Neuropsychological phenotype and psychopathology in seven adult patients with Phelan‐McDermid syndrome: implications for treatment strategy

Abstract

Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is characterized by a variable degree of intellectual disability, impaired speech and language as well as social communicative skills and mild dysmorphic features. The SHANK3 gene is thought to be a major contributor to the phenotype. Apart from the syndrome-associated autistic features, symptoms from the bipolar spectrum can be discerned, in particular behavior instability and fluctuating mood culminating in a (hypo)manic state. In case of coincident major somatic events, a deteriorating course may occur. This study comprises seven adult patients (four females and three males; aged 21-44 years) with genetically proven PMS. Data from medical records were collected and extensive assessment of neuropsychological variables was performed to identify cognitive characteristics and their relation with psychopathology and treatment. All patients showed profound communication deficits and their developmental functioning ranged from 1.0 to 6.3 years. In addition, they had slow speed of information processing, impairment of attentional and executive functions and cognitive alexithymia. As to psychopathology, features from the affective and anxiety domains were prominent findings in these seven patients suggesting the presence of a bipolar spectrum disorder that could be effectively moderated with mood-stabilizing agents. Results are discussed in terms of the putative involvement of structural brain abnormalities, in particular cerebellar vermis hypoplasia and corpus callosum thinning and their cognitive and emotional sequelae. It is concluded that the treatment of 22q13.3-associated psychopathology should include prescription of mood-stabilizing agents in combination with individually tailored contextual neuropsychological measures.

Psychiatric illness and regression in individuals with Phelan-McDermid syndrome

“…Epilepsy is reported in 17% to 70% of individuals with PMS [9,[11][12][13][14]. As individuals with PMS age, they appear to be at increased risk for bipolar disorder [15][16][17][18][19][20] and an associated risk of significant cognitive and behavioral regression [5,6,16,[18][19][20]. Indeed, SHANK3 variants have been implicated in the risk for severe neuropsychiatric disorders, including mood and psychotic disorders [15,16,19,21,22].…”

“…As individuals with PMS age, they appear to be at increased risk for bipolar disorder [15][16][17][18][19][20] and an associated risk of significant cognitive and behavioral regression [5,6,16,[18][19][20]. Indeed, SHANK3 variants have been implicated in the risk for severe neuropsychiatric disorders, including mood and psychotic disorders [15,16,19,21,22]. Gauthier et al (2010) identified sequence variants in the SHANK3 gene in four individuals initially diagnosed with atypical, early-onset schizophrenia, and a history of borderline to mild intellectual disability [21].…”

“…A few previous cross-sectional studies have used systematic methods to characterize the behavioral profile of individuals with PMS across the lifespan [19,[26][27][28]. However, the nature and course of psychiatric symptoms in PMS, and in particular their association with regression occurring much later than the early childhood regressions typical of ASD, have not been extensively documented.…”

A framework to identify modifier genes in patients with Phelan-McDermid syndrome

“…30 In the literature, brain structural abnormalities were reported in six studies, with a mean rate of 25% (58/233) of cases. 14 Hypoplasia of the cerebellar vermis, 31,32 thin corpus callosum, 16,28,31,33 and abnormalities of white matter were previously reported. In our cohort, brain MRI data was available for 35 patients with 22q13 deletions and 23 had structural anomalies (65.7%), consistent with those already described in PMS (Supplementary Materials and Methods).…”

Phelan‐McDermid syndrome, bipolar disorder and treatment with lithium

“…A series of patients with PMS and affective disturbance appeared to respond well to the combination of valproate and quetiapine (Egger, Zwanenburg, van Ravenswaaij‐Arts, Kleefstra & Verhoeven, ), while valproate has been used in combination with antidepressants for PMS with atypical bipolar disorder (Verhoeven, Egger, Willemsen, de Leijer & Kleefstra, ) and quetiapine has been successful in treating psychosis in those with PMS (Messias, Kaley & McKelvey, ). Carbamazepine has also shown to be effective in atypical bipolar disorder in combination with antipsychotics or other mood stabilisers (Verhoeven, Egger, Cohen‐Snuijf, Kant & de Leeuw, ; Verhoeven et al., ; Vucurovic et al., ), and mood instability has been successfully treated with low doses of risperidone alone (Pasini, D'Agati, Casarelli & Curatolo, ).…”