Brain & Development xxx (2018) xxx–xxx www.elsevier.com/locate/braindev Case Report Anti-MOG antibody encephalitis mimicking neurological deterioration in a case of Rett syndrome with MECP2 mutation Hiroo Tani a,b, Nobutsune Ishikawa a,b,⇑, Yoshiyuki Kobayashi a,b, Shohei Yamaoka c, Yuji Fujii c, Kimihiko Kaneko d, Toshiyuki Takahashi d,e, Masao Kobayashi a a Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan b Epilepsy Center, Hiroshima University Hospital, Hiroshima, Japan c Department of Pediatrics, Funairi Municipal Hospital, Japan d Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan e Department of Neurology, Yonezawa National Hospital, Yamagata, Japan Received 16 March 2018; received in revised form 15 June 2018; accepted 21 June 2018 Abstract Background: Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, resulting in developmental regression after normal development during infancy. Transient presentation of many autistic features is also commonly seen in RTT. Anti-myelin oligodendrocyte glycoprotein (MOG)-antibody encephalitis is an acquired relapsing demyelinating syndrome characterized by a variety of neuroinflammatory symptoms. Here, we report a case of anti-MOG antibody encephalitis in a patient with genetically confirmed RTT, which mimicked many of the features of RTT. Case report: A three-year-old girl presented with subacute verbal and motor dysfunction, along with involuntary movements and marked irritability. Magnetic resonance imaging (MRI) revealed extensive white matter lesions, with anti-MOG antibodies detected in the serum and cerebrospinal fluid, resulting in an initial diagnosis of anti-MOG antibody encephalitis. However, additional testing of the MECP2 gene was performed in response to persistent involuntary hand movements in combination with progressive verbal and motor deterioration. Sequencing analysis revealed a known pathogenic mutation in MEPC2, indicating a concurrent diagnosis of RTT. Conclusion: Both RTT and anti-MOG antibody encephalitis are rare conditions. Similarities in disease presentation suggest that anti-MOG antibody encephalitis may mimic many of the symptoms of RTT. Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Anti-MOG antibody encephalitis; Rett syndrome; MECP2; Mutation; MRI 1. Introduction ⇑ Corresponding author at: Department of Pediatrics, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan. E-mail address: ishikan@hiroshima-u.ac.jp (N. Ishikawa). Rett syndrome (RTT) is a neurodevelopmental disorder almost exclusively seen in females, characterized by profound cognitive impairment, poor communication skills, and stereotypic hand movements. Patients typically present with neurological regression beginning https://doi.org/10.1016/j.braindev.2018.06.011 0387-7604/Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Please cite this article in press as: Tani H et al. Anti-MOG antibody encephalitis mimicking neurological deterioration in a case of Rett syndrome with MECP2 mutation. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.06.011 2 H. Tani et al. / Brain & Development xxx (2018) xxx–xxx between 6 and 18 months of age after a period of apparently normal development, including acquisition of fine motor skills and language. During the regression period, fine motor skills, effective eye contact, and communication are lost. Features of autism, including limited eye contact, poor socialization, and interaction with irritability, often occur during this period. Typically, autistic features are transient, lasting from weeks to many months [1]. Disease etiology is strongly linked to mutations in methyl-CpG-binding protein 2 (MECP2), which is considered the primary cause of RTT [2]. Despite significant heterogeneity in clinical presentation, growing evidence supports a diagnosis of myelin oligodendrocyte glycoprotein (MOG) antibodyassociated disease in children with relapsing acquired demyelinating syndromes whose sera test positive for anti-MOG antibodies [3]. Recent reports of anti-MOG antibody-associated diseases in children include cases of subacute onset encephalopathy with ataxia and motor regression, and encephalopathy with irritability [3]. Here, we report a case of anti-MOG antibody encephalitis in a patient with genetically confirmed RTT. This is an unusual case in that symptoms caused by anti-MOG antibody encephalitis mimicked features of RTT. Convergence of these two diseases may lead to a better understanding of autoimmunity in RTT. This case also highlights the need to consider the possibility of multiple rare conditions during clinical diagnosis. 2. Case report A three-year-old girl was transferred to our hospital with symptoms of subacute verbal and motor dysfunction, along with involuntary movement and marked irritability. The patient was the first child of nonconsanguineous parents. No family history of neurological or metabolic disorders was reported. The mother’s pregnancy and delivery were uncomplicated. Her early developmental milestones were not obviously delayed (single-word speech at 12 months and two-word sentences at 24 months; standing alone at 12 months and walking without support at 13 months), and no specific involuntary movements had been observed during infancy. Initial signs of motor dysfunction first appeared after Streptococcus pyogenes and influenza infection one year prior to admission, although symptoms gradually improved without treatment. However, a decline in verbal expression and an increase in autism-like behaviors began two weeks prior to admission. Before being transferred to our facility, the patient had been admitted to another hospital due to motor dysfunction and marked irritability with repetitive hand-wringing after a febrile episode. Initial magnetic resonance imaging (MRI) revealed extensive white matter lesions in the brain (Fig. 1), which were further investigated upon transfer to our hospital. At the time of admission, cerebrospinal fluid (CSF) analyses revealed white blood cell count of 138 cells/lL (neutrophils 64, monocytes 74), protein Fig. 1. MRI findings (axial FLAIR imaging). (A and E) Evidence of extensive white matter lesions at the time of admission. (B and F) Decreases in initial lesion size concomitant with the occurrence of a novel lesion (arrow) 14 days after the first MRI. (C, D, and G) Follow-up studies revealed marked resolution of lesions 9 months after the first MRI. Please cite this article in press as: Tani H et al. Anti-MOG antibody encephalitis mimicking neurological deterioration in a case of Rett syndrome with MECP2 mutation. