Clinical report and biochemical analysis of a patient with fumarate hydratase deficiency.

Fumarate hydratase deficiency (FHD) is a rare metabolic disease caused by two defective copies of the FH gene, which encodes the Krebs cycle enzyme fumarase. FHD is associated with brain and developmental abnormalities, seizures, and high childhood mortality. We describe the symptoms and treatment of a patient with FHD. While infantile spasms are common in FHD, the patient presented with epileptic spasms later in childhood. Also unexpectedly, the patient responded excellently to lacosamide for her non-convulsive status epilepticus and epileptic spasms after three first-line medication trials failed. We biochemically analyzed the patient's two fumarase variants (E432Kfs*17 and D65G). While E432Kfs*17 was extremely enzymatically defective, D65G exhibited only a mild defect, possibly playing a role in the patient's longer survival.

Individual and Combined Associations of Cognitive and Mobility Limitations on Mortality Risk in Older Adults.

OBJECTIVE: To evaluate the potential independent and combined associations of cognitive and mobility limitations on risk of all-cause mortality in a representative sample of the US older adult population who, at baseline, were free of cardiovascular and cerebrovascular disease. PATIENTS AND METHODS: Data from the 1999 to 2002 National Health and Nutrition Examination Survey were used to identify 1852 adults (age, 60-85 years) with and without mobility and/or cognitive limitations. Hazard ratios (HRs) for mortality risk were calculated for 4 mutually exclusive groups: no limitation (group 1 as reference), mobility limitation only (group 2), cognitive limitation only (group 3), both cognitive and mobility limitations (group 4). RESULTS: Compared with group 1, the adjusted HRs (95% CI) for groups 2, 3, and 4 were 1.72 (1.24-2.38), 2.00 (1.37-2.91), and 2.18 (1.57-3.02), respectively. The mortality risk when comparing group 4 (HR, 2.18) with group 3 (HR, 2.00), however, was not statistically significant (P=.65). Similarly, the mortality risk when comparing group 4 (HR, 2.18) with group 2 (HR, 1.72) was not statistically significant (P=.16). CONCLUSION: Although the highest mortality risk occurred in those with both limitations (group 4), this point estimate was not statistically significantly different when compared with those with cognitive or mobility limitations alone.

Perioperative risk factors for impaired neurodevelopment after cardiac surgery in early infancy.

OBJECTIVE: Historical cohort studies have reported adverse neurodevelopment following cardiac surgery during early infancy. Advances in surgical techniques and perioperative care have coincided with updating of neurodevelopmental assessment tools. We aimed to determine perioperative risk factors for impaired neurodevelopment at 2 years following surgery for congenital heart disease (CHD) in early infancy. DESIGN AND PATIENTS: We undertook a prospective longitudinal study of 153 full-term infants undergoing surgery for CHD before 2 months of age. Infants were excluded if they had a genetic syndrome associated with neurodevelopmental impairment. OUTCOME MEASURES: Predefined perioperative parameters were recorded and infants were classified according to cardiac anatomy. At 2 years, survivors were assessed using the Bayley Scales of Infant Development-III. RESULTS: At 2 years, 130 children (98% of survivors) were assessed. Mean cognitive, language and motor scores were 93.4±13.6, 93.6±16.1 and 96.8±12.5 respectively (100±15 norm). Twenty (13%) died and 12 (9%) survivors had severe impairment (score <70), mostly language (8%). The lowest scores were in infants born with single ventricle physiology with obstruction to the pulmonary circulation who required a neonatal systemic-to-pulmonary artery shunt. Additional risk factors for impairment included reduced gestational age, postoperative elevation of lactate or S100B and repeat cardiac surgery. CONCLUSIONS: In the modern era of infant cardiac surgery and perioperative care, children continue to demonstrate neurodevelopmental delays. The use of updated assessment tools has revealed early language dysfunction and relative sparing of motor function. Ongoing follow-up is critical in this high-risk population.

Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency.

