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ARTICLES: P. Francalanci, E. Eymard–Pierre, C. Dionisi–Vici, R. Boldrini, F. Piemonte, R. Virgili, G. Fariello, C. Bosman, F.M. Santorelli, O. Boespflug–Tanguy, and E. Bertini Fatal infantile leukodystrophy: A severe variant of CACH/VWM syndrome, allelic to chromosome 3q27 Neurology 2001; 57: 265-270 [Abstract] [Full text] [PDF]

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Reply to Black et al.

Enrico Bertini   (19 September 2001)

Fatal infantile leukodystrophy: A severe variant of CACH/VWM syndrome, allelic to chromosome 3q27

D Black, "A Bearskin, R Harris, R Schiffmann, K Wong"   (19 September 2001)

Reply to Black et al. 19 September 2001
Enrico Bertini Bambino Gesu' Hospital IRCCS Rome Italy Send Correspondence to journal: Re: Reply to Black et al. ebertini{at}tin.it Enrico Bertini	We are very pleased to receive the letter from Black et al. who suggested that Cree leukoencephalopathy (CLE) should be included along with CACH / VWM as potential allelic variants. Both childhood leucoencephalopathies have an acute or subacute onset of neurologic deterioration in the setting of febrile illness, as observed in other demyelinating leukodystrophies (cerebral form of adrenoleukodystrophy for example). Compared to classical form of CACH/VWM, the case we reported has a particularly early onset (before 1) and severe evolution (death after respectively 7 and 3 months of disease duration) without relapsing episodes as described in CLE by the group of Black [1,2]. Massive, symmetrical attenuation of cerebral white matter on CT and MRI are classically found in early onset leukoencephalopathies with myelin loss. The normally early myelinated areas (cerebellum, brainstem, internal capsule, corpus callosum) are generally less affected leading in the CNS to a rostro-caudal gradient of lesions severity. In the great majority of cases abnormalities affect the periventricular white matter before the subcortical white matter (U fibers). Diffuse attenuation of cerebral myelin with minimal sudanophilia, sparse macrophages, absence of intracellular storage products, preserved neurons, absent or minimal inflammation on light microscopic examination is also found in other sudanophilic leukodystrophies particularly with a defect in myelin formation. Therefore, we agree with Black et al., to consider that CACH/VWM including our severe variant of CACH and CLE can be categorized in the same, heterogeneous group of sudanophilic leukoencephalopathies with an early onset myelin loss. However, major features distinct the two entities: (1) CACH/VWM is a cystic/spongy degeneration of the white matter. Presence of CSF-like white matter areas on proton density (PD) or fluid- attenuated inversion recovery (FLAIR) MRI is a diagnostic criteria of CACH/VWM, found in our two cases but not reported in CLE by Alorainy et al. Identically, a frankly cavitated white matter is mentioned in only 1/8 CLE patients reported by Black et al [1]. (2) Globus pallidus (100% of cases) or thalamus (67% of CLE) involvement reported in CLE on MRI by Alorainy et al was not observed in our two cases, as well as in CACH/VWM patients. (3) Increased density of oligodendrocytes contrasting with absence of astrogliosis, a proposed hallmark of CACH/VWM [3], was present in our two cases, in which an even shrinking of astrocytes was observed. In CLE the initial paper by Black et al [1] mentioned a normal or slightly reduced number of astrocytes whereas more recently Alorany et al [2] noticed a severe astrogliosis. We read with great interest that in CLE, Wong et al found “foamy” oligodendroglial cells identical to those recently reported in CACH/VWM. [4] Considering that isolated populations have less genetic heterogeneity and help to increase statistical power for the identification of genes [4], genetic linkage, including the 3q27 CACH/VWM locus, in CLE affected families would be of great interest to further delineated leukoencephalopathies of unknown origins presently categorized according to clinical, electrophysiological, NMR and neuropathological criteria. References: 1. Black D, Watters G, Andermann E, et al. Leukoencephalopathy among native Indian infants in Northern Quebec and Manitoba. Ann Neurol 1998;24:490-496 2. Alorainy IA, Patenaude YG, O'Gorman AM, Black DN, Meagher- Villemure K. Cree leukoencephalopathy: neuroimaging findings. Radiology 1999;213:400-406. 3. Rodriguez D, Gelot A, della Gaspera B, et al. Increased density of oligodendrocytes in childhood ataxia with diffuse central hypomyelination (CACH) syndrome: neuropathological and biochemical study of two cases. Acta Neuropathol (Berl)1999;97(5):469-480. 4. Wong K, Armstrong RC, Gyure KA, et al. Foamy cells with oligodendroglial phenotype in childhood ataxia with diffuse central nervous system hypomyelination syndrome. Acta Neuropathol (Berl) 2000;100:635-646. 5. Shifman S & Darvasi A. The value of isolated populations. Nature Genetics 2001;28:309 – 310.
Fatal infantile leukodystrophy: A severe variant of CACH/VWM syndrome, allelic to chromosome 3q27 19 September 2001
D Black Hopital Louis-H. Lafontaine Montreal Canada, "A Bearskin, R Harris, R Schiffmann, K Wong" Send Correspondence to journal: Re: Fatal infantile leukodystrophy: A severe variant of CACH/VWM syndrome, allelic to chromosome 3q27 sandi_moriarity{at}urmc.rochester.edu D Black, et al.	Francalanci et al.[1] described two sisters with a severe infantile variant of CACH/VWM leukodystrophy, which begins after an infectious illness and runs a progressive course to death within seven months of onset. We describe a similar, severe infantile leukoencephalopathy in the indigenous Cree population of Northern Quebec in 1988. [2] The distinguishing clinical features of Cree leukoencephalopahty (CLE) are: 1) Acute or subacute onset of neurologic deterioration in mid-infancy in the setting of a febrile illness. 2) Massive, symmetrical attenuation of cerebral white matter on CT and MRI. 3) Death in 100% of cases by 21 months. 4) Diffuse attenuation of cerebral myelin with minimal sudanophilia, absence of intracellular storage products, preserved neurons, absent or minimal inflammation on light microscopic examination. Our cases also had negative systemic and metabolic studies for the known leukodystrophies and a similar rostrocaudal gradient of hypomyelination. The neuropathology of CLE shows absence of cerebral white matter sparing the U-fibers with sparse macrophages. White matter vacuolation is not as prominent as in CACH and axons are less well preserved. There are large foamy cells that are negative for CD-68, LCA (leukocyte common antigen), and S-100 (non-macrophages), but immunoreactive for MOG (myelin oligodendrocyte glycoprotein), a recent unpublished observation by Wong and Schiffmann. These observations suggest that Cree leukoencephalopathy should be included along with CACH and VWN as potential allelic variants. References: 1) Francalanci P, Eymard-Pierre E, Dionisi-Vici C et al. Fatal infantile leukodystrophy: A severe variant of CACH/VWM syndrome, allelic to chromosome 3q27. Neurology 2001;57:265-270. 2) Black DN, Booth F, Watters GV et al. Leukoencephalopathy among native Indian infants in Northern Quebec and Manitoba. Annals of Neurology 1988;24:483-489.