Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora's progressive myoclonic epilepsy

Background

Lafora''s progressive myoclonic epilepsy (Lafora''s disease) is an autosomal recessive neurodegenerative disorder characterised by the presence of polyglucosan intracellular inclusions called Lafora bodies. Mutations in two genes, EPM2A and NHLRC1, have been shown to cause the disease. A previous study showed mutations in the EPM2A gene in 14 Lafora''s disease families and excluded the involvement of this gene in five other families who were biopsy proven to have the disease.

Objective

To relate the genetic findings to the clinical course of the disease.

Methods

As part of an ongoing mutational study of the Lafora''s disease genes, five new families with the disease were recruited and the genetic analysis was extended to screen the entire coding region of the NHLRC1 gene. Genotype–phenotype correlations were carried out.

Results

Seven NHLRC1 mutations were identified, including five novel mutations (E91K, D195N, P218S, F216_D233del, and V359fs32), in eight families with Lafora''s disease. On relating the genetic findings to the clinical course of the disease it was shown that patients with NHLRC1 mutations had a slower rate of disease progression (p<0.0001) and thus appeared to live longer than those with EPM2A mutations. A simple DNA based test is described to detect the missense mutation C26S (c.76T→A) in the NHLRC1 gene, which is prevalent among French Canadians.

Conclusions

Patients with NHLRC1 mutations have a slower rate of disease progression than those with EPM2A mutations.     

Clinical Characteristics and Genotype-Phenotype Correlation of Korean Patients with Spinal and Bulbar Muscular Atrophy

Purpose

Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuron disease characterized by proximal muscle weakness, muscle atrophy, and fasciculation. Although SBMA is not uncommon in Korea, there is only one study reporting clinical characteristics and genotype-phenotype correlation in Korean patients.

Materials and Methods

In this study, age at the onset of symptoms, the score of severity assessed by impairment of activities of daily living milestones, and rate of disease progression, and their correlations with the number of CAG repeats in the androgen receptor (AR) gene, as well as possible correlations among clinical characteristics, were analyzed in 40 SBMA patients.

Results

The median ages at onset and at diagnosis were 44.5 and 52.5 years, respectively, and median interval between onset and diagnosis and median rate of disease progression were 5.0 years and 0.23 score/year, respectively. The median number of CAG repeats in the AR gene was 44 and the number of CAG repeats showed a significant inverse correlation with the age at onset of symptoms (r=-0.407, p=0.009). In addition, patients with early symptom onset had slower rate of disease progression.

Conclusion

As a report with the largest and recent Korean cohort, this study demonstrates clinical features of Korean patients with SBMA and reaffirms the inverse correlation between the age at disease onset and the number of CAG repeats. Interestingly, this study shows a possibility that the rate of disease progression may be influenced by the age at onset of symptoms.     

Screening of calpain-3 autolytic activity in LGMD muscle: a functional map of CAPN3 gene mutations

Background

The diagnosis of calpainopathy is obtained by identifying calpain‐3 protein deficiency or CAPN3 gene mutations. However, in many patients with limb girdle muscular dystrophy type 2A (LGMD2A), the calpain‐3 protein quantity is normal because loss‐of‐function mutations cause its enzymatic inactivation. The identification of such patients is difficult unless a functional test suggests pursuing a search for mutations.

Materials and methods

A functional in vitro assay, which was able to test calpain‐3 autolytic function, was used to screen a large series of muscle biopsy specimens from patients with unclassified LGMD/hyperCKaemia who have previously shown normal calpain‐3 protein quantity.

Results

Of 148 muscle biopsy specimens tested,17 samples (11%) had lost normal autolytic function. CAPN3 gene mutations were identified in 15 of 17 patients (88%), who account for about 20% of the total patients with LGMD2A diagnosed in our series.

