Uncertain significance mutation in the POLR3B gene in a Syrian boy with leukodystrophy: a case report

Annals of Medicine and Surgery · 2 authors, 2 centres

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TL;DR

This is a case report of a 4-year-old boy who presented with progressive neurologic symptoms and hypomyelination on MRI, ultimately diagnosed with POLR3-related leukodystrophy after whole-exon sequencing identified a homozygous variant of uncertain significance in the POLR3B gene.

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The paper presents a case of a 4-year-old boy with delayed psychomotor development and progressive neurologic symptoms from age 20 months. Clinical examination revealed ataxia, delayed dentition, and global developmental delay. Whole-exon sequencing identified a homozygous missense variant of uncertain significance in the POLR3B gene (c.3005T>C; p.Ile1002Thr), leading to a diagnosis of POLR3-related leukodystrophy. The case highlights the diagnostic challenge of rare leukodystrophies and the crucial role of genetic testing for confirmation. The authors recommend genetic counseling for future pregnancies.

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case_report

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neurology

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ORIGINAL PAPER

PMC10406027

Uncertain significance mutation in the POLR3B gene in a Syrian boy with leukodystrophy: a case report

Annals of Medicine and Surgery

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ABSTRACT

Introduction: 4H leukodystrophy, one of the POLR3-related leukodystrophy, is a rare hereditary brain white matter disease with characteristic clinical presentation and imaging findings. Hypomyelination, hypodontia, and hypogonadotropic hypogonadism is mainly presented in patients with 4H leukodystrophy. Case presentation: A 4-year-old boy presented in the neurologic clinic with delayed psychomotor development and progressive neurologic symptoms that started from the age of 20 months. Physical examination revealed ataxic features and a global development delay. The MRI was significant for hypomyelination. The most common causes of leukodystrophy were rolled out. He was referred to an inherited metabolic disease specialist under suspect of inborn metabolic errors because of laboratory analysis, which showed elevated levels of lactic acid, pyruvate, 4-Hydroxy-Phenylactic acid, 3-Hydroxy propionic acid, and decreased levels of PCO2, HCO3, total CO2, 25-Hydroxyvitamin D. These results were unspecific and mitochondrial disease was highly suspected. However, the genetic study was requested to get a defined diagnosis and treatment; the whole exon sequencing result showed a homozygous variant of uncertain significance mutation; related to an amino acid change from Ile to Thr at position 1002 in the POLR3B gene, which helped us to reveal the final diagnosis, and the genetic counseling were recommended for the next pregnancies. Conclusion: POLR3-related Leukodystrophy is a very rare disease. The early diagnosis should be raised depending on clinical history and MRI findings after other conditions were rolled out, and the confirmed diagnosis depends on the genetic study. Keywords: 4H leukodystrophy, hypomyelination, POLR3B, POLR3-related leukodystrophy

CITATION EXPORT

Zulfiqar Hamdan, Diana Alasmar. Uncertain significance mutation in the POLR3B gene in a Syrian boy with leukodystrophy: a case report. Annals of Medicine and Surgery. (2023). https://doi.org/10.1097/MS9.0000000000001033

AUTHORS

2 · 2 CENTRES

Zulfiqar Hamdan, Diana Alasmar

aFaculty of Medicine
bPediatric Department, Damascus University Damascus, Syria