The overview of the clinical and molecular data is presented in table . There were no peculiarities during pregnancy, birth or neonatal period. Except for patient 3, each individual was able to walk independently before the age of 18 months. In all patients, language development was severely retarded (first words between 2 years and 6 months and 6 years). Currently, all function at a severe to profound level of ID. Five are in residential care, the 2 youngest attend special education and live in their home environment, combined with semi-residential care. All of them attended special education, and none are able to work in a sheltered environment.
Overview of clinical characteristics and developmental data
Patient 2 inherited the deletion from her mother; this 36-year-old mother with a moderate ID had normal early motor milestones, and her early language milestones were not markedly delayed either. At present, she is able to construct elementary sentences, works in a sheltered environment and needs major assistance from her parents to take care of her daughter. There is no history of somatic or psychiatric problems.
The results of the questionnaires regarding the 7 observed patients are summarized in figures and , and table .
DBC-profiles in del22q13.3 (n = 7).
Vineland-Z profiles in del22q13.3 (n = 7).
Scores of the 7 individuals with del22q13.3 on the PDD-MRS
In figure , the DBC-profiles of all 7 patients with a del22q13.3 are shown. All individuals show severe challenging behaviour; all have a total problem score between Pc. 75–90. Most prominent problem behaviours are self-absorbing behaviour, problems with social relating and disruptive behaviour. In 1 individual (patient 5), anxiety is the most problematic.
Figure shows the Vineland-Z profiles of all 7 patients with a del22q13.3. In 6 out of 7 patients, communication is very poor, and 5 out of 7 have prominent problems within the domain of socialisation. Daily living skills seem to be well developed in 5 out of 7 patients.
In table , the total PDD-MRS score of all 7 patients is reported. Four individuals have a score within the PDD-spectrum: most typical for these patients are the unpredictable outbursts, stereotypic behaviours (clapping, biting) and obsessive traits.
Although all individuals have always shown autistic-like behaviour, like low or absent social reciprocity, poor nonverbal skills, stereotypic behaviour and rigidity, none have been specifically examined and assessed for autism. This is probably due to the severe to profound level of ID. Our observations and gathered data indicate that the criteria for a diagnosis of PDD may be fulfilled in several individuals.
Four patients have been evaluated by a psychiatrist. Due to extreme overactive and impulsive behaviour with a very short attention span, patient 2 was diagnosed with ADHD, responding well to treatment with methylphenidate. Four others (patients 4, 5, 6, and 7) received a formal diagnosis of bipolar disorder (BPD) because of the presence of at least one manic episode with irritable mood, psychomotor agitation, decreased need for sleep, and increased speech (increased babbling and talking). The latter was unexpected because these patients otherwise did not talk.
Remarkably, many patients show a progressive loss of skills during their life. This is the most subtle in the 2 youngest children, with regard to language skills, e.g. losing acquired words when they are no longer practiced. The other individuals also showed deterioration in language over years, like a decline in receptive and expressive language or a regression in pronunciation. Several other developmental domains are also affected. Concerning gross and fine motor skills, parents, caregivers and therapists observed, for instance, deterioration in balance and coordination, progressive rigidity of the posture with shuffling gait, loss of the ability to do handwork, and to eat with a knife and fork. With regard to social skills, a reduced eye-contact and diminished social interest were perceived.
In addition, several patients showed severe and sudden loss of skills after acute events which could not always be regained.
Patient 4 was diagnosed with a BPD, rapid cycling type with psychotic symptoms. The response of neuroleptics and benzodiazepines to the excessive mood and activity swings was poor, thus requiring higher doses. Due to a rise in temperature and the fear of a neuroleptic malignant syndrome, the neuroleptics were stopped. Few days later, she was hospitalized for a day because of a sudden blood pressure fall with decreased consciousness, presumably because of an overdose of benzodiazepines. This was immediately followed by an apathetic and catatonic period, in which she stopped moving and talking. Afterwards, her level of functioning had become very different than before. She was not able to use the language she knew, stopped interacting with others and did no longer recognize her mother. The mood swings became even more explicit than they had been before. She stopped eating independently and also lost continence.
Patient 6 was hospitalized in intensive care for a malignant neuroleptic syndrome during a substantial manic episode at the age of 27, treated with high doses of haloperidol. Afterwards, he lost the ability to walk or eat independently, needing a long period of rehabilitation to recover. At 40 years, he was hospitalized again for septic shock due to aspiration pneumonia. Thereafter, he lost even more skills (loss of active and passive language, loss of walking, independently eating and dressing, and loss of continence) that could not be regained at all. Currently, he is spastic and wheelchair bound.
Patient 7 became totally dependent and bedridden after a prolonged epileptic state.