Conclusions

The loss of calpain‐3 autolytic activity is highly predictive of primary calpainopathy, and the use of this test as part of calpainopathy diagnosis would improve the rate of disease detection markedly. This study provides the first evidence of the pathogenetic effect of specific CAPN3 gene mutations on the corresponding protein function in LGMD2A muscle and offers new insights into the structural–functional relationship of the gene and protein regions that are crucial for the autolytic activity of calpain‐3.Limb girdle muscular dystrophies (LGMDs) comprise a clinically and genetically heterogeneous group of diseases usually characterised by progressive muscle weakness and wasting of pelvic and shoulder girdles. LGMD type 2A (LGMD2A, MIM 253600) was the first form of LGMD to be mapped and molecularly characterised, probably because it is the most frequent.^1,2,3,4,5 LGMD2A is caused by mutations in the CAPN3 gene (MIM 114240) that encodes for a non‐structural protein, the enzyme called calpain‐3.¹ Calpain‐3 is the muscle‐specific member of a family of Ca²⁺‐dependent proteases, which are supposed to play a part in many intracellular processes, including cell motility, apoptosis, differentiation and cell cycle regulation, by modulating the biological activity of their substrates through limited and strictly controlled proteolysis. Calpain‐3 is composed of four functional domains, and has three exclusive sequence inserts (NS, IS1 and IS2). The activation of calpain‐3 depends on phospholipids and Ca²⁺ ions,^6,7 takes place after unknown stimuli, and results in partial autolytic degradation.^8,9,10,11,12The molecular diagnosis of calpainopathy is complex because of the variability of clinical phenotypes, the effort required to identify point mutations in a relatively large gene, and incomplete sensitivity and specificity of calpain‐3 protein analysis on muscle biopsy specimen.^{13,14,15,16,17,18,19}An increasing number of studies have reported patients with LGMD2A whose diagnosis had been obtained by mutation identification despite normal levels of calpain‐3 protein in their muscle biopsy specimen.^4,15,20,21 As calpain‐3 is an enzyme, some mutations may not cause a reduction in protein content but its functional inactivation. Clinicians are increasingly aware that although the number of patients with LGMD2A showing normal calpain‐3 levels is marked, the identification of such cases is difficult. In patients with abnormal calpain‐3 protein levels, the effort required to search for mutations is justified because it will almost certainly confirm the LGMD2A diagnosis.¹⁶ Conversely, in patients with normal calpain‐3 protein content, an alternative diagnosis is usually pursued. For this reason, many patients with LGMD2A remain undiagnosed, unless a search is conducted for the CAPN3 gene mutation even if protein results are not indicative. To overcome this problem, we have developed a functional in vitro assay that is able to test the calpain‐3 autolytic activity in muscle samples,¹⁵ and showed that the loss of this function is associated with specific CAPN3 gene mutations.We report the results of extensive use of this functional assay as a screening tool in muscle biopsy specimens from patients with unclassified LGMDs and normal calpain‐3 protein quantity. Besides identifying patients with loss‐of‐function mutations, which would improve the rate of detection of the disease, we aimed at designing a functional map of the mutations and the protein regions involved in the autolytic activity to determine how single mutations exert their deleterious effect on the mutant protein.     

Is 8860 variation a rare polymorphism or associated as a secondary effect in HCM disease?

Introduction

mtDNA defects, both deletions and point mutations, have been associated with hypertrophic cardiomyopathies. The aim of this study was to establish a spectrum for mtDNA mutations in Iranian hypertrophic cardiomyopathy (HCM) patients.

Material and methods

The control group was chosen among the special medical centre visitors who did not have hypertrophic cardiomyopathy or any related heart disease. Hypertrophic cardiomyopathy (HCM) is widely accepted as a pluricausal or multifactorial disease. Because of the linkage between energy metabolism in the mitochondria and cardiac muscle contraction, it is reasonable to assume that mitochondrial abnormalities may be responsible for some forms of HCM. Point mutations and deletions in the two hot spot regions of mtDNA were investigated by PCR and sequencing methods.

Results

Some unreported point mutations have been found in this study but no deletion was detected. Meanwhile some of these point mutations have been investigated among HCM patients for the first time.

Conclusions

A8860G transition was detected in a high proportion, raising the question whether this rare polymorphism is associated as a secondary effect in HCM disease.     

Screening for hotspot mutations in PI3K, JAK2, FLT3 and NPM1 in patients with myelodysplastic syndromes

INTRODUCTION:

Myelodysplastic syndromes encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, refractory cytopenia and a tendency to progress toward acute myeloid leukemia. The accumulation of genetic alterations is closely associated with the progression of myelodysplastic syndromes toward acute myeloid leukemia.

OBJECTIVE:

To investigate the presence of mutations in the points most frequent for mutations (hotspot mutations) in phosphatidylinositol-3-kinase (PI3K), Janus kinase 2 (JAK2), FMS-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1), which are involved in leukemia and other cancers, in a population of Brazilian MDS patients.

