Neurodevelopmental profile and stages of regression in Phelan-McDermid syndrome.

AIM: To characterize the neurodevelopmental profile of patients with Phelan-McDermid syndrome (PMS) and describe the nature and trajectory of regression. METHOD: This was a retrospective, monocentric study examining the clinical and developmental data of 24 patients (average age = 25 years 6 months, range = 6-56 years, n = 13 males) with a confirmed 22q13.3 terminal deletion carried out at the Centre for Human Genetics, University Hospital Leuven. The neurodevelopmental profile of individuals with PMS was examined, combining both cross-sectional and longitudinal data obtained by systematic review of digital medical records. RESULTS: Remarkable loss of skills was present in 19 individuals affecting both language and motor skills. The first manifestations of neurodevelopmental regression occurred, on average, at the age of 7 years 6 months (range = 5-11 years). Language skills (active vocabulary) were primarily affected followed by, in order of loss, psychosocial adaptability, fine motor skills, and walking ability. The course of regression was characterized by a distinctive four-stage pattern. The first stage often occurred around mid-childhood and was defined by a pronounced and abrupt decline of language skills. This stage was generally followed by the second stage where a (prolonged) period of stagnation of regression was seen. The third stage was defined by acute neuropsychiatric decline (e.g. catatonia, hallucinations, psychosis). Acute events such as severe sickness, hormonal shifts, and psychosocial stress frequently preceded the fourth and final stage, which was characterized by severe neuromotor degeneration. INTERPRETATION: Neurodevelopmental regression should be considered as a key feature of PMS. We present a four-stage model of neurodevelopmental regression, entailing language skills, fine and gross motor function, and psychosocial adaptation, which can be applied in future practice and research.

Neurodevelopmental risk copy number variants in adults with intellectual disabilities and comorbid psychiatric disorders.

BACKGROUND: Copy number variants (CNVs) are established risk factors for neurodevelopmental disorders. To date the study of CNVs in psychiatric illness has focused on single disorder populations. The role of CNVs in individuals with intellectual disabilities and psychiatric comorbidities are less well characterised.AimsTo determine the type and frequency of CNVs in adults with intellectual disabilities and comorbid psychiatric disorders. METHOD: A chromosomal microarray analysis of 599 adults recruited from intellectual disabilities psychiatry services at three European sites. RESULTS: The yield of pathogenic CNVs was high - 13%. Focusing on established neurodevelopmental disorder risk loci we find a significantly higher frequency in individuals with intellectual disabilities and comorbid psychiatric disorder (10%) compared with healthy controls (1.2%, P<0.0001), schizophrenia (3.1%, P<0.0001) and intellectual disability/autism spectrum disorder (6.5%, P < 0.00084) populations. CONCLUSIONS: In the largest sample of adults with intellectual disabilities and comorbid psychiatric disorders to date, we find a high rate of pathogenic CNVs. This has clinical implications for the use of genetic investigations in intellectual disability psychiatry.Declaration of interestNone.

MECP2 mutations are an infrequent cause of mental retardation associated with neurological problems in male patients.

Mutations in the methyl-CpG-binding protein 2 (MECP2) gene located on Xq28, cause Rett syndrome (RTT) in female patients. Meanwhile, nonmosaic MECP2 mutations unknown in girls have been found in an increasing number of male patients with a normal 46, XY karyotype. They can cause a broad spectrum of neurodevelopmental disorders which often show a combination of mental retardation (MR) with neurological symptoms. We present the results of MECP2 analysis in a group of 72 male patients with an unexplained combination of MR and neurological features, and review the mutational reports published on male patients since the discovery of the MECP2 gene. Analysis included sequencing of exon 1 which thus far was mostly omitted from DNA screening. One pathogenic mutation has been found in a patient with Rett variant, in addition to an unclassified variant and a series of nonpathogenic changes. No changes have been found in exon 1. Criteria for testing of male patients are classic RTT, severe neonatal encephalopathy, and RTT variant which may be clinically underrecognized. Testing can also be considered in males with a combination of unexplained MR and (progressive) neurological manifestations although the yield of MECP2 analysis is probably low in this situation. Based on the literature, MECP2 testing in males with MR only is debatable.