Kleefstra syndrome [OMIM: 610253] is caused by a 9q34.3 micro-deletion or an intragenic mutation in the EHMT1 gene. Its core phenotype comprises intellectual disability, childhood hypotonia and distinct dysmorphisms. The syndrome can be associated with congenital anomalies, epilepsy, cardiac arrhythmias and a typical sleep pattern. Starting from adult age, a regressive phenotype may develop.

Further delineation of the neuropsychiatric phenotype.

Formulating a comprehensive treatment approach.

Detailed examination of two patients with EHMT1 mutation.

Patient 1, male aged 34 years, showed recurrent behavioral problems with aggression and self-injuries as well as obstipation. Elsewhere, a diagnosis of autism was established. Aged 24, he suffered from some epileptic seizures. Recently, paroxysmal atrial fibrillation was diagnosed. Neither treatment with pipamperone and risperidone nor with valproate was effective for behavioral control. Array analysis and metabolic screening did not reveal abnormalities. Whole exome sequencing revealed an intragenic EHMT1 mutation. Patient 2, female aged 53 years, was known with childhood epilepsy and developed gradual decline of general functioning with motor slowing from her third decade. In her thirties, a mood/anxiety disorder was suspected for which several antidepressants were given without any effect. Array analysis was normal. A pathogenic nucleotide deletion was identified resulting in a frame-shift in exon 21 of the EHMT1 gene. In both patients marked apathy was observed (AES = 62 and 64, respectively).

Apathy syndrome in Kleefstra syndrome should be differentiated from depression and autism. Apart from treatment with selected psychotropics, individually targeted contextual measures should always be implemented.

The authors have not supplied their declaration of competing interest.