REVIEW ARTICLE

Neurological Manifestations of Primary

How to Cite This Article: Chavoshzadeh Z, Hashemitari A, Darougar S. Neurological Manifestations of Primary Immunodeficiencies. Iran J Child Neurol. 2018; 12(3): 7-23

Zahra CHAVOSHZADEH MD1, Abstract Amir HASHEMITARI MD2, Objective: Primary immunodeficiencies (PID) are a heterogeneous Sepideh DAROUGAR MD3 group of disorders with a variable clinical spectrum of manifestations. The central nervous system may be involved in PID with symptoms which may present initially or develop at later stages. The purpose of this study was to review the neurological manifestations of different PID syndromes.

Materials & Methods: We focused on 104 selected studies on PID with certain neurological abnormalities which may accompany these disorders or may later signify a PID in their course.

Results: Diverse neurological deficits accompanying certain PIDs may be mild or they may greatly influence the course of the disease with major impacts on the quality of life of these patients.

1. Department of and Conclusion: Early recognition and treatment is important to prevent or , Mofid’s Children Hospital, Shahid Beheshti University of Medical Sciences, reduce future irreversible neurological sequelae. Therefore Tehran, Iran 2. East London NHS Foundation should be aware of the neurological features accompanying PID. Trust,London,United Kingdom Keywords: Neurological; Primary immunodeficiencies; Neurologic 3. Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran Introduction

Corresponding author: Primary immunodeficiencies (PID) are a heterogeneous group of 354 Darougar S. MD distinct disorders with 344 different gene defects (1) with a variable clinical Email: [email protected] Address: Dr.Masih Daneshvari Hospital, spectrum of manifestations. A diagnosis of PID will often be considered Daar-Abad, Niavaran,Tehran, Iran. Phone Number:+989122881975 with a predisposition to frequent, severe or unusual , autoimmune disorders and malignancies or allergic disorders (2). Received: 29- May -2018 Last Revised: 30- May -2018 PIDs have been classified practically according to the affected immune Accepted: 11- June -2018 function to the following groups: immunodeficiencies affecting cellular and humoral immunity, combined immunodeficiencies with associated

Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 7 Neurological Manifestations of Primary Immunodeficiencies or syndromic features, deficiencies, sequelae. The categorization of the inborn errors diseases of immune dysregulation, congenital of immunity is based on the International Union defects of phagocytes, defects in intrinsic and of Immunological Societies: 2017 Primary innate immunity, autoinflammatory disorders, Diseases Committee Report on complement deficiencies and phenocopies of PIDs Inborn Errors of Immunity (1). (3). The central nervous system may be involved in Materials & Methods PIDs with symptoms which may present initially or develop at later stages. The neurological The last version of IUIS Primary Immunodeficiencies symptoms may vary from mild cognitive defects Committee Report (1) on Inborn Errors of to severe disabilities (4). Physical examination Immunity was reviewed first to select certain PIDs may give the clinician valuable clues to the cause with neurological manifestations. Then a review of PIDs that underlie the neurological signs. of literature was started according to specific PID Certain neurological abnormalities may later associated with neurological manifestations with a signify a PID. Therefore physicians should be focus on 104 selected studies. aware of the neurological features accompanying Discussion immunodeficiencies. Neuromascular abnormality presenting with ataxia may be the first indicator of Immunodeficiencies affecting cellular and humoral ataxia-telengiectasia. Flaccid paralysis after live immunity poliovirus immunization may suggest combined Severe combined immunodeficiencies defined by immunodeficiency or antibody defects. Pernicious CD3 T cell lymphopenia anaemia may later result in neurological deficits in untreated CVID patients. Cognitive impairment, Adenosine Deaminase deficiency (ADA) and cerebellar, spinal and peripheral ADA is a ubiquitous enzyme in purine salvage neuropathies are neurologic features seen in pathway which is also expressed in both the Chediac-Higashi Syndrome. Patients with Griscelli peripheral and central nervous systems (6). ADA syndrome may present with , ataxia and deficiency is caused by mutations in the ADA gene occulomotor and reflex abnormalities. DiGeorge and is known as one of the most prevalent forms anomaly may present with subtle developmental of severe combined immunodeficiencies (6). The delays later manifesting as problem with school most common manifestations include recurrent and performances (5). Early recognition and treatment opportunistic fungal, viral and bacterial infections, may prevent or reduce future irreversible lymphopenia and failure to thrive (7). The main neurological sequelae (4). neurologic manifestations of these diseases result Neurological manifestations will be discussed from accumulation of adenosine metabolites in basal in detail according to the specific classification ganglia and thalamus which are rich in adenosine of primary immunodeficiencies to assist the receptors. These neurologic abnormalities include treating physicians’ timely diagnosis and prompt motor delay, hypotonia, mental retardation, treatment in order to avoid irreversible neurologic learning disability, hyperactivity, attention deficit, behavioural abnormalities, reduced verbal

8 Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 Neurological Manifestations of Primary Immunodeficiencies expression, and sensorineural deafness (4, of one or more classes of immunoglobulin, failure 8). One infant has been reported with nystagmus to make in response to vaccines and and difficulty in focusing gaze was found to have lymphopenia (19). The ataxia telengiectasia brain atrophy on MRI (9). mutated (ATM) gene is involved in the response to DNA damage in the nervous system which leads to DNA Ligase IV deficiency impaired apoptosis and elimination of the damaged This autosomal recessive form of SCID is caused by neurons and neurodegeneration (4). Progressive an impairment of the DNA damage repair process neurodegeneration which mainly occurs with a with a pronounced radiosensitivity (10). DNA widespread loss of Purkinje cells in cerebellum is double-strand break repair via non-homologous the hallmark of ataxia-telengiectasia, manifesting end-joining (NHEJ) is involved in recombination as head and trunk swaying and gait abnormalities of immunoglobulin and T-cell receptor genes. (8, 13). It is followed by basal ganglia dysfunction Mutations in NHEJ components may lead to later in the course of the disease characterised and immunodeficiency (11).The by hypotonia, tremor and choreoathetosis. These neurological manifestations of this disease include patients are usually confined to a wheelchair by microcephaly and developmental delay (12). the age of 10-12 years. In physical examination, further evaluation reveals diminished or absent Cernunnos deficiency tendon reflexes, positive Babinski sign, loss This is another rare autosomal recessive form of vibration sense, abnormal ocular motility, of SCID with severe T and B lymphopenia reduction in sensory conduction velocity and and dysgammaglobulinemia in addition to axonal degeneration of peripheral nerves (8). radiosensitivity caused by mutations in the CERNUNNOS or XRCC4-like factor (XLF). There are also Ataxia Telengiectasia-Like Disorders Microcephaly and developmental delay are the (ATLD) which are clinically similar to ataxia prominent neurological features (4, 8). telengiectasia although without telangiectasia and a slower progression of neurologic manifestations. CID with associated or syndromic features These patients remain ambulatory until their third Ataxia-Telengiectasia decades of lives (8, 20).

