Incontinentia Pigmenti: Learning Disabilities Are a Fundamental Hallmark of the Disease

Abstract

Studies suggest that genetic factors are associated with the etiology of learning disabilities. Incontinentia Pigmenti (IP, OMIM#308300), which is caused by mutations of the IKBKG/NEMO gene, is a rare X-linked genomic disorder (1∶10000/20∶000) that affects the neuroectodermal tissues. It always affects the skin and sometimes the hair, teeth, nails, eyes and central nervous system (CNS). Data from IP patients demonstrate the heterogeneity of the clinical phenotype; about 30% have CNS manifestations. This extreme variability suggests that IP patients might also have learning disabilities. However, no studies in the literature have evaluated the cognitive profile of IP patients. In fact, the learning disability may go unnoticed in general neurological analyses, which focus on major disabling manifestations of the CNS. Here, we investigated the neuropsychological outcomes of a selected group of IP-patients by focusing on learning disabilities. We enrolled 10 women with IP (7 without mental retardation and 3 with mild to severe mental retardation) whose clinical diagnosis had been confirmed by the presence of a recurrent deletion in the IKBKG/NEMO gene. The participants were recruited from the Italian patients' association (I.P.A.SS.I. Onlus). They were submitted to a cognitive assessment that included the Wechsler Adult Intelligence scale and a battery of tests examining reading, arithmetic and writing skills. We found that 7 patients had deficits in calculation/arithmetic reasoning and reading but not writing skills; the remaining 3 had severe to mild intellectual disabilities. Results of this comprehensive evaluation of the molecular and psychoneurological aspects of IP make it possible to place “learning disabilities” among the CNS manifestations of the disease and suggest that the IKBKG/NEMO gene is a genetic determinant of this CNS defect. Our findings indicate the importance of an appropriate psychoneurological evaluation of IP patients, which includes early assessment of learning abilities, to prevent the onset of this deficit.

Cognitive-behavioural phenotype in a group of girls from 1.2 to 12 years old with the Incontinentia Pigmenti syndrome: Recommendations for clinical management

“…Until now the cognitive profile of 10 women affected by IP has been described (Pizzamiglio et al, 2014). From this sample of adults it emerged that 3/10 presented intellectual deficiencies and 7/10 had a normal development without any discrepancies between verbal and performance IQ.…”

“…Indeed, neonates with cutaneous lesions, seizures and ocular abnormalities show more diffuse brain lesions, whereas neonates with mild cutaneous lesions and without neurological symptoms do not have any brain lesions. To our knowledge only Pizzamiglio et al (2014) have described the neuropsychological profile of this disease in a group of 10 women with IP. Their results showed that approximately 30% presented intellectual deficiencies and approximately 70% presented a normal development without any discrepancies between verbal and performance IQ.…”

NF-κB-Related Genetic Diseases

“…CYLD, which can hydrolyze K63-linked or linear chain, acts on RIPK-1, NEMO, and TRAF2 [30][31][32]. USP2 is another DUB that also acts at the level of RIPK1 [33]. Finally, OTULIN has been shown to be a DUB with specific affinity for linear ubiquitin chains that counteracts LUBAC activity [34,35].…”

“…An attempt to treat one IP patient with glucocorticoid has been reported [32]. The cognitive function, especially learning ability, of IP patients can also be surveyed in order to propose some reeducational training [33].…”

Incontinentia Pigmenti in a newborn: Case report and review of the literature

“…Morbidity and mortality essentially result from extracutaneous ophthalmologic and neurologic complications, the last affecting approximately 30% of patients [9].…”