[Scorbut, historic disease ?] / Le cas clinique du mois. Scorbut, maladie historique ?

Scurvy, a disease caused by a deficit in vitamin C, is again described in Europe nowadays. This condition is associated with poverty and malnutrition, as found in developing countries. However, denutrition may also occur with a "western" lifestyle that can lead to nutriment deficiencies. In the following report is described a case of scurvy in a person suffering from alcoholism.

Le scorbut, expression clinique du déficit en vitamine C, est une maladie en recrudescence dans nos sociétés souffrant d'une précarité grandissante et adoptant de façon systématique une alimentation «occidentale¼ carencée en fruits et légumes. Le cas présenté illustre ce problème chez une personne éthylique à risque.

Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology.

We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.

[Clinical case of the month. Hepatitis B reactivation in an Ag HBs negative patient]. / Le cas clinique du mois. Un cas de réactivation virale B chez un patient Ag HBs négatif.

A 66-year-old man, Ag HBs negative, suffering from glomerulonephritis was treated with prednisone. Hepatitis B reactivation was observed after increasing and regression of corticotherapy. Pathogenesis, efficient therapy and prevention of reactivation of hepatitis B will be reviewed.

Phase II trial of pirfenidone in adults with neurofibromatosis type 1.

We performed an open-label phase II trial of oral pirfenidone in 24 patients with neurofibromatosis type 1 (NF1). Tumors were monitored by three-dimensional MRI. At the end of treatment, four patients had a decrease in tumor volume by 15% or more, three had tumor progression, and 17 remained stable. Pirfenidone warrants further investigation in NF1, which has until now lacked an effective control therapy.

Progression of familial and non-familial dilated cardiomyopathy: long term follow up.

BACKGROUND: It is unknown whether progression of familial idiopathic dilated cardiomyopathy differs from progression in the non-familial form. It has been suggested that familial disease indicates a worse prognosis, and that this should be considered when planning the timing of heart transplantation. OBJECTIVE: To compare five year survival or time to heart transplantation in an unselected series of patients with dilated cardiomyopathy who had been evaluated for familial v non-familial disease through the echocardiographic investigation of first degree relatives. DESIGN: Medical records were reviewed and questionnaires were mailed to all patients who had previously participated in a family based study of dilated cardiomyopathy. Information was gathered about survival, heart transplantation, and left ventricular ejection fraction (LVEF) measurements. Survival data were censored at the time of cardiac transplantation. RESULTS: Follow up data were obtained for 99 of 101 patients (69 with non-familial and 30 with familial disease). Five year survival was 55% for non-familial and 51% for familial patients (NS). The main predictor of mortality was an LVEF of < 30%. Familial status did not predict mortality. There was no significant difference in follow up LVEF values between the groups. CONCLUSIONS: Five year survival is not significantly different in the familial and non-familial forms of dilated cardiomyopathy.

[Clinical case of the month. Adult onset Still's disease: a rare cause of acute febrile hepatitis]. / Le cas clinique du mois. La maladie de still de l'adulte: une cause rare d'hépatite aiguë fébrile.

A 63-year-old woman was hospitalized for the third time in one year for asthenia, fever and chills, jaundice, cytolysis and cholestasis. An adult onset Still's disease was diagnosed. Hepatic manifestations, diagnostic criteria and efficient therapy of AOSD will be reviewed.

Familial frontotemporal dementia associated with a novel presenilin-1 mutation.

We report a kindred with three cases of dementia. The proband presented with forgetfulness and personality changes at age 56, followed shortly thereafter by behavioral dyscontrol, hyperphagia, hypersexuality, delusions, illusions, disinhibition and double incontinence. Neuroimaging studies were consistent with frontotemporal dementia (FTD). In one allele, an arginine insertion at codon 352 in the presenilin 1 (PSEN1) gene was identified; no mutation was identified in the amyloid precursor protein or tau genes. We conclude that the clinical features of the Kluver-Bucy syndrome and FTD can be associated with PSEN1 mutations. Furthermore, presenilin analyses may be helpful to characterize kindreds with familial dementing illnesses regardless of the phenotype, particularly if no tau mutation is present.

The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas.