METHODS:

Fifty-one myelodysplastic syndromes patients were included in the study. According to French-American-British classification, the patients were distributed as follows: 31 with refractory anemia, 8 with refractory anemia with ringed sideroblasts, 7 with refractory anemia with excess blasts, 3 with refractory anemia with excess blasts in transformation and 2 with chronic myelomonocytic leukemia. Bone marrow samples were obtained and screened for the presence of hotspot mutations using analysis based on amplification with the polymerase chain reaction, sequencing, fragment size polymorphisms or restriction enzyme digestion. All patients were screened for mutations at the time of diagnosis, and 5 patients were also screened at the time of disease progression.

RESULTS:

In the genes studied, no mutations were detected in the patients at the time of diagnosis. One patient with chronic myelomonocytic leukemia was heterozygous for a Janus kinase 2 mutation after disease progression.

CONCLUSIONS:

These results show that hotspot mutations in the PI3K, JAK2, FLT3 and NPM1 genes are not common in MDS patients; nevertheless, JAK2 mutations may be present in myelodysplasia during disease progression.     

A novel mutation in the mitochondrial tRNA(Ser(AGY)) gene associated with mitochondrial myopathy, encephalopathy, and complex I deficiency

Purpose

To identify molecular defects in a girl with clinical features of MELAS (mitochondrial encephalomyopathy and lactic acidosis) and MERRF (ragged‐red fibres) syndromes.

Methods

The enzyme complex activities of the mitochondrial respiratory chain were assayed. Temporal temperature gradient gel electrophoresis was used to scan the entire mitochondrial genome for unknown mitochondrial DNA (mtDNA) alterations, which were then identified by direct DNA sequencing.

Results

A novel heteroplasmic mtDNA mutation, G12207A, in the tRNA^Ser(AGY) gene was identified in the patient who had a history of developmental delay, feeding difficulty, lesions within her basal ganglia, cerebral atrophy, proximal muscle weakness, increased blood lactate, liver dysfunction, and fatty infiltration of her muscle. Muscle biopsy revealed ragged red fibres and pleomorphic mitochondria. Study of skeletal muscle mitochondria revealed complex I deficiency associated with mitochondrial proliferation. Real time quantitative PCR analysis showed elevated mtDNA content, 2.5 times higher than normal. The tRNA^Ser(AGY) mutation was found in heteroplasmic state (92%) in the patient''s skeletal muscle. It was not present in her unaffected mother''s blood or in 200 healthy controls. This mutation occurs at the first nucleotide of the 5′ end of tRNA, which is involved in the formation of the stem region of the amino acid acceptor arm. Mutation at this position may affect processing of the precursor RNA, the stability and amino acid charging efficiency of the tRNA, and overall efficiency of protein translation.

Conclusion

This case underscores the importance of comprehensive mutational analysis of the entire mitochondrial genome when a mtDNA defect is strongly suggested.     

Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations

Purpose

This study was designed to investigate the characteristics of Korean patients with calpainopathy.

Materials and Methods

Thirteen patients from ten unrelated families were diagnosed with calpainopathy via direct or targeted sequencing of the CAPN3 gene. Clinical, mutational, and pathological spectra were then analyzed.

Results

Nine different mutations, including four novel mutations ({"type":"entrez-nucleotide","attrs":{"text":"NM_000070","term_id":"27765081","term_text":"NM_000070"}}NM_000070: c.1524+1G>T, c.1789_1790inA, c.2184+1G>T, and c.2384C>T) were identified. The median age at symptom onset was 22 (interquartile range: 15-28). Common clinical findings were joint contracture in nine patients, winged scapula in four, and lordosis in one. However, we also found highly variable clinical features including early onset joint contractures, asymptomatic hyperCKemia, and heterogeneous clinical severity in three members of the same family. Four of nine muscle specimens revealed lobulated fibers, but three showed normal skeletal muscle histology.

Conclusion

We identified four novel CAPN3 mutations and demonstrated clinical and pathological heterogeneity in Korean patients with calpainopathy.     

Predicting disease genes using protein-protein interactions

Background

The responsible genes have not yet been identified for many genetically mapped disease loci. Physically interacting proteins tend to be involved in the same cellular process, and mutations in their genes may lead to similar disease phenotypes.

Objective

To investigate whether protein–protein interactions can predict genes for genetically heterogeneous diseases.

Methods

72 940 protein–protein interactions between 10 894 human proteins were used to search 432 loci for candidate disease genes representing 383 genetically heterogeneous hereditary diseases. For each disease, the protein interaction partners of its known causative genes were compared with the disease associated loci lacking identified causative genes. Interaction partners located within such loci were considered candidate disease gene predictions. Prediction accuracy was tested using a benchmark set of known disease genes.

