Search

The human SNRPN (small nuclear ribonucleoprotein polypeptide N) gene is one of a gene family that encode proteins involved in pre-mRNA splicing and maps to the smallest deletion region involved in the Prader-Willi syndrome (PWS) within chromosome 15q11-q13. Paternal only expression of SNRPN has previously been demonstrated by use of cell lines from PWS patients (maternal allele only) and Angelman syndrome (AS) patients (paternal allele only). We have characterized two previously unidentified 5' exons of the SNRPN gene and demonstrate that exons -1 and 0 are included in the full-length transcript. This gene is expressed in a wide range of somatic tissues and at high, approximately equal levels in all regions of the brain. Both the first exon of SNRPN (exon -1) and the putative transcription start site are embedded within a CpG island. This CpG island is extensively methylated on the repressed maternal allele and is unmethylated on the expressed paternal allele, in a wide range of fetal and adult somatic cells. This provides a quick and highly reliable diagnostic assay for PWS and AS, which is based on DNA-methylation analysis that has been tested on > 100 patients in a variety of tissues. Conversely, several CpG sites approximately 22 kb downstream of the transcription start site in intron 5 are preferentially methylated on the expressed paternal allele in somatic tissues and male germ cells, whereas these same sites are unmethylated in fetal oocytes. These findings are consistent with a key role for DNA methylation in the imprinted inheritance and subsequent gene expression of the human SNRPN gene.

A 9-year-old female MELAS patient with myoclonus is reported, with emphasis on the results of electrophysiological studies of the myoclonus. At age 5 years she experienced a stroke-like episode, and a diagnosis of MELAS was made at age 6 years on the basis of muscle biopsy findings. At age 9 years spontaneous and segmental myoclonus, predominantly affecting the upper extremities, developed because of complications. Electrophysiological examination, including of somatosensory-evoked potentials (SEPs) and averaged EMG for long loop reflexes, revealed the so-called “giant SEP” and enhanced long loop reflexes reflecting cortical hyperexcitability. Jerk-locked averaging yielded no myoclonus related spikes, but myoclonus-contingent 4-5 Hz theta bursts appeared. These findings suggest that some types of MELAS may be associated with cortical types of myoclonus.

Wiedemann-Beckwith syndrome (WBS) is a genetic disorder with overgrowth and predisposition to Wilms` tumor. The putative locus of the gene responsible for this syndrome is assigned to chromosome region 11p15.5, and genomic imprinting in this region has been proposed: the paternally derived gene(s) at 11p15.5 is selectively expressed, while the maternally transmitted gene(s) is inactive. The authors examined 18 patients for the parental origin of their 11p15 regions. DNA polymorphism analyses using 6 loci on chromosome 11 showed that 2 patients with duplications of 11p15 regions from their respective fathers and one from the mother, indicating the transmission of an excessive paternal gene at 11p15 to each patient. The result, together with the previous findings in karyotypically normal or abnormal patients and in overgrowth mouse experiments, are consistent with imprinting hypothesis that overexpression of paternally derived gene(s) at 11p15.5, probably the human insulin-like growth factor II (IFG-II) gene, may cause the phenotype. Total constitutional uniparental paternal disomy (UPD) or segmental UPD for the 6 loci examined of chromosome 11 was not observed in our 12 sporadic patients. In order to explain completely the inheritance of this syndrome in patients with various chromosomal constitutions, the authors propose an alternative imprinting mechanismmore » involving the other locus that may be paternally imprinted and may suppress the expression of this gene. 28 refs., 3 figs., 1 tab.« less

Background: Danon disease is due to primary deficiency of lysosome-associated membrane protein-2.Objective: To define the clinicopathologic features of Danon disease.Methods: The features of 20 affected men and 18 affected women in 13 families with genetically confirmed Danon disease were reviewed.Results: All patients had cardiomyopathy, 18 of 20 male patients (90%) and 6 of 18 female patients (33%) had skeletal myopathy, and 14 of 20 male patients (70%) and one of 18 female patients (6%) had mental retardation. Men were affected before age 20 years whereas most affected women developed cardiomyopathy in adulthood. Muscle histology revealed basophilic vacuoles that contain acid phosphatase–positive material within membranes that lack lysosome-associated membrane protein-2. Heart transplantation is the most effective treatment for the otherwise lethal cardiomyopathy.Conclusions: Danon disease is an X-linked dominant multisystem disorder affecting predominantly cardiac and skeletal muscles.

Editor—Oculocutaneous albinism type 2 (OCA2) is an autosomal recessive disorder characterised by defective melanin production of the skin, hair, and eyes,1 which is caused by mutations of the P gene.2 3The specific function of P has not been clarified, although it is likely to act as a transporter in the melanosomal membrane.2 4 The P gene is located in 15q11-q13, which is deleted in the majority of patients with Angelman syndrome (AS) and Prader-Willi syndrome (PWS).2 5 The P gene is not imprinted and both alleles are expressed. PWS and AS patients with typical deletions are thus hemizygous for P . It is also well established that AS and PWS deletion patients usually show hypopigmentation of the skin and hair, and P is suggested to be responsible for this hypopigmentation as well,6 7 although the mechanism has not yet been established. A small intragenic deletion and a V443I missense mutation of the P gene were identified in the maternally inherited alleles of two PWS plus OCA2 patients who had a paternally inherited deletion of 15q11-q13.2 3 Here we describe the first evidence that a P gene mutation is responsible for OCA2 associated with AS. The male patient was born at 38 weeks' gestation to unrelated Japanese parents. There were no complications of pregnancy or delivery, but the birth weight, 1850 g, was small for gestational dates. Generalised albinism was noted at birth. Motor development was delayed, and he had a generalised tonic-clonic convulsion at the age of 18 months. He was admitted to hospital at the …

Prader-Willi syndrome(PWS) is a complex multisystem genetic disorder, of which characteristic phenotypes include neonatal hypotonia, hyperphagia resulting in obesity, mental retardation, hypogonadism, and behavioral and psychiatric problems. The diagnosis can be obtained as early as during neonatal period thanks to development of genetic testing. Clinical features of PWS will change depending on age, although core phenotypes of hyperphagia, obesity and psychiatric issues stay for lifetime. Therefore, integrated multidisciplinary approach starting from neonatal period is mandatory to ensure optimal management to improve lifelong quality of life. For successful transition from childhood to adulthood, multidisciplinary team need to share clinical information, and should keep the same policy about food, environment and psychiatric issues.