IMPORTANCE: The impact of betaine treatment on outcome in patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency is presently unclear. OBJECTIVE: To investigate the effect of betaine treatment on development and survival in patients with severe MTHFR deficiency. DATA SOURCES: MEDLINE, EMBASE, and Cochrane databases between January 1960 and December 2012. STUDY SELECTION: Studies that described patients with severe MTHFR deficiency who received betaine treatment. DATA EXTRACTION AND SYNTHESIS: We identified 15 case reports and case series, totaling 36 patients. Data included the following: (1) families with 2 or more patients with severe MTHFR deficiency, of whom at least 1 received betaine, or (2) single patients with severe MTHFR deficiency treated with betaine. To define severe MTHFR deficiency, methionine, homocysteine, MTHFR enzyme activity in fibroblasts, or mutations (in the MTHFR gene) had to be described as well as the effect of treatment (survival and/or psychomotor development). We compared the outcome in treated vs untreated patients and early- vs late-treated patients. Sensitivity analysis was performed to address definition of early treatment. To further assess the impact of treatment on mortality, we performed a subanalysis in families with at least 1 untreated deceased patient. MAIN OUTCOMES AND MEASURES: Survival and psychomotor development. RESULTS: Eleven of 36 patients (31%) died. All deaths occurred in patients who did not receive treatment or in patients in whom treatment was delayed. In contrast, all 5 early-treated patients survived. Subgroup analysis of patients with deceased siblings-their genotypically identical controls-revealed that betaine treatment prevented mortality (P = .002). In addition, psychomotor development in surviving patients treated with betaine was normal in all 5 early-treated patients but in none of the 19 surviving patients with delayed treatment (P < .001). CONCLUSIONS AND RELEVANCE: Early betaine treatment prevents mortality and allows normal psychomotor development in patients with severe MTHFR deficiency, highlighting the importance of timely recognition through newborn screening.

Influence of gestational age on death and neurodevelopmental outcome in premature infants with severe intracranial hemorrhage.

OBJECTIVE: To determine whether death and/or neurodevelopmental impairment (NDI) after severe intracranial hemorrhage (ICH; grade 3 or 4) differs by gestational age (GA) at birth in extremely low birth weight (ELBW) infants. STUDY DESIGN: Demographic, perinatal and neonatal factors potentially contributing to NDI for ELBW infants (23 to 28 weeks gestation) were obtained retrospectively; outcome data came from the ELBW Follow-up Study. NDI was defined at 18 to 22 months corrected age as moderate/severe cerebral palsy, Bayley Scales of Infant Development II cognitive or motor score <70, and/or blindness or deafness. Characteristics of younger versus older infants with no versus severe ICH associated with death or NDI were compared. Generalized linear mixed models predicted death or NDI in each GA cohort. RESULT: Of the 6638 infants, 61.8% had no ICH and 13.6% had severe ICH; 39% of survivors had NDI. Risk-adjusted odds of death or NDI and death were higher in the lower GA group. Lower GA increased the odds of death before 30 days for infants with severe ICH. Necrotizing enterocolitis (particularly surgical NEC), late onset infection, cystic periventricular leukomalacia and post-natal steroids contributed to mortality risk. NDI differed by GA in infants without ICH and grade 3, but not grade 4 ICH. Contributors to NDI in infants with severe ICH included male gender, surgical NEC and post-hemorrhagic hydrocephalus requiring a shunt. CONCLUSION: GA contributes to the risk of death in ELBW infants, but not NDI among survivors with severe ICH. Male gender, surgical NEC and need for a shunt add additional risk for NDI.

[Risk assessment of pre-term infants]. / Risiken bei Zustand nach Frühgeburt. Grundlagen für die medizinische Risikoprüfung.

Pre-term birth occurs when a baby is born before 37 weeks of gestation are completed. Many recent publications on neurodevelopmental and somatic outcome parameters of premature infants are of interest for insurance medicine. Infants born before the 28th week are called extremely pre-term. When examined at five years, 85% had already received or still needed special treatment or support. The results of examinations in early childhood have quite a low predictive value for the further development of the child. In the very and moderately pre-term stages, long-term risks are continuously declining with the length of gravidity. Even "late pre-term" birth (34 to 36 weeks of gestation) is associated with a nearly doubled rate of developmental impairment and chronic disease in childhood and adolescence. Various studies performed in early adulthood showed that former pre-term infants suffered more often from asthma and psychiatric disorders. On average, they also had higher blood pressure, lower insulin sensitivity, and a reduced exercise capacity. It remains to be evaluated how much these risk factors contribute to cardiovascular or pulmonary morbidity and mortality later in life. At least, general mortality after preterm birth seems to be increased up to the oldest age group statistically evaluated up to now, i.e. 18 to 36 years.

Outcome in pediatric hydrocephalus: a comparison between previously used outcome measures and the hydrocephalus outcome questionnaire.