Results

Almost 300 candidate disease gene predictions were made. Some of these have since been confirmed. On average, 10% or more are expected to be genuine disease genes, representing a 10‐fold enrichment compared with positional information only. Examples of interesting candidates are AKAP6 for arrythmogenic right ventricular dysplasia 3 and SYN3 for familial partial epilepsy with variable foci.

Conclusions

Exploiting protein–protein interactions can greatly increase the likelihood of finding positional candidate disease genes. When applied on a large scale they can lead to novel candidate gene predictions.     

Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum

Background

Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance‐associated protein 6).

Objective

To investigate the mutation spectrum of ABCC6 and possible genotype–phenotype correlations.

Methods

Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high‐performance liquid chromatography‐based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype–phenotype correlations were assessed.

Results

In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster in exons 24 and 28, corresponding to the second nucleotide‐binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23–29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype–phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease.

Conclusions

This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.     

Analysis of the LRRK2 p.G2019S mutation in Colombian Parkinson's Disease Patients

Introduction:

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2 or Dardarin) are considered to be a common cause of autosomal dominant and sporadic Parkinson´s disease, but the prevalence of these mutations varies among populations.

Objective:

to analyzed the frequency of the LRRK2 p.G2019S mutation (c.6055 G>A transition) in a sample of Colombian patients.

Methods:

In the present study we have analyzed the frequency of the LRRK2 p.G2019S mutation in 154 patients with familial or sporadic Parkinson Disease, including early and late onset patients, and 162 normal controls.

Results:

Our results show occurrence of this mutation in two cases (2/154, 1.3%) with classical Parkinson´s signs, and one completely asymptomatic control (1/162, 0.6%).

Conclusion:

The p.G2019S mutation is not an important causal factor of Parkinson Disease in Colombia having similar frequencies to those reported in other Latin American populations.     

Persistent Short-Term Memory Defects Following Sleep Deprivation in a Drosophila Model of Parkinson Disease

Study Objectives:

Parkinson disease (PD) is the second most common neurodegenerative disorder in the United States. It is associated with motor deficits, sleep disturbances, and cognitive impairment. The pathology associated with PD and the effects of sleep deprivation impinge, in part, upon common molecular pathways suggesting that sleep loss may be particularly deleterious to the degenerating brain. Thus we investigated the long-term consequences of sleep deprivation on short-term memory using a Drosophila model of Parkinson disease.

Participants:

Transgenic strains of Drosophila melanogaster.

Design:

Using the GAL4-UAS system, human α-synuclein was expressed throughout the nervous system of adult flies. α-Synuclein expressing flies (αS flies) and the corresponding genetic background controls were sleep deprived for 12 h at age 16 days and allowed to recover undisturbed for at least 3 days. Short-term memory was evaluated using aversive phototaxis suppression. Dopaminergic systems were assessed using mRNA profiling and immunohistochemistry.

Measurments and Results:

When sleep deprived at an intermediate stage of the pathology, αS flies showed persistent short-term memory deficits that lasted ≥ 3 days. Cognitive deficits were not observed in younger αS flies nor in genetic background controls. Long-term impairments were not associated with accelerated loss of dopaminergic neurons. However mRNA expression of the dopamine receptors dDA1 and DAMB were significantly increased in sleep deprived αS flies. Blocking D1-like receptors during sleep deprivation prevented persistent short-term memory deficits. Importantly, feeding flies the polyphenolic compound curcumin blocked long-term learning deficits.

Conclusions:

These data emphasize the importance of sleep in a degenerating/reorganizing brain and shows that pathological processes induced by sleep deprivation can be dissected at the molecular and cellular level using Drosophila genetics.

Citation:

Seugnet L; Galvin JE; Suzuki Y; Gottschalk L; Shaw PJ. Persistent short-term memory defects following sleep deprivation in a drosophila model of parkinson disease. SLEEP 2009;32(8):984-992.     

Novel nonsense mutation of BRCA2 gene in a Moroccan man with familial breast cancer

Background

Breast cancer is the most common cancer in women worldwide. About 5 to 10% of cases are due to an inherited predisposition in two major genes, BRCA1 and BRCA2, transmitted as an autosomal dominant form. Male breast cancer is rare and is mainly due to BRCA2 than BRCA1 germline mutations.