This autosomal recessive complex disorder with Nijmegan Breakage Syndrome substantial severity in affected individuals (13) This is a rare autosomal recessive, multisystemic is characterized by ataxia, ocular and cutaneous disease of chromosomal instability presenting at telengiectasia, radiosensitivity, immunodeficiency, birth with microcephaly but no additional neurologic increased predisposition to malignancies (14) manifestation (21). The mutated gene (NBS) has and elevated serum alpha fetoprotein level. a critical role in responding to DNA damage. The Sinopulmonary infections (15-17) are common defect leads to neuronal loss and microcephaly. in these patients with development of chronic “Other manifestations include combined cellular lung disease in 25% (18). The most common and humoral immunodeficiency with recurrent immunologic abnormalities are low serum levels

Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 9 Neurological Manifestations of Primary Immunodeficiencies sinopulmonary infections, a strong predisposition and increased radiosensitivity accompanied by to develop malignancies and radiosensitivity” neurologic symptoms and growth delay due to (21). Due to the radiation hypersensitivity in these an increased apoptosis and reduced proliferative patients, they are at increased risk of developing capacity during brain development presenting as brain malignancies such as medulloblastoma (22). mild motor control and learning difficulties (28). These patients may exhibit progressive mental DiGeorge Syndrome retardation which becomes more evident after age of 14 years (23). as well as brain developmental In addition to the characterizing triad of abnormalities including partial collosal agenesis, cardiac defects, hypocalcemia and cellular hydrocephaly, colpocephaly, neuronal migration immune deficiency, there may be neurological abnormalities. The volume of the frontal lobe manifestations which present with developmental may be reduced and the gyral pattern may become delay in motor, language and speech areas, simplified (24). neuropsychiatric problems and epilepsy (4). Most patients show a hemizygous chromosome Immunodeficiency, Centromeric Region 22q11.2 deletion, and most of them with Instability and Facial Anomalies Syndrome DiGeorge syndrome show mild to moderate T This genetic disease is due to a mutation in DNA cell lymphopenia. The most common neurologic methylteransferase gene (25) which causes DNA manifestations include cognitive, neurologic hypomethylation. It is not identified how these and psychiatric abnormalities (8). Nearly 50% hypomethylated areas of the genome result in percent of school-age patients have problems with the features of this syndrome but it appears that persistent language difficulties while their full- the expression pattern of the genes essential scale IQ scores are within normal to moderately for a functional immune system, craniofacial retarded range with math scales lower than reading development and neurogenesis are altered in and spelling (29, 30). Behavioural abnormalities the deficient cells (26). ICF patients have severe include anxiety disorders, schizophrenia, ADHD, respiratory infections and recurrent gastrointestinal mood disorders and flat effect in childhood infections due to immune abnormalities which (31) and schizophrenia and bipolar disorders include despite normal later during adulthood. Neural tube defects, B cell counts and a mild reduction in immune polymicrogyria, volume reduction in the corpus response. Reduced T cell counts have been detected callosum, amygdalae and temporoparietal regions in approximately half of the cases (99). Affected (29, 32) and myelomeningocele (33) are structural patients exhibit mental retardation, hypotonia and malformations which have been described in these ataxia in addition to above immune abnormalities patients. (25, 27). Hyper-immunoglobulin E syndrome Riddle Syndrome These syndromes are characterized by recurrent This syndrome is characterized by a defect in skin and pulmonary infections in the presence of DNA damage response causing immunodeficiency elevated IgE concentration and usually eosinophilia.

10 Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 Neurological Manifestations of Primary Immunodeficiencies

The hyper-IgE syndromes have four distinct genetic intrinsic neurovascular defects are considered as causes including mutations in signal transducer the underlying pathologic involvement causing the and activator of transcription 3 (STAT3), dedicator above manifestations (44). of cytokinesis 8 (DOCK8), tyrosine kinase2 Hoyeraal-Hreidarsson syndrome (TYK2) and phosphoglucomutase 3 (PGM3) (1, 34). Vascular abnormalities, impaired myelination This is an X-linked recessive disorder of telomere or autoimmunity are the main suggested causes dysfunction which represents a severe form of for neurologic manifestations in these patients dyskeratosis congenita characterized by a classic (35, 36). Intracranial manifestations including triad of reticular skin pigmentation, dysplastic nails Chiari I malformations and focal hyperintensities and oral leukoplakia (45). Pancytopenia and severe on brain MRI are the two findings in AD-HIED combined immunodeficiency (characterized by a which are typically asymptomatic (37). Other CNS decreased B cells count and Natural Killer cells reported abnormalities include vasculitis resulting and low immunoglobulin levels that can affect a right parietal infarction and thrombosis of the all immunoglobulin subtypes) may eventually left posterior inferior cerebellar artery (38, 39). develop (46). Dyskerin, a highly conserved In DOCK8 deficiency neurologic manifestations protein is the product of DKC1 gene, involved in include vasculitis, ischemic infarction, hemiplegia, ribosome biogenesis and acts as a component of facial paralysis, subarachnoid hemorrhages and telomerase complex (8). Since proper telomerase progressive multifocal leukoencephalopathy (34, activity is essential for early development of neural 40). Patients with PGM3 mutations are reported progenitor cells and neurons, its defective function to carry a high risk of early onset neurological may lead to increased susceptibility to DNA impairment including developmental delay, ataxia, damage and apoptosis and the resultant neurologic dysarthria, psychomotor retardation, hypotonia, deficits. These neurological abnormalities include sensorineural hearing loss, seizures and myoclonus microcephaly, psychomotor retardation, spasticity, (34, 41). cerebellar hypoplasia, ataxia (8), seizures and axial hypotonia (47). Schimke Immuno-osseous Dysplasia Purine Nucleoside Phosphorylase Deficiency This autosomal recessive disorder is caused by mutation in the SMARCAL1 gene which encodes This rare autosomal recessive metabolic disorder, a chromatin remodeling protein. Defective cellular similar to ADA deficiency, results from impaired immunity causes recurrent bacterial, fungal and viral purine salvage pathway which causes combined infections which in association with short stature immunodeficiency in association with prominent and progressive renal insufficiency characterizes neurological abnormalities (48). “Mutations the disorder (4). Neurological manifestations in PNP results in impaired function of enzyme include early-onset cerebral ischemic attacks, leading to accumulation of purine metabolites such Migraine-type headaches (42), optic neuropathy, as deoxy-guanosine triphosphate (dGTP) which seizures, mental retardation and behavioural preferentially is accumulated in mitochondria changes (4, 43). Progressive aterosclerosis and and will affect adversely mitochondrial DNA

Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 11 Neurological Manifestations of Primary Immunodeficiencies repair and therefore may induce subsequent (52, 53). neuronal cell apoptosis” (8). Patients present with Predominantly Antibody deficiency T- (49). Infectious complications include recurrent upper and lower respiratory tract Common variable immunodeficiencies and infections and otitis media (48, 49). Neurological agammaglobulinemia (x-linked or autosomal findings found in more than half of the patients recessive) are the most frequent forms of often precede infections and autoimmunity (4) presentations of antibody deficiency. Symptoms and include motor system dysfunction, cerebral mainly consist of respiratory or gastrointestinal palsy, hyper/ hypotonia, spastic paresis, tremor, involvement. However, neurologic manifestations ataxia, mental retardation, developmental delay, may also occur. behavioural problems, cerebrovascular accidents Common Variable Immunodeficiency and sensorineural deafness (4, 8, 48, 50). Neurologic manifestations are a complex of Hepatic Veno-Occlusive Disease with diverse and rare complications of CVID including Immunodeficiency brain or spinal cord infections (meningitis as This is caused by homozygous mutation in the the most common neurologic manifestation), autosomal SP110 gene. The onset of clinical autoimmune involvements (featuring as axonal features usually occurs before the age of six sensorimotor polyneuropathy) (54), transverse months with hepatic sinusoidal obstruction. Serum myelitis (55), progressive neurodegeneration (56), Ig levels are low. T cell subsets and B-cell numbers cerebral vasculitis (causing recurrent occipital are reduced. Neurological abnormalities include headaches), brain granulomatous lesions (57), free leukodystrophy and extensive cerebral necrosis on radical mediated neuronal damage due to vitamin postmortem examination are found in one third of E deficiency (including sensory loss, ataxia, the patients (51). retinitis pigmentosa) (58, 59), subacute combined degeneration of the cord secondary to vitamin B12 VICI Syndrome (Immunodeficiency with Cleft deficiency, peroneal muscular atrophy, Guillain- Lip/Palate, , Hypopigmentation and Barre syndrome and myasthenia gravis (55). Absent Corpus Collasum) Agammaglobulinemia This rare autosomal recessive disorder is caused by mutation in the EPG5 gene which results In patients with agammaglobulinemia in defective autophagy (52). Clinical findings symptoms mainly consist of recurrent include , cleft lip and palate, progressive respiratory or gastrointestinal infections. Serum cardiomyopathy, variable pigmentary defects immunoglobulins are severely decreased and and combined immunodeficiencies. Neurologic usually undetectable (60). CNS complications may manifestations include microcephaly, seizures, arise from persistent enteroviral infections which nystagmus, callosal agenesis, hypotonia and severe may lead to fatal encephalitis or dermatomyositis- psychomotor and growth retardation (53). Some meningoencephalitis syndrome (61). “Also, a patients show more structural CNS abnormalities progressive encephalopathy of unknown etiology

12 Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 Neurological Manifestations of Primary Immunodeficiencies has been described in patients with x-linked Familial Hemophagocytic Lymphohistiocytosis agammaglobulinemia with a uniform clinical FHL comprises a group of autosomal recessive course including cognitive and movement life-threatening disorders characterized disorders” (62). by uncontrolled proliferation of activated Disorders of Immune Regulation lymphocytes and macrophages associated with massive secretion of cytokines infiltrating into Chediac Higashi Syndrome organs including lymph nodes, marrow, liver, Patients with this autosomal recessive lethal disorder spleen and central nervous system (70, 71). CNS present with recurrent respiratory and bacterial infiltration begins in the meninges, progressing to skin infections due to severe immunodeficiency, diffuse infiltration of the white matter followed by partial oculocutaneous albinism, bleeding tendency necrosis and focal demyelination (4, 71). Therefore and progressive neurological features (63). This neurological manifestations vary depend on the syndrome is caused by mutations in the lysosomal areas involved including seizures, decreased trafficking regulator gene (LYST) (4, 8). Neurologic level of consciousness, facial palsy, irritability, abnormalities include weakness, areflexia, sensory bulging fontanel, dysphagia, dysarthria, CSF deficits, peripheral polyneuropathy, progressive abnormalities (leukocytosis), ataxia, nystagmus, neurodegeneration, cognitive defects, dementia, visual disturbance, neck stiffness, cranial nerve ataxia, tremor, seizures, autonomic dysfunction palsies and brain death (72-74). and parkinsonian syndrome (64). Unfortunately Congenital defects of phagocytic number or the progression of neurological manifestations is function not arrested by HSCT (64, 65). Chronic Granulomatous Disease Hermansky-Pudlak syndrome type 2 Chronic granulomatous disease is the most Among Hermansky Pudlak syndromes, this type common inherited disorder of phagocytic cells. It is characterized by an immunodeficiency due results from an inability of phagocytes to produce to neutropenia and T lymphocyte dysfunction bactericidal superoxide anions due to defects of the which differentiates it from other types of this NADPH oxidase system and it leads to the defect syndrome (66). These patients usually suffer in killing of a specific spectrum of bacteria and from recurrent bacterial infections, particularly fungi resulting in concomitant hyper-inflammation respiratory illnesses, hepatosplenomegaly, lung and tissue granuloma formation (75). Neurological fibrosis, dysmorphia, oculocutaneous albinism, manifestations are reported due to brain abscesses thrombocytopenia and neurological abnormalities which are rare events in CGD (76). Other (67). Neurological manifestations include complications include white matter disease, CNS developmental delay, generalized seizures, granulomatous disease and leptomeningeal and microcephaly, hearing impairment and intention focal brain infiltration by pigmented lipid-laden tremor (68, 69). macrophages (75).

Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 13 Neurological Manifestations of Primary Immunodeficiencies

Severe Congenital Neutropenia Other neurologic manifestations include autistic features, microcephaly, muscular hypotonia This term is used for a heterogeneous group of and cerebral atrophy (83, 84). Strong delays in primary immunodeficiencies including sporadic directional movement and severe retardation in autosomal recessive, autosomal dominant and speech development have been also reported (84). x-linked types (39) of which the autosomal Impaired fucose metabolism has been suggested as recessive type with a homozygous mutation in the cause of neurologic manifestations (85). antiapoptotic protein, HAX1, accounts for one third of these patients and has been identified β-Actin deficiency as the only subtype associated with neurologic This autosomal dominant immunodeficiency abnormalities (40). Neurologic manifestations disorder caused by a non-lethal mutation, include developmental delay, cognitive defects, characterized by defects in neutrophil migration, speech defects, attention deficit, hyperactivity, mental retardation, short stature, thrombocytopenia learning disabilities and epilepsy (77-79). and photosensitivity (86). The hallmark of Schwachman-Diamond Syndrome the disorder is recurrent bacterial and fungal infections without pus formation. The neurologic This is a multisystem disorder characterized by bone manifestations of this defect are due to the marrow failure, exocrine pancreatic insufficiency contribution of β-actin in neuronal migration and and metaphyseal chondrodysplasia. These features development and particularly includes mental are attributed to mutation in SBDS gene (80). retardation. However the precise pathologic pathways with the potential ability to disrupt the protein’s function Autoinflammatory Disorders remain to be identified. Neurological findings Mevalonate Kinase Deficiency (MKD) include neuropsychological abnormalities. These patients not only suffer from behavioural problems This is a term used for a wide clinical spectrum but also experience developmental retardation, of autosomal recessive disorders due to a low intelligence, cognitive deficits, hypotonia and congenital error in cholesterol biosynthesis, with visual motor dysfunction (81). Brain structural hyperimmunoglobulinemia D syndrome as the anomalies including callosal agenesis, delayed benign variant of the disorder and Mevalonic myelination and decreased gray and white matter aciduria as the more severe form of MKD (3). volumes have been detected (82). Mevalonate kinase is an important enzyme in the biosynthesis of cholesterol. Recurrent, non- Leukocyte Adhesion Deficiency type 2 infectious febrile episodes lasting 4 to 6 days, LAD syndromes consist of rare autosomal usually accompanied by cervical or abdominal recessive disorders among which only LAD type lymphadenopathies, splenomegaly, vomiting, 2 presents with neurologic abnormalities. These diarrhoea, arthralgia and erythematous/ urticarial patients are characterized by recurrent bacterial rash are characteristic. Although the pathogenic infections without pus formation in the first years mechanisms causing the neurological defects are of life and severe mental retardation later (83). not understood, the role of cholesterol in brain

14 Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 Neurological Manifestations of Primary Immunodeficiencies development and neuronal function cannot be joints, eyes and skin (95-97) and is caused by ignored. The neurological manifestations in a mutation in pattern recognition receptor NOD2 subset of patients with hyperimmunoglobulinemia gene encoding a protein known as an intracellular D syndrome include mental retardation, ataxia and sensor for bacterial products (98, 99). This protein epilepsy (87). In patients with mevalonic aciduria is activated after receiving signals from bacterial due to complete MVK deficiency, neurological components resulting in activation of NFkB manifestations may include dysmorphic pathway which regulates innate responses (99). craniofacial features, psychomotor retardation, Neurological manifestations are rare and include developmental delay, hypotonia and progressive cranial neuropathies (hearing loss) and transient cerebellar ataxia (88, 89). 6th nerve palsy, cerebral vasculitis and cerebral infarction (100, 101). Neonatal Onset Multisystem Inflammatory Disorder Aicardi-Goutieres syndrome

The disease results from mutations in the CIAS- This is a genetically determined encephalopathy 1 gene which encodes cryopyrin (90). Cryopyrin caused by mutations in TREX1 genes encoding in association with other proteins form a protein RNAs involved in removing RNA, leading to the complex called the inflammasome which activates accumulation of endogenous RNA, triggering Toll- IL-1β to its proinflammatory form. These like receptor-dependent interferon-α production in mutations cause which aberrant activation of the the brain with the resultant activation of neurotoxic inflammasome (91) are supposed to be responsible lymphocytes and immune system in addition for the persistent upregulation of this inflammatory to the inhibition of angiogenesis (102, 103). pathway (92). Therefore like other involved organs, Neurological manifestations include early infantile the increased IL-1β activity (93) in the brain seems onset of irritability, spasticity, dystonic posturing, to cause the neurological symptoms which are the psychomotor retardation and microcephaly, prominent manifestations of this disorder. These resulting in death in early childhood (104). abnormalities include chronic aseptic meningitis In conclusion, neurological manifestations of which may cause increased intracranial pressure primary immunodeficiencies are common with resulting in hydrocephalus, papilledema and optic diverse pathologic mechanisms. Neurological nerve atrophy, spastic diplegia, hypotonia, transient deficits may be mild or they may greatly influence episodes of hemiplegia, mental retardation, the course of the disease with major impacts on developmental delay, brain atrophy, headache, the quality of life of the patients. Some of these early morning nausea, vomiting, progressive complications may even cause death. Neurological sensorineural hearing loss and seizures (94). manifestations may have an early onset, beginning Blau syndrome at birth or they may appear later which in both situations may lead to misdiagnosis and delayed This rare autosomal dominant syndrome clinically . Therefore a high suspicion of an underlying resembles early onset sarcoidosis characterized primary immunodeficiency is important in any type by granulomatous inflammation mostly involving

Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 15 Neurological Manifestations of Primary Immunodeficiencies of neurological problems occurring with recurrent Middleton’s Allergy Principles &Practice. infections. 2. 8th ed. Philadelphia: Elsevier Saunders; 2014. p. 1140. Authors’ Contribution 6. Whitmore KV, Gaspar HB. Adenosine All three authors were involved in data collection, deaminase deficiency–more than just and writing the article. an immunodeficiency. Front Immunol Conflict of Interest 2016;7:314.

