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A novel mutation in RNF216 gene in a Turkish case with Gordon Holmes syndrome
BMC Medical Genomics volume 16, Article number: 98 (2023)
Abstract
Background
Gordon Holmes syndrome (GHS) is a rare autosomal recessive disorder characterized by hypogonadotropic hypogonadism, cognitive decline, and cerebellar ataxia. Mutations in the Ring Finger Protein 216 (RNF216) gene have been known to be associated with GHS therewithal RNF216 mutations have been detected in cases with Huntington-like disease, 4H syndrome (hypodontia, hypomyelination, ataxia and hypogonadotropic hypogonadism), and congenital hypogonadotropic hypogonadism.
Case presentation
Here we report a novel homozygous frameshift mutation in RNF216 gene c.1860_1861dupCT (p.Cys621SerfsTer56) in a patient with hypogonadotropic hypogonadism, ataxia, and cognitive decline diagnosed with GHS also co-occurrence of parkinsonism and dystonia which was not reported before.
Conclusions
We report an extremely rare case of GHS. The core features of GHS are well defined, but genotype–phenotype correlations are still limited. To understand the pathophysiology of different phenotypes, the type and localization of novel mutations need to be defined, and the effect of these different variants on clinical features needs to be determined. Further studies should explain the factors of phenotypic variability present in GHS patients with RNF216 mutations.
Background
Gordon Holmes syndrome (GHS) (MIM #212840) is a rare autosomal recessive neurodegenerative disorder. It was first described by British neurologist Holmes in 1907 [1] and characterized by hypogonadotropic hypogonadism, cognitive decline, and cerebellar ataxia. Recently, mutations in Ring Finger Protein 216 (RNF216), OTUD4, STUB1 and PNPLA6 genes were reported to be associated with GHS [2]. RNF216 and PNPLA6 are the most frequently mutated genes in GHS. RNF216 encodes the E3 ubiquitin-protein ligase that is responsible for regulation of autophagy and regulates synaptic transmission and plasticity in neurons [3, 4]. In addition to GHS, RNF216 mutations have been detected in cases with Huntington-like disease (HLD), 4H syndrome (hypodontia, hypomyelination, ataxia and hypogonadotropic hypogonadism), and congenital hypogonadotropic hypogonadism (HH) [5,6,7].
Here we report a novel homozygous frameshift mutation in RNF216 gene c.1860_1861dupCT (p.Cys621SerfsTer56) in a patient with hypogonadotropic hypogonadism, ataxia, dystonia, and cognitive decline diagnosed with GHS.
Case presentation
The proband (IV:4) is a-23-year-old male with a four-year history of difficulty in walking and frequent falls. He also has clumsiness in both his arms and hands and complains about speech difficulty for about the last six months. The patient was the product of consanguineous parents and he was born by successful vaginal delivery with normal birth parameters. His mental and psychomotor history revealed that he left school at the age of 14 due to learning difficulties. In his medical history, at age 18, he was found to have gynecomastia and small testicles in his routine examination before military compulsory service.
Physical and neurologic examination
Physical examination revealed eunuchoid body proportions, short stature, gynecomastia, and poor facial hair growth with generalized jaundice appearance. His neurological examination showed dysarthria, and severe ataxia making his walking impossible without assistance. He had appendicular dysmetria and dysdiadochokinesia, especially in both lower extremities, slightly generalized chorea while talking, hypomimia, mild bradykinesia, slight dystonia in the left hand, brisk deep tendon reflexes in lower extremities. Eye examination showed fragmented pursuit eye movements with slow hypometric saccades, vertical gaze palsy, and square wave jerks in horizontal pursuit (Additional file 1: Video 1). In the psychiatric examination, he had regressed speech, and looked small compared to his peers, there was no delirium suicide, no homicidal thoughts, and no euthymic perception deviation. His IQ test reported borderline mental capacity (Table 1). His Kent EGY intelligence test verbal performance was 85.71. He couldn't get a calculable score from the50 Porteus maze test.
Imaging
Brain magnetic resonance imaging (MRI) revealed progressive cerebellar, vermian, and cerebral cortical atrophy, and periventricular confluent white matter hyperintensities in 2022 compared to 2018. Mild mesencephalic atrophy is similar in both dates (Fig. 1). Basal ganglia hyperintense lesions began to appear in 2022 (Fig. 2).
