POLR3A‐Related Disorder Presenting with Late‐Onset Dystonia and Spastic Paraplegia

https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312945-sup-v001.htm

POLR3‐related disorders are a group of autosomal recessive neurodegenerative diseases that usually cause leukodystrophy with an overlapping of other symptoms, such as spasticity, ataxia, tremor, hypodontia, mental retardation, and progressive motor decline. It often starts in childhood, ranging from the neonatal period to late childhood. These disorders are caused by mutations in the POLR3A, POLR3B, POLR1C, and POLR3K genes.1, 2 The largest subunit of human RNA polymerase III is encoded by POLR3A; the RNA polymerase III transcribes untranslated RNA that are necessary for translation, transcription, and protein translocation; and RNA polymerase III is involved in the regulation of growth and the differentiation of cells.3, 4

Herein we describe a case of a POLR3A gene mutation presenting with a phenotype characterized by adult‐onset spastic paraplegia and dystonia and minor changes in brain magnetic resonance imaging (MRI).

Case Report

A 35‐year‐old woman born from nonconsanguineous parents presented with a very slow progressive difficulty in walking that started when she was 24 years old. Nine years prior, when she was 15 years old, she developed a mild right‐arm writing tremor. During the following years, she developed a head tremor. Her gait worsened, and she became dependent on a walking stick 2 years ago. Cognition was normal. Her mother and aunt also had tremor, probably related to essential tremor. Examination disclosed mild pes cavus, brisk deep tendon reflexes, weakness and spasticity in the lower limbs with bilateral Babinski sign, and head dystonic tremor with a marked tilt of her head to the right. The tremor had a transient improvement if the patient touched her mental region, and this phenomenology was interpreted as a sensory trick. She also had a paraparetic gait (Video S1). General blood tests, albumin, alpha‐fetoprotein, vitamin E, and phytanic acid were normal. Brain MRI showed a mild and bilateral hyperintense signal in the superior cerebellar peduncles (Fig. 1). Electromyography showed dystonic tremor with activation of sternocleidomastoids, bilateral splenium capitis, and right trapezius (Fig. 2). Somatosensory evoked potential showed prolonged latencies. Genetic testing for the most common spinocerebellar ataxias (1, 2, 3, 6, 7, 10), dentatorubral‐pallidoluysian atrophy, Friedreich ataxia and fragile X–associated tremor, and ataxia syndrome were negative. Whole‐exome sequencing was performed and revealed compound heterozygous mutations NM_007055.3 (POLR3A): c.1909 + 22G > A and NM_007055.3 (POLR3A): c.1114G > A (p.Asp372Asn) of the POLR3A gene, which were classified as definitely pathogenic mutations. Segregation with genetic testing in the parents also showed the aforementioned mutations. Variant c.1909 + 22G > A was identified as heterozygous in her mother, and variant p.Asp372Asn was found in the father. Therefore, the variants are found in different alleles in our patient. Multidisciplinary treatment with oral baclofen 30 mg daily and physiotherapy were started. Oral biperiden 4 mg daily has partially improved the head dystonic tremor.

Figure 1.

Brain magnetic resonance imaging of the patient with POLR3A gene mutations. (A) Para‐coronal fluid attenuated inversion recovery–weighted and (B) axial fluid attenuated inversion recovery–weighted brain magnetic resonance imaging show bilateral hyperintense signal along the superior cerebellar peduncle, extending from the midbrain to the dentate nucleus (arrows). (C) Coronal T2‐weighted brain magnetic resonance imaging discloses no white matter changes.

Figure 2.

While the patient kept head in a neutral position, there was continuous spontaneous activity in the SCM bilaterally. It is possible to observe overlapping regular and bilateral 4 to 5 Hz bursts (dystonic tremor) in the SCM (arrow) and in the SPC. A: 200 ms/div; B: 50 ms/div. A similar pattern of tremor and overlapping continuous muscular activity was observed in the trapezius muscle when the patient assumed an orthostatic position. L, left; R, right; SCM, sternocleidomastoid; SPC, splenius capitis.

Discussion

The POLR3A mutations identified in our patient were previously reported as responsible for leukodystrophy and white matter changes related to central hypomyelination and associated with variable degrees of the following findings: hypodontia and hypogonadotropic hypogonadism (the 4H syndrome), tremor ataxia, ataxia and delayed dentition, atrophy and hypoplasia of the corpus callosum, and oligodontia.5, 6, 7, 8, 9

Recently, Minnerop and colleagues3 described a patient with POLR3A mutations who presented with late‐onset progressive spastic ataxia and tremor with involvement of the central sensory tracts and dental problems with no signs of hypomyelination or white matter changes.3 In this same report, an MRI demonstrated bilateral hyperintense signals along the superior cerebellar peduncles.3 In our report, we observed clinical features similar to the patient reported by Minnerop and colleagues.3 Interestingly, our patient had the same variant (c.1909 + 22G > A) described by Minnerop and colleagues.3 This variant is an intronic mutation and is qualified to the intron 14 and predicted in silico to activate a cryptic splice site.

The other variant found in our patient is described as pathogenic. The c.1114G > A variant occurs by mutation in exon 8, favoring the replacement of the amino acid aspartate of position 372 by asparagine (p.Asp372Asn).6, 7

In conclusion, our case report expands the clinical spectrum of POLR3‐related disorders for late‐onset spastic paraplegia associated with dystonia. Therefore, patients with undetermined spastic paraplegia and dystonic features should be investigated for POLR3 gene mutations. Also, we propose that POLR3 gene mutations should be included in the causal genetic forms of hereditary spastic paraplegia, particularly those cases with late onset. Finally, subtle MRI abnormalities instead of white matter changes, such as mild hyperintense signals in the superior cerebellar peduncles, may be observed in patients with POLR3 gene mutations.

Author Roles

(1) Research Project: A. Conception and Execution, B. Organization; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

P.C.A.A.P.M.: 1A, 1B, 1C, 3A

M.T.D.G.: 1B, 1C, 3A

M.L.E.B.: 1C, 2A, 2B

A.J.R.: 1C, 2A, 2B

O.G.P.B.: 1A, 2C, 3B

J.L.P.: 1A, 2C, 3B

Disclosures

Ethical Compliance Statement

The authors confirm that the approval of an institutional review board was not required for this work. We confirm that patient consent has been sought and allowed for this case and its publication. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest

The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for the Previous 12 Months

The authors have no financial disclosures to report.

Supporting information

Video S1. Patient with POLR3A gene mutations presenting with spasticity and weakness in lower limbs (paraparetic gait) associated with head dystonic tremor.