Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy

Abstract

ObjectiveTo expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes.MethodsWe performed an international cross-sectional study on patients with genetically proven POLR3-related leukodystrophy and atypical phenotypes to identify 6 children, 3 males and 3 females, with an extremely severe phenotype compared with that typically reported. Clinical, radiologic, and molecular features were evaluated for all patients, and functional and neuropathologic studies were performed on 1 patient.ResultsEach patient presented between 1 and 3 months of age with failure to thrive, severe dysphagia, and developmental delay. Four of the 6 children died before age 3 years. MRI of all patients revealed a novel pattern with atypical characteristics, including progressive basal ganglia and thalami abnormalities. Neuropathologic studies revealed patchy areas of decreased myelin in the cerebral hemispheres, cerebellum, brainstem, and spinal cord, with astrocytic gliosis in the white matter and microglial activation. Cellular vacuolization was observed in the thalamus and basal ganglia, and neuronal loss was evident in the putamen and caudate. Genotypic similarities were also present between all 6 patients, with one allele containing a POLR3A variant causing a premature stop codon and the other containing a specific intronic splicing variant (c.1771-7C>G), which produces 2 aberrant transcripts along with some wild-type transcript.ConclusionsWe describe genotype-phenotype correlations at the extreme end of severity of the POLR3-related leukodystrophy spectrum and shed light on the complex disease pathophysiology.

POLR3-Related Leukodystrophy: Exploring Potential Therapeutic Approaches

“…Research is ongoing regarding the investigation of the pathophysiology of POLR3-HLD; recent modeling of the disease has been accomplished in yeast (Moir et al, 2020 ), as well as in a conditional mouse model (pre-print data, not yet peer-reviewed; Merheb et al, 2020 ). Moreover, a variety of different types of pathogenic variants are known to cause POLR3-HLD, including nonsense, missense, intronic, synonymous, and splice site variants, as well as large exonic deletions, and small insertions or deletions (Bernard et al, 2011 ; Tétreault et al, 2011 ; Potic et al, 2012 ; Terao et al, 2012 ; Daoud et al, 2013 ; Takanashi et al, 2014 ; Wolf et al, 2014b ; Gutierrez et al, 2015 ; Thiffault et al, 2015 ; La Piana et al, 2016 ; Jurkiewicz et al, 2017 ; Richards et al, 2017 ; Al Yazidi et al, 2019 ; Gauquelin et al, 2019 ; Harting et al, 2020 ; Hiraide et al, 2020b ; Perrier et al, 2020 ). It is hypothesized that loss of POLR3 function disrupts the transcription of tRNAs, thereby resulting in dysregulation of global translation during peak periods of myelin development which require synthesis of large amounts of proteins (Pfeiffer et al, 1993 ; Elbaz and Popko, 2019 ).…”

“…Recently, the spectrum of severity and the associated clinical and MRI features of POLR3-HLD expanded significantly, from very mild to extremely severe. Very mild presentations include asymptomatic young adults, or patients with intellectual disability and milder hypomyelination on MRI compared to the typical phenotype, discovered incidentally during unrelated investigations (Wolf et al, 2014b ; Degasperis et al, 2020 ; Perrier et al, 2020 ). Isolated hypogonadotropic hypogonadism without evidence of hypomyelination has also been described on the mild end of the POLR3-HLD spectrum (Richards et al, 2017 ).…”

“…Isolated hypogonadotropic hypogonadism without evidence of hypomyelination has also been described on the mild end of the POLR3-HLD spectrum (Richards et al, 2017 ). Patients with the severe form of POLR3-HLD present much earlier compared to the typical phenotype, exhibiting developmental regression, failure to thrive, and severe dysphagia in the first few months of life, with some passing in early childhood due to respiratory complications (Wu et al, 2019 ; Harting et al, 2020 ; Perrier et al, 2020 ). These patients also present with a unique MRI phenotype, in fact not meeting the criteria for hypomyelination, but primarily showing neuronal involvement in specific brain regions (predominantly the putamen and thalamus) with some evidence of insufficient myelin deposition (Perrier et al, 2020 ).…”

“…Patients with the severe form of POLR3-HLD present much earlier compared to the typical phenotype, exhibiting developmental regression, failure to thrive, and severe dysphagia in the first few months of life, with some passing in early childhood due to respiratory complications (Wu et al, 2019 ; Harting et al, 2020 ; Perrier et al, 2020 ). These patients also present with a unique MRI phenotype, in fact not meeting the criteria for hypomyelination, but primarily showing neuronal involvement in specific brain regions (predominantly the putamen and thalamus) with some evidence of insufficient myelin deposition (Perrier et al, 2020 ). It is hypothesized that the neuronal presentation is likely linked to a specific splicing variant in POLR3A , given the common neuronal phenotype shared with other patients harboring the same, or an adjacent, splicing variant in a homozygous or compound heterozygous state (Azmanov et al, 2016 ; Minnerop et al, 2017 ; Wu et al, 2019 ; Harting et al, 2020 ; Hiraide et al, 2020a ).…”

POLR3-related leukodystrophy: How do mutations affecting RNA polymerase III subunits cause hypomyelination?

“…What was initially described as 4H syndrome 10 was renamed POLR3-related leukodystrophy when the first two genes ( POLR3A and POLR3B ) were identified 3 – 5 . As the disease spectrum widens 11 – 17 , with hypomyelination not always present, and mutations in POLR3 genes being found to explain other previously described disorders, they are collectively increasingly referred to as POLR3-related disorders 11 – 13 , 18 – 22 . With this new definition, one other POLR3 gene, POLR3GL , was added to the list of genes with biallelic mutations causing disorders with overlapping manifestations but without a leukodystrophy 23 , 24 .…”