JNS-13325; No of Pages 3 Journal of the Neurological Sciences xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene☆ Christian Denier a,⁎, Laurent Balu b, Béatrice Husson c, Ghaidaa Nasser c, Lydie Burglen d, Diana Rodriguez e, Pierre Labauge f, Laurent Chevret a a
Department of Neurology, Bicêtre Hospital, Assistance-Publique–Hôpitaux de Paris (AP-HP), France Department of Pediatry, Bicêtre Hospital, Assistance-Publique–Hôpitaux de Paris (AP-HP), France Department of Radiology, Bicêtre Hospital, Assistance-Publique–Hôpitaux de Paris (AP-HP), France d Department of Genetics, Trousseau Hospital, AP-HP, France e Department of Pediatry, Robert Debré Hospital, AP-HP, France f Department of Neurology, Montpellier Hospital, France b c
a r t i c l e
i n f o
Article history: Received 7 April 2014 Received in revised form 8 July 2014 Accepted 10 July 2014 Available online xxxx Keywords: IIAE3 Infection-induced acute encephalopathy-3 IIAE3 Acute necrotizing encephalopathy RANBP2
a b s t r a c t Background: Acute necrotizing encephalopathy (ANE) is a rare and severe parainfectious central nervous system disease in which previously healthy children develop rapidly progressive coma following viral illness. While most ANE are sporadic, familial autosomal dominant ANE due to mutations in the RANBP2 gene has been recently reported (ANE1 or infection-induced acute encephalopathy-3 (IIAE3)). To date, only few IIAE3 families with ADANE episodes have been described. Objective: To report a new family with ADANE, describe clinical and radiological features and discuss differential diagnosis including Leigh syndrome or multiple sclerosis. Observation: The family included 3 symptomatic individuals and one 59 year-old asymptomatic obligate carrier. Patients presented acute episodes of encephalopathy few days after common viral infection. Ages of onset ranged from 6 months to 5 years. Episodes not only occurred in childhood but also recurred in adulthood. Initial neurological signs included coma, focal neurological deficits and seizures. MRI showed typical necrotizing lesions primarily in the thalamus and brainstem, and in the temporal lobes and insula. CSF cell count and cultures were normal during episodes. RANBP2 gene screening identified pathogenic heterozygous c.1754CNT mutation (p.Thr585Met). Episodes led to cognitive or physical handicap in 2 patients and were fatal in one child. Conclusion: IIAE3 or ADANE due to RANBP2 mutations has a large clinical heterogeneity. Our family illustrates the associated phenotypes from asymptomatic carrier to severe episodes of encephalopathy. Based on MRI features, the genetic IIAE3 diagnosis is important since prophylaxis and symptomatic management of infections may be beneficial, possibly in association with steroid or gammaglobulins. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Isolated sporadic acute necrotizing encephalopathy (ANE) is a rare but well recognized disorder, especially in Asia. In ANE, previously healthy young children develop rapidly progressive encephalopathy, coma, seizures or focal neurological within days of onset of viral infection, with no evidence of infection of the central nervous system [1]. During acute phase, cerebral MR imaging in ANE typically shows symmetric lesions affecting primarily not only the thalami but also the upper brainstem tegmentum, putamina, deep periventricular white matter and cerebellum [1]. Most ANE are sporadic and non-recurrent. ☆ Financial disclosure statement: The authors have nothing to disclose. ⁎ Corresponding author at: Department of Neurology, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France. Tel.: +33 1 45 21 26 18; fax: +33 1 45 21 31 49. E-mail address: [email protected] (C. Denier).