OBJECT: The objectives of this study were to assess, in a cohort of children with recently treated hydrocephalus, the correlation between scores on the Hydrocephalus Outcome Questionnaire (HOQ) and the children's type of schooling and motor functioning, and to assess the overall outcome of the children. METHODS: The health status of 142 pediatric patients (85 boys) with previous hydrocephalus, born between 1995 and 1999, was assessed. Outcomes were determined using the HOQ, type of schooling, and motor functioning. Data were obtained from parental interviews and patient medical records. RESULTS. Twelve patients died (8.5%). Responses to the HOQ were obtained from 107 patients (65 boys). The mean age of the patients was 7 years and 9 months +/- 1.42 years (range 6-10 years). The Physical Health score of the HOQ correlated well with the motor functioning score (r = 0.652) as did the Cognitive Health score with the type of schooling (r = 0.672). Fifty-nine percent of the patients were able to attend a school for students with normal intelligence. Disabling motor functioning was found in only 30% of patients. Epilepsy was present in 14%. CONCLUSIONS: The results show a good correlation between the type of schooling and the Cognitive HOQ score and between the Physical HOQ score and the motor functioning score. The HOQ is a simple and very useful measurement for determining outcome in pediatric hydrocephalus.

Drawing impairment predicts mortality in severe COPD.

BACKGROUND: Cognitive impairment frequently occurs in elderly COPD patients, but little is known about its prognostic implications. We aimed at evaluating the prognostic role of cognitive impairment in patients with severe COPD. METHODS: Our series consisted of 149 stable patients (mean [+/- SD] age, 68.7 +/- 8.5 years) with COPD and a Pao(2) of < 57 mm Hg at rest (n = 97) or at the end of the 6-min walking test (n = 37) who were enrolled in a prospective observational study. After a multidimensional baseline assessment, patients were followed up by telephone calls for a mean duration of 32.5 +/- 9.2 months (minimal follow-up duration, 24 months); 134 patients were successfully tracked. We used multivariable Cox proportional hazard analysis to identify predictors of death among clinical/functional variables that previously were shown to have prognostic implications and among neuropsychological indexes selected on the basis of univariate analysis. RESULTS: We observed 29 deaths over a median follow-up time of 32 months. Only the two following variables were independently associated with the outcome: an abnormal score on the copy with landmark test (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.34 to 6.39); and a 6-min walk distance of < 300 m (HR, 3.46; 95% CI, 1.15 to 10.5). A Pao(2) of < 57 mm Hg at rest (HR, 2.19; 95% CI, 0.93 to 5.18) and an FEV(1) of < 40% predicted (HR, 2.74; 95% CI, 0.99 to 7.57) were nearly significantly associated with the outcome, while Paco(2), body mass index, physical dependence, comorbid diseases, and the impairment of cognitive domains other than drawing impairment were unrelated to the outcome. CONCLUSIONS: Drawing impairment is a risk factor for mortality and might improve the assessment of hypoxemic COPD patients.

High sensitivity of northern pike larvae to UV-B but no UV-photoinduced toxicity of retene.

In order to investigate whether increased UV-B radiation is a risk factor, a series of acute laboratory experiments was conducted with larval stages of the northern pike (Esox lucius L.), hatching in Nordic waters in May. Further, a comparative investigation on the acute phototoxicity of retene (7-isopropyl-1-methylphenanthrene), a PAH compound recently revealed to posses UV-B-induced phototoxicity in larval coregonids, was conducted with pike larvae. In semi-static experiment, larvae were pre-exposed to retene (3, 9, 30 and 82 microg/g), with relevant controls, for 24 h and then irradiated for 3 h once a day (two consecutive days) with three UV-B doses (CIE-weighted 1.0, 1.8 or 2.7 kJ/m2 per day) or with visible light only. In 3 days, the UV-B exposure alone increased mortality by 10-20% in all applied dose rates. Retene (up to 82 microg/l) had no direct UV-B-induced toxicity in pike. However, pike larvae were very sensitive to UV-B even in low doses, indicated as severe neurobehavioral disorders. Monitoring of pike with the neurobehavioral syndrome revealed substantial late mortality. As UV-B had no influence on CYP1A content in larval pike, retene (9-82 microg/l) induced this protein substantially with and without UV-B. In pike, the applied UV-B radiation and water retene alone both decreased HSP70 concentrations. Neither UV nor retene changed SOD activity significantly. Overall, data on pike suggest that only a minor increase in ambient UV-B coming to the earth's surface may cause lethal effects to larval fish.

Perinatal factors affecting survival and survival without disability of extreme premature infants at two years of age.

