Neuro / Head & Neck for Tuesday, April 8th, 2025

Contributed by Mass General Hospital
Sergio Valencia, and Camilo Jaimes.

History

5 year old boy with profound developmental delay who presents with altered mental status and news weakness. 


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Question

Which of the following genetic/metabolic disorders is the most likely culprit of this appearance?

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Correct answer

Mitochondrial disorder

Discussion

Leukoencephalopathy with an LYRM7 mutation is a rare mitochondrial disorder characterized by progressive white matter abnormalities with multifocal cavitations. This condition results from mitochondrial complex III deficiency, leading to impaired oxidative phosphorylation and subsequent neurodegeneration. While many genetic and metabolic disorders may present with white matter signal abnormalities, caveating leukoencephalopathies are highly specific to some mitochondrial disorders. 

Brain MRI findings:

  • Bilateral, symmetric white matter involvement, predominantly affecting the periventricular and deep white matter.
  • Multifocal cavitations, which are distinctive and resemble cystic degeneration.
  • Fluctuating areas of diffusion restriction in the white matter, that lead to formation of cavitary areas
  • Relative sparing of the U-fibers and corpus callosum, helping differentiate it from other leukodystrophies.

Differential diagnosis

  • Kearns Sayre, a mitochondrial disorder related to a large deletion, which presents with signal abnormalities but no cavitation.
  • Vanishing white matter disease – A hypomyelinating leukodystrophy with progressive loss of white matter associated with episodes of physiologic stress. 
  • X-linked adrenoleukodystrophy – Periventricular demyelination that progresses in a posterior-to-anterior pattern but lacks cavitations.
  • Leigh syndrome – A mitochondrial disorder affecting both the deep gray nuclei and brainstem, often with lactate elevation.


References

  • Dallabona C, Abbink TE, Carrozzo R, Torraco A, Legati A, van Berkel CG, Niceta M, Langella T, Verrigni D, Rizza T, Diodato D, Piemonte F, Lamantea E, Fang M, Zhang J, Martinelli D, Bevivino E, Dionisi-Vici C, Vanderver A, Philip SG, Kurian MA, Verma IC, Bijarnia-Mahay S, Jacinto S, Furtado F, Accorsi P, Ardissone A, Moroni I, Ferrero I, Tartaglia M, Goffrini P, Ghezzi D, van der Knaap MS, Bertini E. LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance. Brain. 2016 Mar;139(Pt 3):782-94. doi: 10.1093/brain/awv392. Epub 2016 Jan 29. Erratum in: Brain. 2018 Nov 1;141(11):e82. doi: 10.1093/brain/awy194. PMID: 26912632.
  • Alfattal R, Alfarhan M, Algaith AM, Albash B, Elshafie RM, Alshammari A, Alahmad A, Dashti F, Alsafi R, Alsharhan H. LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes. Am J Med Genet A. 2023 May;191(5):1401-1411. doi: 10.1002/ajmg.a.63143. Epub 2023 Feb 9. PMID: 36757047.