Leukoencephalopathy, Brain Calcifications, And Cysts

A number sign (#) is used with this entry because of evidence that leukoencephalopathy, brain calcifications, and cysts (LCC) is caused by homozygous or compound heterozygous mutations in the SNORD118 gene (616663) on chromosome 17p13.

Description

Leukoencephalopathy, brain calcifications, and cysts (LCC), also known as Labrune syndrome, is characterized by a constellation of features restricted to the central nervous system, including leukoencephalopathy, brain calcifications, and cysts, resulting in spasticity, dystonia, seizures, and cognitive decline (summary by Labrune et al., 1996).

See also cerebroretinal microangiopathy with calcifications and cysts (CRMCC; 612199), an autosomal recessive disorder caused by mutation in the CTC1 gene (613129) that shows phenotypic similarities to Labrune syndrome. CRMCC includes the neurologic findings of intracranial calcifications, leukodystrophy, and brain cysts, but also includes retinal vascular abnormalities and other systemic manifestations, such as osteopenia with poor bone healing, a high risk of gastrointestinal bleeding, hair, skin, and nail changes, and anemia and thrombocytopenia. Although Coats plus syndrome and Labrune syndrome were initially thought to be manifestations of the same disorder, namely CRMCC, molecular evidence has excluded mutations in the CTC1 gene in patients with Labrune syndrome, suggesting that the 2 disorders are not allelic (Anderson et al., 2012; Polvi et al., 2012).

Clinical Features

Labrune et al. (1996) reported 3 unrelated children with progressive calcifications in the cerebrum and cerebellum and leukodystrophy on MRI. The changes were noted between early infancy and adolescence. Clinical features included slowing of cognition, seizures, and a movement disorder with pyramidal, extrapyramidal, and cerebellar features. Two patients became wheelchair-bound. All developed parenchymal cysts in the cerebellum or supratentorial regions. Brain biopsy of 1 patient showed angiomatous changes consisting of numerous small tortuous blood vessels with calcifications, irregular Rosenthal fibers, and hyaline deposits. Retinal abnormalities were not reported. Labrune et al. (1996) postulated a diffuse cerebral microangiopathy resulting in microcystic and macrocystic parenchymal degeneration.

Jenkinson et al. (2016) reported 40 patients from 33 unrelated families, mostly of European origin, with LCC. The patients had been collected over a period of 12 years. The age at presentation ranged between infancy and 54 years, although the vast majority of patients presented with neurologic features in the first months or years of life. Features were highly variable and included developmental delay, progressive motor disturbances, impaired gait, seizures, spasticity, dystonia, ataxia, dysarthria, and hemiparesis. Some individuals were severely impaired with mental retardation, loss of speech, and inability to walk, whereas a few patients had onset of mild motor symptoms in adulthood. Brain imaging characteristically showed white matter abnormalities in the periventricular, deep, and subcortical white matter, cysts in the deep matter, and calcifications. Brain biopsy of 1 adult patient showed numerous abnormal blood vessels resembling angioma, evidence of old hemorrhage, vascular and parenchymal calcification, and extensive gliosis with Rosenthal fibers.

Molecular Genetics

In 40 patients from 33 unrelated families with LCC, Jenkinson et al. (2016) identified biallelic mutations in the SNORD118 gene (see, e.g., 616663.0001-616663.0006). Mutations in the first families were found by a combination of linkage and haplotype analysis and exome sequencing; mutations in subsequent families were found by direct sequencing of the SNORD118 gene. All mutations were confirmed by Sanger sequencing and segregated with the disorder in the families where DNA was available. A total of 36 rare putative pathogenic variants were found, including 13 that were not present in the ExAC database or in an in-house database of over 5,000 exomes. Screening a panel of 677 European controls found that 4 individuals carried 2 rare SNORD118 variants on distinct alleles (4 of 677 compared to 20 of 20 LCC probands; p less than 0.000005). In vitro functional studies of several selected variants showed that they either impaired transcription, reduced binding to the SNU13 (601304) gene, or interfered with processing of the SNORD118 precursor RNA, consistent with a loss-of-function effect. Patient fibroblasts showed decreased SNORD118 expression and had poor growth and proliferation compared to wildtype, although there was no evidence for increased apoptosis or disturbance in the cell cycle. Additional studies showed no evidence for telomere dysfunction or disruption of TMEM107 (616183). Jenkinson et al. (2016) concluded that most patients were compound heterozygous for 1 severe and 1 mild mutation, and noted that the presence of mild recurrent variants in the general population suggested that these alleles are hypomorphic. For example, the ExAC database contained a small number of homozygotes for 5 of the 36 putative causal mutations identified. The hypomorphic variants likely contribute to the extensive phenotypic variability observed in this disorder. Jenkinson et al. (2016) also commented that since SNOR118 is a non-protein-coding portion of genomic DNA, it is more challenging to assess the biologic effects of mutations.

Exclusion Studies

Anderson et al. (2012) excluded mutations in the CTC1 gene in 21 families with Labrune syndrome. Polvi et al. (2012) also excluded mutations in the CTC1 gene in 2 probands with cerebral calcifications, leukoencephalopathy, and brain cysts without systemic manifestations. These studies suggested that Labrune syndrome is not allelic to CRMCC.