The role of psychological stress in inflammatory bowel disease: quality assessment of methods of 18 prospective studies and suggestions for future research

BACKGROUND: Enquiries among patients on the one hand and experimental and observational studies on the other suggest an influence of stress on inflammatory bowel diseases (IBD). However, since this influence remains hypothetical, further research is essential. We aimed to devise recommendations for future investigations in IBD by means of scrutinizing previously applied methodology. METHODS: We critically reviewed prospective clinical studies on the effect of psychological stress on IBD. Eligible studies were searched by means of the PubMed electronic library and through checking the bibliographies of located sources. RESULTS: We identified 20 publications resulting from 18 different studies. Sample sizes ranged between 10 and 155 participants. Study designs in terms of patient assessment, control variables, and applied psychometric instruments varied substantially across studies. Methodological strengths and weaknesses were irregularly dispersed. Thirteen studies reported significant relationships between stress and adverse outcomes. CONCLUSIONS: Study designs, including accuracy of outcome assessment and repeated sampling of outcomes (i.e. symptoms, clinical, and endoscopic), depended upon conditions like sample size, participants' compliance, and available resources. Meeting additional criteria of sound methodology, like taking into account covariates of the disease and its course, is strongly recommended to possibly improve study designs in future IBD research.

Diseases in neonatal foals. Part 1: the 30 day incidence of disease and the effect of prophylactic antimicrobial drug treatment during the first three days post partum

REASONS FOR PERFORMING STUDY: Neonatal diseases have been grouped and analysed but up-to-date statistically significant information about the incidence and prevalence of diseases in foals is limited. Since the 1950s it has been a common management practice to administer a 3 day course of antimicrobial drugs to neonatal foals. This was shown to significantly reduce the incidence of infections (Platt 1977). Since then management practices have improved and it is widely believed that prophylactic antimicrobial drugs are no longer necessary in foal rearing. OBJECTIVES: To determine the 30 day incidences or prevalences (depending on case definition) of various diseases and conditions in the neonatal foal and ascertain the influence of a prophylactic 3 day treatment on the frequency of infections. METHODS: The population consisted of Thoroughbred foals born on stud farms in the Newmarket (UK) area in 2005 (n = 1031). Depending on the stud farm's practice in the use of prophylactic antimicrobial drugs, 2 groups of newborn foals (treated and untreated) were identified and followed for 30 days. RESULTS: The 30 day incidences of infectious diseases under study were between 0.2% (osteomyelitis) and 5.85% (systemic disease with diarrhoea). The overall incidence for 'total infectious diseases' was 8.27%. The most commonly observed noninfectious condition was limb deformities (12.11% of all foals). There was no significant difference in the incidence of infectious diseases between the 2 groups. CONCLUSION: Infectious diseases are still an important problem in neonatal foals requiring further investigation as to which factors other than antimicrobial prophylaxis are relevant for disease prevention. POTENTIAL RELEVANCE: The results provide an up-to-date overview about the frequencies of various neonatal foal diseases. They do not support the traditional prophylactic use of antimicrobials to prevent infectious diseases in healthy newborn foals. However, it should be noted that this study was not a randomised controlled trial and therefore does not provide the strongest possible evidence for this conclusion.

Proliferative kidney disease in rainbow trout: time- and temperature-related renal pathology and parasite distribution

Proliferative kidney disease is a parasitic infection of salmonid fishes caused by Tetracapsuloides bryosalmonae. The main target organ of the parasite in the fish is the kidney. To investigate the influence of water temperature on the disease in fish, rainbow trout Oncorhynchus mykiss infected with T bryosalmonae were kept at 12 degrees C and 18 degrees C. The number of parasites, the type and degree of lesions in the kidney and the mortality rate was evaluated from infection until full development of disease. While mortality stayed low at 12 degrees C, it reached 77% at 18 degrees C. At 12 degrees C, pathological lesions were dominated by a multifocal proliferative and granulomatous interstitial nephritis. This was accompanied by low numbers of T. bryosalmonae, mainly located in the interstitial lesions. With progression of the disease, small numbers of parasites appeared in the excretory tubuli, and parasite DNA was detected in the urine. Parasite degeneration in the interstitium was observed at late stages of the disease. At 18 degrees C, pathological lesions in kidneys were more severe and more widely distributed, and accompanied by significantly higher parasite numbers. Distribution of parasites in the renal compartments, onset of parasite degeneration and time course of appearance of parasite DNA in urine were not clearly different from the 12 degrees C group. These findings indicate that higher mortality at 18 degrees C compared to 12 degrees C is associated with an enhanced severity of renal pathology and increased parasite numbers.

