Elsevier

Brain and Development

Volume 27, Issue 5, August 2005, Pages 378-382
Brain and Development

Original article
Epilepsy and neurological findings in 11 individuals with 1p36 deletion syndrome

https://doi.org/10.1016/j.braindev.2005.02.004Get rights and content

Abstract

The 1p36 deletion syndrome is a newly delineated multiple congenital anomalies/mental retardation syndrome characterized by mental retardation, growth delay, epilepsy, congenital heart defects, characteristic facial appearance, and precocious puberty. We analyzed 11 patients by fluorescence in situ hybridization (FISH) using commercially available bacterial artificial chromosome and P1-derived artificial chromosome genomic clones to define the chromosomal deletion responsible for the 1p36 deletion syndrome. Cytogenetic investigation revealed two cases with a terminal deletion of 1p36. Nine patients had an apparently normal karyotype with standard G-bands by trypsin using Giemsa (GTG), but FISH screening with the highly polymorphic genetic marker D1Z2, which is mapped to 1p36.3 and contains an unusual reiterated 40-bp variable number tandem repeat, revealed a submicroscopic deletion. All patients had severe to profound mental retardation. Based on the University of California Santa Cruz Genome Browser, we constructed a deletion map and analyzed the relationship between neurological findings and chromosomal deletions for the 11 cases. Six cases had intractable epilepsy and three had no seizures. The common deletion interval was about 1 million base pairs (Mbp) located between RP11-82D16 and RP4-785P20 (Rho guanine exchange factor (GEF) 16). The severity of clinical symptoms correlates with the size of the deletion. This is demonstrated by the 3 patients with at least 8 Mbp deletions that display profound mental retardation and congenital heart defects. Although haploinsufficiency of the potassium channel beta-subunit (KCNAB2) is thought to be responsible for intractable seizures in the 1p36 deletion syndrome, this was not the case for 3 of the 11 patients in this study. Further investigation of the 1p36 region is necessary to allow identification of genes responsible for the 1p36 deletion syndrome.

Introduction

Mental retardation (MR) is one of the most frequent causes of serious neurological handicap that occurs in 2–3% of the human population. The underlying causes of MR are heterogeneous and may involve genetic and/or environmental factors. The causes of mental retardation are unexplained in more than half of all cases. The study of MR etiology has always been a challenge [1]. Attention has recently focused on cryptic subtelomeric chromosome rearrangements as a cause of dysmorphology and mental retardation [2], [3], [4], [5]. Technological advancement in the development of subtelomere fluorescence in situ hybridization (FISH) probes and the clinical application of detection kits for subtelomere rearrangements has enabled large-scale surveys of patients with mental retardation and/or multiple congenital anomalies. Cryptic subtelomeric rearrangements now account for 5–7.4% of moderately or severely mentally handicapped children, who had no identifiable causes [5].

Terminal deletion of 1p is recognized as a syndrome with multiple congenital anomalies and mental retardation [6], [7], [8], [9]. The syndrome is characterized by severe mental retardation, growth retardation, intractable seizures, hypotonia, precocious puberty, characteristic facial appearance, and cardiomyopathy. The prevalence of the syndrome is estimated to be one in 5000–10,000, making it the most common terminal deletion syndrome. Maternally derived de novo deletions are significantly more frequent than paternally derived deletions. The deletion size varies in each family, providing phenotypic variability as a result of haploinsufficiency of different genes. The critical region for moderate to severe mental retardation is defined distally by D1S243 and proximally by D1S468 [7]. In most cases, FISH confirmed the deletion with probes D1Z2 and p58. The subtelomere assay using the Chromophore Multiprobe-T Cytocell device (Cytocell) is also used to detect the 1p36 deletion in patients with unclassified multiple congenital anomalies/mental retardation (MCA/MR) syndromes [4]. Disadvantages of these methods for widespread screening are the cost and the fact that it is not available to all clinical settings [10].

To elucidate the clinical characteristics of the newly delineated 1p36 deletion syndrome, we studied 11 Japanese patients with the 1p36 deletion syndrome and reviewed the clinical findings. We further refined the common critical deletion interval among patients with the disorder. This information is important for health practitioners and families supporting patients with the disorder.

Section snippets

Patients and methods

Eleven Japanese patients with the 1p36 deletion syndrome were included in this study. Of the 11 patients, 9 were diagnosed clinically according to facial appearance, neurological features and characteristic physical symptoms. Diagnoses were confirmed by FISH analysis with the midisatellite probe p1-79/D1Z2 (ATCC, Rockville, MD), which maps to 1p36.3. Cases 8 and 10 were diagnosed by standard G-bands by trypsin using Giemsa (GTG) technique and high resolution banding procedures. All patients

Results

Phenotypic data based on medical records was analyzed for 11 patients (four male and seven female). The clinical details are summarized in Table 1. Severe developmental delay and feeding difficulties were common to all cases during the infantile period. Prenatal growth retardation was noted in patients with a visible deletion within 1p36.3 detected by standard GTG technique (patient 8 and 10). This observation may not be significant in the 1p36 deletion syndrome as prenatal growth retardation

Discussion

The 11 patients described in this study all have severe mental retardation and similar facial features, but other congenital anomalies are variable. Two patients had a deletion within 1p36 that was detected by standard GTG technique. The other 9 patients had submicroscopic deletions confirmed using FISH using the D1Z2 probe.

The mutations in all patients were sporadic, and the possibility of cryptic translocation was not evaluated. Growth parameters were prenatally retarded in patients with

Acknowledgements

The Kawano Masanori Memorial Foundation for Promotion of Pediatrics supported this study. The authors are grateful to Dr Yoshikatsu Eto (Jikei University) for his valuable comments. The authors also wish to thank the patients and their families for contribution to this study.

References (16)

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The Paper is based on the Lecture given at the Sixth Annual Meeting of the Infantile Seizure Society, Tokyo, March 15–16, 2003.

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