The authors declare that there is no Conflict of 7. Gaspar HB, Aiuti A, Porta F, Candotti Interest. F, Hershfield MS, Notarangelo LD. How I treat ADA deficiency. Blood References 2009;114(17):3524-32. 1. Picard C, Gaspar HB, Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, et 8. Dehkordy SF, Aghamohammadi A, Ochs al. International Union of Immunological HD, Rezaei N. Primary immunodeficiency Societies: 2017 Primary Immunodeficiency diseases associated with neurologic Diseases Committee report on inborn manifestations. J Clin Immunol errors of immunity. J Clin Immunol 2012;32(1):1-24. 2018;38(1):96-128. 9. Nofech-Mozes Y, Roifman C. Neurological manifestations in severe combined 2. Samarghitean C, Ortutay C, Vihinen M. Systematic classification of primary immunodeficiency secondary to adenosine immunodeficiencies based on clinical, deaminase deficiency: Three case reports pathological, and laboratory parameters. J and review of the literature. J Allergy Clin Immunol 2009;183(11):7569-75. Immunol 2005;115(2):S78. Chistiakov DA, Voronova NV, Chistiakov 3. Bousfiha A, Jeddane L, Picard C, Ailal F, 10. Gaspar HB, Al-Herz W, et al. The 2017 AP. Ligase IV syndrome. Eur Journal Med IUIS Phenotypic Classification for Primary Genet 2009 Nov-Dec;52(6):373-8. Immunodeficiencies. J Clin Immunol 11. IJspeert H, Warris A, Flier M, Reisli I, Keles 2018;38(1):129-43. S, Chishimba S, et al. Clinical spectrum of LIG4 deficiency is broadened with severe 4. Aydin ÖF, Anlar B. Neurological Manifestations of Primary dysmaturity, primordial dwarfism, and Immunodeficiency Diseases. Clin Pediatr neurological abnormalities. Hum Mutat 2017:0009922817737083. 2013;34(12):1611-4. Enders A, Fisch P, Schwarz K, Duffner 5. M B, HK L. Approach to the patient with 12. recurrent infections. In: NF AJ, BS B, W U, Pannicke U, Nikolopoulos E, et al. B, WW B, ST H, RF LJ, et al., editors. A severe form of human combined immunodeficiency due to mutations in DNA

16 Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 Neurological Manifestations of Primary Immunodeficiencies

ligase IV. J Immunol 2006;176(8):5060-8. treatment. Semin Pediatr Neurol 2003 Sep;10(3):173-82. 13. Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford 21. Chrzanowska KH, Gregorek H, TO, Lederman HM. Ataxia telangiectasia: Dembowska-Baginska B, Kalina MA, a review. Orphanet J Rare Dis 2016 Nov Digweed M. Nijmegen breakage syndrome 25;11(1):159. (NBS). Orphanet J Rare Dis 2012 Feb 28;7:13. 14. Frappart P-O, McKinnon PJ. Ataxia- telangiectasia and related diseases. 22. Distel L, Neubauer S, Varon R, Holter Neuromolecular Med 2006;8(4):495-511. W, Grabenbauer G. Fatal toxicity following radio‐and chemotherapy 15. Nowak-Wegrzyn A, Crawford TO, of medulloblastoma in a child with Winkelstein JA, Carson KA, Lederman unrecognized Nijmegen Breakage HM. Immunodeficiency and infections Syndrome. Pediatr Blood Cancer in ataxia-telangiectasia. J Pediatr 2003;41(1):44-8. 2004;144(4):505-11. 23. Wegner R-D, German JJ, Chrzanowska 16. Lockman JL, Iskander AJ, Bembea M, KH, Digweed M, Stumm M. Chromosomal Crawford TO, Lederman HM, McGrath- instability syndromes other than ataxia- Morrow S, et al. The critically ill patient telangiectasia.In:Ochs HD,Smith CIE,Puck with ataxia–telangiectasia: A case series. J, editors. Primary immunodeficiency Pediatr Crit Care Med 2012;13(2):e84-e90. diseases A molecular and genetic approach. 17. Schroeder SA, Zielen S. Infections of the 2007;2. respiratory system in patients with ataxia- 24. Bekiesinska-Figureatowska M, telangiectasia. Pediatr Pulmonol 2014 Chrzanowska KH, Jurkiewicz E, Apr;49(4):389-99. Wakulinska A, Rysiewskis H, Gladkowska- 18. Crawford T, Skolasky R, Fernandez Dura M, et al. Magnetic resonance imaging R, Rosquist K, Lederman H. Survival of brain abnormalities in patients with probability in ataxia telangiectasia. Arch the Nijmegen breakage syndrome. Acta Dis Child 2006;91(7):610-1. Neurobiol Exp 2004;64(4):503-9.