[Livestock owners with specifically increased disease awareness for Bluetongue: A new approach to disease surveillance]

For the first time in Switzerland, specifically trained livestock owners were included in a national disease surveillance program by the Federal Veterinary Office. A questionnaire on data about clinical and epidemiological aspects of Bluetongue Disease (BT) as well as on herd management was completed by 26 sheep owners three months after they had attended a training course about BT. The control group, consisted of 264 randomly selected sheep and cattle owners who had not visited a training course. Results showed that disease awareness for BT after attending the training course was considerably increased. This was especially evident in the better knowledge of the participants about the great number of possible symptoms. Training courses with the objective of increased disease awareness of livestock owners are an efficient, cost-effective instrument in control programs for exotic diseases.

Little-known Swiss contributions to the description, diagnosis, and surgery of lumbar disc disease before the Mixter and Barr era

The understanding of lumbar spine pathologies made substantial progress at the turn of the twentieth century. The authors review the original publication of Otto Veraguth in 1929 reporting on the successful resection of a herniated lumbar disc, published exclusively in the German language. His early report is put into the historical context, and its impact on the understanding of pathologies of the intervertebral disc (IVD) is estimated. The Swiss surgeon and Nobel Prize laureate Emil Theodor Kocher was among the first physicians to describe the traumatic rupture of the IVD in 1896. As early as 1909 Oppenheim and Krause published 2 case reports on surgery for a herniated lumbar disc. Goldthwait was the first physician to delineate the etiopathogenes is between annulus rupture, symptoms of sciatica, and neurological signs in his publication of 1911. Further publications by Middleton and Teacher in 1911 and Schmorl in 1929 added to the understanding of lumbar spinal pathologies. In 1929, the Swiss neurologist Veraguth (surgery performed by Hans Brun) and the American neurosurgeon Walter Edward Dandy both published their early experiences with the surgical therapy of a herniated lumbar disc. Veraguth's contribution, however, has not been appreciated internationally to date. The causal relationship between lumbar disc pathology and sciatica remained uncertain for some years to come. The causal relationship was not confirmed until Mixter and Barr's landmark paper in 1934 describing the association of sciatica and lumbar disc herniation, after which the surgical treatment became increasingly popular. Veraguth was among the first physicians to report on the clinical course of a patient with successful resection of a herniated lumbar disc. His observations should be acknowledged in view of the limited experience and literature on this ailment at that time.

High altitude journeys and flights are associated with an increased risk of flares in inflammatory bowel disease patients

BACKGROUND AND AIMS Hypoxia can induce inflammation in the gastrointestinal tract. However, the impact of hypoxia on the course of inflammatory bowel disease (IBD) is poorly understood. We aimed to evaluate whether flights and/or journeys to regions lying at an altitude of >2000m above the sea level are associated with flare-ups within 4weeks of the trip. METHODS IBD patients with at least one flare-up during a 12-month observation period were compared to a group of patients in remission. Both groups completed a questionnaire. RESULTS A total of 103 IBD patients were included (43 with Crohn's disease (CD): mean age 39.3±14.6years; 60 with ulcerative colitis (UC): mean age 40.4±15.1years). Fifty-two patients with flare-ups were matched to 51 patients in remission. IBD patients experiencing flare-ups had more frequently undertaken flights and/or journeys to regions >2000m above sea level within four weeks of the flare-up when compared to patients in remission (21/52 [40.4%] vs. 8/51 [15.7%], p=0.005). CONCLUSIONS Journeys to high altitude regions and/or flights are a risk factor for IBD flare-ups occurring within 4weeks of travel.

Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial

IMPORTANCE International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown. OBJECTIVE To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids. DESIGN, SETTING, AND PATIENTS REDUCE: (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011. INTERVENTIONS Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%. MAIN OUTCOME AND MEASURE Time to next exacerbation within 180 days. RESULTS Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently. CONCLUSIONS AND RELEVANCE In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN19646069.

Differential effect of p47phox and gp91phox deficiency on the course of Pneumococcal Meningitis.

Bacterial meningitis is a severe inflammatory disease of the central nervous system and is characterized by massive infiltration of granulocytes into the cerebrospinal fluid (CSF). To assess the role of NADPH oxidase-derived reactive oxygen species (ROS) in pneumococcal meningitis, mice deficient in either the gp91 subunit (essential for functioning of the phagocyte enzyme) or the p47 subunit (essential for functioning of homologous enzymes in nonphagocytic cells) were intracisternally infected with live Streptococcus pneumoniae, and defined disease parameters were measured during the acute stage of infection. While none of the parameters measured (including CSF bacterial titers) were significantly different in gp91(-/-) and wild-type mice, the infection in p47(-/-) mice was associated with significantly increased inflammation of the subarachnoid and ventricular space, disruption of the blood-brain barrier, and the presence of interleukin-1 beta, tumor necrosis factor alpha, and matrix metalloproteinase 9 in the cortex. These changes were associated with approximately 10-fold-higher CSF bacterial titers in p47(-/-) mice than in wild-type mice (P < 0.001). In contrast to infection with live bacteria, the inflammatory response, including CSF leukocytosis, was significantly attenuated in p47(-/-) mice (but not gp91(-/-) mice) challenged with a fixed number of heat-inactivated pneumococci. Impairment of the host defense appeared to be responsible for the higher bacterial titers in p47(-/-) mice. Therefore, these results indicate that ROS generated by a gp91-independent NADPH oxidase(s) are important for establishing an adequate inflammatory response to pneumococcal CSF infection.

Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn's disease

BACKGROUND: Influence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn's disease (CD). METHODS: 85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD). RESULTS: Chronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213). CONCLUSIONS: These data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants.

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the "REGISTRY" cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.

Event-relating to potential dementia. Semantic processing in the course of healthy and pathological aging

While most healthy elderly are able to manage their everyday activities, studies showed that there are both stable and declining abilities during healthy aging. For example, there is evidence that semantic memory processes which involve controlled retrieval mechanism decrease, whereas the automatic functioning of the semantic network remains intact. In contrast, patients with Alzheimer’s disease (AD) suffer from episodic and semantic memory impairments aggravating their daily functioning. In AD, severe episodic as well as semantic memory deficits are observable. While the hallmark symptom of episodic memory decline in AD is well investigated, the underlying mechanisms of semantic memory deterioration remain unclear. By disentangling the semantic memory impairments in AD, the present thesis aimed to improve early diagnosis and to find a biomarker for dementia. To this end, a study on healthy aging and a study with dementia patients were conducted investigating automatic and controlled semantic word retrieval. Besides the inclusion of AD patients, a group of participants diagnosed with semantic dementia (SD) – showing isolated semantic memory loss – was assessed. Automatic and controlled semantic word retrieval was measured with standard neuropsychological tests and by means of event-related potentials (ERP) recorded during the performance of a semantic priming (SP) paradigm. Special focus was directed to the N400 or N400-LPC (late positive component) complex, an ERP that is sensitive to the semantic word retrieval. In both studies, data driven topographical analyses were applied. Furthermore, in the patient study, the combination of the individual baseline cerebral blood flow (CBF) with the N400 topography of each participant was employed in order to relate altered functional electrophysiology to the pathophysiology of dementia. Results of the aging study revealed that the automatic semantic word retrieval remains stable during healthy aging, the N400-LPC complex showed a comparable topography in contrast to the young participants. Both patient groups showed automatic SP to some extent, but strikingly the ERP topographies were altered compared to healthy controls. Most importantly, the N400 was identified as a putative marker for dementia. In particular, the degree of the topographical N400 similarity was demonstrated to separate healthy elderly from demented patients. Furthermore, the marker was significantly related to baseline CBF reduction in brain areas relevant for semantic word retrieval. Summing up, the first major finding of the present thesis was that all groups showed semantic priming, but that the N400 topography differed significantly between healthy and demented elderly. The second major contribution was the identification of the N400 similarity as a putative marker for dementia. To conclude, the present thesis added evidence of preserved automatic processing during healthy aging. Moreover, a possible marker which might contribute to an improved diagnosis and lead consequently to a more effective treatment of dementia was presented and has to be further developed.

