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Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant recurrent neuropathy affecting the brachial plexus. HNA is triggered by environmental factors such as infection or parturition. We report three mutations in the gene septin 9 (SEPT9) in six families with HNA linked to chromosome 17q25. HNA is the first monogenetic disease caused by mutations in a gene of the septin family. Septins are implicated in formation of the cytoskeleton, cell division and tumorigenesis.

Orthostatic hypotension is very common in the elderly. It increases morbidity and is an independant predictor of all cause mortality. It is defined as a fall in systolic blood pressure greater than 20 mm Hg or a fall in diastolic blood pressure greater than 10 mm Hg within 3 minutes of standing. Symptoms include light headedness, weakness, blurred vision, fatigue and lethargy and falls. Most patients have orthostatic hypotension due to non neurogenic causes. Drugs like antihypertensives and tricyclic antidepressants are very common causes of orthostatic hypotension. Diagnosis is based on the history and a thorough clinical examination. Based on the history and physical examination, further testing of the heart, kidneys and autonomic nervous system may be required in selected patients. Non pharmacological methods like slow position change, increased fluid and sodium intake, compression stockings and elevation of head of the bed are the key to management of orthostatic hypotension. After these methods, pharmacological treatment with fludrocortisone and midodrine should be tried. Other drugs like desmopresin acetate, xamoterol, erythropoetin and ocreotide can be used as second line agents in selected patients.

Several retinal dystrophies, including retinitis pigmentosa type 12 and Leber congenital amaurosis, are caused by a large variety of mutations in the CRB1 (Crumbs homologue 1) gene. This discovery led to an increased focus on the function of CRB1 and the Drosophila homologue Crumbs. In the present study, we review the current knowledge on Crumbs and its vertebrate homologues, their function in cell polarity and their pathogenicity in retinal degeneration.

Loss of Crumbs homologue 1 (CRB1) function causes either the eye disease Leber congenital amaurosis or progressive retinitis pigmentosa, depending on the amount of residual CRB1 activity and the genetic background. Crb1 localizes specifically to the sub-apical region adjacent to the adherens junction complex at the outer limiting membrane in the retina. We show that it is associated here with multiple PDZ protein 1 (Mupp1), protein associated with Lin-7 (Pals1 or Mpp5) and Mpp4. We have produced Crb1(-/-) mice completely lacking any functional Crb1. Although the retinas are initially normal, by 3-9 months the Crb1(-/-) retinas develop localized lesions where the integrity of the outer limiting membrane is lost and giant half rosettes are formed. After delamination of the photoreceptor layer, neuronal cell death occurs in the inner and outer nuclear layers of the retina. On moderate exposure to light for 3 days at 3 months of age, the number of severe focal retinal lesions significantly increases in the Crb1(-/-) retina. Crb2, Crb3 and Crb1 interacting proteins remain localized to the sub-apical region and therefore are not sufficient to maintain cell adhesion during light exposure in Crb1(-/-) retinas. Thus we propose that during light exposure Crb1 is essential to maintain, but not assemble, adherens junctions between photoreceptors and Müller glia cells and prevents retinal disorganization and dystrophy. Hence, light may be an influential factor in the development of the corresponding human diseases.

