Episodic psychosis, ataxia, motor neuropathy with pyramidal signs (PAMP sydrome) caused by a novel mutation in ADPRHL2 (AHR3)

Background The protein "ADP-Ribosylarginine Hydrolase-Like Protein 2" is encoded by ADPRHL2 and reverses ADP-ribosylation. Recently, mutations in ADPRHL2 were found to be associated with a very rare childhood onset severe neurodegeneration syndrome with episodic, stress-induced seizures, ataxia, and axonal neuropathy. In this study, we evaluate a novel mutation in ADPRHL2 leading to an unknown adult onset syndrome "episodic psychosis, ataxia, motor neuropathy with pyramidal signs (PAMP syndrome)." Design/methods Four patients with episodic psychosis, ataxia, and motor neuropathy with pyramidal signs were included in this study. Results An index patient presented ataxia, postural tremor in the hands, and hallucinations at age 20 years, which had started after a viral infection. She improved within 3 months without any treatment. Her neurological exam revealed mild distal weakness, brisk DTRs, bilateral Babinski sign, impaired vibration sensation, position, and ataxia. Pes cavus and hammer toes were also noted. EMG revealed neurogenic changes in distal muscles and normal sensory nerve conduction studies. Cranial MRI was normal. She had three more severe episodes in recent years, and her neurologic findings got progressively worse. Two of her older 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 NM_017825.3:c.838G>A (p.Ala280Thr) mutations in a highly conserved region of ADPRHL2. Western blot analyses demonstrated that ADPRHL2 was not expressed in these patients. Conclusions Here, we describe a novel mutation in ADPRHL2, which further expands the phenotypic and genetic spectrum of the patients harboring these mutations.