Gordon Holmes syndrome – first time diagnosed in Croatia

Abstract

We present a 38-year-old woman with clinical presentation of ataxia, cognitive impairment, and secondary amenorrhea with remarkable brain hyperintensities on brain magnetic resonance imaging (MRI). Clinical symptoms began at the age of 20 years with the development of secondary amenorrhea, instability, and cognitive dysfunction. Although this set of medical symptoms of ataxia, primary/secondary amenorrhea due to hypogonadotropic hypogonadism, and cognitive impairment are known as Gordon Holmes syndrome, such has not been described in Croatia so far. Because of this, the patient was unsuccessfully diagnostically investigated in various neurological institutions on different neurodegenerative diseases, primarily based on ataxia, cognitive impairment, and remarkable brain hyperintensities on brain MRI. We started to analyze a large group of possible genetically triggered autosomal-recessive degenerative ataxias, and noticed compatibility of clinical symptoms: cerebellar ataxia, cognitive impairment, and hypogonadotropic hypogonadism, along with brain MRI changes characterized with significant subcortical white matter, thalamic, and brain steam confluent patchy areas of hyperintensity and cerebellar atrophy, that constitute a syndrome caused by ATM RNF216 gene mutation, Gordon Holmes syndrome (GHS). Genetic analysis in Variantyx laboratory in the USA performing whole-exome sequencing showed compound heterozygous for RNF 216 mutation, which confirmed the diagnosis of GHS, for the first time diagnosed in Croatia.

Keywords

• cerebellar ataxia – complications
• genetics; hypogonadism – complications
• genetics; amenorrhea – etiology; gonadotropin-releasing hormone – deficiency
• genetics; mutation; ubiquitin-protein ligases – genetics; ubiquitination; cognitive dysfunction – complications; brain – diagnostic imaging