Recently, familial incompletely penetrant autosomal dominant ANE (ADANE) due to mutations in the RANBP2 gene has been reported (ANE1 or IIAE3 i.e. infection-induced acute encephalopathy-3 (MIM 608133)) with recurrent rapid onset episodes occurring essentially in childhood and triggered by viral febrile illnesses as in sporadic ANE [2, 3]. To date, only 16 IIAE3 families with ADANE episodes have been reported of European, Asian or African descents [3–8]. We herein describe the clinical, radiological and molecular findings of a new three-generation ADANE family in order to describe its clinical variability with incomplete penetrance and long term follow-up, and to discuss radiological specificity and differential diagnosis. 2. Family report This family includes symptomatic and symptom free individuals (Fig. 1). In addition of one clinically and radiologically unaffected obligate
http://dx.doi.org/10.1016/j.jns.2014.07.025 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Denier C, et al, Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.025
2
C. Denier et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
carrier (case I.2), three affected individuals illustrate the clinical and radiological spectrum of infection-induced acute encephalopathy-3 (IIAE3) with ADANE episodes (cases II.1, II.2 and III.1) (Fig. 1). Neurological episodes included coma, focal deficits and seizures. Most episodes followed febrile viral illnesses. Antibiotics and antiviral were prescribed in most of the cases despite normal CSF study. Affected individuals presented one to 3 encephalopathy episodes with an age of onset from 6 months to 5 years. ADANE recurrence also occurred in adulthood with one ANE episode at age 23 in II.2. Outcome was variable after the 8 episodes occurring in the 3 symptomatic patients: there were 4 complete spontaneous recoveries, 3 associated residual permanent physical or cognitive handicaps and one death. Family history was established following III.1's first and recent neurological episodes. His mother II.2 and grandfather I.2 were then examined, and the medical reports of previously dead II.1 were thereafter studied. For the mutation analysis, blood samples from the patients were collected after having obtained written informed consents. Genomic DNA was extracted from peripheral blood lymphocytes using the Flexigene DNA kit (Qiagen, Courtaboeuf, France). The RANBP2 (NM_006267.4) coding exons 12 and 14 (in which mutations were previously reported) and intron–exon junctions were PCR-amplified using 2 primer pairs (sequences available on request) [3]. PCR products were then sequenced with Big Dye Terminator cycle sequencing kit and ABI 3730xl automated sequencer (PE Applied Biosystems). Sequencing revealed the c.1754CNT mutation predicting the p.Thr585Met missense mutation in the proband (III.1). Analysis of RANBP2 exon 12 in patient II.3, mother of the proband, revealed the same mutation.
nasopharyngitis with mild fever. On examination, she presented right hemiparesis and stupor requiring admission to intensive care during several weeks. Her status deteriorated and progressed into a state of coma, with flaccid tetraplegia, facial diplegia and laryngo-pharyngeal palsies requiring mechanical ventilation. Repeated lumbar punctures, viral tests and EEG were unremarkable. Recovery was slow but complete with a motor improvement beginning at day 10 to be complete at day 21. At age 2, she presented seizures while she had fever attributed to flu. Confusion persisted during 48 h. Subsequent developmental progress was normal. At age 6, coma recurred during nasopharyngitis. Biological testing including infection and metabolic screen, and lumbar puncture analysis was normal (including viral PCR-based CSF testing and culture). Brain CT showed hypodensities in the brainstem. “Leigh syndrome” diagnosis was suspected despite the absence of metabolic abnormalities. Spontaneous recovery occurred with persistence of residual ataxia. Following this episode, some learning difficulties also appeared. The last episode appeared during adulthood following a flu episode at 23-years-old: she presented severe confusion associated with cerebellar ataxia for a few days. MRI showed T2-weighted lesions in the brainstem, temporal lobes and thalami. CSF studies only showed isolated mild hyperproteinorachy (0.5 g/L). She progressively improved over one week. Ten years later, she only presented slight symptoms of cerebellar ataxia. At 35 years-old, MRI showed symmetric cavitating abnormalities affecting the insula and temporal lobes, in association with the cerebellar and hippocampic atrophy (Fig. 1, upper panel). Following neurological episodes in her daughter III.1, the diagnosis was revised to ADANE; RANBP2 gene screening identified heterozygous c.1754CNT mutation confirming IIAE3 (p.Thr585Met).
2.1. Case I.2
2.4. Case III.1
This unaffected individual was lastly examined at age 59 when his granddaughter III.1 presented coma. He was a likely obligate carrier since he had two affected descendants from two different wives. However, as the patient declined to be tested, the genetic analysis has not been performed and we can't rule out the possibility of a germinal mosaicism. No peculiar familial history was found among his descendants, or neurological episode during his life, even following usual seasonal viral infections or vaccinations. MRI at age 59 was strictly normal (protocol including diffusion-, T1- and T2-weighted, FLAIR sequences and spectroscopy; not shown).
