POLR3B-associated leukodystrophy: clinical, neuroimaging and molecular-genetic analyses in four patients: clinical heterogeneity and novel mutations in POLR3B gene

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064165%3A_____%2F19%3A10401058" target="_blank" >RIV/00064165:_____/19:10401058 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11110/19:10401058 RIV/65269705:_____/19:00072336 RIV/00064190:_____/19:N0000086

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=Gn4Dj9yo2u" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=Gn4Dj9yo2u</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.5603/PJNNS.a2019.0042" target="_blank" >10.5603/PJNNS.a2019.0042</a>

Result language

angličtina

Original language name

POLR3B-associated leukodystrophy: clinical, neuroimaging and molecular-genetic analyses in four patients: clinical heterogeneity and novel mutations in POLR3B gene

Original language description

Introduction and aim of the study. White matter disorders represent a spectrum of neurological diseases frequently associated with an unfavourable prognosis and a delay in diagnostics. We report the broad phenotypic spectrum of a rare hypomyelinating leukodystrophy and three novel mutations. Further, we aim to explore the role of the combined clinical and neuroimaging diagnostic approach in the era of whole exome sequencing. Materials and methods. We present a clinical, neuroimaging and molecular-genetic characterisation of four patients from three families suffering from a rare genetic leukoencephalopathy. Two severely affected siblings (P1, P2) manifested a profound developmental delay, cerebellar symptomatology, microcephaly, failure to thrive, short stature and delayed teeth eruption with oligodontia. The other two patients (P3, P4), on the contrary, suffer from substantially less serious impairment with mild to moderate developmental delay and cerebellar symptomatology, delayed teeth eruption, or well-manageable epilepsy. In all four patients, magnetic resonance revealed cerebellar atrophy and supratentorial hypomyelination with T2-weight hypointensities in the areas of the ventrolateral thalamic nuclei, corticospinal tract and the dentate nuclei. Results. Using whole-exome sequencing in P1, P2 and P3, and targeted sequencing in P4, pathogenic variants were disclosed in POLR313, a gene encoding one of 17 subunits of DNA-dependent RNA polymerase Ill - all patients were compound heterozygotes for point mutations. Three novel mutations c.727A&gt;G (p.Met243Val) and c.2669G&gt;A (p.Arg890His) (P1, P2), and c.1495G&gt;A (p.Met499Val) (P3) were found. Magnetic resonance revealed the characteristic radiological pattern of POLR3-leukodystrophies in our patients. Conclusion and clinical implications. The diagnosis of POLR3-associated leukodystrophies can be significantly accelerated using the combined clinical and neuroradiological recognition pattern. Therefore, it is of crucial importance to raise the awareness of this rare disorder among clinicians. Molecular-genetic analyses are indispensable for a swift diagnosis confirmation in cases of clear clinical suspicion, and for diagnostic search in patients with less pronounced symptomatology. They represent an invaluable tool for unravelling the complex genetic background of heritable white matter disorders.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10600 - Biological sciences

Project

<a href="/en/project/NV19-07-00136" target="_blank" >NV19-07-00136: Characterization of the molecular basis of rare genetic diseases of pediatric onset using new methods of genome analysis</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2019

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Neurologia i Neurochirurgia Polska

ISSN

0028-3843

e-ISSN

—

Volume of the periodical

53

Issue of the periodical within the volume

5

Country of publishing house

PL - POLAND

Number of pages

8

Pages from-to

369-376

UT code for WoS article

000494337600009

EID of the result in the Scopus database

2-s2.0-85074307390