Objective

Molecular study of BRCA2 gene in man with familial breast cancer.

Methods

PCR and direct sequencing of BRCA2 gene.

Results

Identification of novel heterozygous germline mutation c.6428C>A ; p.Ser2143Stop of BRCA2 gene.     

The 13042G --> A/ND5 mutation in mtDNA is pathogenic and can be associated also with a prevalent ocular phenotype

Background

Overlapping phenotypes including LHON, MELAS, and Leigh syndrome have recently been associated with numerous mtDNA point mutations in the ND5 gene of complex I, now considered a mutational hot spot.

Objective

To identify the mtDNA defect in a family with a prevalent ocular phenotype, including LHON‐like optic neuropathy, retinopathy, and cataract, but characterised also by strokes, early deaths, and miscarriages on the maternal line.

Results

Sequencing of the entire mitochondrial genome from the proband''s muscle DNA identified the heteroplasmic 13042G→A transition, which was previously described only once in a patient with a different mitochondrial disease. This mutation fulfils the major pathogenic criteria, inducing an amino acid change (A236T) at an invariant position in a highly conserved domain of the ND5 gene. Phosphorus magnetic resonance spectroscopy in the proband disclosed an in vivo brain and skeletal muscle energy metabolism deficit.

Conclusions

These findings conclusively establish the pathogenic role of the 13042G→A mutation and underscore its variable clinical expression.     

Phenotype-genotype analysis of dystrophinopathy caused by duplication mutation in Dystrophin gene in an African patient

Background

The dystrophinopathies, duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are common X-linked genetic myopathies resulting from mutations in the dystrophin gene. Duplication is an uncommon mechanism of mutation occurring in about 5% of DMD cases. The global prevalence of DMD is reported as 1/18,000 males. There is little clinical or epidemiological data on African patients.

Objective

To present the genotype-phenotype analysis of dystrophinopathy with an exon 8 through 9 duplication mutation in a patient of African/Ghanaian descent and his asymptomatic mother.

Methods

Investigations including a biopsy of the vastus lateralis muscle and genetic testing of the patient and his mother.

Results

Genetic testing demonstrated a duplication of exons 8 through 9 of the dystrophin gene in both the patient and his mother. The muscle biopsy of the patient showed partial expression of the dystrophin protein. In the absence of a family history of dystrophinopathy, we hypothesize that this is a sporadic mutation occurring in the grand maternal lineage.

Conclusion

This case extends the world wide epidemiology of this disease to include the African/Ghanaian population and confirms the vulnerability of the dystrophin gene to recurrent spontaneous mutations at the exon 8 and 9 site.     

Testing association between LRRK2 and Parkinson's disease and investigating linkage disequilibrium

Background

We and others recently identified the gene underlying PARK8 linked Parkinson''s disease (PD). This gene, LRRK2, contains mutations that cause an autosomal dominant PD, including a mutation, G2019S, which is the most common PD causing mutation identified to date. Common genetic variability in genes that contain PD causing mutations has previously been implicated as a risk factor for typical sporadic disease.

Methods

We undertook a case‐control association analysis of LRRK2 in two independent European PD cohorts using 31 tagging single nucleotide polymorphisms (tSNPs) and five potentially functional SNPs. To assess the structure of this locus in different populations, we have performed linkage disequilibrium (LD) analysis using these variants in a human diversity panel.

Results

We show that common genetic variability in LRRK2 is not associated with risk for PD in the European populations studied here. We also show inter‐population variability in the strength of LD across this locus.

Conclusions

To our knowledge this is the first comprehensive analysis of common variability within LRRK2 as a risk factor for PD.     

Genotype-phenotype correlations of 39 patients with Cornelia De Lange syndrome: the Dutch experience

Background

Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly syndrome characterised by a distinctive facial appearance, prenatal and postnatal growth deficiency, psychomotor delay, behavioural problems, and malformations of the upper extremities. Recently mutations in NIPBL, the human homologue of the Drosophila Nipped‐B gene, were found to cause CdLS. Mutations have been found in 39% of reported cases.

Methods

Patients were enrolled in the study and classified into one of four groups based on clinical examination: classic, mild, possible, or definitively not CdLS. Three dimensional photography was taken of 20 subjects, and compared between groups. Behaviour was assessed with specific attention to autism. We searched for mutations in NIPBL and correlated genotype with phenotype.

Results

: We found mutations in 56% of cases.

