Clinical and Neuroimaging Findings of Cree Leukodystrophy: A Retrospective Case Series

Discussion

CLD is a demyelinating disease that is known to affect infants of Cree and Chippewayan descent. Previously, the diagnosis was based on the clinical presentation and neuroimaging findings. Recently, CLD has been linked to homozygous missense mutations in the eIF2B5 gene, resulting in histidine replacing arginine at position 195 of the ε subunit of eIF2B. eIF2B converts eIF2 (the protein synthesis initiation factor) from an inactive form to an active form, which plays an essential role in the initiation of messenger RNA translation.^4,6 It also regulates the translation of RNA to protein, particularly under stress conditions.⁷ VWM, a less severe but progressive neurologic disorder seen predominantly in older children of NorthernEuropean ancestry,³ has been associated with mutations in any of the eIF2B5 subunit genes (eIF2B1–5).⁸ This not only supports the molecular basis of CLD but also demonstrates that CLD is allelic to VWM.

Two theories have been postulated as to how this missense mutation leads to the diffuse demyelination seen in CLD. The first hypothesis is that this mutation causes the accumulation of denatured proteins, whereas the second theory postulates that this missense mutation leads to a lack of eIF2 recycling and subsequent decreased rates of protein translation initiation and cell growth.^9,10 The precise reason for the susceptibility of cerebral white matter to eIF2B dysfunction has yet to be determined. This recent advance in the molecular basis of the disease has allowed the genetic confirmation of the diagnosis and the recognition of carriers for the disease.⁴

CLD affects developmentally healthy infants between the ages of 3 and 9 months. Although our case series includes 4 female infants and 1 male infant, a sex predilection, to our knowledge, has not been described in the reviewed literature. The disease is often preceded by an upper respiratory tract illness or minor trauma and is followed by seizures, spasticity, decreased level of consciousness, and eventual progression to death.¹ CLD is invariably fatal by 21 months of age.

The neuroimaging hallmark of CLD has been said to be diffuse extensive symmetric white matter abnormality in the brain stem, cerebellum, and cerebrum with sparing of the caudate nuclei and putamen on MR imaging.² The infants in our review had neuroimaging findings similar to those previously described in the literature. There were changes affecting the periventricular, lobar, and subcortical white matter identified early after the onset of illness. CT demonstrated diffuse symmetric hypoattenuation of the cerebral and cerebellar white matter, globus pallidus, and brain stem with sparing of the caudate nuclei and putamen. MR imaging demonstrated corresponding T2 hyperintensity in these regions with sparing of the red nucleus. Patchy involvement of the thalami, caudate nuclei, putamen, and substantia nigra was noted in our series.

Based on the neuroimaging findings alone, there are differential diagnostic considerations for this appearance, including leukodystrophies that predominantly involve the white matter, which include Canavan, Alexander, and VWM diseases. The former 2 classically present with macrocephaly, which is an important distinguishing finding when present. In addition, Canavan disease presents in a different ethnic group, and Alexander disease tends to classically demonstrate periventricular frontal enhancement after contrast administration. Macrocephaly and contrast enhancement have not been described with CLD. Canavan disease has a similar appearance, but the pattern of white matter involvement is usually centripetal, beginning in the subcortical arcuate fibers.² Alexander disease is also similar, but it is usually predominantly frontal in distribution with cysts and ventricular enlargement. Severe acute disseminated encephalomyelitis could also be considered, but this entity almost always presents in older children and tends to be less symmetric, often with associated enhancement and mass effect.

VWM/CACH has a similar appearance, as expected, because CLD is considered within this spectrum of disease. A categorization system described by van der Knaap et al¹⁰ suggests that CLD would be a category B2 leukoencephalopathy, similar to VWM. The most important distinction is clinical: VWM has a slower clinical course and a later onset.² Involvement of deep gray matter in CLD is another distinguishing feature. While the neuroimaging features may also be in keeping with other leukodystrophies, rapid progression along with Cree or Chippewayan ethnicity is highly suggestive of CLD.

Clinically, CLD may behave like Krabbe disease; however, the difference can be discerned on neuroimaging. Krabbe disease may have hyperattenuations in the thalami, corona radiata, and cerebellar cortex on CT and high T2 signal intensity in the periventricular and cerebellar white matter on MR imaging. Krabbe disease also has generally progressive brain atrophy.¹¹ In contrast, CLD diffusely affects the white matter with no preservation of the subcortical region and little or no atrophy.

The findings noted on DWI showing regional differences with increased diffusibility anteriorly and diffusion restriction related to the corpus callosum and in the subcortical U-fibers of the parieto-occipital lobes have not been previously described in VWM, to our knowledge. Although no enhancement was seen, this may represent an acute demyelinating margin, similar to that seen in adrenoleukodystrophy.

MRS demonstrated diminished NAA in affected white matter, in keeping with neuronal loss or dysfunction. Elevated choline was also seen and has been described in the setting of demyelination. The presence of lactate is in keeping with anaerobic metabolism. These features suggest destruction of normal brain parenchyma as well as metabolic stress in the regions of demyelination.

This retrospective study has some limitations. Most notably, genetic testing and postmortem examination were not performed on all of the infants in our study. Genetic testing only became available for the last 2 infants included in this series. Retrospective tissue analysis was attempted on previous samples but was not successful.