Kathleen M. Gorman

Case Report: Benefits and Challenges of Long-term Eculizumab in Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is caused by dysregulation of the complement system, leading to complement overactivation. A humanized anti-C5 monoclonal antibody, eculizumab, has been available for the treatment of aHUS since 2011. The long-term safety and efficacy of this novel drug in the pediatric population remain under review. We present a child with a hybrid CFH/CFHR3 gene who, having had multiple disease relapses despite optimal treatment with plasma exchange, commenced eculizumab therapy in August 2010. She remains relapse free in follow-up at 52 months, and treatment has been well tolerated. The risk of meningococcal disease during this treatment is recognized. Despite vaccination against meningococcal disease and appropriate antibiotic prophylaxis, our patient developed meningococcal bacteremia 30 months into treatment. She presented with nonspecific symptoms but recovered without sequelae with appropriate treatment. We recommend that children be vaccinated against invasive meningococcal infection before beginning eculizumab therapy and take appropriate antibiotic prophylaxis during treatment, and we suggest that vaccine responses should be checked and followed annually. Clinicians need to maintain a high index of suspicion for invasive meningococcal disease. Neither vaccination nor antibiotic prophylaxis provides complete protection in patients on eculizumab therapy. The appropriate dosage of eculizumab needed to achieve remission in aHUS in the pediatric population is unknown. Having achieved remission in our patient, we monitor eculizumab and CH50 levels to evaluate ongoing blockade of the terminal complement cascade. Such information may help guide dosing intervals in the future.

NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy.

Next‐generation sequencing has accelerated the identification of disease genes in many rare genetic disorders including early‐onset epileptic encephalopathies (EOEEs). While many of these disorders are caused by neuronal channelopathies, the role of synaptic and related neuronal proteins are increasingly being described. Here, we report a 6‐year‐old girl with unexplained EOEE characterized by multifocal seizures and profound global developmental delay. Recessive inheritance was considered due to parental consanguinity and Irish Traveller descent. Exome sequencing was performed. Variant prioritization identified a homozygous nonsense variant in the N‐ethylmaleimide‐sensitive factor attachment protein, beta (NAPB) gene resulting in a premature stop codon and 46% loss of the protein. NAPB plays a role in soluble N‐ethylmaleimide‐sensitive fusion attachment protein receptor (SNARE)‐complex dissociation and recycling (synaptic vesicle docking). Knockout mouse models of the murine ortholog Napb have been previously reported. These mice develop recurrent post‐natal epileptic seizures in the absence of structural brain changes. The identification of a disease‐causing variant in NAPB further recognizes the importance of the SNARE complex in the development of epilepsy and suggests that this gene should be considered in patients with unexplained EOEE.

Status dystonicus in two patients with SOX2-anophthalmia syndrome and nonsense mutations.

Status Dystonicus in Two Patients with SOX2-Anophthalmia Syndrome and Nonsense Mutations Kathleen M. Gorman,* Sally A. Lynch, Adele Schneider, Dorothy K. Grange, Kathleen A. Williamson, David R. FitzPatrick,** and Mary D. King Department of Neurology and Clinical Neurophysiology, Temple Street Children’s University Hospital, Dublin 1, Ireland Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 1, Ireland Clinical Genetics, Temple Street Children’s University Hospital, Dublin 1, Ireland Genetics Division, Einstein Medical Center, Philadelphia, Pennsylvania Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom

Bacillus Calmette–Guérin Scar Erythema: “Haloing” the Diagnosis in Kawasaki Disease

