RNASEH2B Pathogenic Gene Variant in Uncomplicated Hereditary Spastic Paraplegia: Report of a New Patient

Dear Sir,

Following detection of a homozygous variant in the ribonuclease H2 Subunit B (RNASEH2B; NM_024570.3) gene in a patient with sporadic, pure hereditary spastic paraplegia (HSP), we reviewed the literature to find only four published cases (three by Crow[1] and one by Travaglini).[2]

An 18-year-old normocephalic young man, born to nonconsanguineous, healthy parents, has been followed-up since infancy for motor delay and pyramidal signs in his lower limbs. No disease progression has emerged, and cognitive function is normal, as well as computed tomography (CT) scan (at 18 years of age) and serial brain magnetic resonance imaging (MRI) scans (the last one performed at 18 years of age). He has a stable slight asymmetry of the optic papillae excavation, but no overt atrophy. After negative neurometabolic, cerebrospinal fluid (CSF) neurotransmitters, and single HSP-related genes testing, he underwent whole exome sequencing (WES), identifying the homozygous c.529G > A, p.(Ala177Thr) variant on RNASEH2B gene, confirmed by Sanger sequencing. Complement, immunoglobulins, lymphocyte subset distribution, and anti-diuretic hormone (ADH) are normal.

Pathogenic variants in RNASEH2B gene have mainly been linked to the Aicardi-Goutières syndrome (AGS),[2] but our long follow-up allows further confirmation of the association with nonsyndromic, apparently nonprogressive HSP.[1] [2] [3] Despite the possible occurrence of slowly progressive cases,[4] the oldest reported patient has pure HSP at 34 years,[3] just as our 18 years old boy.

The specific mutation we detected is the same described in all previously published RNASEH2B-related HSP cases,[1] [2] suggesting potential genotype–phenotype correlations. Although it was also described in the majority of AGS type-2 cases, RNASEH2B-related AGS is milder than AGS secondary to pathogenic variants in other genes.[5]

In summary, our case further confirms previous (yet extremely rare)[1] [2] reports on the causative role of RNASEH2B gene variants in pure HSP. Increasing WES availability might give a better insight into the real epidemiology of RNASEH2B-related HSP, and a better understanding of determinants of phenotypic variability, accounting for the existence of a phenotypical spectrum between AGS and pure HSP.

• References

• 1 Crow YJ, Zaki MS, Abdel-Hamid MS. , et al. Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia. Neuropediatrics 2014; 45 (06) 386-393
• 2 Travaglini L, Aiello C, Stregapede F. , et al. The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes. Neurogenetics 2018; 19 (02) 111-121
• 3 Crow YJ, Leitch A, Hayward BE. , et al. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection. Nat Genet 2006; 38 (08) 910-916
• 4 Livingston JH, Crow YJ. Neurologic phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutières syndrome and beyond. Neuropediatrics 2016; 47 (06) 355-360
• 5 Rice G, Patrick T, Parmar R. , et al. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am J Hum Genet 2007; 81 (04) 713-725