Overlap syndrome between FMF and TRAPS in a patient carrying MEFV and TNFRSF1A mutations.

OBJECTIVE: Familial Mediterranean Fever (FMF) and TNF-Receptor Associated Periodic Syndrome (TRAPS) are two inheritable inflammatory disorders. They share some clinical manifestations but their treatments are different. We present here the case of an overlap syndrome of FMF and TRAPS in a patient carrying a mutation in both the MEFV and TNFRSF1A genes. CASE REPORT: A 20-year-old woman of Mediterranean origin had suffered since childhood from attacks of fever and arthritis, with skin and ophthalmic manifestations. The initial diagnosis was FMF. The symptoms responded poorly to colchicine but regressed with steroids. Genetic analysis revealed a homozygous M694V mutation in MEFV and a heterozygous R92Q mutation in TNFRSF1A. We discuss the complexity of this combined FMF-TRAPS phenotype. CONCLUSION: This case shows that mutations in MEFV and TNFRSF1A can occur together in a single patient, a condition that may modify its response to treatment. It would be interesting to evaluate the role of the R92Q mutation in TNFRSF1A in patients of Mediterranean origin with FMF unresponsive to colchicine.

An accidental decapitation resulting from head protruding out of bus.

Decapitation is the separation of the head from the neck. Accidental decapitation is rare, and very few cases are cited in the literature. In this case, the victim was asleep during an overnight trip with her head sticking out of the window, and she was decapitated by a truck travelling in the opposite direction. Lack of security grilles on windows, high-speed driving, narrow roads and night travel were contributing factors. This case is presented for its rarity and pattern of injuries during the fatal mishap and to consider possible preventive measures.

Deletion of CPEB1 Gene: A Rare but Recurrent Cause of Premature Ovarian Insufficiency.

CONTEXT: Premature ovarian insufficiency (POI) may be secondary to chemotherapy, radiotherapy, or environmental factors. Genetic causes are identified in 20-25% of cases, but most POI cases remain idiopathic. OBJECTIVE: This study aimed to identify new genes involved in POI and to characterize the implication of CPEB1 gene in POI. DESIGN AND SETTING: This was a case report and cohort study replicate conducted in academic medical centers. PATIENTS AND METHODS: A deletion including CPEB1 gene was first identified in a patient with primary amenorrhea. Secondly, 191 sporadic POI cases and 68 familial POI cases were included. For each patient, karyotype was normal and FMR1 premutation was excluded. Search for CPEB1 deletions was performed by quantitative multiplex PCR of short fluorescent fragments or DNA microarray analysis. Gene sequencing of CPEB1 was performed for 95 patients. RESULTS: We identified three patients carrying a microdeletion in band 15q25.2. The proximal breakpoint, for the three patients, falls within a low-copy repeat region disrupting the CPEB1 gene, which represents a strong candidate gene for POI as it is known to be implicated in oocyte meiosis. No mutation was identified by sequencing CPEB1 gene. Therefore, heterozygous deletion of CPEB1 gene leading to haploinsufficiency could be responsible for POI in humans. CONCLUSION: Microdeletions of CPEB1 were identified in 1.3% of patients with POI, whereas no mutation was identified. This microdeletion is rare but recurrent as it is mediated by nonallelic homologous recombination due to the existence of low-copy repeats in the region. This result demonstrates the importance of DNA microarray analysis in etiological evaluation and counseling of patients with POI.

Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations.

Seventy-nine unrelated Lebanese patients were tested for 15 mutations in the MEFV gene: A761H, A744S, V726A, K695R, M694V, M694I, M694del, M6801 (G --> C), M680I (G --> A) in exon 10, F479L in exon 5, P369S in exon 3, T267I, E167D and E148Q in exon 2, using PCR digestion, ARMS, DGGE and/or sequencing. Mutations were detected in patients belonging to all communities, most interestingly the Maronite, Greek orthodox, Greek catholic, Syriac and Chiite communities. The most frequent mutations are M694V and V726A (27% and 20% of the total alleles respectively). M694I, E148Q and M680I mutations account respectively for 9%, 8% and 5%. Each of the K695R, E167D and F479L mutations was observed once and all the remaining mutations were not encountered. Of the alleles 33% do not carry any of the studied mutations. The mutation spectra, clinical features and severity of the disease differed among the Lebanese communities. The genotype-phenotype analysis showed a significant association (P < 0.001) between amyloidosis and the presence of mutations at codon 694 in exon 10 (both M694V and M694I). None of the patients carrying other mutations developed amyloidosis.

