RANBP2 mutation causing autosomal dominant acute necrotizing encephalopathy attenuates its interaction with COX11.

PURPOSE: Autosomal dominant acute necrotizing encephalopathy (ADANE) is caused by missense mutations in the gene encoding Ran-binding protein 2 (RANBP2), a nuclear pore protein regulating mitochondrial localization and function. Previous studies have found that RANBP2 binds to COX11 and suppresses its inhibitory activity over hexokinase1. To further elucidate mitochondrial dysfunction in ADANE, we analyzed the interaction between mutated RANBP2 and COX11. METHODS: We extracted cDNA from a patient and constructed pGEX wild-type or mutant-type vectors including RANBP2 c.1754C>T, the commonest variant in ADANE. We transformed E. coli competent cells with the vectors and had them express GST-RANBP2 recombinant protein, and conducted a pull-down assay of RANBP2 and COX11. RESULTS: The amount of COX11 bound to mutated RANBP2 was significantly smaller than that bound to the wild-type RANBP2. CONCLUSION: Mutated RANBP2 had an attenuated binding ability to COX11. Whether this change indeed decreases ATP production remains to be further explored.

Anti-CV2/CRMP5 antibody-associated hemorrhagic leukoencephalomyelitis treated with steroids, intravenous immunoglobulin, plasmapheresis, and cyclophosphamide.

Anti-CV2 or anti-collapsing response-mediator protein-5 (CRMP5) autoantibodies (anti-CV2/CRMP5-Ab) are associated with various paraneoplastic neurological disorders. The best therapy is typically removal of the underlying cancer. We describe a previously healthy elderly male who had no known malignancy. He presented with a demyelinating encephalomyelitis and later developed hemorrhagic changes on neuroimaging. He was treated with intravenous immunoglobulin (IVIG), intravenous steroids, and plasmapheresis; however, sustained clinical and radiographic stabilization and improvement only occurred following cyclophosphamide. He unexpectedly died of a cardiac arrest. postmortem, his serum paraneoplastic screen was found to be weakly positive for anti-CV2/CRMP5-Ab.

Gadolinium enhancement patterns of tumefactive demyelinating lesions: correlations with brain biopsy findings and pathophysiology.

Tumefactive demyelinating lesions (TDLs) can mimic brain tumors on radiological images. TDLs are often referred to as tumefactive multiple sclerosis (TMS), but the heterogeneous nature and monophasic course of TDLs do not fulfill clinical and magnetic resonance imaging (MRI) criteria for multiple sclerosis. Redefining TDLs, TMS and other inflammatory brain lesions is essential for the accurate clinical diagnosis of extensive demyelinating brain lesions. We retrospectively analyzed MRI from nine TDL cases that underwent brain biopsy. Patterns of gadolinium enhancement on MRI were categorized as homogenous, inhomogeneous, patchy and diffuse, open ring or irregular rim, and were compared with pathological hallmarks including demyelination, central necrosis, macrophage infiltration, angiogenesis and perivascular lymphocytic cuffing. All cases had coexistence of demyelinating features and axonal loss. Open-ring and irregular rim patterns of gadolinium enhancement were associated with macrophage infiltrations and angiogenesis at the inflammatory border. An inhomogeneous pattern of gadolinium enhancement was associated with perivascular lymphocytic cuffing. Central necrosis was seen in cases of severe multiple sclerosis and hemorrhagic leukoencephalopathy. These results suggest that the radiological features of TDLs may be related to different pathological processes, and indicate that MRI may be useful in understanding their pathophysiology. Further investigation is needed to determine the precise disease entity of these inflammatory demyelinating brain lesions.

Atypical timing and presentation of periventricular haemorrhagic infarction in preterm infants: the role of thrombophilia.

AIM: Periventricular haemorrhagic infarction (PVHI) is a complication of preterm birth associated with cardiorespiratory instability. To date, the role of thrombophilia as a possible additional risk factor in infants with atypical timing and presentation of PVHI has not been investigated. METHOD: This was a retrospective cohort study of preterm infants who developed PVHI with an atypical timing and presentation either of antenatal onset or late in the postnatal course in the absence of a preceding sudden deterioration of their clinical condition. In infants with atypical PVHI mutation analysis of the factor V Leiden (G1691A), prothrombin (G20210A) gene, and C677T and A1298C polymorphisms in the MTHFR gene was performed, and plasma lipoprotein(a) and homocysteine levels were measured. RESULTS: Sixty-two preterm infants who presented with a PVHI were studied. Seventeen had an atypical presentation (seven males, 10 females; median birthweight 1170g [range 580-1990g]; median gestational age 30.6wks [range 28.7-33.7wks]). The typical PVHI group comprised 28 males and 17 females (median birthweight 1200g [range 670-2210g]; median gestational age 29.6wks [range 25.3-33.6wks]). Among the 17 infants with atypical presentation, the factor V Leiden mutation was found in seven infants (41%) as well as in the mothers of six of these seven infants; in one infant this was concomitant with a prothrombin gene mutation. A polymorphism in the MTHFR gene was also present in these infants. In two infants with an atypical presentation who were tested for this, a mutation in the COL4A1 gene was found (reported previously). All but two of the infants with an atypical presentation developed spastic unilateral cerebral palsy. INTERPRETATION: An atypical presentation of PVHI in preterm infants tends to occur more often in the presence of thrombophilia. Testing of thrombophilia, especially factor V Leiden and prothrombin gene mutation, is recommended in these infants.

Use of therapeutic plasma exchange in the management of acute hemorrhagic leukoencephalitis: a case report and review of the literature.

BACKGROUND: Acute hemorrhagic leukoencephalitis (AHLE) is a rare, fatal, central nervous demyelinating disease characterized by a rapid fulminant clinical course. Successful management requires early diagnosis, aggressive management of cerebral edema, and immunosuppression. Therapeutic plasma exchange (TPE) is infrequently used and commences after initial management fails. CASE REPORT: A 31-year-old man presented with right arm weakness, whose symptoms rapidly progressed to hemiplegia and aphasia. The patient was initially managed with glucocorticosteroids. Decompressive craniotomy and brain biopsies were performed when his intracranial pressure increased. Brain biopsy findings were consistent with AHLE. Mycoplasma pneumonia immunoglobulin G and immunoglobulin M serologies revealed recent infection. Despite surgical and medical management, he decompensated on Day 11, and TPE was initiated. The patient received a total of 10 TPE treatments. On the fourth day of TPE treatment, he was extubated. Twenty-one days after TPE began, he was ambulating with near normal muscle strength and was discharged. Four months after initial presentation, the patient has normal strength and is working full-time. CONCLUSIONS: AHLE has a fulminant course requiring accurate and rapid diagnosis. Successful therapy requires aggressive management of intracranial pressure and immunosuppression. Two other reports of AHLE document successful management with TPE. Each of these patients survived with minimal neurologic impairments. Given the likely immune-mediated nature of this disease, combined treatment of steroids, surgery, and TPE may lead to shorter hospital stays and improved neurologic outcomes. Clinical studies are needed to further study the effect of TPE on neurologic outcome in AHLE.