This healthy 5-year-old girl developed ataxia and confusion and became unresponsive 5 days following febrile upper respiratory symptoms. Initial standard biology and CT scan were normal. CSF study showed isolated mild hyperproteinorachy (0.46 g/L). Patient's state deteriorated within 24 h with stupor. Physical findings included Glasgow coma score of 4 and bilateral Babinski signs. She was admitted in intensive care unit for ventilation. MRI in acute phase revealed diffusion- and T2-weighted hyperintensities in the lateral centrosylvian and insular cortex, external capsules, medial temporal lobes and amygdalae, hippocampi, thalami, midbrain and pons (Fig. 1; lower panel). T1-weighted MRI showed decreased signal within the same corresponding areas, with no gadolinium enhancement. Knowing the familial history and cerebral MRI pattern, RANBP2 gene screening identified heterozygous c.1754CNT mutation (p.Thr585Met) leading to the IIAE3 diagnosis. She was treated with steroids followed by plasma exchanges. After 4 weeks of ventilation, she subsequently required tracheostomy for additional weeks. She progressively improved over 2 months with mild residual cognitive impairment and ataxia.
2.2. Case II.1 This boy died at age of 9-years-old following a third and severe ANE episode. Previously healthy, he developed convulsions at 12 month-old after 48 h of cough and fever. Repetition of generalized seizures with left-side hemiplegia required admission to intensive care. Computed Tomography (CT) showed symmetric temporal and basal ganglia hypodensities. Lumbar puncture was normal including viral testing. EEG demonstrated excess of slow activities. Complete recovery progressively occurred in 10 days. “Viral encephalitis” diagnosis was retained. Identical recurrence appeared one year later following coryza. Permanent residual cognitive impairment persisted following the second episode with adapted schooling. The third episode appeared at age 9, a few days after nasopharyngitis. Initial clinical symptoms were confusion and progressive lethargy, leading to coma and death 24 h after the onset. CT scan showed hypodensities of the brainstem and thalami. “Leigh syndrome” diagnosis was retained. Further information on the medical history and file could not be available (hospital is now closed). 2.3. Case II.2 The medical history of II.2 was investigated following the ANE episode of her daughter III.1. When she was 6-month-old, this case, II.1's half-sister, presented unresponsiveness and dyspnea after 7 days of
3. Discussion Our family report resumes the large clinical and radiological spectrum of IIAE3. We herein described incomplete clinical and MRI penetrance which has been previously estimated to be of 50% [2,3] and high clinical variability. Known to affect mainly children before age of 4, ADANE/IIAE3 can also recur in adulthood as in our case III.2 with an ANE episode at age 23, and in literature with episodes recurring until 27 years-old [2,3]. Concerning severity, our 3-generation family report describes presentation of ADANE. One to 3 encephalopathy episodes by the patient occurred with an age at onset ranging from 6 months to 5 years. Out of these 8 identified episodes, there were 4 complete spontaneous recovery, 3 leading to permanent physical or cognitive impairment and one leading to death, as previously reported [2,3,5,6]. To date, necrotizing encephalopathies affecting the brainstem are mainly associated with three conditions, namely Wernicke's
Please cite this article as: Denier C, et al, Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.025
C. Denier et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
3
