingivitis and ulcers that did not correlate to neutrophil level. For the majority of his life, the full blood count was normal, though at times he had a mild microcytic anaemia. He had an average haemoglobin level of 12.0 g/dl with a mean corpuscular volume never lower than 70 fl. Serum ferritin was always elevated, peaking at 449 µg/l. Serum transferrin and iron levels were normal to low. Although the patient was initially fed orally, oral feeding deteriorated slowly and a nasogastric tube was inserted at 4 years of age. He proceeded to a percutaneous gastrostomy tube. He had multiple episodes of vomiting, some of which were associated with urinary tract infections, and was trialled on anti-emetics, prokinetics and prophylactic antibiotics. Recurrent vomiting led to a trial of feeds via a percutaneous jejunostomy tube and he underwent a fundoplication. In the final year of his life, due to feed intolerance, he spent more time admitted in hospital than at home. He required intravenous analgesia and support for nutrition. He was unable to tolerate hydrolysed feeds even at a slow continuous rate due to abdominal pain and distress. After a period of further weight loss, total parenteral nutrition was trialled in a final effort to provide gut rest, hydration and additional calories. He experienced some comfort off enteral feeds. Ultimately, feeds were unable to be introduced and he died from fungal sepsis and malnutrition. Trio exome sequencing of the patient and his parents was performed as part of the Australian Genomics Acute Care study with Human Research Ethics Committee approval HREC/16/MH251. Massively parallel sequencing was performed using SureSelect QXT CRE exome capture (Agilent Technologies) on a NextSeq 500 sequencer (Illumina, San Diego, CA, USA), with a targeted mean coverage of 100× and a minimum of 90% of bases sequenced to at least 15×. Variants were characterized using the DRAGENTM (Dynamic Read Analysis for GENomics) Bio-IT Platform (Illumina) to generate annotated variant calls within the target region (coding exons ±2 base pa