Conclusions

Truncating mutations were generally found to cause a more severe phenotype but this correlation was not absolute. Three dimensional facial imaging demonstrated the potential for classifying facial features. Behavioural problems were highly correlated with the level of adaptive functioning, and also included autism. No correlation of behaviour with the type of mutation was found     

Coats' disease in Tanzania: first case report and literature review

Background

Coats'' disease is an exudative retinal detachment with vascular telangiectasis occurring mostly in male children, the age group most affected by retinoblastoma.

Objectives

Compare the differential diagnoses of Coats'' diseaseEstablish recommendation to early disease detection.

Materials and Methods

A 3-year-old female child was referred to Muhimbili National Hospital (MNH), Tanzania, in September 2011. She had presented at the peripheral hospital with gradual onset of left eye leukocoria for 1 year and pain for 2 months. B-scan showed a mass in the left eye. A clinical diagnosis of retinoblastoma was made. Left eye enucleation was performed; the patient was referred to MNH, with the enucleated specimen.

Results

Brain and orbits scan revealed no residual tumour. The globe measured 2x1.8 cm, the optic nerve stump measured 3 mm. A whitish mass filled the vitreous, with complete retinal detachment. Microscopy showed retinal gliosis, detachment with sub retinal PAS positive exudates, vacuolation and cholesterol clefts. Foreign body giant cells were present; telangiectatic thin-walled blood vessels were identified. Clinico-pathological findings were of stage 4 Coats'' disease.

Conclusion

Coats'' disease is an important differential diagnosis of retinoblastoma. Delay to detect Coats'' disease leads to vision loss which necessitates eye enucleation as was in this child.     

The effect of experimental streptococcus infection in myocarditis on some biochemical and inflammatory markers in albino rats

Background

Myocarditis is an uncommon disease that presents with a wide range of symptoms in children and adults. It is histologically characterized by varying degrees of myocardialnecrosis, edema and cellular infiltration myocardial inflammation is a nonspecificresponse to many triggers such as bacterial infection, cardio toxic agents, ormechanical injury.

Objective

This study was carried out to investigate the experimental Streptococcus faecalis induction of myocarditis and its effect on some blood parameters, inflammatory markers and histopathological changes in male albino rats.

Methods

Rats were infected by intraperitoneal injection of 10 8 CFU/ml of Streptococcus faecalis and sacrificed after one, two and seven days post infection. Biochemical analyses of blood were carried out to investigate the serum biomarkers of inflammation, liver function tests, cardiac enzymes & kidney function tests.

Results

All biochemical analyses showed statistically significant increase in the measured parameters due to bacterial infections except for blood urea which appear to be normal. A significant positive correlation was observed between lactate dehydrogenase enzyme (LDH) with creatinine (r =0.778, P<0.01). In the 7 days group, there were significant positive correlations between aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (r=0.675, P<0.05), erythrocyte sedimentation rate (ESR) with Urea (r=0.659, P<0.05) and alkaline phosphatase (ALP) with C-reactive protein (CRP) (r=0.765, p<0.01).

Conclusion

Many of these biomarkers will provide important new insights into pathophysiology and aid in the diagnosis and management of cardiovascular patients.     

Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia

Background

Mutilating sensory neuropathy with spastic paraplegia is a very rare disease with both autosomal dominant and recessive modes of inheritance. We previously mapped the locus of the autosomal recessive form to a 25 cM interval between markers D5S2048 and D5S648 on chromosome 5p. In this candidate interval, the Cct5 gene encoding the epsilon subunit of the cytosolic chaperonin‐containing t‐complex peptide‐1 (CCT) was the most obvious candidate gene since mutation in the Cct4 gene encoding the CCT delta subunit has been reported to be associated with autosomal recessive mutilating sensory neuropathy in mutilated foot (mf) rat mutant.

Methods

A consanguineous Moroccan family with four patients displaying mutilating sensory neuropathy associated with spastic paraplegia was investigated. To identify the disease causing gene, the 11 coding exons of the Cct5 gene were screened for mutations by direct sequencing in all family members including the four patients, parents, and six at risk relatives.

Results

Sequence analysis of the Cct5 gene revealed a missense A492G mutation in exon 4 that results in the substitution of a highly conserved histidine for arginine amino acid 147. Interestingly, R147 was absent in 384 control matched chromosomes tested.

Conclusion

This is the first disease causing mutation that has been identified in the human CCT subunit genes; the mf rat mutant could serve as an animal model for studying these chaperonopathies.