encephalopathy, Leigh syndrome and ANE [2,3,5,6]. Differential diagnosis also includes inflammatory or demyelinating cerebral disease and acute disseminating encephalomyelitis (ADEM). The authors also reported that some adults with manifestations of ADANE could be misdiagnosed with multiple sclerosis (MS) [3]. Facing acute encephalopathy, Wernicke's encephalopathy is suspected in patients with poor nutritional status and is rare in children. MS is also uncommon in children and rarely presenting with encephalopathy as an initial symptom. Concerning differential diagnosis between IIAE3, ANE and Leigh, ADEM and other encephalitis, MRI is helpful. MRI hallmarks of IIAE3/ADANE include symmetrical and focal necrotic lesions in the thalami, lateral centrosylvian and insular cortex, internal capsule, medial temporal lobes, midbrain and pons. The hippocampi, cerebellum and supratentorial white matter are variably involved ([2,3,5,6] and Fig. 1). Classical lesions are T2-weighted hyperintensities, hypo-T1 with no enhancement following gadolinium administration in acute stages. Evolution of lesions can lead to cavitations Fig. 1) [2,3,5,6]. While additional studies remain needed to understand its pathophysiological basis, IIAE3 diagnosis is important to be firmly done, since prophylaxis, preventive measures and prompt treatment of infections and symptomatic management of fever may be beneficial. In addition, rapid deterioration of the neurological condition often requires intensive care. Lastly, some authors suggested that acute necrotizing encephalopathy episodes could be gammaglobulin- and/or steroidresponsive [7,9,10]. 4. Conclusion Our family illustrates the IIAE3 — associated phenotype which includes severe cases with ADANE episodes and asymptomatic mutation carriers. While clinical presentation is non-specific, radiological features are typical and include multifocal symmetric necrotic lesions of the thalamus and pons. Although the function and role of RANBP2 protein remain unclear, genetic diagnosis is important; prophylaxis and symptomatic management of infections may be beneficial, possibly in association with steroid or gammaglobulins. References
Fig. 1. Genealogical tree and cerebral MRI imaging in autosomal dominant acute necrotizing encephalopathy IIAE3. Genealogical tree and brain MR imaging of patients II.2 and III.1 are shown. Squares denote men, circles denote women, slashes denote subjects who have died, open symbols denote healthy subjects, and solid symbols denote subjects affected by ANE episodes. In II.2, MRI at 35 years-old showed symmetric cavitating abnormalities affecting insula and temporal lobes, in association with cerebellar and hippocampic atrophy (upper panel). In III.1, during an episode at 6 years-old, MRI in acute phase revealed diffusion- and T2-weighted hyperintensities in the lateral centro-sylvian and insular cortex, external capsules, medial temporal lobes and amygdala, thalami, midbrain and pons (lower panel). T1-weighted MRI showed decreased signal within the same corresponding areas, with no gadolinium enhancement.
[1] Mizuguchi M, Abe J, Mikkaichi K, Noma S, Yoshida K, Yamanaka T, et al. Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions. J Neurol Neurosurg Psychiatry 1995; 58:555–61. [2] Neilson DE, Eiben RM, Waniewski S, Hoppel CL, Varnes ME, Bangert BA, et al. Autosomal dominant acute necrotizing encephalopathy. Neurology 2003;61:226–30. [3] Neilson DE, Adams MD, Orr CM, Schelling DK, Eiben RM, Kerr DS, et al. Infectiontriggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet 2009;84:44–51. [4] Loh NR, Appleton DB. Untreated recurrent acute necrotising encephalopathy associated with RANBP2 mutation, and normal outcome in a Caucasian boy. Eur J Pediatr 2010;169:1299–302. [5] Gika AD, Rich P, Gupta S, Neilson DE, Clarke A. Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family. Dev Med Child Neurol 2010;52:99–102. [6] Lönnqvist T, Isohanni P, Valanne L, Olli-Lähdesmäki T, Suomalainen A, Pihko H. Dominant encephalopathy mimicking mitochondrial disease. Neurology 2011; 76:101–3. [7] Wolf K, Schmitt-Mechelke T, Kollias S, Curt A. Acute necrotizing encephalopathy (ANE1): rare autosomal-dominant disorder presenting as acute transverse myelitis. J Neurol 2013;260:1545–53. [8] Di Meglio C, Cano A, Milh M, Girard N, Burglen L, Chabrol B. Postinfectious family case of acute necrotizing encephalopathy caused by RANBP2 gene mutation. Arch Pediatr 2014;21:73–7. [9] Okumura A, Mizuguchi M, Kidokoro H, Tanaka M, Abe S, Hosoya M, et al. Outcome of acute necrotizing encephalopathy in relation to treatment with corticosteroids and gammaglobulin. Brain Dev 2009;31:221–7. [10] Bergamino L, Capra V, Biancheri R, Rossi A, Tacchella A, Ambrosini L, et al. Immunomodulatory therapy in recurrent acute necrotizing encephalopathy ANE1: is it useful? Brain Dev 2012;34:384–91.
