[Cancer-associated genodermatoses]. / Tumorassoziierte Genodermatosen.

Hereditary tumor syndromes are characterized by a familial occurrence of tumors/cancer. A hereditary tumor syndrome should be suspected if a familial occurrence of cancer is seen and/or persons at younger age are affected. Some of the currently known tumor syndromes are associated with specific skin symptoms that can aid the physician in establishing the correct diagnosis. Examples are fibrofolliculoma in Birt-Hogg-Dubé syndrome, epidermal cysts, sebaceous cysts, neurofibroma in Gardner syndrome and sebaceous neoplasms or keratoacanthoma in Muir-Torre syndrome. If a genetic tumor syndrome is suspected, genetic testing and counselling should be performed in the index patient and is also recommended for family members. Affected patients should be offered regular clinical surveillance by the appropriate medical disciplines. Since curative therapy does not exist so far, preventive screening is of great importance.

Delayed diagnosis of Birt-Hogg-Dubé syndrome due to marked intrafamilial clinical variability: a case report.

BACKGROUND: Birt-Hogg-Dubé syndrome is a genetic syndrome caused by mutations in the FLCN gene. The main symptoms are lung bullae and pneumothorax, benign and malignant kidney tumors, and facial fibrofolliculoma. The risk of pneumothorax is considerable between ages 20-40 years, but decreases markedly after this age range and first-time pneumothorax after age 50 years is rare. Fibrofolliculomas usually occur between ages 35 and 45 years, while the risk for kidney cancer increases steadily with age, starting in young adulthood. However, we demonstrate here that within the same family patients might develop symptoms significantly before or after the usual age range, obscuring the typical clinical pattern and delaying diagnosis. CASE PRESENTATION: The 43 year old index patient had a history of lung bullae and recurrent pneumothoraces starting 14 years earlier. His father (age 83 years) and one of the paternal uncles experienced their first pneumothorax unusually late after the age of 60 years. The uncle subsequently had four more pneumothoraces, and was diagnosed with kidney in his early 70s. Considerable differences in age of onset were also observed with regard to facial fibrofolliculomas that both paternal uncles developed very early around age 20 years, but which the father only started to show in his eighth decade. Birt-Hogg-Dubé syndrome was finally diagnosed when the index patient started to develop fibrofolliculomas within the typical age range. CONCLUSIONS: The family described here illustrates that Birt-Hogg-Dubé syndrome can be difficult to recognize, if presenting with considerable intrafamilial clinical variability. With a life-time kidney cancer risk of about 14-35% the consequences of delayed diagnosis might be grave for the affected family members. The possibility of Birt-Hogg-Dubé syndrome should therefore be taken into consideration in apparently sporadic patients presenting with lung bullae and pneumothorax.

Upstream open reading frames regulate cannabinoid receptor 1 expression under baseline conditions and during cellular stress.

The cannabinoid receptor subtype 1 gene CNR1 is not only associated with phenotypes such as cognitive performance, addiction and anxiety, but is also known to be crucially involved in responses to acute and chronic psychological and cellular stress conditions. Functional analysis of the 5' untranslated regions of the five known mRNA variants of the human CNR1 gene revealed that two of these variants contain upstream open reading frames that are able to modulate gene expression both under baseline condition and conditions of cellular stress including hypoxia, glucose restriction and hyperthermia. The upstream open reading frames might provide a mechanism that enables the cannabinoid 1 receptor to escape the general repression of protein synthesis that is typical for conditions of cellular stress.

Neuronal nicotinic acetylcholine receptors: from the genetic analysis to neurological diseases.