CAG/CTG repeat expansions at the Huntington's disease-like 2 locus are rare in Huntington's disease patients.

The authors report a large series of patients with Huntington disease (HD)-like phenotype without CAG repeat expansions in the IT15 gene that were screened for the newly identified CAG/CTG expansion in the gene encoding junctophilin-3. Normal alleles in controls had from 8 to 28 repeats. A single patient of North African origin with typical HD carried an allele with 50 uninterrupted repeats, representing approximately 2% of the non-IT15 HD patients tested. Therefore, further genetic heterogeneity is expected in HD.

Interaction of human gamma-carboxyglutamic acid domainless prothrombin with phospholipids.

The conversion of prothrombin into thrombin occurs at the surface of stimulated platelets. In order to see the influence of gamma-carboxyglutamic acid in the interaction of prothrombin with phospholipid, we investigated the direct interaction of the peptide 1-41 and prothrombin (des 1-44) with phospholipid monolayers of various compositions. Adsorption of the labeled proteins was determined by surface radioactivity measurements. Penetration of the proteins into the lipid layers was inferred from capacitance variation of the monolayer, measured by a.c. polarography. Prothrombin (des 1-44) was found both to adsorb and to penetrate the lipid monolayers, in the presence and in the absence of Ca++. The effects are higher on 100% PS than on 25% PS. This protein was also found to increase the permeability of vesicles containing 25% PS to T1+ ions, in the presence and in the absence of Ca++. Comparison with prothrombin shows that Gla residues are clearly involved in the interaction at 25% PS; nevertheless, the peptide 1-41 does not penetrate. A model of interaction of prothrombin with phospholipid, including both adsorption of prothrombin by Gla residues and its penetration by another domain, is proposed.

Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autosomal recessively inherited disease affecting patients of the Mediterranean basin. FMF is characterized by recurrent episodes of fever accompanied with topical signs of inflammation. Some patients can develop a renal amyloidosis associated (AA) amyloidosis. The administration of colchicine is an effective preventive treatment of both the attacks and amyloidosis. The FMF gene (MEFV) was cloned and missense mutations were found to be responsible for the disease. We investigated a large series of 303 unselected and unrelated patients of various ethnic backgrounds with a clinical suspicion of FMF to confirm or invalidate the diagnosis of FMF and to determine the spectrum of MEFV mutations. Molecular analysis focused on all the most frequent mutations identified so far, and an exhaustive analysis of exon 10, containing the mutational hotspot, was performed through DNA sequencing. Sixty-two percent of Sephardic, North African Arabs, Armenian and Turkish patients were either homozygous or compound heterozygous for MEFV mutations. In other populations surrounding the Mediterranean Sea such as Greek, Italian, Portuguese, Kurdish and Lebanese populations, mutations were also found. In general, patients without Mediterranean origin had no mutations in the MEFV gene. Two new mis-sense mutations were identified in exon 10 of the MEFV gene: the S675N in an Italian patient and the M680L in a French patient without any known at-risk ethnic ancestry.

Clinical versus genetic diagnosis of familial Mediterranean fever.

The diagnosis of familial Mediterranean fever (FMF) has until recently been based on clinical signs alone. Discovery of the MEFV gene has enabled a molecular approach to diagnosis, which is already well established for diagnosing typical clinical forms of FMF. We evaluated the utility of this molecular approach in a large series of patients with various clinical presentations and ethnic origins. We looked for mutations in the MEFV gene in 303 unselected consecutive patients with a variable (from high to low) clinical suspicion of FMF. Two mutations were found in 133 patients (44%). In 22 patients (7%), the clinical diagnosis of FMF was unlikely according to the Tel Hashomer clinical criteria. Our results suggest that the spectrum of FMF-associated signs is broader than previously believed. Wider indications for genotyping should lead to more frequent diagnosis of FMF.

Diagnosis of "sporadic" Huntington's disease.

