Overt Hypogonadism May Not Be a Sentinel Sign of RING Finger Protein 216: Two Novel Mutations Associated with Ataxia, Chorea, and Fertility

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We describe a fertile patient presenting a Huntington‐like disorder, normal peripheral nerve conduction, and atypical magnetic resonance imaging (MRI) findings who harbored 2 novel mutations in RING Finger Protein 216 (RNF216).

A 44‐year‐old woman developed progressive walking difficulties at the age of 37 years. Writing difficulties were reported previously. She had 10 years of education. Involuntary movements were present, but the patient could not clearly state the onset because she appeared to be unaware of them. Her past medical history was negative. She was married and had 2 successful pregnancies. There was no family history of neurological diseases. At examination she showed wide‐based gait with marked instability, broken smooth pursuit without nystagmus, marked dysarthria, dysmetria, brisk knee jerks with extensor plantar responses, reduced vibration sense, facial and appendicular choreic movements, and hand dystonia. She complained of oligomenorrhea. Her relatives reported irritability and poor insight.

MRI showed severe cerebellar atrophy affecting both the vermis and the hemispheres, with a relative sparing of the inferior portion of the posterior lobe (lobule VIII); normal midbrain and pons; supratentorial atrophy predominantly affecting the parietal and occipital lobes; few and scattered supratentorial white matter hyperintense foci; mild hyperintensity of dentate nuclei, partly extending to the pons (Fig. 1A). A peripheral nerve conduction study was normal in the sural (sensory conduction velocity 58.6 m/sec, normal value (n.v.) ≥ 44 m/sec; sensory action potential 11.4 μV, n.v. ≥5 μV) and peroneal nerves (motor conduction velocity 48.5 m/sec, n.v. ≥ 45 m/sec; compound motor action potential 7.6 mV, n.v. ≥ 5 mV). Somatosensory cortical potentials were delayed at the upper limbs (13.8 milliseconds, n.v. ≤ 8 milliseconds), with N20 amplitude decreased (1 μV, n.v. ≥ 2 μV) and undetectable at the lower limbs. These findings suggest a selective involvement of central sensory axons with preservation of the peripheral sensory axons. Routine blood chemistry was normal and endocrine studies showed follicle‐stimulating hormone (3.1 mu/mL [n.v. 5–30]) and luteinizing hormone (3.9 mu/mL [n.v. 5–60]) levels slightly below normal, with normal values of progesterone and estradiol. The neuropsychological examination showed a multiple domain cognitive impairment with borderline Mini‐Mental State Examination values (24/30).

Figure 1.

(A) Magnetic resonance imaging. 1. Coronal T2‐weighted image showing diffuse cerebellar atrophy, increased signal of dentate nucleus (white arrow), and parietal atrophy. 2. Sagittal T1‐weighted image showing atrophy of the cerebellum, with sparing of the pons and midbrain. 3‐4. Axial fluid attenuated inversion recovery images showing the presence of scattered white matter lesions affecting both the deep and periventricular white matter. (B) Pedigree showing the presence of the intronic mutation (c.2061+3A>G) in the mother, the missense mutation (c.1849A>G p.M617V) in the brother, and both in the proband. het, heterozygote.

The patient, who tested negative for spinocerebellar ataxia (SCA) 1, 2, 3, 6, 7, 17, dentatorubral pallidoluysian atrophy (DRPLA), Fragil X Tremor Ataxia Syndrome, Spastic Paraplegia type 7, Autosomal Recessive Spastic Ataxia Charlevoix‐Saguenay and mitochondrial gene mutations, underwent a massive multigene panel sequencing encompassing 273 genes related to ataxia (Table S1), which identified the following 2 novel mutations in RNF216 (NM_207111) predicted to be deleterious in silico: one intronic (c.2061+3A>G) and one missense (c.1849A>G;p.M617V) that affected a highly conserved amino acid residue and displayed a very low frequency in the polymorphic dataset gnomAD (https://gnomad.broadinstitute.org/; allele frequency = 0.00001066). Family segregation analyses showed a heterozygous status in the unaffected mother and brother (Fig. 1B). No variants were found in the OTU Deubiquitinase 4 (OTUD4) gene.

RNF216 mutations alone or combined with OTUD4 mutations have initially been associated with ataxia and hypogonadotropic hypogonadism (Gordon‐Holmes syndrome) and dementia.1 The phenotype successively widened to include chorea with behavioral problems2 and possibly features of the 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism).3 A total of 17 patients from 10 families have been so far reported, and 12 missense and truncating mutations have been found.1, 2, 3, 4, 5 The mean age at onset (± standard deviation) of cerebellar signs is 30.5 ± 9.8 years (range 20–55). The typical MRI shows constant diffuse supratentorial white matter hyperintensities and almost constant cerebellar atrophy (16/17), frequently associated with cerebral atrophy (10/17) and rarely with the brainstem, basal ganglia, and thalamus atrophy/signal changes. Hypogonadism appears to be fairly constant and to be of hypothalamic origin because of a negative/insufficient answer to Gonadotropin Releasing Hormone in the few examined patients.1 No spontaneous puberty and poor development of secondary sexual characteristics usually occur, but normal puberty has been reported in some cases followed by oligomenorrhea and amenorrhea in women and erectile dysfunction in men.1 Fertility has been reported in 2 cases.2

We highlight some aspects of our patient, who showed preserved fertility, normal peripheral nerve conduction, and atypical MRI findings. The presence of fertility suggests that hypogonadism may not be a sentinel sign of the disease. The study of peripheral nerve conduction has not previously been performed. Therefore, we cannot state if absence of neuropathy is a useful sign for the diagnosis. Increased signal of dentate, possibly related to gliosis, has not been reported so far.

Finally, we underscore that RNF216 should be taken in consideration in differential diagnosis with other forms of ataxia associated with chorea/dystonia that include either recessive (as ataxia with oculomotor apraxia type 1 and 2, ataxia telangiectasia, Spinocerebellar ataxia recessive type 16, Niemann Pick type C) or dominant forms (as SCA2, SCA3, SCA17, SCA48, DRPLA).

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

M.L.: 1A, 1C, 2A

D.G.: 1A, 1C, 2A

A.R.: 1C, 2B

S.C.: 1C, 2B

G.P.: 2A

T.F.: 2B

C.P.: 1B

F.S.: 1C, 2B

G.D.M.: 1B, 2B

F.M.S.: 1A, 1C, 2A

A.F: 1A, 1C, 2A

Disclosures

Ethical compliance statement

The authors confirm that the approval of an institutional review board was not required for this work. All persons gave their informed consent before their inclusion in the study. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest

The authors declare that there are no conflicts of interest and no sources of funding.

Financial Disclosures for the Previous 12 Months

The authors have no conflict of interests to report in relation to the present manuscript.

Supporting information

Table S1. Multigene panel sequencing encompassing 273 genes related to ataxia.

Video S1. Segment 1: Unstable wide‐based gait. Segment 2: Broken smooth pursuit. Dysarthria. Facial choreic movements. Segment 3: Dysmetria. Hand dystonia and facial choreic movements. Segment 4: Brisk knee jerks.