Altered Electrophysiology of Semantic Word Processing in Alzheimer's Disease and Semantic Dementia

With the progressing course of Alzheimer's disease (AD), deficits in declarative memory increasingly restrict the patients' daily activities. Besides the more apparent episodic (biographical) memory impairments, the semantic (factual) memory is also affected by this neurodegenerative disorder. The episodic pathology is well explored; instead the underlying neurophysiological mechanisms of the semantic deficits remain unclear. For a profound understanding of semantic memory processes in general and in AD patients, the present study compares AD patients with healthy controls and Semantic Dementia (SD) patients, a dementia subgroup that shows isolated semantic memory impairments. We investigate the semantic memory retrieval during the recording of an electroencephalogram, while subjects perform a semantic priming task. Precisely, the task demands lexical (word/nonword) decisions on sequentially presented word pairs, consisting of semantically related or unrelated prime-target combinations. Our analysis focuses on group-dependent differences in the amplitude and topography of the event related potentials (ERP) evoked by related vs. unrelated target words. AD patients are expected to differ from healthy controls in semantic retrieval functions. The semantic storage system itself, however, is thought to remain preserved in AD, while SD patients presumably suffer from the actual loss of semantic representations.

Effectiveness of integrated cognitive remediartion therapy for schizophrenia outpatients: Early versus long-term course of illness – results from an international RCT

Background Nowadays there is extensive evidence available showing the efficacy of cognitive remediation therapies. Integrative approaches seem superior regarding the maintenance of proximal outcome at follow-up as well as generalization to other areas of functioning. To date, only limited evidence about the efficacy of CRT is available concerning elder schizophrenia patients. The Integrated Neurocognitive Therapy (INT) represents a new developed cognitive remediation approach. It is a manualized group therapy approach targeting all 11 NIMH-MATRICS dimensions within one therapy concept. In this study we compared the effects of INT on an early course group (duration of disease<5 years) to a long-term group of schizophrenia outpatients (duration of disease>15 years). Methods An international multicenter study carried out in Germany, Switzerland and Austria with a total of 90 outpatients diagnosed with Schizophrenia (DSM-IV-TR) were randomly assigned either to an INT-Therapy or to Treatment-As-Usual (TAU). 50 of the 90 Patients were an Early-Course (EC) group, suffering from schizophrenia for less than 5 years (Mean age=29 years, Mean duration of illness=3.3 years). The other 40 were a Long-term Course (LC) group, suffering from schizophrenia longer than 15 years (Mean age= 45 years, Mean duration of illness=22 years). Treatment comprised of 15 biweekly sessions. An extensive assessment battery was conducted before and after treatment and at follow up (1 year). Multivariate General Linear Models (GLM) (duration of illness x treatment x time) examined our hypothesis, if an EC group of schizophrenia outpatients differ in proximal and distal outcome from a LC group. Results Irrespective of the duration of illness, both groups (EC & LC) were able to benefit from the INT. INT was superior compared to TAU in most of the assessed domains. Dropout rate of EC group was much higher (21.4%) than LC group (8%) during therapy phase. However, interaction effects show that the LC group revealed significantly higher effects in the neurocognitive domains of speed of processing (F>3.6) and vigilance (F>2.4). In social cognition the EC group showed significantly higher effects in social schema (F>2.5) and social attribution (blame; F>6.0) compared to the LC group. Regarding more distal outcome, patients treated with INT obtained reduced general symptoms unaffected by the duration of illness during therapy phase and at follow-up (F>4.3). Discussion Results suggest that INT is a valid goal-oriented treatment to improve cognitive functions in schizophrenia outpatients. Irrespective of the duration of illness significant treatment, effects were evident. Against common expectations, long-term, more chronic patients showed higher effects in basal cognitive functions compared to younger patients and patients without any active therapy (TAU). Consequently, more integrated therapy offers are also recommended for long-term course schizophrenia patients.

