Cohort study describes the molecular pathology of LCC

Using data from the largest cohort of patients yet studied, Prof Yanick Crow’s research team describe the clinical spectrum and molecular pathology of the disease leukoencephalopathy with calcification and cysts (also known as Labrune syndrome). October 20.

Leukoencephalopathy with calcification and cysts (LCC) is a rare Mendelian condition with features including seizures, motor difficulties and cognitive decline.  The disease affects the small blood vessels in the brain, termed a microangiopathy.  Presentation can occur at any age from early infancy to late adulthood, and leads to a significant morbidity and early mortality in those affected.  There are currently no effective treatments for the disease.

The Crow group previously described LCC to be due to mutations in the gene SNORD118.  SNORD118 encodes the small nucleolar RNA (snoRNA) U8 that plays a key role in the biology of ribosomes – an integral component of the cellular translation machinery.

A new publication in the American Journal of Medical Genetics, led by Prof Yanick Crow and Dr Andrew Badrock, investigated the largest cohort of patients with LCC yet studied.  The paper describes the clinical spectrum and the molecular pathology of LCC in 64 affected individuals from 56 families, with disease due to 44 distinct variants in SNORD118. The cohort showed an extraordinarily wide range of age at first presentation of the disease, from 3 weeks to 67 years old (with 12.5% of patients presenting over the age of 40 years). Importantly, no obvious genotype-phenotype correlation to age of onset was found, suggesting the influence of environmental or other genetic factors.

All patients with classical features of LCC were found to harbour biallelic rare variants in the SNORD118 gene, suggesting that the disease is genetically homogeneous.  However, despite being a rare autosomal recessive disease, there was a very low frequency of homozygous alleles.  These data reinforce the previous suggestion that biallelic null mutations are likely incompatible with development, an interpretation supported by another recent publication by the same team, showing that the null mutant zebrafish is embryonically lethal (a zebrafish model of u8 snoRNA deficiency). Taken together, the data indicate that LCC most frequently arises from a combination of one null and one milder mutation affecting a novel 5’ end to 3’ extension base-pairing region of pre-U8.

This new study is important because it provides the most comprehensive overview yet of the clinical and molecular spectrum of LCC.  Furthermore, since SNORD118 is a non-protein encoding gene, these results will have immediate translational relevance in informing molecular diagnostic testing, and will help us to think about future therapeutic strategies for this devastating disease.

Links

Article in the American Journal of Medical Genetics https://doi.org/10.1002/ajmg.a.61907

Prof Yanick Crow’s research Group Website 

More information on LCC