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated channels that mediate, in the peripheral nervous system, fast neurotransmission at the neuromuscular junction and in ganglia. Widely expressed in the central nervous system neuronal nAChRs are thought to contribute both to neurotransmission and modulation of neuronal activity. To date, eleven genes encoding for these receptors have been identified in the mammalian genome and their structure is well conserved throughout evolution. Progresses made in the field of genetics and the identification of a large number of small genetic variants such as single nucleotide polymorphisms raise new questions about the physiologic and pharmacologic consequences of such variations. The finding of associations between polymorphisms in the genes encoding for the neuronal nAChRs and neurological disorders such as schizophrenia and Alzheimer disease illustrate the importance of getting a better understanding of these receptors from the gene to function. In this work we present an overview over the progress that has been made in understanding the role of nAChR genes in monogenic disorders such as familial epilepsy, and review the latest knowledge about genetic variants of the nAChR genes and their relationship with common disorders and behavioural traits of complex etiology.

Compound heterozygosity for three common MEFV mutations in a highly consanguineous family with familial Mediterranean fever.

Consanguinity is not the only factor influencing the occurrence of autosomal recessive disorders such as familial Mediterranean fever (FMF). The extended, multiple consanguineous Turkish pedigree presented here demonstrates that the population frequency of certain mutations (so-called "ancient" mutations) can be at least equally important. In high-risk populations different combinations of mutations can occur within the same family, increasing not only the intrafamilial clinical variability, but also causing considerable recurrence risks even in marriages with unrelated spouses.

Benign familial neonatal convulsions: always benign?

BACKGROUND: Benign familial neonatal convulsions (BFNC) is a rare autosomal dominant seizure disorder usually described to be characterized by a benign course, spontaneous remission and normal psychomotor development. The latter statement had come under consideration when a few case reports of families with less than favorable outcomes were published. METHODS: Since 1998 a total of 112 families suspected to have BFNC have been referred to our lab for genetic testing. Within this sample we identified private KCNQ2 mutations in 17 BFNC families. For 10 of those 17 families follow up information about the psychomotor development and the outcome were available. RESULTS: In 4 (40%) of the 10 families at least 1 affected individual showed delayed psychomotor development or mental retardation. Three of the four mutations were familial, while the fourth mutation was de novo. Mutations associated with an unfavorable outcome tended to be located within the functionally critical S5/S6 regions of the KCNQ2 gene. CONCLUSIONS: Our data raise the question if BFNC can indeed be described as a benign disorder, and which are the genetic and/or environmental factors that influence the outcome.

LGI1: a gene involved in epileptogenesis and glioma progression?

The leucine-rich, glioma inactivated gene 1 (LGI1) gene on human chromosome 10q24 was first identified as a candidate tumor suppressor gene for glioma. Surprisingly, mutations in LGI1 were also shown to cause an idiopathic epilepsy syndrome, autosomal dominant lateral temporal lobe epilepsy (ADLTE). LGI1 is one of the only two currently known non-ion channel genes whose mutations cause idiopathic epilepsy in humans. In this review we summarize the current data on structure and function of the LGI1 protein and discuss clinical aspects of ADLTE and their correlation with LGI1. We also propose that the evidence supporting the tumor suppressor role of LGI1 in malignant gliomas is weak and that further work is necessary to establish LGI1 role in glial cells.

Congenital myasthenic syndrome of Brahman cattle in South Africa.

A congenital myasthenic syndrome in Brahman cattle is caused by a homozygous 20 base pair deletion (470del20) in the gene coding for the epsilon subunit of the acetylcholine receptor at the neuromuscular junction. It causes a progressive muscle weakness starting either at birth or within the first month. A PCR-based DNA test, using blood or semen stored on FTA paper, was developed and validated; the test makes it possible to differentiate rapidly and accurately between homozygous wild-type, heterozygous and homozygous affected animals. Preliminary testing of Brahman cattle in South Africa has revealed several carrier animals, some of them influential animals in the breeding population.

Cloning and mutation analysis of the human potassium channel KCNQ2 gene promoter.