The authors compared evaluations by parents and teachers of the communicative abilities of deaf children. Such comparisons between parents' and professionals' assessments of the language development of children who are deaf can provide useful information on which to base ecologically valid intervention approaches. A secondary interest of the authors was to investigate the possible influences on language development of gender, the presence or absence of cochlear implantation, and communication modality (i.e., auditory-verbal or bilingual). The study included the mothers and teachers of 14 deaf children educated in auditory-verbal or bilingual programs. Two scales from a survey instrument, Profiles of the Hearing Impaired (Webster & Webster, 1995), were used. No significant differences between the teachers' and parents' evaluations were found. Gender, cochlear implantation, and communication modality were found to have no significant effect on the evaluations.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant inherited demyelinating neuropathy typically characterized by recurrent episodes of acute painless peripheral nerve palsies often preceded by minor trauma or compression at entrapment sites. However, less classical phenotypes have been reported. A 1.5 Mb deletion in chromosome 17 p11.2 has been shown to be the genetic basis of the disease in the majority of HNPP patients. The few families without this deletion harbored a mutation in the PMP22 gene. We performed a clinical, neurophysiological and molecular genetic study of 6 Spanish HNPP families. Five families (22 individuals) showed the classical chromosome 17 p11.2 deletion and one family (3 individuals) had a novel 3'splice-site mutation in PMP22. Neurophysiological abnormalities were detected in all symptomatic (n=21) and asymptomatic (n=4) deletion or mutation carriers, even in childhood. In addition to the typical presentation we observed other phenotypes: recurrent focal short-term sensory symptoms, a progressive mononeuropathy, a Charcot-Marie-Tooth (CMT) disease-like chronic progressive polyneuropathy, a chronic sensory polyneuropathy and a chronic inflammatory demyelinating polyneuropathy. We report new or very rare phenotypesThese atypical clinical aspects and intrafamilial heterogeneity are present in families with the HNPP deletion as well as in the family with the PMP22 mutation. However, the CMT disease-like chronic polyneuropathy was more common in the PMP22 mutation family. Intrafamilial heterogeneity also seemed to be more pronounced in this kinship. Patients in this family had a mild chronic motor and sensory polyneuropathy neurophysiologically characterized by delayed distal latencies, reduced nerve conduction velocities (NCV) within the demyelinating range, mildly decreased amplitudes of motor and sensory evoked potentials and absence of conduction blocks. In contrast, patients with the common HNPP deletion, regardless of their phenotype, had a diffuse increase in distal motor latencies contrasting with moderately reduced motor NCVs, preserved sensory nerve action potentials, slowing of NCVs at the common entrapment sites and occasionally conduction blocks. In this study we confirm the clinical and molecular heterogeneity of HNPP, emphasizing the need for a mutation analysis of the PMP22 gene when the common 17p11.2 deletion is not found in clinically suspected HNPP patients. We conclude that the 3'splice-site mutation in PMP22 and the common HNPP deletion have largely the same functional consequences although some clinical and neurophysiological differences were observed.

Distal hereditary motor neuropathies (distal HMNs) are characterised by degeneration of anterior horn cells of the spinal cord resulting in muscle weakness and atrophy. Distal HMN type II is genetically linked to chromosome 12q24.3 and located within a 13 cM region flanked by markers D12S86 and D12S340. We previously excluded the human phospholipase A2 group 1B gene (PLA2G1B) as the disease causing gene. Here, we report the mutation analysis of five other candidate genes localised within the distal HMN II region: the cytoskeletal proteins paxillin (PXN) and restin (RSN); the acidic ribosomal phosphoprotein, large P0 subunit (RPLP0); a nucleoside diphosphate kinase (NME2B); and the beta 3 subunit of the voltage-gated calcium channel (CACNB3). DNA sequencing of the coding regions was performed but no disease causing mutations could be identified, hence excluding these five genes for distal HMN type II.

Hereditary Neuralgic Amyotrophy (HNA) is an autosomal dominantly inherited recurrent focal neuropathy affecting mainly the brachial plexus. Linkage to markers on chromosome 17q25 was found in 1996 and subsequent reports confirmed linkage of HNA to this locus. Recently a family with a chronic undulating rather than remitting-relapsing clinical course of HNA was described by a Dutch group. This family did not have linkage to the 17q25 locus. Here we describe for the first time clinically and genetically two families with classic remitting-relapsing HNA that are not linked to the previously described HNA locus on chromosome 17q25. These results demonstrate that clinically homogeneous classical HNA is genetically heterogeneous.

Contactin associated protein 1 (Caspr1/Paranodin/Neurexin IV) is an axonal transmembrane molecule mainly localised at the paranodal junction. Since molecular alterations in septate-like junctions at the paranodes might have important consequences for the function of the nerve fiber, we considered that Caspr1 could be involved in the pathogenesis of inherited peripheral neuropathies. In this study, we physically mapped the Caspr1 gene on chromosome 17q21.1 and determined its genomic structure. We performed a mutation analysis of the Caspr1 gene in a cohort of 64 unrelated patients afflicted with distinct inherited peripheral neuropathies. Since no disease causing mutations were found, we suggest that Caspr1 is probably not a common cause of inherited peripheral neuropathies.

Hereditary neuralgic amyotrophy (HNA) belongs to the group of recurrent focal neuropathies, the other major representative being hereditary neuropathy with liability to pressure palsies. The search for the HNA gene has now focused on a locus on chromosome 17q24-q25. Most HNA families show linkage to this locus, but recent evidence indicates that HNA is genetically heterogeneous. Detailed analysis of these unlinked families has broadened our perception of the HNA phenotype, and currently two different clinical courses can be discerned: the classical relapsing-remitting course and a chronic undulating course. After 5 years of molecular genetic research, this disease remains enigmatic. At present, we can only speculate how such very diverse stimuli as immunizations, childbirth, infections, strenuous exercise, and immobilization can trigger painful attacks of brachial plexus palsies in genetically susceptible individuals.

