SCAMP5, NBEA and AMISYN: three candidate genes for autism involved in secretion of large dense-core vesicles.

Autism is a neurodevelopmental disorder characterized by impaired social reciprocity, impaired communication and stereotypical behaviors. Despite strong evidence for a genetic basis, few susceptibility genes have been identified. Here, we describe the positional cloning of SCAMP5, CLIC4 and PPCDC as candidate genes for autism, starting from a person with idiopathic, sporadic autism carrying a de novo chromosomal translocation. One of these genes, SCAMP5 is silenced on the derivative chromosome, and encodes a brain-enriched protein involved in membrane trafficking, similar to the previously identified candidate genes NBEA and AMISYN. Gene silencing of Nbea, Amisyn and Scamp5 in mouse beta-TC3 cells resulted in a 2-fold increase in stimulated secretion of large dense-core vesicles (LDCVs), while overexpression suppressed secretion. Moreover, ultrastructural analysis of blood platelets from the patients with haploinsufficieny of one of the three candidate genes, showed morphological abnormalities of dense-core granules, which closely resemble LDCVs. Taken together, this study shows that in three independent patients with autism three different negative regulators of LDCV secretion are affected, respectively, suggesting that in at least a subgroup of patients the regulation of neuronal vesicle trafficking may be involved in the pathogenesis of autism.

Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis.

OBJECTIVES: To develop a comprehensive mutation analysis system with a high rate of detection, to develop a tool to predict the chance of detecting a mutation in the L1CAM gene, and to look for genotype-phenotype correlations in the X-linked recessive disorder, L1 syndrome. METHODS: DNA from 367 referred patients was analysed for mutations in the coding sequences of the gene. A subgroup of 100 patients was also investigated for mutations in regulatory sequences and for large duplications. Clinical data for 106 patients were collected and used for statistical analysis. RESULTS: 68 different mutations were detected in 73 patients. In patients with three or more clinical characteristics of L1 syndrome, the mutation detection rate was 66% compared with 16% in patients with fewer characteristics. The detection rate was 51% in families with more than one affected relative, and 18% in families with one affected male. A combination of these two factors resulted in an 85% detection rate (OR 10.4, 95% CI 3.6 to 30.1). The type of mutation affects the severity of L1 syndrome. Children with a truncating mutation were more likely to die before the age of 3 than those with a missense mutation (52% vs 8%; p=0.02). CONCLUSIONS: We developed a comprehensive mutation detection system with a detection rate of almost 20% in unselected patients and up to 85% in a selected group. Using the patients' clinical characteristics and family history, clinicians can accurately predict the chance of finding a mutation. A genotype-phenotype correlation was confirmed. The occurrence of (maternal) germline mosaicism was proven.

Rett syndrome and long-term disorder profile.

In a cohort of 103 females clinically diagnosed with Rett syndrome (RTT), 91 had a detectable MECP2 mutation. Emphasis on details of natural history facilitated grouping of females with the same MECP2 mutation and the development of so-called disorder profiles. Some examples of disorder profiles of different recurrent MECP2 mutations are discussed. RTT females with the frequently recurrent R133C and R306C missense mutations and those with intragenic deletions in the C-terminus of MECP2 deserve more attention in larger studies as their development is different and milder in the long term. RTT females with the T158M missense mutation are often atypical with mainly behavioral characteristics in infancy and childhood but become classic RTT in adolescence after a slower, protracted course.

Lymphedema in Prader-Willi syndrome.

A 20-year-old woman with Prader-Willi syndrome presented with heaviness and swelling in the lower legs and feet, which had developed after a fall. Lymphoscintigraphy showed a disturbed lymphatic drainage pattern in both lower extremities. Based on the clinical findings and the results of lymphoscintigraphic examination we made the diagnosis of lymphedema. The patient was successfully treated with manual lymphatic drainage in combination with multilayer compressive bandaging. After edema reduction, elastic compressive stockings were fit. To the best of our knowledge, this is the first report on primary lymphedema in a patient with Prader-Willi syndrome, an association that is probably often missed.

Aging in people with specific genetic syndromes: Rett syndrome.

The aging process of people with intellectual disabilities has been a topic of interest in recent years. Good knowledge of the specific healthcare problems in adults with intellectual disabilities and anticipating on these problems are important issues in providing support and healthcare for these persons. Nevertheless little is known about the aging process of people with specific syndromes, like Rett syndrome. In association with the Dutch Rett syndrome parent association, 70 postal questionnaires were sent to the contact persons of the females aged at least 16 years with a clinical diagnosis of Rett syndrome. The questionnaire consisted of general questions, questions about living conditions, skills, physical and psychiatric morbidity. The response rate was 76% (n = 53). In general adults with Rett syndrome seemed to be reasonably healthy, whereas neurological, respiratory and behavioral morbidity appeared to be of great influence. High care dependency was confirmed. In contrast with underweight, overweight showed to be an under-ascertained feature. The general disorder profile was confirmed, considering the increase with age regarding kyphosis and the better communication and autonomic dysfunction in the oldest age group compared to the younger age groups. Features of autonomic dysfunction deserve more medical attention, especially the interrelation between quality of sleep, respiration and behavior in Rett syndrome. Longitudinal studies including genotype-phenotype analyses are needed for insight in individual changes in support needs and health.

Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: Delineation of the critical region for a consensus phenotype.

The deletion 9p syndrome is caused by a constitutional monosomy of part of the short arm of chromosome 9. It is clinically characterized by dysmorphic facial features (trigonocephaly, midface hypoplasia, and long philtrum), hypotonia and mental retardation. Deletion 9p is known to be heterogeneous and exhibits variable deletion sizes. The critical region for a consensus phenotype has been reported to be located within a approximately 4-6 Mb interval on 9p22. In the present study, deletion breakpoints were determined in 13 Dutch patients by applying fluorescence in situ hybridization (FISH) and in some specific cases by array-based comparative genomic hybridization (array CGH). No clear genotype-phenotype correlation could be established for various developmental features. However, we were able to narrow down the critical region for deletion 9p syndrome to approximately 300 kb. A functional candidate gene for trigonocephaly, the CER1 gene, appeared to be located just outside this region. Sequence analysis of this gene in nine additional patients with isolated trigonocephaly did not reveal any pathogenic mutations.

Management of a severe forceful breather with Rett syndrome using carbogen.

We have used a novel neurophysiological technique in the NeuroScope system in combination with conventional electroencephalography (EEG) to monitor both brainstem and cortical activity simultaneously in real-time in a girl with Rett syndrome. The presenting clinical features in our patient were severe sleep disturbances, irregular breathing in the awake state dominated by Valsalva's type of breathing followed by tachypnoea and very frequent attacks of seizures and vacant spells. Our novel neurophysiological data showed that the patient was a Forceful Breather according to the breathing categories in Rett syndrome. She had frequent abnormal spontaneous brainstem activation (ASBA) preceded by severe attacks of hypocapnoea, which was caused by a combination of Valsalva's type of breathing and tachypnoea and all these together were responsible for the seizures and non-epileptic vacant spells. The ASBA was not detectable in conventional EEG and there were no epileptiform changes in the EEG during the seizures and vacant spells caused by the hypocapnic attacks, therefore these were pseudo-seizures. The record of brainstem activity confirmed that these were autonomic events, a kind of "brainstem epilepsy". We successfully treated the sleep disturbance with Pipamperone, a 5-hydroxytryptophan antagonist of receptor type 2 and we prevented the severe hypocapnoea during Valsalva's type of breathing and during tachypnoea using carbogen (a mixture of 5% carbon dioxide and 95% oxygen), which we gave by inhalation. Our treatment drastically reduced the autonomic events, promoted whole night sleep and significantly improved the quality of life in our patient. She can now participate in normal family activity which was previously impossible before treatment.

Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2).

Mutations in the MECP2 (methyl-CpG-binding protein 2) gene are known to cause Rett syndrome, a well-known and clinically defined neurodevelopmental disorder. Rett syndrome occurs almost exclusively in females and for a long time was thought to be an X-linked dominant condition lethal in hemizygous males. Since the discovery of the MECP2 gene as the cause of Rett syndrome in 1999, MECP2 mutations have, however, also been reported in males. These males phenotypically have classical Rett syndrome when the mutation arises as somatic mosaicism or when they have an extra X chromosome. In all other cases, males with MECP2 mutations show diverse phenotypes different from classical Rett syndrome. The spectrum ranges from severe congenital encephalopathy, mental retardation with various neurological symptoms, occasionally in association with psychiatric illness, to mild mental retardation only. We present a 21-year-old male with severe mental retardation, spastic tetraplegia, dystonia, apraxia and neurogenic scoliosis. A history of early hypotonia evolving into severe spasticity, slowing of head growth, breathing irregularities and good visual interactive behaviour were highly suggestive of Rett syndrome. He has a de novo missense mutation in exon 3 of the MECP2 gene (P225L). The clinical spectrum and molecular findings in males with MECP2 mutations are reviewed.

Classical Scheuermann disease in male monozygotic twins: further support for the genetic etiology hypothesis.

STUDY DESIGN: Classic cases of Scheuermann disease in male monozygotic twins are reported. OBJECTIVES: To report classic cases of Scheuermann disease or Scheuermann kyphosis in male monozygotic twins, and to discuss the previous two cases of classic Scheuermann disease in monozygotic twins and the genetic etiology theory of Scheuermann kyphosis. SUMMARY OF BACKGROUND DATA: The etiology of Scheuermann disease remains unclear. Both genetic and mechanical factors or a combination of the two have been postulated to explain Scheuermann disease. The genetic etiology hypothesis has been explained by an autosomal dominant inheritance pattern. In support of this genetic etiology hypothesis, two cases of Scheuermann disease in monozygotic twins have been reported in the English literature. METHODS: The criteria of Sørensen and Sachs et al were used to diagnose Scheuermann kyphosis. Clinical examination and lateral spinal radiographs were performed on a male monozygotic twin. Both parents were clinically investigated for signs of a kyphotic deformity. RESULTS Scheuermann disease was noted in both patients at the same vertebral levels. The Cobb angle of the kyphosis was 74 degrees and 48 degrees, respectively. Clinical examination of both parents did not show any kyphotic abnormality. CONCLUSIONS: These cases of classic Scheuermann disease in monozygotic male twins support the theory that there is a genetic contribution in classic Scheuermann disease.