Pituitary MRI showed a normal pituitary gland height (4 mm) for his age. Testicular atrophy detected on ultrasound (right testis 12 × 6 × 15mm, 0.56 ml, left 10 × 4.5 × 14 mm, 0.32 ml). In the X-ray evaluation of his hands at 24, it was noted that the growth plate of the distal radius, which normally starts at the age of 17 to 19 and should fuse at the most at the age of 20, did not fuse.
Laboratory
Laboratory findings including total blood count, renal and liver functions, thyroid hormone, thyroid antibodies, and vitamin E levels were normal. His blood glucose level [121 mg/dl (70–110)], HbA1c [5.8% (3.5–5.6)], and serum lipid levels (cholesterol [216 mg/dl (118–199)], LDL [156.9 mg /dl (66–129)] were slightly high. His HDL level [34 mg/dl (40–63)] was slightly low, and triglyceride level [121 mg/dl (44–149)] was normal. His basal hormonal evaluation was normal, but his follicle-stimulating (FSH) and luteinizing hormone (LH) levels [FSH < 0.3 (1.5–12.4 mIU/mL), LH: < 0.3 (1.7–8.6 mIU/mL)], respectively), testosteron level [0.44 nmol/L (9.9–27.8 nmol)], and free androgen index 2.75% (14.8–94.8) were low.
His growth hormone was higher than normal [4.18 ng/ml (0.030–2.47)], which was consistent with HH. The patient described here consistently presented with ataxia, cognitive deterioration, and HH, leading to the clinical diagnosis of GHS.
Molecular analyses
Genomic DNA was isolated from peripheral blood using QIAamp DNA Blood Mini Kit), according to the recommendations of the manufacturer. Genetics analyses were performed by next-generation sequencing (NGS) using a Custom Target Capture Neuromuscular NGS Panel, consisting of 293 genes (Additional file 2) related to genetic neuromuscular diseases (Celemics, Korea). Variant calling and analysis were performed using “SEQ” variant analysis software (Genomize, Istanbul, Turkey) according to the reference genome of GRCh37 (hg19). Variants with a minor allele frequency (MAF) higher than 0.1% in Genome Aggregation Database (http://gnomad.broadinstitute.org/) were filtered out. We interpreted the identified variants using The Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/), ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/), and literature search. Variants were classified according to the American College of Medical Genetics and Genomics guidelines for the interpretation of sequence variants (ACMG) [8]. Segregation analyses and variant validation were performed by direct sequencing using capillary electrophoresis (3130xl Genetic Analyzer, Applied Biosystems).
Genetic analysis results
The next-generation sequencing analyses of the proband (IV:4) identified a novel homozygous frameshift mutation (ENST00000389902.3):c.1860_1861dupCT (p.Cys621SerfsTer56) in exon 12 of the RNF216 gene. This novel variant is predicted to result in a truncated protein by forming a premature stop codon and was classified as pathogenic along with PVS1 (null variant), PM2 (absent from controls (gnomAD, 1000 Genomes Project) and highly conserved position), PP3 (pathogenic computational predictions), PP4 (Patient’s phenotype is highly specific for a disease with a single genetic etiology) according to American College of Medical Genetics and Genomics guidelines. The mutation with heterozygous state was carried by consanguineous parents (III:3, III:4). The unaffected brother (IV:3) and uncle of the proband (III:5) had the same frameshift mutation with heterozygous state (Fig. 3).
Discussion and conclusions
Here, we report a novel homozygous RNF216 p.Cys621SerfsTer56 mutation in a Turkish patient presenting with Gordon Holmes syndrome.
