Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants.

We prosepctively studied 200,000 newborns to determine the frequency and clinical characteristics of alpha1-antitrypsin deficiency. One hundred and twenty Pi Z, 48 Pi SZ, two PI Z-and one Pi S-infants were identified and followed to the age of six months. Fourteen of 120 Pi Z infants had prolonged obstructive jaundice, nine with severe clinical and laboratory evidence of liver disease. Five had only laboratory evidence of liver disease. Eight other Pi Z infants had minimal abnormalities in serum bilirubin and hepatic enzyme activity and variable hepatosplenomegaly. All 22 Pi Z infants with hepatic abnormalities, two thirds of whom were made, appeared healthy at six months of age. Ninety-eight Pi Z infants did not have clinical liver disease, but liver-function tests gave abnormal results in 44 of 84 at three months, and in 36 of 60 at six months of age. The number of small-for-gestational-age infants was greater (P less than 0.001) among those with clinical liver disease. None of the 48 Pi SZ infants had clinical liver disease, but 10 of 42 at three months and one of 22 at six months of age had abnormal liver function. The Pi Z and Pi SZ phenotypes are associated with covert or readily apparent hepatic dysfunction in the first three months of life.     

A new alpha 1-antitrypsin mutation, Thr–Met 85, (PI Zbristol) associated with novel electrophoretic properties

A new AAT allele ( PI Z _bristol ) has been discovered in a woman with an obstetric history of three perinatal deaths from fulminant liver disease and no living offspring. She and her father were both PI M1Z _bristol heterozygotes. The Z_bristol protein is active as a proteinase inhibitor but appeared to be deficient in the plasma to about the same degree as the S protein in MS heterozygotes. It focuses on the basic side of Z and lacks the normal pattern of secondary isoforms associated with the commonly occurring AAT variants and migrates faster than normal on an SDS electrophoresis gel. The Z _bristol mutation was found to be a C to T transition at codon 85 changing A C G (Thr) to A T G (Met). This disrupts the N -glycosylation site starting at Asn 83 preventing glycosylation at residue 83 in the PI Z_bristol protein and explains the protein isoelectric focusing and SDS gel electrophoresis results. An analysis of haplotypes in the propositus and her father indicated that the Z _bristol mutation occurred on the common M1 ( Val 213 ) genetic background. The new mutation also led to the generation of an Nla III restriction endonuclease recognition site. Cell lines from two offspring tested for the presence of this Nla III site revealed that one had the variant and the other did not. Thus, the relationship between Z_bristol and fulminant liver disease in the offspring is unclear.     

Occurrence of alpha-1-antitrypsin deficiency in 155 patients with alcoholic liver disease

Liver biopsies from 155 patients with alcoholic liver disease were examined for periodic-acid-Schiff-positive, diastase-resistant (PAS-DR) intracytoplasmic globules in hepatocytes. Seven patients had these PAS-DR globules: each was a heterozygote for a deficiency allele of alpha-1-antitrypsin (AAT), or alpha-1-protease inhibitor, with the PAS-DR globules distributed in a pattern characteristic of this deficiency. One further patient with normal AAT had a few intracytoplasmic PAS-DR globules in occasional hepatocytes. The prevalence of AAT heterozygotes in this series did not differ from that in the reference population. The seven heterozygotes included five of PI (protease inhibitor) type MZ, one of PI type SZ, and one heterozygous for a rare deficiency allele, PI type MMmalton. The M and Mmalton alleles may be difficult to distinguish because they have similar mobilities with isoelectric focusing technics. Therefore, if PAS-DR inclusions are found in the liver of a patient with an apparently normal phenotype, the presence of a defective M variant allele, such as Mmalton, should be considered.     

Pi-Z phenotypes in a pulmonary clinic. Their prevalence and physiologic state.

A series of 1,458 consecutive patients referred to the Cleveland Veterans Administration Pulmonary Clinic for pulmonary function studies was evaluated for alpha 1-antitrypsin deficiency by determination of serum trypsin inhibitory capacity (STIC). Protease inhibitor (Pi) phenotyping was performed on all sera with STIC values less than 1.6 mg/ml. The following non-MM phenotypes were found: 1FZ, 32MZ, 2ZZ, 3SZ, 5SS, 33MS, 21M. The prevalence of Pi Z heterozygosity is 2.74%. This figure is not significantly greater than that observed in a healthy population. A group ( n = 12) with heterozygous Z phenotype (MZ + SZ) was compared with a control (MM) group (n = 13) matched for age, race and smoking history from this same population. Our findings indicate similar deviations from predicted normal values in both control (MM) and Z-heterozygotic groups for physiologic tests of airway resistance, lung volumes, diffusing capacity, and static and dynamic compliance. There was no significant difference between MM controls and MZ heterozygotes in the physiologic variables measured.     

