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Background <p>Recessive mutations in <i>POLR3A</i> exhibit considerable phenotypic diversity, spanning from severe childhood-onset hypomyelinating leukodystrophic syndrome to less severe gait disorders, which may present later in life and may be accompanied by additional non-neurological symptoms. In this study, we report a new case of rare <i>POLR3A</i> variants in a 6-year-old female patient sharing common genetic and neuropsychological profiles of <i>POLR3</i>-related disorders, although without revealing the classic MRI phenotype and severe clinical signs of <i>POLR3</i>-related leukodystrophy, such as diffuse hypomyelination.</p> Case presentation <p>Our probe was born after full term pregnancy complicated by Intrauterine Growth Restriction and risk of preterm birth treated with tocolytics during the last weeks of pregnancy. On the second day of life, tremors in the lower and upper limbs were detected and lasted until the second month of life. At the age of 6 months, she was diagnosed with hypotonia. The child showed a delay in the stages of psychomotor development and a slowing of the language. Brain MRI performed at the age of 5 years revealed mild and symmetrical ectasia of the lateral ventricles, mild hypoplasia of the cerebellar vermis and brainstem with wide communication between the fourth ventricle and the cisterna magna. Neurological examination revealed dyslalia, mild generalized hypotonia, ataxic gait, motor coordination and balance deficits, while the Wechsler Intelligence Scale for Children revealed the presence of mild intellectual disability. A clinical exome and neurodevelopmental multigenic analysis revealed two variants of the <i>POLR3A</i> gene in compound heterozygosity (c.1795&#xa0;C &gt; A and c.1289 + 3&#xa0;A &gt; G) previously described in the literature and a novel and not yet reported <i>CACNA2D2</i> variant (c.2929&#xa0;C &gt; T).</p> Conclusions <p>Beside the shared genetic and neuropsychological findings, the distinctive MRI and classical clinical signs of <i>POLR3</i>-related leukodystrophy have not been revealed in our case. This finding underscores the need to expand the diagnostic approach for <i>POLR3A</i>-related disorders, highlighting the significance of differentiating subtle clinical signs and promoting the use of genetic testing, especially in younger patients who may not yet display the typical clinical and MRI patterns. Further studies are necessary to shed light on different pathogenic mechanisms potentially responsible for the heterogeneous phenotype associated with <i>POLR3</i>-related disorders.</p>

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POLR3A rare variants in a patient with intellectual disability, ataxic gait and cortical malformations: a case-report

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  • 发表日期：

    2025年6月15日

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  • Caterina Angela Florio,
  • Federica Mirabella,
  • Adriana Prato,
  • Andrea Longhitano,
  • Rita Barone,
  • Renata Rizzo

摘要

Background

Recessive mutations in POLR3A exhibit considerable phenotypic diversity, spanning from severe childhood-onset hypomyelinating leukodystrophic syndrome to less severe gait disorders, which may present later in life and may be accompanied by additional non-neurological symptoms. In this study, we report a new case of rare POLR3A variants in a 6-year-old female patient sharing common genetic and neuropsychological profiles of POLR3-related disorders, although without revealing the classic MRI phenotype and severe clinical signs of POLR3-related leukodystrophy, such as diffuse hypomyelination.

Case presentation

Our probe was born after full term pregnancy complicated by Intrauterine Growth Restriction and risk of preterm birth treated with tocolytics during the last weeks of pregnancy. On the second day of life, tremors in the lower and upper limbs were detected and lasted until the second month of life. At the age of 6 months, she was diagnosed with hypotonia. The child showed a delay in the stages of psychomotor development and a slowing of the language. Brain MRI performed at the age of 5 years revealed mild and symmetrical ectasia of the lateral ventricles, mild hypoplasia of the cerebellar vermis and brainstem with wide communication between the fourth ventricle and the cisterna magna. Neurological examination revealed dyslalia, mild generalized hypotonia, ataxic gait, motor coordination and balance deficits, while the Wechsler Intelligence Scale for Children revealed the presence of mild intellectual disability. A clinical exome and neurodevelopmental multigenic analysis revealed two variants of the POLR3A gene in compound heterozygosity (c.1795 C > A and c.1289 + 3 A > G) previously described in the literature and a novel and not yet reported CACNA2D2 variant (c.2929 C > T).

Conclusions

Beside the shared genetic and neuropsychological findings, the distinctive MRI and classical clinical signs of POLR3-related leukodystrophy have not been revealed in our case. This finding underscores the need to expand the diagnostic approach for POLR3A-related disorders, highlighting the significance of differentiating subtle clinical signs and promoting the use of genetic testing, especially in younger patients who may not yet display the typical clinical and MRI patterns. Further studies are necessary to shed light on different pathogenic mechanisms potentially responsible for the heterogeneous phenotype associated with POLR3-related disorders.