A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report

Tewari, Vishal Vishnu; Mehta, Ritu; Sreedhar, C M; Tewari, Kunal; Mohammad, Akbar M.; Gupta, Neerja; Gulati, Sheffali; Kabra, Madhulika

doi:10.1186/s12887-018-1108-9

Cited by 15 publications

(17 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is also depicted in a report of a patient with hypomyelination and a previously unreported homozygous variant of c.2423G > A in exon 18 ( Fig. 2a in [20]). Involvement of the red nucleus as a relay station of SCP was reported for the three patients homozygous for the c.1771-6C > G variant [10].…”

Section: Discussionmentioning

confidence: 68%

POLR3A variants with striatal involvement and extrapyramidal movement disorder

et al. 2020

View full text Add to dashboard Cite

Biallelic variants in POLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants in POLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygous POLR3A variants and predominant striatal changes were retrospectively reviewed in order to characterize the striatal variant of POLR3A-associated disease. Prominent extrapyramidal involvement was the predominant clinical sign in all patients. The three youngest children were severely affected with muscle hypotonia, impaired head control, and choreic movements. Presentation of the six older patients was milder. Two brothers diagnosed with juvenile parkinsonism were homozygous for the c.1771-6C > G variant in POLR3A; the other seven either carried c.1771-6C > G (n = 1) or c.1771-7C > G (n = 7) together with another variant (missense, synonymous, or intronic). Striatal T2-hyperintensity and atrophy together with involvement of the superior cerebellar peduncles were characteristic. Additional MRI findings were involvement of dentate nuclei, hila, or peridentate white matter (3, 6, and 4/9), inferior cerebellar peduncles (6/9), red nuclei (2/9), and abnormal myelination of pyramidal and visual tracts (6/9) but no frank hypomyelination. Clinical and MRI findings in patients with a striatal variant of POLR3A-related disease are distinct from 4H leukodystrophy and associated with one of two intronic variants, c.

show abstract

Section: Discussionmentioning

confidence: 68%

POLR3A variants with striatal involvement and extrapyramidal movement disorder

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Patients with POLR3B mutations typically present slightly earlier but have a milder disease course than those with POLR3A mutations. 5,7 It is unusual for a 4H leukodystrophy patient to have absent neurologic deficits by age 26 years.…”

Section: Discussionmentioning

confidence: 99%

4H leukodystrophy

et al. 2020

View full text Add to dashboard Cite

Hypomyelinating leukodystrophy with hypodontia and hypogonadotropic hypogonadism (4H leukodystrophy), also known as POLR3-related leukodystrophy, is a genetic disorder caused by autosomal recessive mutations in the POLR3A, POLR3B, POLR1C, or POLR3K genes. 1-3 Most patients have progressive motor deficits. 4 We present 2 siblings with a milder phenotype and lack of disease progression previously reported within a larger cohort of patients. 5 Case presentationCase 1 A 16-year-old previously healthy girl was referred to our neurology clinic with a 3-week history of numbness in her lower extremities, headaches, and blurred vision in her right eye. On examination, she had ataxic gait because of decreased sensation to touch in her lower extremities and hyperreflexia. MRI showed enhancement of the right optic nerve, diffuse symmetric signal abnormalities in the white matter of both cerebral hemispheres, and multiple spinal cord lesions (figure). The CSF analysis revealed oligoclonal bands. She was diagnosed with right optic neuritis and a hypomyelinating leukodystrophy.

show abstract

“…POLR3A, POLR3B, and POLR1C mutations are associated with Pol III-related leukodystrophies. The former two genes encode the two largest subunits of Pol III, which is composed of 17 subunits, while defects in the POLR1C gene impair assembly and nuclear import of POLR3 and thereby lead to decreased binding to its target genes [5]. Pol III transcribes a series of small non-coding RNAs (i.e., tRNAs, 5S RNA, 7S RNA, U6 RNA), which participate in the regulation of vital cellular processes, such as transcription, RNA processing, and translation [9], leading to a series of neuronal and nonneurological features.…”

Section: Case Presentationmentioning

confidence: 99%

“…These genes are responsible for encoding the two largest subunits of RNA polymerase III (Pol III), which has been hypothesized to be crucial for the synthesis of small RNAs, such as 5SrRNA and transfer RNAs (tRNAs). Many genetic factors, especially biallelic mutations in POLR3A (OMIM: 614258) or POLR3B (OMIM: 614366), have been reported in this hereditary disease [5][6][7][8]. Mutations in these genes cause abnormal tRNA and non-coding RNA transcription in a cell type and growth state dependent manner, and can impact cellular growth, differentiation, and apoptosis [5,9].…”

Section: Introductionmentioning

confidence: 99%

“…Many genetic factors, especially biallelic mutations in POLR3A (OMIM: 614258) or POLR3B (OMIM: 614366), have been reported in this hereditary disease [5][6][7][8]. Mutations in these genes cause abnormal tRNA and non-coding RNA transcription in a cell type and growth state dependent manner, and can impact cellular growth, differentiation, and apoptosis [5,9]. Patients with POLR3A mutations have a more severe disease course and an unfavorable prognosis compared to cases with POLR3B mutations.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel mutations of POLR3A Gene caused hypomyelinating leukodystrophy type 7 (HLD7) in a Chinese family: a Case Report

Bai

Dong

et al. 2019

Preprint

View full text Add to dashboard Cite

Background Hypomyelinating leukodystrophy 7 (HLD7) is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive motor decline that manifests as spasticity, ataxia, tremor, and cerebellar symptoms, as well as mild cognitive regression and hypodontia. HLD7 belongs to the family of RNA polymerase III-related leukodystrophy, which are caused by biallelic mutations in the POLR3A or POLR3B gene. Case presentation In this study, we report a female child with HLD7 manifesting as cognitive decline, moderate dysarthria, intellectual disability, cerebellar syndrome, short stature, dysphagia, hypodontia, and aberrant brain imaging. Interestingly, polytrichia and bronchodysplasia were first observed in the HLD7 patient. Medical exome sequencing with high coverage depth was employed to identify potential genetic variants in the patient. Novel compound heterozygous mutations of the POLR3A gene, c.1771-6C>G and c.2611del (p.M871Cfs*8), were detected. One of them is an uncommon splice site mutation, and this is the first report of this mutation in a Chinese family. The father was determined to be a heterozygous carrier of the c.2611del (p.M871Cfs*8) mutation and the mother a heterozygous carrier of the c.1771-6C>G mutation. Conclusion The patient’s newly emerged clinical features and mutations provide useful information for further exploration of genotype-phenotype correlations of HLD7.

show abstract

A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report

Cited by 15 publications

References 19 publications

POLR3A variants with striatal involvement and extrapyramidal movement disorder

POLR3A variants with striatal involvement and extrapyramidal movement disorder

4H leukodystrophy

Novel mutations of POLR3A Gene caused hypomyelinating leukodystrophy type 7 (HLD7) in a Chinese family: a Case Report

Contact Info

Product

Resources

About