Emergence of enterovirus 71 “double-recombinant” strains belonging to a novel genotype D originating from southern China: first evidence for combination of intratypic and intertypic recombination events in EV71

Hand–foot–mouth disease due to enterovirus 71 (EV71) and coxsackievirus A16 (CA16) has recently caused large outbreaks in mainland China in 2008. We performed complete genome sequencing on two EV71 (SZ/HK08-5 and SZ/HK08-6) and two CA16 (SZ/HK08-3 and SZ/HK08-7) strains from patients in Shenzhen, China. Phylogenetic, similarity plot and bootscan analyses revealed recombination between EV71 genotypes B and C at the 2A–2B junction, and between EV71 genotype B and CA16 strain G-10 in the 3C region for EV71 strains. A similar phenomenon was also found upon further gene sequencing with other EV71 strains. Recombination between CA16 strain G-10 and EV71 genotype A at the 2A–2B junction was also observed for CA16 strains. The present “double-recombinant” EV71 strains circulating in China and other EV71 subgenotype “C4” strains represent an additional genotype, D. CA16 strains should also be classified into two genotypes. This represents the first evidence for a combination of intratypic and intertypic recombination in EV71 strains.     

Insights from the examination of verbal and spatial memory errors in relation to clinical symptoms of patients with recent-onset schizophrenia

Introduction. Memory deficits in patients with schizophrenia (SZ) are considered as a key feature of the clinical manifestations of the disease. In order to further examine the role and nature of memory deficits in SZ, the pattern of errors in verbal and spatial serial recall tasks committed by SZ patients was compared to that of healthy controls. We also tested the relationship between these memory errors and clinical symptoms.

Methods. Twenty-seven outpatients with recent-onset SZ and 27 age and gender matched healthy controls had to remember sequences of items (digits or localisations) in a serial recall task. Clinical symptoms were assessed with the PANSS and the SAPS.

Results. The results indicate that the number of omissions, intrusions, and transpositions can differentiate patients with SZ from healthy controls. Intrusions and transpositions committed in the verbal domain were associated with the negative subscale of the PANSS. Transposition errors were associated with delusions whether the to-be-remembered information was verbal or spatial.

Conclusion. The examination of the pattern of errors, in particular that of transpositions, is a more informative cognitive index than the mere analysis of overall performance, and provides a promising target for treatment.     

Study of lipoprotein (a) phenotypes in Ivorian subject

The objective of this study was to identify the apo (a) phenotypes and to find a correlation between apo (a) isoform size and Lp (a) plasma level in Ivorian subjects. This study involved 30 healthy subjects (11 females and 19 males) aged of 35 +/- 2 years. Lp (a) plasma levels have been determined by technical ELISA, while phenotypes of apo (a) have been identified by agarose high resolution electrophoresis followed by Western blot. The Lp (a) plasma level in our population was 329 +/- 291 mg/l and 30% of our population's Lp (a) plasma levels were above 300 mg/l. 70% of our subjects have homozygous phenotype and 30% have heterozygous phenotype. Three apo (a) isoforms (S2, S3, S4) have been identified in homozygous subjects whereas four apo (a) isoforms (B, S2, S3, S4) have been detected in heterozygous subjects. Their sizes varied from 13 to 33 kringle 4.77% of our subjects had apo (a) isoforms whose sizes were above 22 kringle 4. No correlation has been observed between the size of apo (a) isoforms and the Lp (a) plasma level in homozygous subjects. Our results highlight apo (a) polymorphism in Ivorians. Homozygous phenotypes and large size apo (a) isoforms predominate in this population.     

Genetic studies on a new deficiency gene (PI*Ztun) at the PI locus.

