Early-onset cerebellar ataxia has a broad range of challenging differential diagnoses. Identification of hypogonadism can assist in narrowing down differential diagnosis in the presentation of progressive ataxia. Gordon Holmes syndrome is a rare autosomal recessive disease characterized by hypogonadotropic hypogonadism, cerebellar ataxia, and progressive cognitive decline. We identify a novel homozygous deletion mutations of RNF216 causing GHS. The proband presented with dysarthria and gait ataxia. Cerebellar atrophy and white matter lesions were found in the cerebral hemispheres and brainstem. Low gonadotropin serum levels were also observed. Whole-exome sequencing and Chromosome analysis by medium coverage whole genome sequencing (CMA-seq) revealed a novel homozygous deletion mutations from exon1 to exon7 in RNF216 (chr7:5762980-5831600). Nested polymerase chain reaction (PCR) and agarose gel electrophoresis were performed to identify the deletion fragments. Sanger sequencing was also performed to find out the accurate breakpoint. We report the first female Chinese patient of GHS. The core features of GHS are well defned. By using the genetic sequencing and chromosome analysis, we identified a novel 68Kb deletion at RNF216 gene. Thus, CMA-seq had promising potentiality in genetic screening of GHS, especially for the novel deletions mutations in RNF216 gene.

Gordon Holmes Syndrome (GDHS) is a hereditary neurodegenerative disease mainly associated with mutations of RNF216. We established a human induced pluripotent stem cell (hiPSC) line, FDHSi003-A, derived from PBMC of a patient baring a mutation of RNF216 c.1948G > T, who shows typical symptoms of GDHS. The generated FDHSi003-A expresses pluripotency markers, displays a normal karyotype, and has the potency to differentiate into all three germ layers. Thus, FDHSi003-A is an ideal model to investigate the mechanism of RNF216 in GDHS.

Gordon Holmes syndrome (GHS) is a neurological disorder associated with neuroendocrine, cognitive, and motor impairments with corresponding neurodegeneration. Mutations in the E3 ubiquitin ligase RNF216 are strongly linked to GHS. Previous studies show that deletion of Rnf216 in mice led to sex-specific neuroendocrine dysfunction due to disruptions in the hypothalamic-pituitary-gonadal axis. To address RNF216 action in cognitive and motor functions, we tested Rnf216 knock-out (KO) mice in a battery of motor and learning tasks for a duration of 1 year. Although male and female KO mice did not demonstrate prominent motor phenotypes, KO females displayed abnormal limb clasping. KO mice also showed age-dependent strategy and associative learning impairments with sex-dependent alterations of microglia in the hippocampus and cortex. Additionally, KO males but not females had more negative resting membrane potentials in the CA1 hippocampus without any changes in miniature excitatory postsynaptic current (mEPSC) frequencies or amplitudes. Our findings show that constitutive deletion of Rnf216 alters microglia and neuronal excitability, which may provide insights into the etiology of sex-specific impairments in GHS.

Early-onset cerebellar ataxia has a broad range of challenging differential diagnoses. Identification of hypogonadism can assist in narrowing down differential diagnosis in the presentation of progressive ataxia. Gordon Holmes syndrome as described by Sir Gordon Holmes in 1908 consists of ataxia with hypogonadism. It is due to mutation in RNF216 and OTUD4 genes which encode for enzymes in the ubiquitin-proteasome system. In this case report, we describe a 30-year-old male presenting with insidious-onset progressive ataxia with hypogonadotropic hypogonadism, cataract, pan-cerebellar atrophy with bilateral cerebral white matter hyperintensities and a positive homozygous mutation for RNF216 making the diagnosis of Gordon Holmes syndrome. The presence of hypogonadism in a patient with ataxia should alert the clinician to look for such a diagnosis.