The diagnosis of Huntington's disease (HD) in patients with progressive chorea and mental impairment, but without similarly affected relatives, remains uncertain and impedes genetic counseling. Twenty patients with suspected HD, but with no family history of the disease underwent molecular analysis of the CAG repeat in the IT15 gene for HD. Eighteen patients displayed the HD expanded allele and two had CAG repeats in the normal range. Neuropsychological tests could be performed in 12 of the 20 patients. Of these 10 with the expanded allele presented the deficits typical of HD, but not the two patients without the HD mutation. This study shows that a neuropsychological pattern is specific to patients with the expanded CAG and that most isolated patients with suspected HD are in fact affected.

MEFV mutations and phenotype-genotype correlations in North African Jews and Armenians with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever is a genetic disease in which some characteristic gene mutations have been found. OBJECTIVES: To analyze the phenotype-genotype correlations in North African Jews and Armenians with FMF. METHODS: We studied MEFV gene mutations and phenotype-genotype correlations in North African Jews and Armenians with Familial Mediterranean Fever living in France. RESULTS: M694V mutation was the most common mutation in Jews and in Armenians. Patients with M680I homozygosity or M680I/M694V compound heterozygosity had a phenotype as severe as patients with M694V homozygosity. CONCLUSIONS: This study characterizes the phenotype-genotype in specific ethnic groups of patients with FMF.

[Tumor necrosis factor receptor superfamily 1A-associated periodic syndrome (TRAPS)]. / Le syndrome de fièvre héréditaire lié à un dysfonctionnement du récepteur du TNF ou Traps.

PURPOSE: Tumor necrosis factor receptor superfamily 1A associated periodic syndrome (TRAPS) belongs to the group of hereditary fever syndromes, also called hereditary auto-inflammatory syndromes. CURRENT KNOWLEDGE AND KEY POINTS: The diagnosis of TRAPS should be evoked in presence of the following clinical signs, whatever the population of the affected patients. TRAPS acute inflammatory access, of 1 to 3 weeks' duration, is characterised by the presence of fever, abdominal pain, myalgias, various types of skin rash including erysepela-like erythema. Long term inflammatory response can lead to AA amyloidosis. Genetic testing will confirm the diagnosis when showing a mutation in the extracellular part of the TNFRSF1A receptor. Therapeutic management of TRAPS is not definitely established. Daily colchicine does not seem to prevent efficiently inflammatory attacks. Corticosteroids, in contrast can attenuate the intensity and diminish the duration of attacks. FUTURE PROSPECTS AND PROJECTS: The value of biological agents that inhibits TNF action is not yet completely determined in TRAPS. Mechanisms of the disease are not yet elucidated. In some families with specific mutations, a relative soluble TNF receptor deficiency has been found in the plasma. However this mechanism does not account for what is observed in other kindreds.

Clinical genetics of Kallmann syndrome.

The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease (KAL1). Mutations in FGFR1 or FGF8, encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance (KAL2). Mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in autosomal recessive monogenic (KAL3) and digenic/oligogenic KS transmission modes. Mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered. Notably, KS may also be part of pleiotropic developmental diseases including CHARGE syndrome; this disease results in most cases from neomutations in CHD7 that encodes a chromodomain helicase DNA-binding protein.

The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al.

Kallmann syndrome (KS) combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to gonadotropin-releasing hormone (GnRH) deficiency, which presumably results from a failure of the embryonic migration of neuroendocrine GnRH cells from the olfactory epithelium to the forebrain. This failure could be a consequence of the early degeneration of olfactory nerve and terminal nerve fibres, because the latter normally act as guiding cues for the migration of GnRH cells. Defects in GnRH cell fate specification, differentiation, axon elongation or axon targeting to the hypothalamus median eminence may, however, also contribute to GnRH deficiency, at least in some genetic forms of the disease. To date, five KS genes have been identified, namely, FGFR1, FGF8, PROKR2, PROK2, and KAL1. Mutations in these genes, however, account for barely 30% of all KS cases. Mutations in FGFR1, encoding fibroblast growth factor receptor 1, underlie an autosomal dominant form of the disease. Mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous or compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic or oligogenic KS transmission modes. Finally, KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked form of the disease. It is believed that anosmin-1 acts as an enhancer of FGF signalling and perhaps of prokineticin signalling too.

Clinical significance of P46L and R92Q substitutions in the tumour necrosis factor superfamily 1A gene.