Benign familial neonatal convulsions (BFNC) have been previously found to be associated with mutations within the coding region of KCNQ2. We have now cloned and analyzed the promoter region of the human KCNQ2 gene. 5'-RACE identified a transcription start site (TSS) located 200 bp upstream of the ATG start codon. The TSS is located close to a repetitive region containing seven copies of a degenerate 42-mer repeat. Several different luciferase (LUC) reporter plas- mids containing fragments from the KCNQ2 5'-flanking region were constructed and expressed in NT2N and SH-SY5Y cell lines. A core promoter region was found to be located between bp 20 and bp 74 upstream of the TSS. Neither the promoter region nor the repetitive region showed any mutations in 13 index patients from unrelated BFNC families.

Genes and mutations in idiopathic epilepsy.

Partial or generalized idiopathic epilepsies, which account for up to 40% of all epilepsies, are characterized by a mostly benign course and no apparent etiology other than a genetic predisposition. So far, the genetic defects underlying three different idiopathic epilepsy syndromes have been identified: mutations in the CHRNA4- or CHRNB subunits of the neuronal nicotinic acetylcholine receptor are found in familial nocturnal frontal lobe epilepsy, while defects in the voltage-gated potassium channels KCNQ2 and KCNQ3 have recently been identified in benign familial neonatal convulsions. The syndrome of "generalized epilepsy with febrile seizures plus" can be caused by mutations affecting the voltage-gated sodium channel subunits SCN1B and SCN1A or the gamma 2-subunit of the GABA(A) receptor. The results of recent molecular studies contributed largely to our understanding of the etiology and pathophysiology of idiopathic epilepsies.

Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel.

KCNQ2 and KCNQ3 are two homologous K(+) channel subunits that can combine to form heterotetrameric channels with properties of neuronal M channels. Loss-of-function mutations in either subunit can lead to benign familial neonatal convulsions (BFNC), a generalized, idiopathic epilepsy of the newborn. We now describe a syndrome in which BFNC is followed later in life by myokymia, involuntary contractions of skeletal muscles. All affected members of the myokymia/BFNC family carried a mutation (R207W) that neutralized a charged amino acid in the S4 voltage-sensor segment of KCNQ2. This substitution led to a shift of voltage-dependent activation of KCNQ2 and a dramatic slowing of activation upon depolarization. Myokymia is thought to result from hyperexcitability of the lower motoneuron, and indeed both KCNQ2 and KCNQ3 mRNAs were detected in the anterior horn of the spinal cord where the cells of the lower motoneurons arise. We propose that a difference in firing patterns between motoneurons and central neurons, combined with the drastically slowed voltage activation of the R207W mutant, explains why this particular KCNQ2 mutant causes myokymia in addition to BFNC.

Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy.

Genetic predisposition plays a major role in the etiology of idiopathic epilepsies. The common epilepsy syndromes display a complex pattern of inheritance, with an unknown number of genes contributing to seizure susceptibility. During the last decade linkage studies have narrowed down several candidate regions for susceptibility loci of idiopathic epilepsies. Several lines of evidence point to the existence of an epilepsy susceptibility gene on chromosome 15q14. Evidence for linkage to this region has thus been reported for juvenile myoclonic epilepsy, common subtypes of idiopathic generalized epilepsy (IGE), in addition to the EEG trait 'centrotemporal spikes' in families with rolandic epilepsy. The chromosomal region 15q14 harbours several candidate genes that are involved in the regulation of neuronal excitability. One of the most promising candidate genes is the brain-expressed potassium chloride cotransporter KCC3, given that this class of ion transporter has been implicated in the regulation of neuronal chloride activity. We therefore performed a mutation analysis of KCC3 in the index patients of 23 IGE-families as well as of 16 families with rolandic epilepsy which where selected by positive evidence for linkage to D15S165. Four novel single nucleotide exchanges (SNPs) were identified, none of which change the coding sequence. These results do not support a major role for KCC3 in the etiology of rolandic epilepsy or common subtypes of IGE.

Immature end-plates and utrophin deficiency in congenital myasthenic syndrome caused by epsilon-AChR subunit truncating mutations.