A comprehensive analysis of somatic and germline mutations related to DNA mismatch-repair (MMR) genes can clarify the prevalence and mechanism of inactivation in colorectal carcinoma (CRC). In the present study, 257 unselected patients referred for CRC resection were examined for evidence of defective DNA MMR. In particular, we sought to determine the frequency of hereditary defects in DNA MMR in this cohort of patients. MMR status was assessed by testing of tumors for the presence or absence of hMLH1, hMSH2, and hMSH6 protein expression and for microsatellite instability (MSI). Of the 257 patients, 51 (20%) had evidence of defective MMR, demonstrating high levels of MSI (MSI-H) and an absence of either hMLH1 (n=48) or hMSH2 (n=3). All three patients lacking hMSH2, as well as one patient lacking hMLH1, also demonstrated an absence of hMSH6. DNA sequence analysis of the 51 patients with defective MMR revealed seven germline mutations-four in hMLH1 (two truncating and two missense) and three in hMSH2 (all truncating). A detailed family history was available for 225 of the 257 patients. Of the seven patients with germline mutations, only three had family histories consistent with hereditary nonpolyposis colorectal cancer. Of the remaining patients who had tumors with defective MMR, eight had somatic mutations in hMLH1. In addition, hypermethylation of the hMLH1 gene promoter was present in 37 (88%) of the 42 hMLH1-negative cases available for study and in all MSI-H tumors that showed loss of hMLH1 expression but no detectable hMLH1 mutations. Our results suggest that, although defective DNA MMR occurs in approximately 20% of unselected patients presenting for CRC resection, hereditary CRC due to mutations in the MMR pathway account for only a small proportion of patients. Of the 257 patients, only 5 (1.9%) appear to have unequivocal evidence of hereditary defects in MMR. The epigenetic (nonhereditary) mechanism of hMLH1 promoter hypermethylation appears to be responsible for the majority of the remaining patients whose tumors are characterized by defective DNA MMR.

Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.

Familial paragangliomas (PGL) are slow-growing, highly vascular, generally benign neoplasms, usually of the head and neck, that arise from neural crest cells. This rare autosomal dominant disorder is highly penetrant and influenced by genomic imprinting through paternal transmission. Timely detection of these tumors may afford the affected individual the opportunity to avoid the potential serious morbidity associated with surgical removal and the mortality that may accompany local and distant metastases. Linkage to two distinct chromosomal loci, 11q13.1 and 11q23, has been previously reported. Recently, germline mutations in SDHD, a mitochondrial complex II gene on chromosome 11q23, have been demonstrated. We evaluated members of seven families with PGL, five previously studied and shown to have linkage to chromosome 11q23. The entire coding region of the SDHD gene was sequenced and yielded four novel mutations and one mutation shared in three of our unrelated families. Novel mutations found included a truncating mutation in exon 2, as well as a missense mutation, a deletion, and an insertion in exon 4. Three of our families had a common mutation in exon 3 (P81L) that has been reported and thought to be a founder mutation. A restriction enzyme assay was developed for initial screening of this mutation. Molecular analysis is now available and recommended for presymptomatic diagnosis in those at-risk individuals and for confirmatory diagnosis in those having PGL.

Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy.

Proteins in cardiac myocytes assemble into contractile units known as sarcomeres. Contractile force is generated by interaction between sarcomeric thick and thin filaments. Thin filaments also transmit force within and between myocytes. Mutations in genes encoding the thin filament proteins actin and tropomyosin cause hypertrophic cardiomyopathy. Mutations affecting functionally distinct domains of actin also cause dilated cardiomyopathy (DCM). We used a non-positional candidate gene approach to test further the hypothesis that dysfunction of sarcomeric thin filaments, due to different mutations in the same gene, can lead to either hypertrophic or dilated cardiomyopathy. Mutational analyses of alpha-tropomyosin 1 were performed in patients with idiopathic DCM. We identified two mutations that alter highly conserved residues and that, unlike hypertrophic cardiomyopathy-associated mutations, cause localized charge reversal on the surface of tropomyosin. Therefore, substitution of different amino acid residues in the same thin filament proteins is associated with the distinct phenotypes of cardiac hypertrophy or congestive heart failure.

Isolated supravalvular aortic stenosis: functional haploinsufficiency of the elastin gene as a result of nonsense-mediated decay.

We have used single-strand conformation and heteroduplex analyses of genomic amplimers to identify point mutations within the elastin gene (ELN) in patients with non-syndromic supravalvular aortic stenosis (SVAS) from a total of eight unrelated families. Six novel point mutations were identified. We have collected detailed clinical information on mutation carriers and demonstrated significant non-penetrance in some of the families. Together with the new mutations described here, 14 point mutations have been reported in SVAS patients, and 10 of these result in premature stop codons (PTCs). We have analyzed the expression of ELN alleles in skin fibroblasts from one SVAS patient and shown that PTC mutations indeed result in selective elimination of mutant transcripts. Inhibition of the nonsense-mediated decay mechanism by cycloheximide resulted in the stabilization of mutant elastin mRNA. Allelic inactivation by the ELN mutation in this patient led to an overall decrease of the steady state levels of elastin mRNA. Finally, we have demonstrated reduced synthesis and secretion of tropoelastin by skin fibroblasts from the same SVAS patient. We conclude that PTC mutations in ELN result in nonsense-mediated decay of mutant mRNA in this patient. Given the predominance of PTC mutations in SVAS, we suggest that functional haploinsufficiency may be a pathomechanism underlying most cases of non-syndromic SVAS.

