A novel POLR3A genotype leads to leukodystrophy type-7 in two siblings with unusually late age of onset.
Age of onset
Brain
Hypomyelinating leukodystrophies
POLR3A mutations
Journal
BMC neurology
ISSN: 1471-2377
Titre abrégé: BMC Neurol
Pays: England
ID NLM: 100968555
Informations de publication
Date de publication:
29 Jun 2020
29 Jun 2020
Historique:
received:
19
03
2020
accepted:
19
06
2020
entrez:
1
7
2020
pubmed:
1
7
2020
medline:
24
10
2020
Statut:
epublish
Résumé
Leukodystrophies are familial heterogeneous disorders primarily affecting the white matter, which are defined as hypomyelinating or demyelinating based on disease severity as assessed at MRI. Recently, a group of clinically overlapping hypomyelinating leukodystrophies (HL) has been associated with mutations in RNA polymerase III enzymes (Pol III) subunits. In this manuscript, we describe two Italian siblings carrying a novel POLR3A genotype. MRI imaging, genetic analysis, and clinical data led to diagnosing HL type 7. The female sibling, at the age of 34, is tetra-paretic and suffers from severe cognitive regression. She had a disease onset at the age of 19, characterized by slow and progressive cognitive impairment associated with gait disturbances and amenorrhea. The male sibling was diagnosed during an MRI carried out for cephalalgia at the age of 41. After 5 years, he developed mild cognitive impairment, dystonia with 4-limb hypotonia, and moderate dysmetria with balance and gait impairment. The present study provides the first evidence of unusually late age of onset in HL, describing two siblings with a novel POLR3A genotype which showed the first symptoms at the age of 41 and 19, respectively. This provides a powerful insight into clinical heterogeneity and genotype-phenotype correlation in POLR3A related HL.
Sections du résumé
BACKGROUND
BACKGROUND
Leukodystrophies are familial heterogeneous disorders primarily affecting the white matter, which are defined as hypomyelinating or demyelinating based on disease severity as assessed at MRI. Recently, a group of clinically overlapping hypomyelinating leukodystrophies (HL) has been associated with mutations in RNA polymerase III enzymes (Pol III) subunits.
CASE PRESENTATION
METHODS
In this manuscript, we describe two Italian siblings carrying a novel POLR3A genotype. MRI imaging, genetic analysis, and clinical data led to diagnosing HL type 7. The female sibling, at the age of 34, is tetra-paretic and suffers from severe cognitive regression. She had a disease onset at the age of 19, characterized by slow and progressive cognitive impairment associated with gait disturbances and amenorrhea. The male sibling was diagnosed during an MRI carried out for cephalalgia at the age of 41. After 5 years, he developed mild cognitive impairment, dystonia with 4-limb hypotonia, and moderate dysmetria with balance and gait impairment.
CONCLUSIONS
CONCLUSIONS
The present study provides the first evidence of unusually late age of onset in HL, describing two siblings with a novel POLR3A genotype which showed the first symptoms at the age of 41 and 19, respectively. This provides a powerful insight into clinical heterogeneity and genotype-phenotype correlation in POLR3A related HL.
Identifiants
pubmed: 32600288
doi: 10.1186/s12883-020-01835-9
pii: 10.1186/s12883-020-01835-9
pmc: PMC7322863
doi:
Substances chimiques
POLR3A protein, human
EC 2.7.7.6
RNA Polymerase III
EC 2.7.7.6
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
258Subventions
Organisme : Ministero della Salute (IT)
ID : Partially Supported By Ministry Of Health (Current Research 2019-2023- Principal Investigator: Identification Of New Variants And / Or New Genes Responsible For Ataxia And Spastic Paraplegia)
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