LAUSR

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). 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 withOTUD4mutations have initially been associated with ataxia and hypogonadotropic hypogonadism (Gordon-Holmes syndrome) and dementia. The phenotype successively widened to include chorea with behavioral problems and possibly features of the 4H syndrome