Encephalopathy, Acute, Infection-Induced, Susceptibility To, 3

A number sign (#) is used with this entry because of evidence that susceptibility to acute infection-induced encephalopathy-3 (IIAE3) is caused by heterozygous mutation in the RANBP2 gene (601181) on chromosome 2q12.

For a discussion of genetic heterogeneity of susceptibility to acute infection-induced encephalopathy, see 610551.

Clinical Features

Neilson et al. (2003) reported a large family in which 11 individuals over 3 generations were affected with an autosomal dominant form of acute necrotizing encephalopathy (ADANE) following febrile illnesses. The family had originally been reported by Eiben et al. (1965). The episodes characteristically occurred in early childhood (most before age 4 years) after a febrile illness. Affected members developed vomiting, seizures, spasticity, rigidity or abnormal posturing, altered mental status, and altered breathing patterns, usually leading to coma. Two patients died, 5 had residual neurologic impairment, and 4 had full recovery. Several affected members had residual weakness, seizures, gait abnormalities, speech disturbance, mental retardation, and mood disorders. Postmortem examination of 2 patients showed brain swelling and hemorrhagic lesions in the thalamus, putamen, and brainstem, as well as pallor of the neurons and myelinated tracts. Analysis of muscle respiration showed loose coupling of oxidative phosphorylation. Neilson et al. (2003) distinguished the disorder from Leigh syndrome (256000), which has a chronic course, but suggested that the pathologic mechanism in this disorder may also involve abnormalities in oxidative phosphorylation. Disease penetrance was estimated at 40%, and recurrent episodes occurred in half of affected individuals.

Neilson et al. (2009) reported 12 additional families with acute necrotizing encephalopathy (ANE). Specific infectious agents identified included influenza A, influenza, B, parainfluenza II, and Mycoplasma pneumoniae. Patients had a high incidence of seizures (59%), coma (100%), and CSF protein elevation (85%). Three patients had later onset at ages 12, 14, and 37 years, respectively. MRI changes showed variability, with classic involvement of the thalamus, brainstem, and pons, as well as the external capsule and claustrum (19 of 26 episodes), medial temporal lobe and limbic structures including amygdala, hippocampus, or medial temporal lobe (19 of 26), and spinal cord (3 of 26 episodes).

Gika et al. (2010) reported the clinical features of 1 of the patients reported by Neilson et al. (2009) who carried a heterozygous mutation in the RANBP2 gene (T585M; 601181.0001). This Caucasian girl presented at age 9 months with encephalopathy and seizures following a febrile illness. Brain MRI showed T2 signals in the thalami and the pons. She required ventilation for 10 days, but then made a slow and complete recovery both clinically and on brain imaging. At age 2 years, she presented with acute onset of right-sided sixth nerve palsy after a viral infection; brain CT was normal and the palsy resolved. She presented again at age 9 years with vomiting and decreased consciousness following a 3-day history of fever associated with influenza A. Her condition deteriorated and she progressed into a coma with hypotonia lasting several months. Brain MRI showed T2 signals similar to, but more extensive than, those seen on her first presentation. Two years after this illness, she was nonambulant and severely affected both neurologically and cognitively. The patient's mother, who also carried the mutation, had an episode of 'encephalitis/polyneuritis' at age 19 years following a viral infection and had a foot drop ever since. Neither of the mother's parents carried the mutation.

Lonnqvist et al. (2011) reported a 3-generation family in which 6 affected individuals with ANE had variable outcomes. Five patients had onset of episodes between age 7 months and 6 years; 1 had a single episode at age 12 years as a sequel to mumps. Two patients had recurrence in childhood. One patient had complete recovery, and 3 patients had recovery with only minor motor impairment, 1 of whom also developed seizures responsive to medication. A fifth patient, who had 2 episodes, was severely mentally retarded with intractable epilepsy at age 35, and a sixth patient had learning disabilities and severe visual impairment. All episodes were preceded by common viral infections. Brain MRI showed that the external capsule and mamillary bodies were affected in all, and the brainstem and thalami in 3. Most lesions resolved after the acute phase. Only 1 patient had cortical changes.

Inheritance

Infection-induced acute encephalopathy-3 is transmitted in an autosomal dominant pattern with reduced penetrance (Gika et al., 2010).

Mapping

By whole-genome mapping of the large affected family reported by Neilson et al. (2003), Neilson et al. (2004) identified a 6.5-Mb region containing the ADANE disease locus on chromosome 2q12.1-q13 (2-point lod score of 3.39 at D2S293). Further analysis showed cosegregation of a 5-marker haplotype, yielding a multipoint lod score of 3.6 across the interval. Sequence analysis showed no disease-causing mutations in 4 candidate genes in the interval: BCL2L11 (603827), ST6GalIII (608472), CHT1, and FLJ20019.

Molecular Genetics

In affected members of 10 unrelated families with acute necrotizing encephalopathy, including the family reported by Neilson et al. (2003, 2004), Neilson et al. (2009) identified a heterozygous mutation in the RANBP2 gene (T585M; 601181.0001). Haplotype analysis did not support a founder effect. Two additional families were found to carry different heterozygous mutations in the RANBP2 gene (601181.0002 and 601181.0003). Neilson et al. (2009) concluded that mutations in the RANBP2 gene predispose to ANE, but by themselves are insufficient to make the phenotype fully penetrant; additional genetic and environmental factors are required. Four more affected families did not carry RANBP2 mutations, indicating genetic heterogeneity.

Lonnqvist et al. (2011) identified the heterozygous T585M mutation in 6 affected members of a 3-generation Finnish family with ANE.