OBJECTIVE: To study obstetrical factors leading to very preterm delivery (between 24 and 28 weeks) and to relate these factors to neonatal outcome and psychomotor development at two years. STUDY DESIGN: Among 144 infants born alive before 28 weeks of gestation at a single perinatal center between January 1993 and December 1996, we analyzed the influence on neonatal outcome and on psychomotor development at 24 months of a variety of perinatal and neonatal factors. Psychomotor development at two years was classified as: normal, borderline, or moderately or severely handicapped. RESULTS: During the study period, 114 women delivered live infants before 28 weeks' gestation: 87 singletons, 25 sets of twins, 1 set of triplets and 1 set of quadruplets. All 144 live-born infants received neonatal resuscitation: 50 died before discharge. At two years of age, 6 of the 94 survivors were lost to follow-up. Assessments of the psychomotor development of the other 88 was normal for 52%; borderline for 20%, moderately handicapped for 20%, and severely handicapped for 8%. Multivariate analysis found that two factors affected survival: birthweight and fetal heart rate. (The 42% of infants with a birthweight below 700 g survived versus 83% above 900 g, P<0.001, OR=5.2, 95% CI (confidence interval) [2.4-11.2].) CONCLUSION: These data show the influence of perinatal factors on the outcome of very preterm infants; birthweight and fetal heart rate are strongly correlated with survival. Gestational age is a good predictor of psychomotor development at two years.

Delirium severity and psychomotor types: their relationship with outcomes after hip fracture repair.

OBJECTIVES: To validate the Memorial Delirium Assessment Scale (MDAS) as a measure of delirium severity in a cohort of patients aged 65 and older; to examine the association between severity of delirium and patient outcomes; and to examine the association between psychomotor variants of delirium and each of those outcomes. DESIGN: Prospective assessment of sample. SETTING: Hospital. PARTICIPANTS: One hundred twenty-two older patients (mean age +/- standard deviation = 79 +/- 8) who had undergone acute hip fracture surgery. MEASUREMENTS: We used standardized instruments to assess prefracture activities of daily living (ADLs), ambulatory status, cognition, and living situation. Postoperatively, each patient was interviewed daily. Delirium was diagnosed using the Confusion Assessment Method (CAM), and delirium severity was measured using the MDAS. The MDAS was also used to categorize the psychomotor types of delirium into "purely hypoactive" or "any hyperactivity." Telephone or face-to-face interviews were conducted at 1 and 6 months to assess survival, ADL function, ambulatory status, and living situation. RESULTS: Of 122 patients, 40% developed CAM-defined delirium. Delirious patients had higher average MDAS scores than nondelirious patients (11.7 vs 2.4, P <.0001). We used the median of the average MDAS score to classify patients into mild or severe delirium. Severe delirium was generally associated with worse outcomes than was mild delirium, and the associations reached statistical significance for nursing home placement or death at 6 months (52% vs 17%, P =.009). Additionally, patients who did not meet full CAM criteria for delirium experienced worse outcomes if they had some symptoms of delirium than if they had no or few symptoms (nursing home placement or death at 6 months: 27% vs 0%, P =.001). Surprisingly, these patients with subsyndromal delirium who did not fulfill CAM criteria for delirium but demonstrated significant delirium symptoms, had outcomes similar to or worse than those with mild CAM-defined delirium. Pure hypoactive delirium accounted for 71% (34/48) of cases and was less severe than was delirium with any hyperactivity (average MDAS score 10.6 vs 14.8, P =.007). In our cohort, patients with pure hypoactive delirium had better outcomes than did those with any hyperactivity (nursing home placement or death at 1 month: 32% vs 79%, P =.003); this difference persisted after adjusting for severity. CONCLUSION: In this study of delirium in older hip fracture patients, the MDAS, a continuous severity measure, was a useful adjunct to the CAM, a dichotomous diagnostic measure. In patients with CAM-defined delirium, severe delirium was generally associated with worse outcomes than was mild delirium. In patients who did not fulfill CAM criteria, subsyndromal delirium was associated with worse outcomes than having few or no symptoms of delirium. Patients with subsyndromal delirium had outcomes similar to patients with mild delirium, suggesting that a dichotomous approach to diagnosis and management may be inappropriate. Pure hypoactive delirium was more common than delirium with any hyperactive features, tended to be milder, and was associated with better outcomes even after adjusting for severity. Future studies should confirm our preliminary associations and examine whether treatment to reduce the severity of delirium symptoms can improve outcomes after hip fracture repair.