OBJECTIVE: Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) has been associated with several mutations in the TNF receptor super family 1A (TNFRSF1A), including most cysteine substitutions. However, the nature of two substitutions, P46L and R92Q, remains a topic of discussion. The aim of this study was to assess the actual role of these two sequence variations in a series of patients with TRAPS. METHODS: The main clinical data of 89 patients with TRAPS have been prospectively registered on a standard form. 84 patients or members of families with recurrent episodes of inflammatory symptoms spanning a period of more than 6 months and harbouring a TNFRSF1A mutation were studied. Clinical data have been analysed according to the nature of the mutation-P46L, R92Q or others. RESULTS: P46L is often seen in patients from Maghreb and is associated with a mild phenotype. P46L appears as a polymorphism with a non-specific role in inflammation. R92Q is associated with a variable phenotype and presents as a low-penetrance mutation. Interpreting these results will require a comparison with clinical signs and genetic background.

Early and severe amyloidosis in a patient with concurrent familial Mediterranean fever and pseudoxanthoma elasticum.

A young woman patient had early and extensive familial Mediterranean fever (FMF)-related amyloidosis and pseudoxanthoma elasticum (PXE). She had the novel G1042S mutation in the ATP-binding cassette subfamily C member 6 (ABCC6) gene, responsible for PXE, and the mutation M694I in MEFV, the FMF gene. Both mutations were homozygous, in agreement with consanguinity in the parents. ABCC6 deficiency may have increased the severity of amyloidosis by increasing the deposition in target tissues of heparan sulphate, which colocalizes spatially and temporally with amyloid proteins, and/or by decreasing the therapeutic activity of colchicine.

Types of alpha+ thalassemia in Southeast Asia refugees.

We have determined alpha+ deletional thalassemia among 143 Southeast Asia refugees (Cambodians, Laotians, and Vietnameses). Gene frequency of alpha+ deletional thalassemia in Vietnameses (0.035) was found lower than in Cambodians and Laotians (0.11). Bam H1 and Bg1 II analysis indicated that both rightward and leftward thalassemias are encountered, the -alpha 3,7 form is being by far more frequent than the -alpha 4.2 one. Only type I cross-over was found by Apa I digestion on -alpha 3.7 chromosomes. The Rsa I polymorphism, 5' to Z alpha 2 block, is associated with -alpha 3.7 type I haplotype and the site is present in 12 out of 23 chromosomes. All these data suggest at least three origins of alpha+-thalassemia in Cambodia and Laos.

Locus assignment of human alpha globin mutations by selective amplification and direct sequencing.

We describe a simple approach for molecular characterization and locus assignment of structural mutants by direct sequencing of enzymatically amplified DNA selective to alpha 1 and alpha 2 globin gene regions. Nucleotide substitution of two structural variants (Stanleyville II alpha 2(78Lys) and J Mexico alpha 2(54Glu) were determined and their encoding loci were specified. The amplified segment encompasses sequences upstream of the CAAT box to downstream of the Poly(A) addition signal. Hence all of the alpha globin structural variants and most of the nondeletion alpha thalassaemic mutants should be characterizable by this approach.

Rapid analysis of -alpha 3.7 thalassaemia and alpha alpha alpha anti 3.7 triplication by enzymatic amplification analysis.

In this report we describe a PCR-based method for the diagnosis of the most common form of alpha thalassaemia, the -alpha 3.7 deletion which occurs throughout all tropical and subtropical regions of the world. The same procedure also identifies the reciprocal recombinant chromosome (alpha alpha alpha anti 3.7). Restriction mapping of the PCR products has enabled us to distinguish between the type I (-alpha 3.7 I), type II (-alpha 3.7 II) and type III (-alpha 3.7 III) deletions. This strategy will be very useful in screening programmes of alpha thalassaemia occurring on its own or in association with beta thalassaemia and sickle cell disease.

Level and composition of fetal hemoglobin expression in normal newborn babies are not dependent on beta cluster DNA haplotype.

Interindividual variations in the level and composition of fetal hemoglobin observed in 604 cord blood samples from normal white and nonwhite newborns, unlike those in adults, are not dependent on beta gene cluster DNA haplotype. The data suggest that the mechanism(s) involved in the neonatal expression of Hb F is distinct from that at the adult stage.