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.06.011 H. Tani et al. / Brain & Development xxx (2018) xxx–xxx 3 23 mg/dL, and glucose 50 mg/dL. The IgG index was 0.68. Congenital metabolic error screening (including amino acid analysis, organic acid analysis, lactic acid/ pyruvate acid analysis, and very long acid chain analysis) revealed no significant findings. No bacteria or viruses were detected. Electroencephalograms (EEG) showed moderate, generalized slowing. Sequential MRIs (Fig. 1) revealed a decrease in white matter lesions without treatment concomitant with the occurrence of novel lesions. Additional symptoms associated with novel lesions were not observed. Cell-based immunoassays revealed anti-MOG antibodies (1:4096 in serum and 1:4 in CSF); tests for anti-aquaporin-4 (AQP4) antibodies and anti-N-methyl-d-aspartate receptor (NMDAR) antibodies were negative. Neither myelin basic protein nor oligoclonal bands were detected. Based on these findings, the patient was diagnosed with anti-MOG antibody encephalitis. During her time in the hospital, the patient’s irritability gradually improved, although her poor balance and altered gait persisted. Administration of methylprednisolone pulse therapy significantly restored motor function. Oral prednisolone therapy (1 mg/kg/day) was subsequently started, followed by gradual decreases in prednisone dosage thereafter. At the time of follow-up, symptoms of motor dysfunction had not recurred by 10 months, although language had not returned. AntiMOG antibody titer had fallen to 1:1024 at 9 months after disease onset. During hospitalization, additional testing of the MECP2 gene was performed in response to persistent involuntary hand movements in combination with progressive verbal and motor deterioration, although microcephaly was not observed (head circumstance was 49.5 cm, indicating 0.8 SD). Sequencing analysis revealed a previously reported T158M mutation in MEPC2, indicating a concurrent diagnosis of RTT. This gene analysis was conducted with approval from the Hiroshima University Institutional Review Board. Written informed consent was obtained from parents. opathies such as these and RTT, particularly in cases of subacute onset. Hacohen et al. reported a patient with genetically confirmed Aicardi-Goutières syndrome combined with anti-AQP4 antibody-positive neuromyelitis optica [4]. We need to pay attention to coexistence genetic syndrome with autoimmune demyelinating diseases for accurate management of these patients. To the best of our knowledge, this is the first report of anti-MOG antibody encephalitis in an RTT patient with confirmed MECP2 mutations. Tightly regulated MECP2 dosing is critical to neuronal morphologic characteristics and dendritic spine density in RTT and animal models [1]. In cultured rat embryonic hippocampal neurons, knockdown of normal MECP2 produces shorter dendrites with normal axon length, whereas MECP2 mutants exhibit shorter axons and dendrites [5]. Evidence of a leukodystrophy-like phenotype in young children may reflect an increased susceptibility of the myelinating brain to MOG antibodymediated disease. In rat studies, expression of MOG occurred after the initiation of myelination, from postnatal day 1 onwards [6]. MOG was detected primarily at the extracellular surface of myelin sheaths and oligodendrocytes, with low levels observed in the lamellae of compacted myelin and the myelin/axon border zone [6,7]. The myelinating brain may be more susceptible to MOG antibody disease caused by MOG expression on uncompacted myelin, resulting in immune-mediated damage and axonal loss [8]. In RTT, shorter axons and dendrites may affect the severity of anti-MOG antibody encephalitis. While emerging evidence suggests a link between MECP2-related RTT and autoimmune diseases, including evidence of antineuronal antibodies in RTT, the relationship between anti-MOG antibody production and MECP2 mutations is not known [9]. Further studies will be necessary to understand fully the mechanisms underlying anti-MOG antibody encephalitis, along with the role of RTT in disease pathology. 3. Discussion This study was partially supported by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (KAKENHI), and a Health and Labor Sciences Research Grant on Intractable Diseases (neuroimmunological diseases) from the Ministry of Health, Labor and Welfare of Japan. Leukodystrophy-like MRI patterns of confluent, largely symmetrical lesions were reported in 7 of 14 children diagnosed with acute disseminated encephalomyelitis (ADEM). All patients were younger than 7 years of age at the time of diagnosis and exhibited mild to moderate disability after a 3-year follow-up [3]. The patient described here demonstrated extensive white matter lesions, similar to those seen in ADEM patients, along with numerous other symptoms, including ataxia, motor regression, tremors, behavioral changes, and irritability [3]. This convergence of clinical symptoms between anti-MOG antibody encephalitis and ADEM highlights the potential overlap between encephalomy- 4. Disclosure of funding References [1] Percy AK. Rett syndrome. Arch Neurol 2011;68:985–9. [2] Shah RR, Bird AP. MeCP2 mutations: progress towards understanding and treating Rett syndrome. Genome Med 2017;9:17. 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