Elsevier

Pediatric Neurology

Volume 24, Issue 2, February 2001, Pages 111-116
Pediatric Neurology

Original article
Relationship between clinical and genetic features in “inverted duplicated chromosome 15” patients

https://doi.org/10.1016/S0887-8994(00)00244-7Get rights and content

Abstract

Inverted duplicated chromosome 15 (Inv dup [15]) syndrome is a genetic disorder characterized by psychologic or intellectual language delay; neurologic signs, such as hypotonia, ataxia, and epilepsy; mental retardation ranging from mild to severe; and facial dysmorphisms. All patients present with a psychopathologic impairment that is highly variable in severity but always classifiable as pervasive developmental disorder (PDD). Many genetic mechanisms have been hypothesized to explain the clinical variability. This article describes the neurologic and psychopathologic features of six Inv dup(15) patients, one male and five females, between 8 and 14 years of age, all with a maternal marker chromosome. Four patients were diagnosed with PDD not otherwise specified, whereas two patients received a diagnosis of autism. Epilepsy was present in three patients (two generalized symptomatic and one focal symptomatic), and a correlation between the severity of the disease and its outcome was not always observed. Nevertheless, the influence of gene content of the marker chromosome, particularly the three γ-aminobutyric acid-A receptor subunit genes, may represent the link between epilepsy, mental retardation, and PDD.

Introduction

Recent advances in cytogenetics and molecular genetics have renewed interest in the study of chromosomal abnormalities, such as subtle chromosomal rearrangements, and marker chromosomes (small accessory chromosomes) as a possible cause for behavioral disturbances and mental retardation [1], [2], [3], [4]. Among the supernumerary marker chromosomes, inverted duplicated chromosome 15 (Inv dup[15]) represents a group of particular interest because of their frequency within the population (0.4/1000) and the involvement of a gene-rich region [5], [6], [7], [8], [9].

The proposed mechanism for its formation is a U-type exchange between nonsister chromatids [10], [11], and the size of the 15 regions involved in the tetrasomy is correlated with the breakpoint of rearrangement. Two regions have been identified that are prone to breakage: one region is more proximal to the 15 centromere, which produces small Inv dup(15), and the other is more distal, which creates larger Inv dup(15) [12], [13]. Deletion of this chromosome region correlates with two other syndromes, namely Prader-Willi syndrome (PWS) and Angelman syndrome (AS) in which, among other symptoms, mental retardation is associated with behavioral disorders.

In the literature the importance of PWS/AS gene dosage has been related to the clinical severity of the phenotype [7], [10], [14], [15], [16], [17]. On the contrary, the correlation with the genic content of the marker and the clinical spectrum of Inv dup(15) syndrome is variable and is still a much-debated issue [6], [7], [9], [10], [12], [14], [15]. The clinical spectrum exhibited by subjects with Inv dup(15) includes muscle hypotonia, motor clumsiness, mild dysmorphisms, epileptic seizures, and cognitive deficits of varying severity that are always associated with severe behavioral disorders, such as distorted communication skills, poor social interaction, and stereotyped behavior. According to the DSM-IV diagnostic criteria [18], these behavioral disorders can be classified as pervasive developmental disorders (PDDs).

PDDs comprise autistic disorder, childhood disintegrative disorder, Rett syndrome, Asperger’s disorder, and also the large group of “PDDs not otherwise specified” that includes cases with atypical symptomatology: subthreshold behavioral manifestations, various neurologic symptoms, or severe-profound mental retardation.

In this study, six patients with Inv dup(15) were monitored, focusing on their neurologic and psychopathologic features, which until now have been only scantily investigated, with the aim to study the behavioral phenotype of the syndrome and identify a possible correlation between the clinical pattern and the genetic one.

Section snippets

Methods

All inpatients with mental retardation and behavioral disorders in the Child Neuropsychiatry Units of Bosisio, Brescia, and Varese General Hospitals usually undergo a karyotype analysis from peripheral blood lymphocytes using the standard technique. During 1995-1998, six patients (one male and five females between 4 and 14 years of age, mean age of 8.83 years) with a diagnosis of Inv dup(15) syndrome were observed.

Results

Genetic analysis revealed the maternal origin of Inv dup(15) in all six patients. In one patient a marker chromosome of paternal origin was suspected at cytogenetic heteromorphism investigations; subsequently, the maternal derivation of the marker was demonstrated by molecular techniques. All our patients displayed the large type of Inv dup(15) correlated with breakage at the distal breakpoint of rearrangement (Fig 1).

The general and neurologic features of the patients examined reflect the

Discussion

All the study patients presented a pathologic phenotype characterized by motor retardation, language delay, facial dysmorphisms, hypotonia, ataxia and/or dyspraxia, mild-to-severe cognitive deficit, and psychopathologic impairment always classifiable as PDD. The same neurologic signs, mental retardation, and autisticlike behavior have been described in almost all patients reported in other studies [7], [8], [9], [14], [16], [17], [23], [24].

The study patients also demonstrated highly varied

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