We aimed to evaluate a novel mutation in ADPRHL2 leading to a new adult onset syndrome “episodic psychosis, ataxia, motor neuropathy and pyramidal signs” in two unrelated families. 

The protein “ADP-Ribosylarginine Hydrolase-Like Protein 2” is encoded by ADPRHL2 and thought to function in the pathway of ADP-ribosylation which is a post-translational modification ‘process’ involved in the regulation of e.g. DNA damage response, aging, immunity, apoptosis. Recently, mutations in ADPRHL2 were found to be associated with a rare childhood onset neurodegeneration with episodic, stress-induced seizures, ataxia, and axonal neuropathy. 

Four patients from two unrelated families with episodic psychosis, ataxia, motor neuropathy and pyramidal signs of unknown cause were included in the study. The mutation identified by WES was validated and its segregation with the disease was ascertained by Sanger sequencing.

Index patient from the first family presented with ataxia, tremor in the hands and hallucinations at age 20 years, which had started after a viral  infection. She improved in three months without any treatment. Three years later, after a minor surgery, she developed psychosis and walking difficulties. Her neurological exam revealed mild distal weakness in upper and lower extremities, brisk DTRs, bilateral Babinski signs, short vibration sensation in distal extremities and mild truncal ataxia. Pes cavus, hammer toes and scoliosis were noted. EMG revealed neurogenic changes in distal muscles. Cranial MRI was normal.

Two of her sisters had much milder phenotypes. The phenotype of the fourth patient from an unrelated family was identical with the index patient.

All affected patients had homozygous novel c.G838A (p.Ala280Thr) mutations in a highly conserved region of ADPRHL2 and  are expected to result in  significant destabilization of the protein and a drastic impairment of its function.

Here, we describe a novel mutation in ADPRHL2 which further expands the phenotypic spectrum of the patients harboring these mutations.