RNF216 gene encodes the E3 ubiquitin-protein ligase that is responsible for the regulation of autophagy and also regulates synaptic transmission and plasticity in neurons [3] Loss-of-function mutations in the RNF216 gene are related to pathological effects on the cerebellum, hippocampus, cerebral white matter, hypothalamus, and pituitary components of the reproductive endocrine cascade [9]. So far, RNF216 mutations have been detected in 13 patients with GHS in nine families [5, 9,10,11,12]. Additionally, RNF216 mutations have also been identified in patients diagnosed with HLD, 4H syndrome, and congenital HH [6, 7, 9, 13,14,15]. Hitherto, the most common clinical features detected in cases with GHS are cognitive decline, ataxia, dysarthria, and poor pubertal development. In our patient, severe ataxia, cognitive deterioration, and dysarthria were also found to be consistent with the literature. The presence of parkinsonism, dystonia, and chorea differs our patient from previous cases (Table 1). Although chorea has been reported as a common symptom of RNF216-related HDL, it was found in only one case diagnosed with RNF216-related GHS. Notably, both cases with GHS chorea had a frameshift variant and a relatively early age of onset [9]. Also inactivating mutations in PNPLA6, STUB1, and OTUD4 have also been identified in GHS which are also ubiquination-related genes. PNPLA6 (19p13.2, (patatin-like phospholipase domain containing 6) encodes neuropathy target esterase, a phospholipid deacetylase converting phosphatidylcholine into fatty acids and glycerophosphocholine. STUB1 ((16p13.3,STIP1 homology and U-box containing protein 1) encodes CHIP which is a key component of general cellular protein homeostasis, which, as RNF216, acts as a ubiquitin ligase. OTUD4 (4q31.21 OTU domain-containing protein 4) encodes deubiquitinase OTUD 4 hich hydrolyzes the isopeptide bond between the ubiquitin C-terminus and the lysine epsilon-amino group of the target protein. The phenotype of GHC cases caused by these genes are summarized in Table 2 [2, 11].
The age of onset of neurological symptoms in GHS was observed at the beginning of the third decade in the cases reported so far. Our patient's first complaint was at the age of 18, and it is the youngest age of symptom onset reported. Brain MRI showed extensive middle and subcortical confluent white matter lesions, cerebral and cerebellar atrophy, which are consistent with the other previous cases. There were also T2 hyperintense areas consistent with putaminal degeneration, which is not common in GHS. Basal ganglia hyperintense lesions were reported by Margolin et al.‘s patient presenting with chorea mentioned before, reported to be associated with RNF216 frameshift mutation. In a recent study, white matter lesions surrounding the basal ganglia were associated with only chorea compared to all RNF216 mutated patients and their imaging findings so far [11], this finding is also compatible with the MRI findings of our case (Fig. 1). Chorea and parkinsonism developed after other symptoms in our patient, and the appearance of hyperintense lesions in the basal ganglia on MRI four years later is consistent with these findings. Neurocognitive assessment batteries were performed in the previous cases, but our patient could not cooperate with the neurocognitive batteries, so cognitive evaluation was performed with IQ tests. Hypogonadotropic hypogonadism is a common feature of GHS and has been demonstrated in all RNF216 mutations, including our case. Our patient is being followed up with testosterone isocaproatetherapy.
Conclusion
Here we present a case with Gordon Holmes syndrome caused by a novel RNF216 mutation. This syndrome is very rare, and it has been recently found to be associated with the RNF216 mutation. Ataxia, cognitive decline, and hypogonadotropic hypogonadism are the core features of this syndrome, but despite thorough literature research, we did not identify a paper that reported co-occurrence of parkinsonism and dystonia with other features in GHS.
Genotype–phenotype correlations are still limited. To understand the pathophysiology of different phenotypes, the type and localization of novel mutations need to be defined, and the effect of these different variants on clinical features needs to be determined.
Availability of data and materials
The datasets generated and/or analysed during the current study has been submitted to the "Global Variome shared LOVD" and that can be accessed using 'https://databases.lovd.nl/shared/individuals/00430226.
Abbreviations
- GHS:
-
Gordon Holmes syndrome
- RNF216 :
-
Ring finger protein 216
- MRI:
-
Magnetic resonance imaging
- HLD:
-
Huntington-like disease
- HH:
-
Hypogonadotropic hypogonadism
- NGS:
-
Next-generation sequencing
References
Holmes G. A form of familial degeneration of the cerebellum. Brain. 1908;30(4):466–89.
Gonzalez-Latapi P, Sousa M, Lang AE. Movement disorders associated with hypogonadism. Movement Disord Clin Pract. 2021;8(7):997–1011.