19. Kraus M, Lev A, Simon AJ, Levran I, 25. Ehrlich M, Jackson K, Weemaes C. Nissenkorn A, Levi YB, et al. Disturbed B Immunodeficiency, centromeric region and T cell homeostasis and neogenesis in instability, facial anomalies syndrome patients with ataxia telangiectasia. J Clin (ICF). Orphanet J Rare Dis 2006;1(1):2. Immunol 2014 Jul;34(5):561-72. 26. Jin B, Tao Q, Peng J, Soo HM, Wu W, 20. Perlman S, Becker-Catania S, Gatti RA. Ying J, et al. DNA methyltransferase 3B Ataxia-telangiectasia: diagnosis and (DNMT3B) mutations in ICF syndrome

Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 17 Neurological Manifestations of Primary Immunodeficiencies

lead to altered epigenetic modifications 33. Kinoshita H, Kokudo T, Ide T, Kondo Y, and aberrant expression of genes regulating Mori T, Homma Y, et al. A patient with development, neurogenesis and immune DiGeorge syndrome with spina bifida function. Hum Mol Genet 2007;17(5):690- and sacral myelomeningocele, who 709. developed both hypocalcemia-induced seizure and epilepsy. Seizure-Eur J Epilep 27. Hagleitner M, Lankester A, Maraschio 2010;19(5):303-5. P, Hulten M, Fryns J-P, Schuetz C, et al. Clinical spectrum of immunodeficiency, 34. Yang L, Fliegauf M, Grimbacher B. centromeric instability and facial Hyper-IgE syndromes: reviewing dysmorphism (ICF syndrome). J Medical PGM3 deficiency. Curr Opin Pediatr Genet 2008;45(2):93-9. 2014;26(6):697-703.

28. Blundred RM, Stewart GS. DNA double- 35. Freeman AF, Holland SM. Clinical strand break repair, immunodeficiency and manifestations, etiology, and pathogenesis the RIDDLE syndrome. Expert Rev Clin of the hyper-IgE syndromes. Pediatr Res Immunol 2011;7(2):169-85. 2009;65(5):32R.

29. DA D, KE S. DiGeorge Syndrome: a 36. Renner ED, Puck JM, Holland SM, Schmitt chromosome 22q11.2 deletion syndrome. M, Weiss M, Frosch M, et al. Autosomal In: Ochs HD SC, Puck JM, editor. Primary recessive hyperimmunoglobulin E Immunodeficiency Diseases A Molecular syndrome: a distinct disease entity. J Pediatr and Genetic Approach. 3rd ed. New York: 2004;144(1):93-9. Oxford University Press; 2014. p. 580-92. 37. Freeman AF, Holland SM. Clinical 30. Gothelf D, Schaer M, Eliez S. Genes, brain manifestations of hyper IgE syndromes. development and psychiatric phenotypes in Dis Markers 2010;29(3, 4):123-30. velo‐cardio‐facial syndrome. Dev Disabil 38. Yavuz H, Chee R. A review on the vascular Res Rev 2008;14(1):59-68. features of the hyperimmunoglobulin 31. Kim E-H, Yum M-S, Lee B-H, Kim H-W, E syndrome. Clin Exp Immunol Lee H-J, Kim G-H, et al. Epilepsy and other 2010;159(3):238-44. neuropsychiatric manifestations in children 39. Rael EL, Marshall RT, McClain JJ. The and adolescents with 22q11. 2 deletion hyper-IgE syndromes: lessons in nature, syndrome. J Clin Neurol 2016;12(1):85-92. from bench to bedside. World Allergy 32. Schaer M, Eliez S. From genes to brain: Organ J 2012;5(7):79. understanding brain development in 40. Ghaffari J, Ahanchian H, Zandieh F. Update neurogenetic disorders using neuroimaging on Hyper IgE syndrome (HIES). J Pediatr techniques. Child Adolesc Psychiatr Clin N Rev 2014;2(1):39-46. Am 2007;16(3):557-79.

18 Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 Neurological Manifestations of Primary Immunodeficiencies

41. Zhang Y, Yu X, Ichikawa M, Lyons JJ, intronic mutation in DKC1 in an infant Datta S, Lamborn IT, et al. Autosomal with Høyeraal–Hreidarsson syndrome. Am recessive phosphoglucomutase 3 (PGM3) J Med Genet A 2008;146(16):2159-61. mutations link glycosylation defects to 48. Yeates L, Slatter MA, Gennery AR. atopy, immune deficiency, autoimmunity, Infusion of Sibling Marrow in a Patient and neurocognitive impairment. J Allergy with Purine Nucleoside Phosphorylase Clin Immunol 2014 May;133(5):1400-9, 9 Deficiency Leads to Split Mixed Donor e1-5. Chimerism and Normal Immunity. Front 42. Kilic SS, Donmez O, Sloan EA, Elizondo Pediatr 2017;5:143. LI, Huang C, André JL, et al. Association 49. La Marca G, Canessa C, Giocaliere E, of migraine‐like headaches with Schimke Romano F, Malvagia S, Funghini S, et al. immuno‐osseous dysplasia. Am J Med Diagnosis of immunodeficiency caused by Genet A 2005;135(2):206-10. a purine nucleoside phosphorylase defect 43. Clewing JM, Antalfy BC, Lucke T, by using tandem mass spectrometry on Najafian B, Marwedel KM, Hori A, et dried blood spots. J Allergy Clin Immunol al. Schimke immuno-osseous dysplasia: 2014;134(1):155-9. e3. a clinicopathological correlation. J Med 50. Ozkinay F, Pehlivan S, Onay H, van den Genet 2007 Feb;44(2):122-30. Berg P, Vardar F, Koturoglu G, et al. Purine 44. Deguchi K, Clewing JM, Elizondo nucleoside phosphorylase deficiency in a LI, Hirano R, Huang C, Choi K, et al. patient with spastic paraplegia and recurrent Neurologic phenotype of Schimke immuno- infections. J Child Neurol 2007;22(6):741-3. osseous dysplasia and neurodevelopmental 51. T R, M W. Hepatic veno-occlusive expression of SMARCAL1. J Neuropathol disease with immunodeficiency. In: Ochs Exp Neurol 2008;67(6):565-77. H, Smith CIE, Puck JM editor. Primary 45. Vulliamy T, Dokal I. Dyskeratosis Immunodeficiency DiseasesA molecular congenita: the diverse clinical presentation and genetic approach. 3rd ed. New York: of mutations in the telomerase complex. Oxford University Press; 2014. p. 501-8. Biochimie 2008;90(1):122-30. 52. Cullup T, Kho AL, Dionisi-Vici C, 46. Glousker G, Touzot F, Revy P, Tzfati Y, Brandmeier B, Smith F, Urry Z, et al. Savage SA. Unraveling the pathogenesis Recessive mutations in EPG5 cause of Hoyeraal–Hreidarsson syndrome, a Vici syndrome, a multisystem disorder complex telomere biology disorder. Br J with defective autophagy. Nat Genet Haematol 2015;170(4):457-71. 2013;45(1):83.