Congenital myasthenic syndromes (CMS) are inborn disorders due to presynaptic, synaptic, or postsynaptic defects of neuromuscular transmission. Some previously described kinships with typical signs of CMS showed a marked deficiency of acetylcholine receptors (AChR) and utrophin at the neuromuscular junctions. Additionally, the end-plate ultrastructure was immature, with reduced enfolding of the postsynaptic membrane. In two such families, we found truncating mutations of the epsilon-AChR subunit. In family 1, both affected siblings were heteroallelic for a epsilon911delT and a epsilonIVS4+1G-->A mutation within the AChR epsilon-subunit gene (CHRNE). In the affected member of family 2, a epsilon1030delC mutation and a previously described epsilonR64X mutation were found. These deleterious epsilonAChR mutations not only result in AChR deficiency, but also affect end-plate maturation, including the formation of secondary synaptic clefts during ontogenesis.

[Benign familial neonatal convulsions: molecular pathology and diagnosis]. / Benigne familiäre Neugeborenenkrämpfe. Molekulare Pathogenese und Diagnostik.

Benign familial neonatal convulsions are a rare monogenic form of idiopathic epilepsy characterized by the onset of frequent brief seizures after the second day of life. The seizures disappear spontaneously within a few weeks, but recurrent seizures later in life are common. Linkage studies located genes to chromosome 20q13.3 and 8q24, and the voltage-gated potassium channels KCNQ2 and KCNQ3 were recently identified. Since then, several mutations have been found leading to haplosufficiency of the ion channel. Functional studies showed that KCNQ2 and KCNQ3 are able to contribute to a heteromeric channel exhibiting kinetic and pharmacological properties similar to those of the native M current, the latter playing an important role in the regulation of neuronal excitability. This overview presents a summary of the molecular, genetic, and electrophysiological findings and discusses them with respect to their clinical relevance.

Severe congenital myasthenic syndrome due to homozygosity of the 1293insG epsilon-acetylcholine receptor subunit mutation.

Recently, a congenital myasthenic syndrome (CMS) with end-plate acetylcholine receptor (AChR) deficiency due to missense mutations in the genes for the AChR subunit was described. The first observed patient with this CMS was heteroallelic for the two epsilon-AChR subunit mutations epsilon1101insT and epsilon1293insG. This patient had only a moderate phenotype with mild muscle weakness and abnormal fatigue. We have now found homozygosity for the epsilon1293insG mutation in a severely affected CMS patient, who lost the ability to walk in midchildhood and shows profound weakness and muscle wasting. Our observation allows a genotype-phenotype correlation illustrating how differences in the AChR mutation haplotype can profoundly influence disease severity.

Expression of nicotinic acetylcholine receptors in Alzheimer's disease: postmortem investigations and experimental approaches.

Nicotinic ligand binding studies have shown rather early that the cholinoceptive system is affected in Alzheimer's disease (AD). Today, molecular histochemistry enables one to study the nicotinic acetylcholine receptor (nAChR) subunit expression on the cellular level in human autopsy brains, in animal models and in in vitro approaches, thus deciphering the distribution of nAChRs and their role as potential therapeutic targets. The studies on the nAChR expression in the frontal and temporal cortex of AD patients and age-matched controls could demonstrate that both, the numbers of alpha4- and alpha7-immunoreactive neurons and the quantitative amount, in particular of the alpha4 protein, were markedly decreased in AD. Because the number of the corresponding mRNA expressing neurons was unchanged these findings point to a translational/posttranslational rather than a transcriptional event as an underlying cause. This assumption is supported by direct mutation screening of the CHRNA4 gene which showed no functionally important mutations. To get more insight into the underlying mechanisms, two model systems organotypic culture and primary hippocampal culture - have been established, both allowing to mimic nAChR expression in vitro. In ongoing studies the possible impact of beta-amyloid (Abeta) on nAChR expression is tested. Preliminary results obtained from primary cultures point to an impaired nAChR expression following Abeta exposure.