During a study of the alpha 1 antitrypsin (AAT) protein and its locus (PI) by high resolution isoelectric focusing and direct molecular analysis of 106 PIZ probands and their families, a new allele (Ztun) was identified that resembles Z in many of its properties. Two sibs, both compound heterozygotes for Ztun and Z, showed similar evidence of mild liver involvement that was indistinguishable from that associated with classical ZZ homozygotes. The Ztun protein appeared to be deficient in the plasma to about the same degree as the Z protein. Allele specific oligonucleotide analysis of amplified genomic DNA indicated that the new allele is the result of a mutation in exon V that is identical to the classical G----A transition at codon 342 that results in the Glu----Lys substitution characteristic of the Z allele. An analysis of DNA haplotypes constructed from polymorphic restriction enzyme recognition sites in and around the PI locus confirmed that Ztun probably represents a new mutation at codon 342 that has occurred on an M2-like genetic background.     

Clinical conference: Severe obstructive lung disease in a 14-year-old girl with alpha-1 antitrypsin deficiency.

Severe, largely irreversible obstructive lung disease, compatible with emphysema, was found in a 14-yr-old white girl who had been considered to have chronic asthma. She also presented a serum alpha-1 antitrypsin deficiency. Serum values for alpha-1 antitrypsin on two occassions were 95 and 105 mg/100 ml; Pi type was SZ. A family survey disclosed a 13-yr-old brother with the same pattern of alpha-1 antitrypsin deficiency. His serum value was 122.5 mg/100 ml; Pi type was SZ. He was asymptomatic and showed minimal pulmonary function abnormalities.     

Relation of protease inhibitor phenotypes to obstructive lung diseases in a community.

To examine the relative risk for the development of obstructive lung disease in persons heterozygous for alpha1-antitrypsin deficiency, we determined protease inhibitor phenotypes in 2944 subjects in a general community population. Phenotype M was found in 89.5 per cent, MS in 7.1 per cent, and MZ in 3.0 per cent of the population. There were two persons of phenotype Z and six of phenotype SZ. The study also included respiratory questionnaires and spirometry. There were no statistically significant differences in the prevalence of respiratory symptoms and diagnoses or of ventilatory impairment among the three major phenotype groups (M, MS and MZ), nor were there differences in the rates of deterioration of function with age or smoking. Consequently, we do not consider population screening for heterozygous alpha1-antitrypsin deficiency to be worthwhile.     

Spatiotemporal and frequency domain analysis of auditory paired stimuli processing in schizophrenia and bipolar disorder with psychosis

Individuals with schizophrenia (SZ) or bipolar disorder with psychosis (BPP) may share neurophysiological abnormalities as measured in auditory paired-stimuli paradigms with electroencephalography (EEG). Such investigations have been limited, however, by quantifying only event-related potential peaks and/or broad frequency bands at limited scalp locations without considering possible mediating factors (e.g., baseline differences). Results from 64-sensor EEG collected in 180 age- and gender-matched participants reveal (i) accentuated prestimulus gamma oscillations and (ii) reduced P2 amplitudes and theta/alpha oscillations to S1 among participants with both SZ and BPP. Conversely, (iii) N1s in those with SZ to S1 were reduced compared to healthy volunteers and those with BPP, whereas (iv) beta range oscillations 200-300 ms following S2 were accentuated in those with BPP but not those with SZ. Results reveal a pattern of both unique and shared neurophysiological phenotypes occurring within major psychotic diagnoses.     

Chromosome 13q13�Cq14 locus overlaps mood and psychotic disorders: the relevance for redefining phenotype

The nosology of major psychoses is challenged by the findings that schizophrenia (SZ) and bipolar disorder (BP) share several neurobiological, neuropsychological and clinical phenotypic characteristics. Moreover, several vulnerability loci or genes may be common to the two DSM disorders. We previously reported, in a sample of 21 kindreds (sample 1), a genome-wide suggestive linkage in 13q13–q14 with a common locus (CL) phenotype that crossed the diagnostic boundaries by combining SZ, BP and schizoaffective disorders. Our objectives were to test phenotype specificity in a separate sample (sample 2) of 27 kindreds from Eastern Quebec and to also analyze the combined sample of 48 kindreds (1274 family members). We performed nonparametric and parametric analyses and tested as phenotypes: SZ alone, BP alone, and a CL phenotype. We replicated in sample 2 our initial finding with CL with a maximum NPL_pair score of 3.36 at D13S1272 (44 Mb), only 2.1 Mb telomeric to our previous maximum result. In the combined sample, the peak with CL was at marker D13S1297 (42.1 Mb) with a NPL_pair score reaching 5.21, exceeding that obtained in each sample and indicating consistency across the two samples. Our data suggest a susceptibility locus in 13q13–q14 that is shared by schizophrenia and mood disorder. That locus would be additional to another well documented and more distal 13q locus where the G72/G30 gene is mapped.     