Figure. BCG “halo”, area of erythema around the BCG inoculation site. A n 8-month-old girl presented with a 3-day history of fever, lethargy, left neck swelling, and 1-day history of generalized blanching rash. Laboratory investigations revealed leukocytosis with predominant neutrophilia (white blood count, 27.7 10/L; neutrophils 21.3 10/L) and elevated C-reactive protein, 251 mg/dL. Intravenous flucloxacillin was commenced for cervical lymphadenitis. The following day, a new area of erythema, resembling a halo around the Bacillus Calmette–Gu erin (BCG) inoculation site was noted (Figure), raising the suspicion of Kawasaki disease (KD). By day-2 of admission, she fulfilled 4 criteria for KD: fever for more than 5 days, unilateral cervical lymphadenopathy, nonpurulent conjunctivitis, and polymorphous exanthema. She received intravenous immunoglobulin (2 g/kg) and per os high dose aspirin. Fever, irritability, rash, and BCG ‘halo’ subsided within 12 hours. Echocardiogram at presentation and 6-week follow-up were normal. KD is an acute systemic vasculitis, and remains the commonest cause of acquired heart disease in childhood in the developed world. Development of coronary artery aneurysms in untreated patients is associated with significant morbidity andmortality. In the continued absence of a specific diagnostic test, the diagnosis remains a clinical one. However, as in this patient, up to 25% of KD cases are incomplete or ‘atypical’ and have a higher risk of complications. Skin changes at the BCG site provide an additional diagnostic aid, especially in incomplete cases. In Japanese patients with KD, 49.9% had erythema at the BCG site, rising to 70% in children less than 2 years of age. In some series, BCG site changes were more prevalent in KD than cervical lymphadenopathy and were a useful diagnostic sign early in the disease course. Where KD is suspected, characteristic BCG site changes should be looked for. Awareness of this clinical sign may lead to earlier diagnosis, treatment, and improved prognosis. n

Catalogue of inherited disorders found among the Irish Traveller population

Background Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios. Objective(s) To catalogue all known inherited disorders found in the Irish Traveller population. Methods We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers. Results We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication. Conclusion We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group.

Novel SMC1A variant and epilepsy of infancy with migrating focal seizures: Expansion of the phenotype

Magnus, University Medical Center, Utrecht, the Netherlands; Pediatric Neurology, University Hospitals KU Leuven, Leuven, Belgium; Department of Neurology; Department of Pediatrics; Department Neuroscience, Montefiore Medical Center, Bronx, New York, U.S.A.; Department of Neurology, Tampere University Hospital, Tampere, Finland; Neurologie et Neurorehabilitation Pediatrique, CHUV, Lausanne, Switzerland; Florey Institute and University of Melbourne, Austin Health and Royal Children’s Hospital, Melbourne, Victoria, Australia; Epilepsy Center, University Medical Center Freiburg, Freiburg, Germany; Faculty of Medicine, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia; Department of Neurology, Jefferson Comprehensive Epilepsy Center, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.; Department of Neurology and Neurosurgery, Unidade de Pesquisa e Tratamento das Epilepsias, S~ao Paulo, Brazil; and Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

Novel European SLC1A4 variant: infantile spasms and population ancestry analysis

SLC1A4 deficiency is a recently described neurodevelopmental disorder associated with microcephaly, global developmental delay, abnormal myelination, thin corpus callosum and seizures. It has been mainly reported in the Ashkenazi–Jewish population with affected individuals homozygous for the p.Glu256Lys variant. Exome sequencing performed in an Irish proband identified a novel homozygous nonsense SLC1A4 variant [p.Trp453*], confirming a second case of SLC1A4-associated infantile spasms. As this is the first European identified, population ancestry analysis of the Exome Aggregation Consortium database was performed to determine the wider ethnic background of SLC1A4 deficiency carriers. p.Glu256Lys was found in Hispanic and South Asian populations. Other potential disease-causing variants were also identified. Investigation for SLC1A4 deficiency should be performed regardless of ethnicity and extend to include unexplained early-onset epileptic encephalopathy.

Sultiame revisited: treatment of refractory absence seizures

Sultiame is recommended for the treatment of benign epilepsy of childhood with centrotemporal spikes, electrical status epilepticus during slow-wave sleep, as well as other genetic (idiopathic) focal epilepsies. Sultiame is not traditionally considered a treatment choice for idiopathic generalised epilepsy, and it does not appear on the list of drugs recommended for treatment of absence seizures. We report the efficacy of sultiame in treating three children with drug-resistant absence seizures and discuss the potential use of sultiame beyond the idiopathic focal epilepsies.