Please cite this article as: Denier C, et al, Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.025
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene☆ Christian Denier a,⁎, Laurent Balu b, Béatrice Husson c, Ghaidaa Nasser c, Lydie Burglen d, Diana Rodriguez e, Pierre Labauge f, Laurent Chevret a a
Department of Neurology, Bicêtre Hospital, Assistance-Publique–Hôpitaux de Paris (AP-HP), France Department of Pediatry, Bicêtre Hospital, Assistance-Publique–Hôpitaux de Paris (AP-HP), France Department of Radiology, Bicêtre Hospital, Assistance-Publique–Hôpitaux de Paris (AP-HP), France d Department of Genetics, Trousseau Hospital, AP-HP, France e Department of Pediatry, Robert Debré Hospital, AP-HP, France f Department of Neurology, Montpellier Hospital, France b c
a r t i c l e
i n f o
Article history: Received 7 April 2014 Received in revised form 8 July 2014 Accepted 10 July 2014 Available online xxxx Keywords: IIAE3 Infection-induced acute encephalopathy-3 IIAE3 Acute necrotizing encephalopathy RANBP2
a b s t r a c t Background: Acute necrotizing encephalopathy (ANE) is a rare and severe parainfectious central nervous system disease in which previously healthy children develop rapidly progressive coma following viral illness. While most ANE are sporadic, familial autosomal dominant ANE due to mutations in the RANBP2 gene has been recently reported (ANE1 or infection-induced acute encephalopathy-3 (IIAE3)). To date, only few IIAE3 families with ADANE episodes have been described. Objective: To report a new family with ADANE, describe clinical and radiological features and discuss differential diagnosis including Leigh syndrome or multiple sclerosis. Observation: The family included 3 symptomatic individuals and one 59 year-old asymptomatic obligate carrier. Patients presented acute episodes of encephalopathy few days after common viral infection. Ages of onset ranged from 6 months to 5 years. Episodes not only occurred in childhood but also recurred in adulthood. Initial neurological signs included coma, focal neurological deficits and seizures. MRI showed typical necrotizing lesions primarily in the thalamus and brainstem, and in the temporal lobes and insula. CSF cell count and cultures were normal during episodes. RANBP2 gene screening identified pathogenic heterozygous c.1754CNT mutation (p.Thr585Met). Episodes led to cognitive or physical handicap in 2 patients and were fatal in one child. Conclusion: IIAE3 or ADANE due to RANBP2 mutations has a large clinical heterogeneity. Our family illustrates the associated phenotypes from asymptomatic carrier to severe episodes of encephalopathy. Based on MRI features, the genetic IIAE3 diagnosis is important since prophylaxis and symptomatic management of infections may be beneficial, possibly in association with steroid or gammaglobulins. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Isolated sporadic acute necrotizing encephalopathy (ANE) is a rare but well recognized disorder, especially in Asia. In ANE, previously healthy young children develop rapidly progressive encephalopathy, coma, seizures or focal neurological within days of onset of viral infection, with no evidence of infection of the central nervous system [1]. During acute phase, cerebral MR imaging in ANE typically shows symmetric lesions affecting primarily not only the thalami but also the upper brainstem tegmentum, putamina, deep periventricular white matter and cerebellum [1]. Most ANE are sporadic and non-recurrent. ☆ Financial disclosure statement: The authors have nothing to disclose. ⁎ Corresponding author at: Department of Neurology, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France. Tel.: +33 1 45 21 26 18; fax: +33 1 45 21 31 49. E-mail address: [email protected] (C. Denier).