Interleukin-22 predicts severity and death in advanced liver cirrhosis: a prospective cohort study

ABSTRACT: BACKGROUND: Interleukin-22 (IL-22), recently identified as a crucial parameter of pathology in experimental liver damage, may determine survival in clinical end-stage liver disease. Systematic analysis of serum IL-22 in relation to morbidity and mortality of patients with advanced liver cirrhosis has not been performed so far. METHODS: This is a prospective cohort study including 120 liver cirrhosis patients and 40 healthy donors to analyze systemic levels of IL-22 in relation to survival and hepatic complications. RESULTS: A total of 71% of patients displayed liver cirrhosis-related complications at study inclusion. A total of 23% of the patients died during a mean follow-up of 196 +/- 165 days. Systemic IL-22 was detectable in 74% of patients but only in 10% of healthy donors (P <0.001). Elevated levels of IL-22 were associated with ascites (P = 0.006), hepatorenal syndrome (P <0.0001), and spontaneous bacterial peritonitis (P = 0.001). Patients with elevated IL-22 (>18 pg/ml, n = 57) showed significantly reduced survival compared to patients with regular ([less than or equal to]18 pg/ml) levels of IL-22 (321 days versus 526 days, P = 0.003). Other factors associated with overall survival were high CRP ([greater than or equal to]2.9 mg/dl, P = 0.005, hazard ratio (HR) 0.314, confidence interval (CI) (0.141 to 0.702)), elevated serum creatinine (P = 0.05, HR 0.453, CI (0.203 to 1.012)), presence of liver-related complications (P = 0.028, HR 0.258 CI (0.077 to 0.862)), model of end stage liver disease (MELD) score [greater than or equal to]20 (P = 0.017, HR 0.364, CI (0.159 to 0.835)) and age (P = 0.011, HR 1.047, CI (1.011 to 1.085)). Adjusted multivariate Cox proportional-hazards analysis identified elevated systemic IL-22 levels as independent predictors of reduced survival (P = 0.007, HR 0.218, CI (0.072 to 0.662)). CONCLUSIONS: In patients with liver cirrhosis, elevated systemic IL-22 levels are predictive for reduced survival independently from age, liver-related complications, CRP, creatinine and the MELD score. Thus, processes that lead to a rise in systemic interleukin-22 may be relevant for prognosis of advanced liver cirrhosis.     

Prenatal diagnosis of alpha 1 antitrypsin deficiency and estimates of fetal risk for disease.

Alpha 1 antitrypsin deficiency is one of the most common metabolic disorders, frequently associated with obstructive lung disease and occasionally with childhood liver cirrhosis. Prenatal diagnosis of this deficiency has been accomplished using a DNA polymorphism detected by the restriction enzyme AvaII. A unique haplotype of DNA fragments is observed in deficient (PI type ZZ) subjects. Diagnosis is therefore possible directly from fetal tissue, unlike other prenatal diagnoses using linkage of a DNA polymorphism within a specific family. This approach must be modified for rare deficiency alleles of alpha 1 antitrypsin (PI* Mmalton, PI* Mdurate, and PI*QO or null). Knowledge of risk of severe disease in the fetus is important for the application of prenatal diagnosis. From the limited data available to date, the risk for a given PI ZZ fetus to develop severe liver disease has been estimated at 13% where a previous PI ZZ sib had no liver disease or liver disease which resolved during early childhood, and a risk of 40% where a previous PI ZZ sib had developed severe liver disease.     

Diagnostic specificity and familiality of early versus late evoked potentials to auditory paired stimuli across the schizophrenia‐bipolar psychosis spectrum

Disrupted sensory processing is a core feature of psychotic disorders. Auditory paired stimuli (PS) evoke a complex neural response, but it is uncertain which aspects reflect shared and/or distinct liability for the most common severe psychoses, schizophrenia (SZ) and psychotic bipolar disorder (BDP). Evoked time‐voltage/time‐frequency domain responses quantified with EEG during a typical PS paradigm (S1‐S2) were compared among proband groups (SZ [n = 232], BDP [181]), their relatives (SZrel [259], BDPrel [220]), and healthy participants (H [228]). Early S1‐evoked responses were reduced in SZ and BDP, while later/S2 abnormalities showed SZ/SZrel and BDP/BDPrel specificity. Relatives' effects were absent/small despite significant familiality of the entire auditorineural response. This pattern suggests general and divergent biological pathways associated with psychosis, yet may reflect complications with conditioning solely on clinical phenomenology.     