47. Pearson T, Curtis F, Al‐Eyadhy A, Al‐ 53. Finocchi A, Angelino G, Cantarutti N, Tamemi S, Mazer B, Dror Y, et al. An Corbari M, Bevivino E, Cascioli S, et al.

Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 19 Neurological Manifestations of Primary Immunodeficiencies

Immunodeficiency in Vici syndrome: a recessive agammaglobulinemia. In: Ochs heterogeneous phenotype. Am J Med Genet H, Smith CIE,Puck JM, editor. Primary A 2012;158(2):434-9. Immunodeficiency DiseasesA molecular and genetic approach. 3rd ed. New York: 54. Larner A, Webster A, Thomas D. Peripheral Oxford University Press; 2014. p. 299-323. neuropathy associated with common variable immunodeficiency. Eur J Neurol 61. Quartier P, Foray S, Casanova J-L, 2000;7(5):573-5. Hau-Rainsard I, Blanche S, Fischer A. Enteroviral meningoencephalitis in 55. Ozdemir O, Okan MS, Kilic SS. X-linked agammaglobulinemia: intensive Chronic inflammatory demyelinating immunoglobulin therapy and sequential polyneuropathy in common variable viral detection in cerebrospinal fluid by immunodeficiency. Pediatr Neurol 2012 polymerase chain reaction. Pediatr Infect Apr;46(4):260-2. Dis J 2000;19(11):1106-8. 56. 56. Nguyen JT-U, Green A, Wilson 62. Sag AT, Saka E, Ozgur TT, Sanal O, MR, DeRisi JL, Gundling K. Neurologic Ayvaz DC, Elibol B, et al. Progressive complications of common variable neurodegenerative syndrome in a patient immunodeficiency. J Clin Immunol with X-linked agammaglobulinemia 2016;36(8):793-800. receiving intravenous immunoglobulin 57. Novo A, Carvalho P, Nogueira A, Pita J, therapy. Cogn Behav Neurol Constanço C, Vieira F, et al. Neurological 2014;27(3):155-9. complications of common variable 63. Kaplan J, De Domenico I, Ward DM. immunodeficiency: the immune system Chediak-Higashi syndrome. Curr Opin in chaos. Int J Clin Neurosci Ment Health Hematol 2008 Jan;15(1):22-9. 2016 March. 64. Tardieu M, Lacroix C, Neven B, Bordigoni 58. Aslam A, Misbah S, Talbot K, Chapel P, de Saint Basile G, Blanche S, et al. H. Vitamin E deficiency induced Progressive neurologic dysfunctions neurological disease in common variable 20 years after allogeneic bone marrow immunodeficiency: two cases and a review transplantation for Chediak-Higashi of the literature of vitamin E deficiency. syndrome. Blood 2005;106(1):40-2. Clin Immunol 2004;112(1):24-9. 65. Dotta L, Parolini S, Prandini A, Tabellini 59. Jolles S. The variable in common variable G, Antolini M, Kingsmore SF, et al. immunodeficiency: a disease of complex Clinical, laboratory and molecular signs of phenotypes. J Allergy Clin Immunol Pract immunodeficiency in patients with partial 2013;1(6):545-56. oculo-cutaneous albinism. Orphanet J Rare 60. CIE S, ME C. X-linked Dis 2013;8(1):168. agammaglobulinemia and autosomal

20 Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 Neurological Manifestations of Primary Immunodeficiencies

66. Jung J, Bohn G, Allroth A, Boztug K, causes a marked neurological phenotype Brandes G, Sandrock I, et al. Identification but no overt immunodeficiency. J Allergy of a homozygous deletion in the AP3B1 Clin Immunol 2015;136(4):1007-17. gene causing Hermansky-Pudlak syndrome, 73. Kim M-M, Yum M-S, Choi H-W, Ko T-S, type 2. Blood 2006;108(1):362-9. Im HJ, Seo J-J, et al. Central nervous 67. Wenham M, Grieve S, Cummins M, system (CNS) involvement is a critical Jones ML, Booth S, Kilner R, et al. Two prognostic factor for hemophagocytic patients with Hermansky Pudlak syndrome lymphohistiocytosis. Korean J Hematol type 2 and novel mutations in AP3B1. 2012;47(4):273-80. Haematologica 2010;95(2):333-7. 74. Janka GE. Familial and acquired 68. Ammann S, Schulz A, Krägeloh-Mann I, hemophagocytic lymphohistiocytosis. Eur Dieckmann NM, Niethammer K, Fuchs S, J Pediatr 2007 Feb;166(2):95-109. et al. Mutations in AP3D1 associated with 75. Song E, Jaishankar GB, Saleh H, Jithpratuck immunodeficiency and seizures define a W, Sahni R, Krishnaswamy G. Chronic new type of Hermansky-Pudlak syndrome. granulomatous disease: a review of the Blood 2016;127(8):997-1006. infectious and inflammatory complications. 69. Badolato R, Parolini S. Novel insights Clin Mol Allergy 2011;9(1):10. from adaptor protein 3 complex deficiency. 76. Finocchi A, Claps A, Serafinelli J, Salfa J Allergy Clin Immunol 2007;120(4):735- I, Longo D, Di Matteo G, et al. Chronic 41. granulomatous disease presenting with 70. Decaminada N, Cappellini M, Mortilla salmonella brain abscesses. Pediatr Infect M, Del Giudice E, Sieni E, Caselli Disease J 2014;33(5):525-8. D, et al. Familial hemophagocytic 77. Carlsson G, Van’t Hooft I, Melin M, lymphohistiocytosis: clinical and Entesarian M, Laurencikas E, Nennesmo I, neuroradiological findings and review et al. Central nervous system involvement in of the literature. Childs Nerv Syst 2010 severe congenital neutropenia: neurological Jan;26(1):121-7. and neuropsychological abnormalities 71. Gupta S, Weitzman S. Primary and secondary associated with specific HAX1 mutations. hemophagocytic lymphohistiocytosis: J Intern Med 2008;264(4):388-400. clinical features, pathogenesis and therapy. 78. Germeshausen M, Grudzien M, Zeidler Expert Rev Clin Immunol 2010;6(1):137- C, Abdollahpour H, Yetgin S, Rezaei N, 54. et al. Novel HAX1 mutations in patients 72. Guo C, Nakazawa Y, Woodbine L, with severe congenital neutropenia reveal Björkman A, Shimada M, Fawcett H, et isoform-dependent genotype-phenotype al. XRCC4 deficiency in human subjects associations. Blood 2008;111(10):4954-7.

Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 21 Neurological Manifestations of Primary Immunodeficiencies

79. Rezaei N, Chavoshzadeh Z, Alaei O, Thrasher AJ. Actin cytoskeletal defects Sandrock I, Klein C. Association of HAX1 in immunodeficiency. Immunol Rev deficiency with neurological disorder. 2013;256(1):282-99. Neuropediatrics 2007;38(05):261-3. 87. Simon A, Kremer H, Wevers R, Scheffer 80. Boocock GR, Morrison JA, Popovic H, De Jong J, Van der Meer J, et al. M, Richards N, Ellis L, Durie PR, et al. Mevalonate kinase deficiency Evidence Mutations in SBDS are associated with for a phenotypic continuum. Shwachman–Diamond syndrome. Nat 2004;62(6):994-7. Genet 2003;33(1):97. 88. van der Burgh R, ter Haar NM, Boes ML, 81. Kerr EN, Ellis L, Dupuis A, Rommens Frenkel J. Mevalonate kinase deficiency, a JM, Durie PR. The behavioral phenotype metabolic autoinflammatory disease. Clin of school-age children with shwachman Immunol 2013;147(3):197-206. diamond syndrome indicates neurocognitive 89. Zhang S. Natural history of mevalonate dysfunction with loss of Shwachman- kinase deficiency: a literature review. Bodian-Diamond syndrome gene function. Pediatr Rheumatol 2016;14(1):30. J Pediatr 2010;156(3):433-8. e1. 90. Feldmann Jm, Prieur A-M, Quartier P, 82. Toiviainen‐Salo S, Mäkitie O, Mannerkoski Berquin P, Certain S, Cortis E, et al. Chronic M, Hämäläinen J, Valanne L, Autti infantile neurological cutaneous and T. Shwachman–Diamond syndrome articular syndrome is caused by mutations is associated with structural brain in CIAS1, a gene highly expressed in alterations on MRI. Am J Med Gene A polymorphonuclear cells and chondrocytes. 2008;146(12):1558-64. Am J Hum Genet 2002;71(1):198-203. 83. Gazit Y, Mory A, Etzioni A, Frydman 91. Sutterwala FS, Ogura Y, Szczepanik M, M, Scheuerman O, Gershoni-Baruch Lara-Tejero M, Lichtenberger GS, Grant R, et al. Leukocyte adhesion deficiency EP, et al. Critical role for NALP3/CIAS1/ type II: long-term follow-up and review Cryopyrin in innate and adaptive immunity of the literature. J Clin Immunol 2010 through its regulation of caspase-1. Mar;30(2):308-13. Immunity 2006;24(3):317-27. 84. Yakubenia S, Wild MK. Leukocyte 92. Kubota T, Koike R. Cryopyrin-associated adhesion deficiency II. The FEBS J periodic syndromes: background 2006;273(19):4390-8. and therapeutics. Mod Rheumatol 85. Etzioni A, Tonetti M. Leukocyte adhesion 2010;20(3):213-21. deficiency II–from A to almost Z. Immunol 93. Hoffman HM, Wanderer AA. Inflammasome Rev 2000;178(1):138-47. and IL-1β-mediated disorders. Curr Allergy 86. Moulding DA, Record J, Malinova D, Asthma Rep 2010;10(4):229-35.

22 Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 Neurological Manifestations of Primary Immunodeficiencies

94. Finetti M, Omenetti A, Federici S, 100. Caso F, Galozzi P, Costa L, Sfriso P, Caorsi R, Gattorno M. Chronic infantile Cantarini L, Punzi L. Autoinflammatory neurological cutaneous and articular granulomatous diseases: from Blau (CINCA) syndrome: a review. Orphanet J syndrome and early-onset sarcoidosis Rare Dis 2016;11(1):167. to NOD2-mediated disease and Crohn’s disease. RMD Open 2015;1(1):e000097. 95. Punzi L, Furlan A, Podswiadek M, Gava A, Valente M, De Marchi M, et al. Clinical and 101. Rosé CD, Pans S, Casteels I, Anton J, genetic aspects of Blau syndrome: a 25-year Bader-Meunier B, Brissaud P, et al. Blau follow-up of one family and a literature syndrome: cross-sectional data from a review. Autoimmun Rev 2009;8(3):228-32. multicentre study of clinical, radiological and functional outcomes. 96. Rosé CD, Doyle TM, McIlvain-Simpson 2014;54(6):1008-16. G, Coffman JE, Rosenbaum JT, Davey MP, et al. Blau syndrome mutation of 102. Pulliero A, Fazzi E, Cartiglia C, Orcesi S, CARD15/NOD2 in sporadic early onset Balottin U, Uggetti C, et al. The Aicardi– granulomatous arthritis. J Rheumatol Goutieres syndrome. Molecular and 2005;32(2):373-5. clinical features of RNAse deficiency and microRNA overload. Mutat Res 97. Kanazawa N. Presence of a sporadic case 2011;717(1):99-108. of systemic granulomatosis syndrome with a CARD15 mutation. J Invest Dermatol 103. Crow YJ, Rehwinkel J. Aicardi-Goutieres 2004;122:851-2. syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. 98. Martin TM, Zhang Z, Kurz P, Rose CD, Hum Mol Genet 2009;18(R2):R130-R6. Chen H, Lu H, et al. The NOD2 defect in Blau syndrome does not result in excess 104. Crow YJ, Hayward BE, Parmar R, Robins interleukin‐1 activity. Arthritis Rheum P, Leitch A, Ali M, et al. Mutations in the 2009;60(2):611-8. gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutieres 99. Brydges S, Kastner D. The systemic syndrome at the AGS1 locus. Nat Genet autoinflammatory diseases: inborn errors 2006;38(8):917. of the innate immune system. Current Concepts in Autoimmunity and Chronic Inflammation: Springer; 2006. p. 127-60.

Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 23