Large Norwegian study confirms earlier research
Mutations in the POLR3A gene were found to be the second most frequent cause of disease in recessively-inherited hereditary ataxia and HSP in this Norwegian study of 521 people affected.
Here we report the results of an independent study of patients with hereditary ataxia and spastic paraparesis (HSP) from Norway, confirming and elaborating the findings reported by Minnerop et al. In exome data from 95 Norwegian patients with a clinical diagnosis of ataxia or HSP without molecular diagnosis, we identified 10 probands and 13 patients with biallelic and presumed disease-causing POLR3A variants.
The patients presented with a remarkably recognizable phenotype combining neurological, dental and MRI findings, strikingly similar to the patients in the study by Minnerop et al. Mean age at onset of the first neurological symptoms was 13.7 years. In 12 of 13 patients symptoms began before the age of 21. The main neurological phenotype comprised ataxia (13/13), severe tremor of the neck/upper limbs (9/13), pyramidal signs in the lower limbs including bilateral extensor plantar responses (13/13), absent/reduced lower limb reflexes (12/13) and proprioceptive loss (12/13). Other neurological findings were lower limb weakness (12/13), muscle atrophy (11/12), reduced superficial sensations (7/13), dystonia (6/13) and urinary urgency (8/13). Interestingly, the tremor was alcohol-responsive. None had overt cognitive impairment. Neuropsychological evaluations in two patients showed well preserved cognitive function in one patient and a pattern compatible with mild cerebellar cognitive affective syndrome in the other (Schmahmann and Sherman, 1998).
Concerning non-neurological features, which were central in the previous debate, our findings are in line with those of Minnerop et al. Dental abnormalities were present in 11/13 patients, including hypodontia, retention of teeth, short dental roots, early dental loss and/or early periodontal disease. Also, one of the patients had developed several superfluous permanent teeth. Myopia was reported in 5 of 12 patients. Optic atrophy was not observed (0/7). Short stature and hormonal dysfunction were not prominent findings in our patient group. None had short stature (as defined by males <166 cm, females <153 cm) and height did not differ compared to other family members. Gonadal dysfunction was identified in one patient. Notably, in most patients, dental problems or hormonal dysfunction were not reported until specifically asked for.
Importantly, biallelic variants in POLR3A were found to be the second most common cause of recessive ataxia or HSP in our Norwegian cohort of 521 probands, second only to Friedreich’s ataxia (Wedding et al., 2015). In this cohort, 322 probands were classified with autosomal recessive or sporadic ataxia or HSP. Even if less than a third of these probands had exome data available for POLR3A analysis in this study, the 10 identified individuals with biallelic variants in POLR3A represent a frequency of 3.1%, similar to the frequency found by Minnerop et al. (2017). No additional carriers of the c.1909+22G>A variant were identified in the 95 exomes. However, our sample size is small and could be prone to several aspects of selection bias, and we thus regard it unsuitable for extrapolating any association (or lack of association) of this variant with ataxia/HSP to a general population of ataxia/HSP. Hence, a properly designed association study would be required to replicate the association results previously reported (Minnerop et al., 2017; Gauqelin et al., 2018).
In summary, our study confirms that biallelic variants in POLR3A are indeed a frequent cause of disease in hereditary ataxia/HSP patients. In particular, the c.1909+22G>A variant is prevalent, illustrating the importance and complexity of variants in non-coding regions. Furthermore, we delineate a highly characteristic and consistent clinical picture, comprising early onset ataxia with or without tremor, combined with pyramidal and posterior column findings, dental abnormalities and the key MRI finding of high intensities along the superior cerebellar peduncles.
The expanding phenotypic spectrum of POLR3A-related syndromes, now including leukodystrophies, a disease of premature ageing—Wiedemann-Rautenstrauch syndrome (Paolacci et al., 2018)—and hereditary ataxia/HSP, calls for future disease classification which includes both clinical and genetic information (Rossi et al., 2018), and for increased awareness of also atypical non-neurological symptoms in complex neurological disorders.
Biallelic POLR3A variants confirmed as a frequent cause of hereditary ataxia and spastic paraparesis
Siri L Rydning,1,2 Jeanette Koht,1,3 Ying Sheng,4 Piotr Sowa,5 Hanne S Hjorthaug,4 Iselin M Wedding,2Anne Kjersti Erichsen,6 Inger Anette Hovden,7 Paul H Backe,8,9 Chantal M E Tallaksen,2 Magnus D Vigeland,1,4and Kaja K Selmer10,11
1 Institute of Clinical Medicine, University of Oslo, Norway
2 Department of Neurology, Oslo University Hospital, Norway
3 Department of Neurology, Vestre Viken Hospital, Norway
4 Department of Medical Genetics, Oslo University Hospital, Norway
5 Department of Radiology and Nuclear Medicine, Oslo University Hospital, Norway
6 Department of Ophthalmology, Oslo University Hospital, Norway
7 Department of Clinical Neurophysiology, Oslo University Hospital, Norway
8 Department of Medical Biochemistry, University of Oslo, Norway
9 Department of Microbiology, Oslo University Hospital, Norway
10 Department of Research and Development, Division of Neuroscience, Oslo University Hospital and the University of Oslo, Norway
11 National Centre for Epilepsy, Oslo University Hospital, Norway