Inherited interstitial deletion of chromosomes 5p and 16q without apparent phenotypic effect: further confirmation.

We describe two families in which an inherited interstitial deletion is present without apparent associated phenotypic abnormalities. The first deletion was discovered in a 19-year-old male with a previously diagnosed peroxisomal disorder. High-resolution chromosome analysis was interpreted as 46,XY,del(5)(p14.1p14.3). The patient's phenotypically normal mother had the same interstitial deletion. Chromosome 5p14 deletion has been reported in a three-generation family without phenotypic anomalies. We hypothesize that the affected son's phenotype may be coincidental or represent unmasking of an autosomal recessive peroxisomal disorder in the deleted region. The second interstitial deletion was detected by amniocentesis for advanced maternal age. High-resolution chromosome analysis was interpreted as 46,XX,del(16)(q13q22). The same deletion was found in the healthy mother and a normal brother. The pregnancy was carried to term and resulted in the birth of a normal girl. We report these cases as further evidence that rare, unbalanced deletion of specific chromosomal regions may result in no phenotypic effect. Consequences may result from expression of an autosomal recessive disorder on the homologous chromosome. Identification of such deletions is especially important for prenatal diagnosis and genetic counselling.

von Hippel-Lindau disease.

An autosomal dominant tumor predisposition syndrome, von Hippel-Lindau disease (VHL) is characterized by the presence of benign and malignant tumors. Hallmark lesions include retinal angiomas, hemangioblastomas of the cerebellum and spinal cord, and renal cell carcinomas. Affected persons may also have angiomatous or cystic lesions of the kidneys, pancreas, and epididymis, as well as adrenal pheochromocytomas. In this article, we discuss the clinical features and diagnostic criteria for this clinically underdiagnosed condition. An update on recent findings regarding the molecular genetics of VHL is provided, including a discussion of the evolving understanding of genotype-phenotype correlations. Understanding the molecular and functional aspects of this condition will lead to the development of strategies for the management and treatment of inherited and sporadic VHL-associated tumors.

Characteristics of two cases with dup(15)(q11.2-q12): one of maternal and one of paternal origin.

PURPOSE: The phenotype correlations for interstitial duplications that include the Prader-Willi/Angelman syndrome critical region are not well established. We describe two such duplication cases, one of which was of maternal origin and the other was paternal. METHODS: High resolution G-banding, fluorescence in situ hybridization (FISH) for SNRP-N and D15S10 were used for cytogenetic analysis. Southern blot analyses based on parent of origin specific DNA methylation at D15S63 (PW71) locus were utilized for detection of methylated and unmethylated fragments. RESULTS: The duplication was established by the FISH analysis. The molecular pattern suggested a maternal origin of the duplication in patient 1 and a paternal origin in patient 2. Patient 1 (2 years old) had developmental and speech delays with pervasive developmental disorder or mild autism, strabismus, and normal growth parameters with seizures. Patient 2 (16 years old) had global developmental delay, verbal IQ of 94, depression, obesity, food-seeking behavior, and significant behavioral problems that included self-injurious tendencies. Neither patient had significant dysmorphic features or abnormalities of internal organs. CONCLUSION: The two cases suggest that some patients with 15q11.2q12 duplication may have significant anomalies, and there appear to be phenotypic differences between maternal and paternal transmission of the duplication.

Severe hypoglycemia as a presenting symptom of carbohydrate-deficient glycoprotein syndrome.

We describe clinical, biochemical, and molecular findings in a 2(1/2)-year-old girl with a phosphomannose isomerase deficiency who presented with severe and persistent hypoglycemia and subsequently developed protein-losing enteropathy, liver disease, and coagulopathy. Six months of therapy with mannose supplementation resulted in clinical improvement and partial correction of biochemical abnormalities.

Guidelines for buccal smear collection in breast-fed infants.