Husain N, Yuan Q, Yen YC, Pletnikova O, Sally DQ, Worley P, et al. TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation. Aging Cell. 2017;16(2):281–92.
Nanetti L, Di Bella D, Magri S, Fichera M, Sarto E, Castaldo A, et al. Multifaceted and age-dependent phenotypes associated with biallelic PNPLA6 gene variants: eight novel cases and review of the literature. Front Neurol. 2022;12:793547.
Calandra CR, Mocarbel Y, Vishnopolska SA, Toneguzzo V, Oliveri J, Cazado EC, et al. Gordon Holmes Syndrome caused by RNF216 novel mutation in 2 Argentinean siblings. Movement Disord Clin Pract. 2019;6(3):259.
Chen KL, Zhao GX, Wang H, Wei L, Huang YY, Chen SD, et al. A novel de novo RNF216 mutation associated with autosomal recessive Huntington-like disorder. Ann Clin Trans Neurol. 2020;7(5):860–4.
Neocleous V, Fanis P, Toumba M, Tanteles GA, Schiza M, Cinarli F, et al. GnRH deficient patients with congenital hypogonadotropic hypogonadism: novel genetic findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A genes in a case series and review of the literature. Front Endocrinol. 2020;11:626.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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(5):405–23.
Margolin DH, Kousi M, Chan Y-M, Lim ET, Schmahmann JD, Hadjivassiliou M, et al. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. N Engl J Med. 2013;368(21):1992–2003.
Alqwaifly M, Bohlega S. Ataxia and hypogonadotropic hypogonadism with intrafamilial variability caused by RNF216 mutation. Neurol Int. 2016;8(2):6444.
Wu C, Zhang Z. Gordon holmes syndrome and huntington-like disease: two types of RNF216-related disorders; 2022.
Mehmood S, Hoggard N, Hadjivassiliou M. Gordon Holmes syndrome: finally genotype meets phenotype. Pract Neurol. 2017;17(6):476–8.
Ganos C, Hersheson J, Adams M, Bhatia KP, Houlden H. The 4H syndrome due to RNF216 mutation. Parkinsonism Relat Disord. 2015;21(9):1122–3.
Lieto M, Galatolo D, Roca A, Cocozza S, Pontillo G, Fico T, et al. Overt hypogonadism may not be a sentinel sign of RING finger protein 216: Two novel mutations associated with ataxia, chorea, and fertility. Movement Disord Clin Pract. 2019;6(8):724.
Santens P, Van Damme T, Steyaert W, Willaert A, Sablonnière B, De Paepe A, et al. RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder. Neurology. 2015;84(17):1760–6.
Acknowledgements
The authors thank the patient and his family for their cooperation.
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NDC, SO, GY and SO performed the examination of the patient. UT performed the imaging data collection and analysis, EE and SA performed the genetic analyses. All authors constructed the interpretation of the analysis and contributed to the writing of the manuscript.
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Supplementary Information
Additional file 1. The neurologic evamination of the patient. Segment 1. Physical examination: revealed eunuchoid body proportions, short stature, gynecomastia, and poor facial hair growth with generalized jaundice appearance, Speech and movements of eyes: The patient is asked “How old are you?” “Do you have a sibling?” “Where do you live?” “Do your brother or sister have a similar disease?” “did you goto school by the examiner. Speech initiation is delayed and speech production is slowed and dysarthric. He is hypomimic. Eye examination showed fragmented pursuit eye movements with slow hypometric saccades, vertical gaze palsy, and square wave jerks in horizontal pursuit. slightly generalized chorea while talking. Segment 2. Movements of the extremities: Movements in the patient revealed slight dystonia in the left hand and head, dystonic tremor while moving his arms. He also has appendicular dysmetria. Segment 3. Walking: The patient has severe ataxia making his walking impossible without assistance.
Additional file 2
. The gene list of neuromuscular Next-Generation sequencing panel.
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Durmaz Çelik, N., Erzurumluoğlu, E., Özben, S. et al. A novel mutation in RNF216 gene in a Turkish case with Gordon Holmes syndrome. BMC Med Genomics 16, 98 (2023). https://doi.org/10.1186/s12920-023-01529-4
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DOI: https://doi.org/10.1186/s12920-023-01529-4