A Homozygous PTRHD1 Missense Variant (p.Arg122Gln) in an Individual with Intellectual Disability, Generalized Epilepsy, and Juvenile Parkinsonism

Abstract

Biallelic variants in PTRHD1 have been associated with autosomal recessive intellectual disability, spasticity, and juvenile parkinsonism, with few reported cases. Here, we present the clinical and genetic findings of a female of Austrian origin exhibiting infantile neurodevelopmental abnormalities, intellectual disability, and childhood-onset parkinsonian features, consistent with the established phenotypic spectrum. Notably, she developed genetic generalized epilepsy at age 4, persisting into adulthood. Using diagnostic exome sequencing, we identified a homozygous missense variant (c.365G > A, p.(Arg122Gln)) in PTRHD1 (NM_001013663). In summary, our findings not only support the existing link between biallelic PTRHD1 variants and parkinsonism with neurodevelopmental abnormalities but also suggest a potential extension of the phenotypic spectrum to include generalized epilepsy.

Keywords

PTRHD1 - parkinsonism - intellectual disability - epilepsy

Ethical Compliance Statement

The authors confirm that no approval of the institutional review board was necessary. An informed consent was given by the patient's mother (legal caregiver). We have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Publication History

Received: 26 August 2023

Accepted: 14 December 2023

Accepted Manuscript online:
29 January 2024

Article published online:
14 February 2024

• References

• 1 Al-Kasbi G, Al-Saegh A, Al-Qassabi A. et al. Biallelic PTRHD1 frameshift variants associated with intellectual disability, spasticity, and Parkinsonism. Mov Disord Clin Pract (Hoboken) 2021; 8 (08) 1253-1257
• 2 Jaberi E, Rohani M, Shahidi GA. et al. Mutation in ADORA1 identified as likely cause of early-onset Parkinsonism and cognitive dysfunction. Mov Disord 2016; 31 (07) 1004-1011
• 3 Elahi E. PTRHD1 and possibly ADORA1 mutations contribute to Parkinsonism with intellectual disability. Mov Disord 2018; 33 (01) 174
• 4 Khodadadi H, Azcona LJ, Aghamollaii V. et al. PTRHD1 (C2orf79) mutations lead to autosomal-recessive intellectual disability and Parkinsonism. Mov Disord 2017; 32 (02) 287-291
• 5 Kuipers DJS, Carr J, Bardien S. et al. PTRHD1 loss-of-function mutation in an African family with juvenile-onset Parkinsonism and intellectual disability. Mov Disord 2018; 33 (11) 1814-1819
• 6 Cheraghi S, Moghbelinejad S, Najmabadi H, Kahrizi K, Najafipour R. The PTRHD1 mutation in intellectual disability. Arch Iran Med 2021; 24 (10) 747-751
• 7 Richards S, Aziz N, Bale S. et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 8 Ishii T, Funakoshi M, Kobayashi H. Yeast Pth2 is a UBL domain-binding protein that participates in the ubiquitin-proteasome pathway. EMBO J 2006; 25 (23) 5492-5503
• 9 Layfield R, Cavey JR, Lowe J. Role of ubiquitin-mediated proteolysis in the pathogenesis of neurodegenerative disorders. Ageing Res Rev 2003; 2 (04) 343-356
• 10 Field M, Tarpey PS, Smith R. et al. Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly. Am J Hum Genet 2007; 81 (02) 367-374
• 11 Matsuura T, Sutcliffe JS, Fang P. et al. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet 1997; 15 (01) 74-77
• 12 Nascimento RMP, Otto PA, de Brouwer APM, Vianna-Morgante AM. UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated in a novel X-linked mental retardation syndrome. Am J Hum Genet 2006; 79 (03) 549-555
• 13 Tarpey PS, Raymond FL, O'Meara S. et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am J Hum Genet 2007; 80 (02) 345-352
• 14 Reuter MS, Tawamie H, Buchert R. et al. Diagnostic yield and novel candidate genes by exome sequencing in 152 consanguineous families with neurodevelopmental disorders. JAMA Psychiatry 2017; 74 (03) 293-299