Cessation and resuming of alglucosidase alfa in Pompe disease: a retrospective analysis.

Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) in late-onset Pompe disease is moderately effective. Little is known about the clinical course after treatment termination and the resumption of ERT. In Switzerland, rhGAA therapy for Pompe disease was temporarily withdrawn after the federal court judged that the treatment costs were greatly out of proportion compared to the benefits. Re-treatment was initiated after the therapy was finally licensed. We retrospectively analysed seven Pompe patients, who underwent cessation and resumption of ERT (median age 43 years). The delay from first symptoms to final diagnosis ranged from 4 to 20 years. The demographics, clinical characteristics, assessments with the 6-min walking test (6-MWT), the predicted forced vital capacity (FVC) and muscle strength were analysed. Before initiation of ERT, all patients suffered from proximal muscle weakness of the lower limbs; one was wheelchair-bound and two patients received night-time non-invasive ventilation. Initial treatment stabilised respiratory function in most patients and improved their walking performance. After treatment cessation, upright FVC declined in most and the 6-MWT declined in all patients. Two patients needed additional non-invasive ventilatory support. Twelve months after resuming ERT, the respiratory and walking capacity improved again in most patients. However, aside for one patient, none of the patients reached the same level of respiratory function or distance walked in 6 min, as at the time of ERT withdrawal. We conclude that cessation of ERT in Pompe disease causes a decline in clinical function and should be avoided. Resuming treatment only partially recovers respiratory function and walking capacity.

Natural course of pontocerebellar hypoplasia type 2A

INTRODUCTION Pontocerebellar hypoplasia Type 2 (PCH2) is a rare autosomal recessive condition, defined on MRI by a small cerebellum and ventral pons. Clinical features are severe developmental delay, microcephaly and dyskinesia.Ninety percent carry a p.A307S mutation in the TSEN54-gene. Our aim was to describe the natural course including neurological and developmental features and other aspects of care in a homogeneous group of PCH2 patients all carrying the p.A307S mutation. PATIENTS AND METHODS Patients were recruited via the German patients' organizations. Inclusion criteria were imaging findings of PCH2 and a p.A307S mutation. Data were collected using medical reports and patient questionnaires discussed in a standardized telephone interview. RESULTS Thirty-three patients were included. When considering survival until age 11 years, 53% of children had died Weight, length and head circumference, mostly in the normal range at birth, became abnormal, especially head circumference (-5.58 SD at age 5 yrs). Neurologic symptoms: Choreathetosis was present in 88% (62% with pyramidal signs), 12% had pure spasticity. Epileptic seizures were manifest in 82%, status epilepticus in 39%. Non-epileptic dystonic attacks occurred in 33%. General symptoms: feeding difficulties were recorded in 100%, sleep disorder in 96%, apneas in 67% and recurrent infections in 52%; gastroesophageal reflux disease was diagnosed in 73%, 67% got percutaneous endoscopic gastrostomy and 36% a Nissen-fundoplication. Neurodevelopmental data: All children made progress, but on a low level: such as fixing and following with the eyes was seen in 76%, attempting to grasp objects (76%), moderate head control (73%), social smile (70%), rolling from prone to supine (58%), and sitting without support (9%). Ten percent lost achieved abilities on follow-up. The presence of prenatal symptoms did not correlate with outcome. CONCLUSION Phenotype of this genetically homogeneous group of PCH2 children was severe with reduced survival, but compatible with some developmental progress. Our data support the hypothesis of an early onset degeneration which thereafter stabilizes.