Clinical and neuroimaging findings of Cree leukodystrophy: a retrospective case series.

BACKGROUND AND PURPOSE: CLD is a rapidly progressive and invariably fatal neurodegenerative disorder. We describe clinical and neuroimaging findings in 5 infants with CLD. MATERIALS AND METHODS: Retrospective review of medical records of infants with CLD from the past 11 years at our institution was performed. Relevant clinical and demographic data were recorded. Specific attention was directed toward postmortem examination findings and genetic testing. CT and MR imaging results were reviewed. RESULTS: Five Cree infants were diagnosed with CLD. CT demonstrated bilateral symmetric hypoattenuation of the white matter and globus pallidus. MR imaging demonstrated corresponding T2 hyperintensity in these regions and abnormal signal intensity in the thalami and substantia nigra. Symmetric restricted diffusion in the deep white matter was seen. MRS demonstrated decreased NAA, elevated choline, and the presence of lactate. Postmortem examination in 1 infant showed corresponding poor myelination in the brain stem, cerebellum, deep gray structures, and the cerebral hemispheres. Genetic testing in 2 infants revealed homozygous mutations in the eIF2B5 gene. CONCLUSIONS: Neuroimaging in CLD is striking and is an important tool in diagnosing CLD. Extensive white matter involvement as well as involvement of the globus pallidus and patchy involvement of the thalami and substantia nigra are characteristic. MRS findings are compatible with destruction of normal brain parenchyma with evidence of anaerobic metabolism in the regions of demyelination. Clinical suspicion of VWM in a Native American infant from this region should prompt the consideration of CLD with appropriate imaging work-up and genetic testing.

Peripheral neuropathy in a child with Cree leukodystrophy.

The authors describe peripheral nerve involvement in a 12-month-old boy with Cree leukodystrophy. Nerve conduction and genetic studies were performed during investigation of his leukodystrophy. Mutation analysis of the eukaryotic initiation factor 2B5 gene detected homozygosity of the R195 mutation, confirming the diagnosis of Cree leukodystrophy. Median and posterior tibial motor nerve conduction study results were normal, but sensory responses in the median nerves were unobtainable bilaterally, in keeping with a sensory axonal neuropathy. Somatosensory-evoked potentials were absent in the upper extremities and delayed in the lower extremities, confirming sensory nerve involvement. This degree of sensory nerve involvement has not been previously reported in patients with eukaryotic initiation factor 2B5-related disorders. Peripheral neuropathy should be looked for both clinically and with electrodiagnostic studies in patients with eukaryotic initiation factor 2B-related disorders.

The population structure of ten Newfoundland outports.

Island populations are most informative in the study of the genetic structure of human aggregates. These populations are often of small size, thus violating the Hardy-Weinberg assumption of infinite size. Some geographically isolated island populations are further subdivided by religion, ethnicity, and socioeconomic factors, reducing their effective sizes and facilitating genetic changes due to stochastic processes. Because of extreme geographic and social isolation, fishing communities or outports of Newfoundland have been investigated for genetic microdifferentiation through the founder effect and genetic drift (Crawford et al. 1995). The purpose of this paper is to examine the population structure of 10 Newfoundland outports using the allelic frequencies derived from 12 red cell antigens. To achieve this goal, first we calculated gene frequencies using maximum-likelihood estimation procedures. Second, we used R-matrix methods to explore population differentiation. Third, we regressed mean per-locus heterozygosity on genetic distance from the gene frequency centroid to identify the most isolated populations. On the basis of this information, the three outports of Seal Cove, Island Harbor, and Tilting were found to be genetically differentiated from the other small populations. Moreover, religious and geographic subdivisions appear to explain the observed genetic variation.

Effects of religion, economics, and geography on genetic structure of Fogo Island, Newfoundland.

The population structure of Fogo Island, Newfoundland is described using geography, religious affiliation, economic factors (such as the presence of a fish-packing plant), and genetic markers. Five different analytic methods, R-matrix analysis, rii VS. mean per locus heterozygosity, predicted kinship (ϕ), mean first passage time, and Mantel matrix comparisons, were applied to the Fogo Island genetic and demographic data. The results suggest that geography plays a role on Fogo Island in the distribution of genes, while religion, ethnicity, and economic factors play less significant roles. The communities with fish-packing plants and tourism serve as migratory "sinks" for Fogo islanders seeking employment. Reproductively, the most isolated village on Fogo Island is Tilting, and this is reflected in its genetic uniqueness, initially caused by Irish settlement and subsequently the action of stochastic processes. © 1995 Wiley-Liss, Inc.

Observations on the heparin neutralizing activity of outdated platelet concentrates.

A crude extract of outdated, washed, frozen and thawed, platelet concentrates was prepared and optimally diluted for use in the A.P.T.T. test as a source of platelet phospholipid (P.F. 3). The extract contained, in addition to P.F. 3, active heparin neutralizing activity (P.F. 4), which was able to neutralize plasma heparin up to a concentration of approximately 0.8 units/ml plasma. Although these observations are of a preliminary nature, it is felt that the extract can be used to follow the "intrinsic" coagulability of plasma samples from patients receiving therapeutic heparin. Utilizing the A.P.T.T. test system, the determination of coagulability and the neturalization of heparin result from the use of this extract in a single test.

Assignment of the red cell antigen, Targett (Rh40), to the Rh blood group system.

Statistical and serological evidence from a large kindred and two unrelated adults indicates that Targett (Tar) is an antigen in the Rh blood group system and that its presence is assocciated with a weak expression of the Rh antigen D. In the numerical notation the Tar antigen is designated Rh40.

Sickle cell crisis treated by exchange transfusion. Treatment of two patients with heterozygous sickle cell syndrome.

In two patients with severe painful sickle cell crisis and a deteriorating clinical course, recovery coincided with large-scale exchange transfusions (6 liters). The one patient, with sickle cell beta thalassemia, achieved a 90% exchange, calculated on the sickle cell hemoglobin present before and after transfusion. The other patient, with sickle cell hemoglobin Hb A, S, and (Hb) C disease, also achieved an 80% exchange calculated on the level of HbA.S. AND C in samples before and after transfusion.

High dose ascorbic acid in the management of thalassaemia leg ulcers--a pilot study.

Eight patients with beta thalassaemia major suffering from leg ulcers, were treated over an 8-week period with 3 g ascorbic acid daily in a controlled double-blind crossover study. The ulcers of all the patients showed a high rate of either complete or partial healing.