Severe obstructive lung disease in a 14-year-old girl with alpha-1 antitrypsin deficiency

Severe, largely irreversible obstructive lung disease, compatible with emphysema, was found in a 14-yr-old white girl who had been considered to have chronic asthma. She also presented a serum alpha-1 antitrypsin deficiency. Serum values far alpha-1 antitrypsin on two occasions were 95 and 105 mg/100 ml; Pi type was SZ. A family survey disclosed a 13-yr-old brother with the same pattern of alpha-1 antitrypsin deficiency. His serum value was 122.5 mg/100 ml; Pi type was SZ. He was asymptomatic and showed minimal pulmonary function abnormalities.     

Decreased serum neurotrophin 3 in chronically medicated schizophrenic males

There is evidence that major psychiatric disorders such as schizophrenia (SZ) are associated with deregulation of synaptic plasticity with downstream alterations of neurotrophins. NT3 is an important neurotrophin in the central nervous system, and performs key biological functions, such as promoting the survival, differentiation, and plasticity of neurons. NT3 has a central role in the early neuronal development; enhancing the survival of dopaminergic neurons, suggesting possible involvement in the physiopathology of dopamine related neuropsychiatric disorders such as SZ. Variations in the NT3 gene increase the risk of SZ. Three groups of chronically medicated DSM-IV patients with SZ, on treatment with clozapine (n=12), haloperidol (n=12), risperidone (n=12) and 10 healthy controls had 5 ml blood samples collected by venipuncture. NT3 serum levels were assessed using sandwich-ELISA and were significantly lower in SZ patients (p<0.005) when compared to either controls. These findings suggest that the NT3 signaling system may play a role in the pathophysiology of SZ and might be related to the course of illness or to treatment variables. Longitudinal studies are warranted.     

Liver disease and the PI ElembergM phenotype of alpha 1-antitrypsin

The purpose of this article is to document clinical and pathologic observations concerning liver disease associated with the PI ElembergM phenotype of alpha 1-antitrypsin. Deposits of alpha 1-antitrypsin that were periodic acid-Schiff positive and stained with an antiserum to alpha 1-antitrypsin were found in the liver of a markedly jaundiced, terminally ill patient with Stage IV primary biliary cirrhosis. A biopsy performed three years earlier failed to reveal alpha 1-antitrypsin deposits. The phenotype PI ElembergM was verified by both acid starch gel electrophoresis and isoelectric focusing in agarose. The deposits of alpha 1-antitrypsin in the liver appear to be a consequence of the patient's disease and age and not due to an association with the PI*Elemberg allele. Accumulation of alpha 1-antitrypsin in the liver of this patient may be due to an accelerated synthesis of this protease inhibitor exceeding the liver's capacity for glycosylation or other steps in its secretion.     

Association analyses suggest GPR24 as a shared susceptibility gene for bipolar affective disorder and schizophrenia.

Linkage analyses suggest that chromosome 22q12-13 may harbor a shared susceptibility locus for bipolar affective disorder (BPD) and schizophrenia (SZ). In a study of a sample from the Faeroe Islands we have previously reported association between both disorders and microsatellite markers in a 3.6 cM segment on 22q13. The present study investigated three candidate genes located in this segment: GPR24, ADSL, and ST13. Nine SNPs located in these genes and one microsatellite marker (D22S279) were applied in an association analysis of two samples: an extension of the previously analyzed Faeroese sample comprising 28 distantly related cases (17 BPD, 11 SZ subjects) and 44 controls, and a Scottish sample including 162 patients with BPD, 103 with SZ, and 200 controls. In both samples significant associations were observed in both disorders with predominantly GPR24 SNPs and haplotypes. In the Faeroese sample overall P-values of 0.0009, 0.0054, and 0.0023 were found for haplotypes in BPD, SZ, and combined cases, respectively, and in the Scottish sample overall P-values of 0.0003, 0.0005, and 0.016 were observed for similar groupings. Specific haplotypes showed associations with lowest P-values of 7 x 10(-5) and 0.0006 in the combined group of cases from the Faeroe Islands and Scotland, respectively. The G protein-coupled receptor 24 encoded by GPR24 binds melanin-concentrating hormone (MCH) and has been implicated with feeding behavior, energy metabolism, and regulation of stress and mood. To our knowledge this is the first study reporting association between GPR24 and BPD and SZ, suggesting that GPR24 variants may confer susceptibility to both disorders.