Identification of Leptomeningeal Medulloblastoma with Contrast-Enhanced Magnetic Resonance Imaging: A Devastating Differential of Acute Disseminated Encephomyelitis: Letters to the Editor

Acute disseminated encephalomyelitis (ADEM) is an autoimmune inflammatory disorder of the central nervous system characterised by encephalopathy and multifocal demyelination. It is often preceded by an infectious process and is reported to affect between 0.07 and 0.4 per 100 000 children per year. Symptoms of ADEM are limited by their lack of specificity, and there is no single confirmatory diagnostic test. Many metabolic, infectious, vasculitic and infilitrative disease processes mimic ADEM. These mimics may be excluded by a careful search for ‘red flags’ that may help distinguish acquired demyelination syndromes from other differential diagnoses as illustrated by a recent case in our neurology department. A 2-year-old presented with a 10-day history of vomiting, lethargy, irritability, headache and ataxia following a confirmed influenza A upper respiratory tract infection. On examination, he was encephalopathic but had no other lateralising neurological signs. Cerebrospinal fluid (CSF) revealed raised protein (1071 mg/L) but was otherwise unremarkable, with 0 white cells/cm, a negative inflammatory antibody screen and negative viral studies. Metabolic workup and ophthalmological examination were normal. Electroencephalogram was consistent with a diffuse encephalopathy without epileptiform abnormalities. Magnetic resonance imaging (MRI) of the brain demonstrated bilateral cerebral, brainstem and cerebellar T2 hyperintensities. A diagnosis of ADEM was suspected. There was no improvement after treatment with intravenous high-dose methylprednisolone (30 mg/kg) and immunoglobulin G (2 g/kg). He became increasingly encephalopathic and had persistent headache and vomiting. Repeat MRI brain and spine with gadolinium 5 days after the initial imaging showed diffuse leptomeningeal enhancement involving the posterior fossa, suprasellar cistern and spinal cord (Fig. 1). The lack of response to therapy and the pattern of enhancement suggested a diffuse neoplastic process. Cytological examination of CSF revealed no malignant cells. Histological examination of a cerebellar biopsy demonstrated a primary, large cell, melanotic, leptomeningeal medulloblastoma of non-sonic hedgehog/Wnt origin with divergent differentiation, without a solid intracranial mass, consistent with an aggressive tumour. The patient continued to deteriorate clinically, and palliative care was implemented. He died 2 weeks after initial presentation. Several features of this patient’s initial presentation were in accordance with a diagnosis of ADEM, including the prodrome, his initial symptoms and signs and the white matter lesions found on non-contrast MRI. However, other features were atypical, most notably, the CSF findings and rapid progression of symptoms despite treatment. This case emphasises the importance of approaching ADEM as a diagnosis of exclusion, particularly if the clinical presentation follows an unusual course.

Status dystonicus due to missense variant in ARX: Diagnosis and management

Movement disorders are increasingly identified in infantile encephalopathies due to single gene disorders (e.g. SCN2A, CDKL5, ARX). The associated movement disorder can be challenging to recognise and treat. We report a 2 year-old boy with a background history of Ohtahara syndrome due to a missense variant in ARX (the aristaless-related homeobox gene) who subsequently developed status dystonicus. ARX is a transcription factor that plays a critical role in cortical neuronal development and is associated with a range of important neurodevelopmental disorders depending on the site of the pathogenic variant. Cases of status dystonicus are described with variants affecting the polyalanine expansion region of ARX but have not been reported previously with variants affecting the aristaless domain of ARX as in this case. Dystonic episodes posed a challenge in recognition and treatment, including confusion with status epilepticus. We discuss the difficulties in diagnosis and management of status dystonicus, an underreported life-threatening emergency in children.