Recently, familial incompletely penetrant autosomal dominant ANE (ADANE) due to mutations in the RANBP2 gene has been reported (ANE1 or IIAE3 i.e. infection-induced acute encephalopathy-3 (MIM 608133)) with recurrent rapid onset episodes occurring essentially in childhood and triggered by viral febrile illnesses as in sporadic ANE [2, 3]. To date, only 16 IIAE3 families with ADANE episodes have been reported of European, Asian or African descents [3–8]. We herein describe the clinical, radiological and molecular findings of a new three-generation ADANE family in order to describe its clinical variability with incomplete penetrance and long term follow-up, and to discuss radiological specificity and differential diagnosis. 2. Family report This family includes symptomatic and symptom free individuals (Fig. 1). In addition of one clinically and radiologically unaffected obligate
http://dx.doi.org/10.1016/j.jns.2014.07.025 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Denier C, et al, Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.025
2
C. Denier et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
carrier (case I.2), three affected individuals illustrate the clinical and radiological spectrum of infection-induced acute encephalopathy-3 (IIAE3) with ADANE episodes (cases II.1, II.2 and III.1) (Fig. 1). Neurological episodes included coma, focal deficits and seizures. Most episodes followed febrile viral illnesses. Antibiotics and antiviral were prescribed in most of the cases despite normal CSF study. Affected individuals presented one to 3 encephalopathy episodes with an age of onset from 6 months to 5 years. ADANE recurrence also occurred in adulthood with one ANE episode at age 23 in II.2. Outcome was variable after the 8 episodes occurring in the 3 symptomatic patients: there were 4 complete spontaneous recoveries, 3 associated residual permanent physical or cognitive handicaps and one death. Family history was established following III.1's first and recent neurological episodes. His mother II.2 and grandfather I.2 were then examined, and the medical reports of previously dead II.1 were thereafter studied. For the mutation analysis, blood samples from the patients were collected after having obtained written informed consents. Genomic DNA was extracted from peripheral blood lymphocytes using the Flexigene DNA kit (Qiagen, Courtaboeuf, France). The RANBP2 (NM_006267.4) coding exons 12 and 14 (in which mutations were previously reported) and intron–exon junctions were PCR-amplified using 2 primer pairs (sequences available on request) [3]. PCR products were then sequenced with Big Dye Terminator cycle sequencing kit and ABI 3730xl automated sequencer (PE Applied Biosystems). Sequencing revealed the c.1754CNT mutation predicting the p.Thr585Met missense mutation in the proband (III.1). Analysis of RANBP2 exon 12 in patient II.3, mother of the proband, revealed the same mutation.
nasopharyngitis with mild fever. On examination, she presented right hemiparesis and stupor requiring admission to intensive care during several weeks. Her status deteriorated and progressed into a state of coma, with flaccid tetraplegia, facial diplegia and laryngo-pharyngeal palsies requiring mechanical ventilation. Repeated lumbar punctures, viral tests and EEG were unremarkable. Recovery was slow but complete with a motor improvement beginning at day 10 to be complete at day 21. At age 2, she presented seizures while she had fever attributed to flu. Confusion persisted during 48 h. Subsequent developmental progress was normal. At age 6, coma recurred during nasopharyngitis. Biological testing including infection and metabolic screen, and lumbar puncture analysis was normal (including viral PCR-based CSF testing and culture). Brain CT showed hypodensities in the brainstem. “Leigh syndrome” diagnosis was suspected despite the absence of metabolic abnormalities. Spontaneous recovery occurred with persistence of residual ataxia. Following this episode, some learning difficulties also appeared. The last episode appeared during adulthood following a flu episode at 23-years-old: she presented severe confusion associated with cerebellar ataxia for a few days. MRI showed T2-weighted lesions in the brainstem, temporal lobes and thalami. CSF studies only showed isolated mild hyperproteinorachy (0.5 g/L). She progressively improved over one week. Ten years later, she only presented slight symptoms of cerebellar ataxia. At 35 years-old, MRI showed symmetric cavitating abnormalities affecting the insula and temporal lobes, in association with the cerebellar and hippocampic atrophy (Fig. 1, upper panel). Following neurological episodes in her daughter III.1, the diagnosis was revised to ADANE; RANBP2 gene screening identified heterozygous c.1754CNT mutation confirming IIAE3 (p.Thr585Met).
2.1. Case I.2
2.4. Case III.1
This unaffected individual was lastly examined at age 59 when his granddaughter III.1 presented coma. He was a likely obligate carrier since he had two affected descendants from two different wives. However, as the patient declined to be tested, the genetic analysis has not been performed and we can't rule out the possibility of a germinal mosaicism. No peculiar familial history was found among his descendants, or neurological episode during his life, even following usual seasonal viral infections or vaccinations. MRI at age 59 was strictly normal (protocol including diffusion-, T1- and T2-weighted, FLAIR sequences and spectroscopy; not shown).
