No abstract

Individuals with permanent neonatal diabetes mellitus usually present within the first three months of life and require insulin treatment. We recently identified a locus on chromosome 10p13-p12.1 involved in permanent neonatal diabetes mellitus associated with pancreatic and cerebellar agenesis in a genome-wide linkage search of a consanguineous Pakistani family. Here we report the further linkage analysis of this family and a second family of Northern European descent segregating an identical phenotype. Positional cloning identified the mutations 705insG and C886T in the gene PTF1A, encoding pancreas transcription factor 1alpha, as disease-causing sequence changes. Both mutations cause truncation of the expressed PTF1A protein C-terminal to the basic-helix-loop-helix domain. Reporter-gene studies using a minimal PTF1A deletion mutant indicate that the deleted region defines a new domain that is crucial for the function of this protein. PTF1A is known to have a role in mammalian pancreatic development, and the clinical phenotype of the affected individuals implicated the protein as a key regulator of cerebellar neurogenesis. The essential role of PTF1A in normal cerebellar development was confirmed by detailed neuropathological analysis of Ptf1a(-/-) mice.

It has been previously reported that a substantial proportion of newly referred neurology out-patients have symptoms that are considered by the assessing neurologist as unexplained by 'organic disease'. There has however been much controversy about how often such patients subsequently develop a disease diagnosis that, with hindsight, would have explained the symptoms. We aimed to determine in a large sample of new neurology out-patients: (i) what proportion are assessed as having symptoms unexplained by disease and the diagnoses given to them; and (ii) how often a neurological disorder emerged which, with hindsight, explained the original symptoms. We carried out a prospective cohort study of patients referred from primary care to National Health Service neurology clinics in Scotland, UK. Measures were: (i) the proportion of patients with symptoms rated by the assessing neurologist as 'not at all' or only 'somewhat explained' by 'organic disease' and the neurological diagnoses recorded at initial assessment; and (ii) the frequency of unexpected new diagnoses made over the following 18 months (according to the primary-care physician). One thousand four hundred and forty-four patients (30% of all new patients) were rated as having symptoms 'not at all' or only 'somewhat explained' by 'organic disease'. The most common categories of diagnosis were: (i) organic neurological disease but with symptoms unexplained by it (26%); (ii) headache disorders (26%); and (iii) conversion symptoms (motor, sensory or non-epileptic attacks) (18%). At follow-up only 4 out of 1030 patients (0.4%) had acquired an organic disease diagnosis that was unexpected at initial assessment and plausibly the cause of the patients' original symptoms. Eight patients had died at follow-up; five of whom had initial diagnoses of non-epileptic attacks. Seven other types of diagnostic change with very different implications to a 'missed diagnosis' were found and a new classification of diagnostic revision is presented. One-third of new neurology out-patients are assessed as having symptoms 'unexplained by organic disease'. A new diagnosis, which with hindsight explained the original symptoms, rarely became apparent to the patient's primary care doctor in the 18 months following the initial hospital consultation.

Objectives To determine the disability, distress and employment status of new neurology outpatients with physical symptoms unexplained by organic disease and to compare them with patients with symptoms explained by organic disease. Methods As part of a cohort study (the Scottish Neurological Symptoms Study) neurologists rated the extent to which each new patient's symptoms were explained by organic disease. Patients whose symptoms were rated as 'not at all' or only 'somewhat' explained by disease were considered cases, and those whose symptoms were 'largely' or 'completely' explained by disease were considered controls. All patients completed self-ratings of disability, health status (Medical Outcomes Study Short Form 12-Item Scale (SF-12)) and emotional distress (Hospital Anxiety and Depression Scale) and also reported their employment and state financial benefit status. Results 3781 patients were recruited: 1144 (30%) cases and 2637 (70%) controls. Cases had worse physical health status (SF-12 score 42 vs 44; difference in means 1.7 (95% CI e2.5 to 0.9)) and worse mental health status (SF-12 score 43 vs 47; difference in means e3.5 (95% CI e4.3 to to 2.7)). Unemployment was similar in cases and controls (50% vs 50%) but cases were more likely not to be working for health reasons (54% vs 37% of the 50% not working; OR 2.0 (95% CI 1.6 to 2.4)) and also more likely to be receiving disabilityrelated state financial benefits (27% vs 22%; (OR 1.3, 95% CI 1.1 to 1.6)). Conclusions New neurology patients with symptoms unexplained by organic disease have more disability-, distress-and disability-related state financial benefits than patients with symptoms explained by disease.

Many patients with a diagnosis of neurological disease, such as multiple sclerosis, have symptoms or disability that is considered to be in excess of what would be expected from that disease. We aimed to describe the overall and relative frequency of symptoms 'unexplained by organic disease' in patients attending general neurology clinics with a range of neurological disease diagnoses. Newly referred outpatients attending neurology clinics in all the NHS neurological centres in Scotland, UK were recruited over a period of 15 months. The assessing neurologists recorded their initial neurological diagnoses and also the degree to which they considered the patient's symptoms to be explained by organic disease. Patients completed self report scales for both physical and psychological symptoms. The frequency of symptoms unexplained by organic disease was determined for each category of neurological disease diagnoses. 3,781 patients participated (91% of those eligible). 2,467 patients had a diagnosis of a neurological disease (excluding headache disorders). 293 patients (12%) of these patients were rated as having symptoms only "somewhat" or "not at all" explained by that disease. These patients self-reported more physical and more psychological symptoms than those with more explained symptoms. No category of neurological disease was more likely than the others to be associated with such symptoms although patients with epilepsy had fewer. A substantial proportion of new outpatients with diagnoses of neurological disease also have symptoms regarded by the assessing neurologist as being unexplained by that disease; no single neurological disease category was more likely than others to be associated with this phenomenon.