Alpha-mannosidosis is characterized by mild to moderate intellectual disability (ID), moderate to severe neurosensory hearing loss, frequent infections, psychomotor disturbances and skeletal dysmorphism. For the first time, a panel of nine alpha-mannosidosis patients with psychiatric symptoms is presented. The clinical picture has several similarities: a physical or psychological stressor precedes a rapid development of a state of confusion, delusions, hallucinations, anxiety and often depression leading to a severe loss of function. This usually lasts 3-12 weeks, and is followed by a period of somnolence and asthenia. It may be more prevalent in females. In four of the described patients search for organic causes of the syndrome was performed, but revealed only negative findings. Because of the limited number of cases no firm conclusion about the benefit of various psychotropic drugs can be drawn from our observation. Psychiatric symptoms could affect as many as 25% of patients with alpha-mannosidosis. First onset is typically in late puberty to early adolescence. The episodes may be recurrent, and of limited duration although medication may be necessary to alleviate symptoms. Our observations indicate that alpha-mannosidosis is associated with an increased risk of psychiatric symptoms. These should not be dismissed as part of the ID but should give rise to the initiation of adequate diagnostic work-up, treatment and support.