Letter to the Editor
RNASEH2B Pathogenic Gene Variant in
Uncomplicated Hereditary Spastic Paraplegia:
Report of a New Patient
Carlotta Spagnoli1 Daniele Frattini1 Grazia Gabriella Salerno1
1 Department of Pediatrics, Child Neurology Unit, Azienda Unità
Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
2 Pediatric Neurophysiology Laboratory, Azienda Unità Sanitaria
Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
Neuropediatrics
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 Crow1 and one by Travaglini).2
An 18-year-old normocephalic young man, born to non-
consanguineous, 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), iden-
tifying the homozygous c.529G > A, p.(Ala177Thr) variant on
RNASEH2B gene, confirmed by Sanger sequencing. Comple-
ment, 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.1–3 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 sug-
gesting 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
received
July 31, 2018
accepted after revision
August 10, 2018
Carlo Fusco1,2
Address for correspondence Carlotta Spagnoli, MD, Department of
Pediatrics, Child Neurology Unit, Azienda Unità Sanitaria Locale-IRCCS
di Reggio Emilia, viale Risorgimento 80, 42123 Reggio Emilia, Italy
(e-mail: carlotta.spagnoli@ausl.re.it).
Downloaded by: The University of British Columbia Library. Copyrighted material.
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 epide-
miology of RNASEH2B-related HSP, and a better under-
standing of determinants of phenotypic variability,
accounting for the existence of a phenotypical spectrum
between AGS and pure HSP.
Study Funding
No funding was secured for this study.
Conflict of Interest
The authors report no conflict of interest.
References
1 Crow YJ, Zaki MS, Abdel-Hamid MS, et al. Mutations in ADAR1,
IFIH1, and RNASEH2B presenting as spastic paraplegia. Neurope-
diatrics 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 cor-
relations 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. Neu-
ropediatrics 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
© Georg Thieme Verlag KG DOI https://doi.org/
Stuttgart · New York 10.1055/s-0038-1672174.
ISSN 0174-304X.