This healthy 5-year-old girl developed ataxia and confusion and became unresponsive 5 days following febrile upper respiratory symptoms. Initial standard biology and CT scan were normal. CSF study showed isolated mild hyperproteinorachy (0.46 g/L). Patient's state deteriorated within 24 h with stupor. Physical findings included Glasgow coma score of 4 and bilateral Babinski signs. She was admitted in intensive care unit for ventilation. MRI in acute phase revealed diffusion- and T2-weighted hyperintensities in the lateral centrosylvian and insular cortex, external capsules, medial temporal lobes and amygdalae, hippocampi, thalami, midbrain and pons (Fig. 1; lower panel). T1-weighted MRI showed decreased signal within the same corresponding areas, with no gadolinium enhancement. Knowing the familial history and cerebral MRI pattern, RANBP2 gene screening identified heterozygous c.1754CNT mutation (p.Thr585Met) leading to the IIAE3 diagnosis. She was treated with steroids followed by plasma exchanges. After 4 weeks of ventilation, she subsequently required tracheostomy for additional weeks. She progressively improved over 2 months with mild residual cognitive impairment and ataxia.
2.2. Case II.1 This boy died at age of 9-years-old following a third and severe ANE episode. Previously healthy, he developed convulsions at 12 month-old after 48 h of cough and fever. Repetition of generalized seizures with left-side hemiplegia required admission to intensive care. Computed Tomography (CT) showed symmetric temporal and basal ganglia hypodensities. Lumbar puncture was normal including viral testing. EEG demonstrated excess of slow activities. Complete recovery progressively occurred in 10 days. “Viral encephalitis” diagnosis was retained. Identical recurrence appeared one year later following coryza. Permanent residual cognitive impairment persisted following the second episode with adapted schooling. The third episode appeared at age 9, a few days after nasopharyngitis. Initial clinical symptoms were confusion and progressive lethargy, leading to coma and death 24 h after the onset. CT scan showed hypodensities of the brainstem and thalami. “Leigh syndrome” diagnosis was retained. Further information on the medical history and file could not be available (hospital is now closed). 2.3. Case II.2 The medical history of II.2 was investigated following the ANE episode of her daughter III.1. When she was 6-month-old, this case, II.1's half-sister, presented unresponsiveness and dyspnea after 7 days of
3. Discussion Our family report resumes the large clinical and radiological spectrum of IIAE3. We herein described incomplete clinical and MRI penetrance which has been previously estimated to be of 50% [2,3] and high clinical variability. Known to affect mainly children before age of 4, ADANE/IIAE3 can also recur in adulthood as in our case III.2 with an ANE episode at age 23, and in literature with episodes recurring until 27 years-old [2,3]. Concerning severity, our 3-generation family report describes presentation of ADANE. One to 3 encephalopathy episodes by the patient occurred with an age at onset ranging from 6 months to 5 years. Out of these 8 identified episodes, there were 4 complete spontaneous recovery, 3 leading to permanent physical or cognitive impairment and one leading to death, as previously reported [2,3,5,6]. To date, necrotizing encephalopathies affecting the brainstem are mainly associated with three conditions, namely Wernicke's
Please cite this article as: Denier C, et al, Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.025
C. Denier et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
3
encephalopathy, Leigh syndrome and ANE [2,3,5,6]. Differential diagnosis also includes inflammatory or demyelinating cerebral disease and acute disseminating encephalomyelitis (ADEM). The authors also reported that some adults with manifestations of ADANE could be misdiagnosed with multiple sclerosis (MS) [3]. Facing acute encephalopathy, Wernicke's encephalopathy is suspected in patients with poor nutritional status and is rare in children. MS is also uncommon in children and rarely presenting with encephalopathy as an initial symptom. Concerning differential diagnosis between IIAE3, ANE and Leigh, ADEM and other encephalitis, MRI is helpful. MRI hallmarks of IIAE3/ADANE include symmetrical and focal necrotic