Hereditary neuralgic amyotrophy (HNA) is a rare autosomal dominant disorder. It is characterised by recurrent episodes of focal neuropathy involving the brachial plexus. Genetic linkage analysis has mapped HNA to chromosome 17q25 within a 3.5-cM interval flanked by the short tandem repeat markers D17S785 and D17S802. Here, we report the mutation analysis of four candidate genes. Mutation analysis was performed on the complete coding regions of these genes. Several exonic and intronic single nucleotide polymorphisms were detected. However, no disease-causing mutations were found, indicating that these genes are most probably not involved in the pathogenesis of HNA. In addition, we have characterised and localised a putative pseudogene of the SEC14-like 1 gene.

Charcot-Marie-Tooth disease, the most common variant of the inherited peripheral neuropathies, has a prevalence of 1/2500. Clinical, electrophysiological, neuropathological and molecular genetic studies have demonstrated extensive heterogeneity. Currently, 30 genetic loci are known for distinct CMT types and related inherited peripheral neuropathies, while many other types have been excluded for linkage to these loci. Recent molecular genetic studies have demonstrated the involvement of 8 genes that encode proteins with very diverse functions. These include a structural protein confined to the compact myelin, a cytoskeletal protein, an adhesion molecule, a gap-junction protein, a transcription factor, a receptor for a neurotrophic factor, a phosphatase and a protein involved in signal transduction and cell cycle regulation.

Hereditary neuralgic amyotrophy (HNA) and hereditary neuropathy with liability to pressure palsies (HNPP) are hereditary focal neuropathies. In this study we describe three families suffering from HNA. These families were examined clinically and electrophysiologically. Linkage analysis with markers from distal chromosome 17 was performed in a three-generation family. HNA could be separated from HNPP in all three families based on clinical and electrophysiological findings. HNA was characterised by recurrent episodes of painful brachial plexus lesions. In contrast to HNPP, no evidence for generalised neuropathy was found in the HNA families. Linkage analysis confirmed the HNA locus on distal chromosome 17. Additionally, we were able to refine the HNA locus to a 16 cM region on chromosome 17q24-q25.

The awareness of osteoporosis as a common problem with a large degree of associated morbidity has increased recently. In this article, three beliefs concerning osteoporosis are examined. These beliefs concern the usefulness of radiologic screening for osteoporosis, the prevalence of osteoporotic fractures, and the benefit of calcium supplementation. It is concluded that as a widely used screening test, radiologic examination does not greatly aid in the estimation of risk of future bone fracture; that fewer than one fourth of women will ever have a meaningful complication from excessive bone loss; and that, although low calcium intake is probably inadvisable, the present data do not allow us to recommend any certain level of calcium intake as being optimal.

This article describes our current understanding of the immunologic effects of glucocorticosteroids and uses this information in an attempt to place the therapeutic dosing of glucocorticosteroids on a more rational basis.

Osteoporosis causes significant morbidity and some mortality among the elderly. Although increasing bone content should reduce the rate of osteoporotic fracture, attention should also be paid to other factors (such as falling). Loss of bone mass is a universal phenomenon with aging, and currently we are not able to use risk factor analysis to accurately predict which people are likely to suffer osteoporotic fracture. Bone densitometry cannot be recommended as a useful screening test in elderly patients. When deciding about treatment of osteoporosis in the elderly, it should be noted that few studies have included patients over 75 years of age and that prevention of bone loss is more effective than restoration of lost bone. Although high-dose calcium appears ineffective, patients ingesting low amounts of calcium should be counselled to increase their daily intake to at least 800 mg. Estrogens are very effective at preserving bone mass at least up to age 70 years, and their use is associated with a reduction in hip fractures. Vitamin D at a dose of 600 to 800 IU per day should be given to elderly subjects who do not get significant exposure of their skin to sunlight. Other specific recommendations regarding the prevention and treatment of osteoporosis await the results of further investigation.

In patient's declared ineligible for longitudinal outpatient care in the Veterans Administration (VA) health care system, it is unclear how health status changes after discharge from the VA or how many patients find a regular provider of care in the private sector. Among 65 patients declared ineligible for longitudinal care at the Gainesville VA Medical Center (GVAMC), 28 (43%) continued to use this facility as their primary source of general medical care. Patients who lived within 50 miles of GVAMC or had used this facility frequently in the past were more likely to return to GVAMC for their general care. In the 37 patients who no longer used GVAMC for general care, 42% could not identify a regular provider of care outside GVAMC nine months after their discharge from this facility. Thirty-six percent had not seen a non-VA physician during this time, and 44% felt their health had worsened since they were released from GVAMC. A large number of patients who are declared ineligible for longitudinal care in the VA system continue to use the VA system for primary care. Among those who stop using the VA, many do not receive any medical care or obtain a regular care provider within the first nine months after their release from the VA system.