lesions in the thalami, lateral centrosylvian and insular cortex, internal capsule, medial temporal lobes, midbrain and pons. The hippocampi, cerebellum and supratentorial white matter are variably involved ([2,3,5,6] and Fig. 1). Classical lesions are T2-weighted hyperintensities, hypo-T1 with no enhancement following gadolinium administration in acute stages. Evolution of lesions can lead to cavitations Fig. 1) [2,3,5,6]. While additional studies remain needed to understand its pathophysiological basis, IIAE3 diagnosis is important to be firmly done, since prophylaxis, preventive measures and prompt treatment of infections and symptomatic management of fever may be beneficial. In addition, rapid deterioration of the neurological condition often requires intensive care. Lastly, some authors suggested that acute necrotizing encephalopathy episodes could be gammaglobulin- and/or steroidresponsive [7,9,10]. 4. Conclusion Our family illustrates the IIAE3 — associated phenotype which includes severe cases with ADANE episodes and asymptomatic mutation carriers. While clinical presentation is non-specific, radiological features are typical and include multifocal symmetric necrotic lesions of the thalamus and pons. Although the function and role of RANBP2 protein remain unclear, genetic diagnosis is important; prophylaxis and symptomatic management of infections may be beneficial, possibly in association with steroid or gammaglobulins. References
Fig. 1. Genealogical tree and cerebral MRI imaging in autosomal dominant acute necrotizing encephalopathy IIAE3. Genealogical tree and brain MR imaging of patients II.2 and III.1 are shown. Squares denote men, circles denote women, slashes denote subjects who have died, open symbols denote healthy subjects, and solid symbols denote subjects affected by ANE episodes. In II.2, MRI at 35 years-old showed symmetric cavitating abnormalities affecting insula and temporal lobes, in association with cerebellar and hippocampic atrophy (upper panel). In III.1, during an episode at 6 years-old, MRI in acute phase revealed diffusion- and T2-weighted hyperintensities in the lateral centro-sylvian and insular cortex, external capsules, medial temporal lobes and amygdala, thalami, midbrain and pons (lower panel). T1-weighted MRI showed decreased signal within the same corresponding areas, with no gadolinium enhancement.
[1] Mizuguchi M, Abe J, Mikkaichi K, Noma S, Yoshida K, Yamanaka T, et al. Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions. J Neurol Neurosurg Psychiatry 1995; 58:555–61. [2] Neilson DE, Eiben RM, Waniewski S, Hoppel CL, Varnes ME, Bangert BA, et al. Autosomal dominant acute necrotizing encephalopathy. Neurology 2003;61:226–30. [3] Neilson DE, Adams MD, Orr CM, Schelling DK, Eiben RM, Kerr DS, et al. Infectiontriggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet 2009;84:44–51. [4] Loh NR, Appleton DB. Untreated recurrent acute necrotising encephalopathy associated with RANBP2 mutation, and normal outcome in a Caucasian boy. Eur J Pediatr 2010;169:1299–302. [5] Gika AD, Rich P, Gupta S, Neilson DE, Clarke A. Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family. Dev Med Child Neurol 2010;52:99–102. [6] Lönnqvist T, Isohanni P, Valanne L, Olli-Lähdesmäki T, Suomalainen A, Pihko H. Dominant encephalopathy mimicking mitochondrial disease. Neurology 2011; 76:101–3. [7] Wolf K, Schmitt-Mechelke T, Kollias S, Curt A. Acute necrotizing encephalopathy (ANE1): rare autosomal-dominant disorder presenting as acute transverse myelitis. J Neurol 2013;260:1545–53. [8] Di Meglio C, Cano A, Milh M, Girard N, Burglen L, Chabrol B. Postinfectious family case of acute necrotizing encephalopathy caused by RANBP2 gene mutation. Arch Pediatr 2014;21:73–7. [9] Okumura A, Mizuguchi M, Kidokoro H, Tanaka M, Abe S, Hosoya M, et al. Outcome of acute necrotizing encephalopathy in relation to treatment with corticosteroids and gammaglobulin. Brain Dev 2009;31:221–7. [10] Bergamino L, Capra V, Biancheri R, Rossi A, Tacchella A, Ambrosini L, et al. Immunomodulatory therapy in recurrent acute necrotizing encephalopathy ANE1: is it useful? Brain Dev 2012;34:384–91.
Please cite this article as: Denier C, et al, Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.025
![[Postinfectious family case of acute necrotizing encephalopathy caused by RANBP2 gene mutation].](/assets/img/hold.png)