Buccal smear analysis is a noninvasive, fast, and relatively inexpensive diagnostic method. It is used commonly where rapid gender identification is necessary or, more recently, for detection of aneusomy, microdeletion syndromes, and a variety of polymerase chain reaction-based molecular genetic tests. Previously we have shown that maternal cells can contaminate buccal smears taken from breast-fed infants, resulting in difficulty with test interpretation. The aim of this study was to determine optimal timing and technique for buccal smear collection in breast-fed infants in order to avoid diagnostic errors. We analyzed prospectively 50 breast-fed male infants for presence of cells with XX signal pattern from buccal mucosa scrapings at different times after breast feeding. The efficiency of mucosal cleaning on elimination of maternal cells was evaluated by comparing the proportion of XX cells before and after wiping of buccal mucosa with a cotton swab. Maternal cells were present in 23 of 48 (47.9%) samples collected within 5 min of feeding. The proportion of XX signal pattern was significantly (P = 0.001) reduced in samples collected at 30 min (8/48, P = 0.001) and > or =60 min (2/29, P = 0.0002) after feeding. Mucosal cleaning prior to smear collection significantly decreased the number of XX positive samples from 23 of 48 to 10 of 48 (P = 0.002). Buccal smears should not be obtained in nursing neonates until at least 60 min after breast feeding. In addition, prior to sample collection, buccal mucosa should be cleaned thoroughly with a cotton swab applicator. The same guidelines are applicable to older nursing infants.

Supravalvular aortic stenosis: a splice site mutation within the elastin gene results in reduced expression of two aberrantly spliced transcripts.

We have screened the elastin gene for mutations responsible for supravalvular aortic stenosis (SVAS) in two large, independently collected families with isolated (nonsyndromic) SVAS. By single-strand conformation polymorphism and heteroduplex analysis, we have identified a C to G transversion within the acceptor splice site of exon 16 in SVAS patients from both families. This mutation segregates in both families with high penetrance of SVAS, and all affected individuals carry the mutation. Haplotype analysis by using closely linked polymorphisms, including a previously unreported BfaI restriction fragment length polymorphism within the 3'-UTR of the elastin gene, indicates that the mutations found in the two apparently non-overlapping kindreds are identical by descent. To study the effect of the mutation on the expression of the mutant allele, we have established a primary skin fibroblast culture from one of the affected individuals. Reverse transcription/polymerase chain reaction analysis of elastin mRNA species indicates that the mutation results in two abnormal elastin mRNA species. One mutant elastin mRNA is generated by the activation of a cryptic splice site that lies within intron 15 and that adds 44 bp of intronic sequence to the sequence encoded by exon 16. This insertion creates a frame shift that results in a 59-amino-acid-long abnormal protein sequence and leads to a termination codon in the mRNA sequence encoded by exon 17. The smaller abnormal mRNA species arises as a consequence of the skipping of exon 16. This study demonstrates, for the first time, the expression of mutant alleles of the elastin gene in patients with isolated SVAS.

Childhood-onset schizophrenia associated with parkinsonism in a patient with a microdeletion of chromosome 22.

The deletion of a gene or genes on chromosome 22q11 is responsible for the velocardiofacial syndrome (VCFS), which is associated with cardiac anomalies, short stature, palate abnormalities, learning disabilities, and developmental delay. Herein we describe a 30-year-old man with VCFS in whom a chronic psychotic disorder originated during childhood. A 10% rate of psychotic disorders has been reported in association with this genetic syndrome. In our patient, the clinical manifestation was complicated by extrapyramidal symptoms that predated the onset of psychotic symptoms. To our knowledge, extrapyramidal symptoms have not previously been reported in a patient with VCFS. The diagnosis of VCFS was confirmed with the fluorescence in situ hybridization probe for VCFS. The role of the atypical antipsychotic drug clozapine is discussed with respect to treating this patient who has severe psychotic symptoms coexisting with extrapyramidal symptoms and seizures. In light of the observation that patients with VCFS have an unexpectedly high rate of psychotic disorders, issues concerning the genetics of schizophrenia are intriguing.

Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion.

Autosomal dominant cerebellar ataxias are a heterogeneous group of neurodegenerative disorders that generally present in adulthood. Spinocerebellar ataxia type 2 typically presents with progressive cerebellar symptoms, slow ocular saccades, and peripheral neuropathy. The onset of symptoms is usually between 20 and 40 years. We describe an infant who presented with neonatal hypotonia, developmental delay, and dysphagia. Ocular findings of retinitis pigmentosa were noted at 10 months. Her father had mild spinocerebellar ataxia first noted at age 22 years. Molecular studies of the SCA2 gene showed a CAG expansion of 43 repeats in the father and an extreme CAG repeat expansion of more than 200 in the baby. Our report expands the known phenotype and genotype of SCA2. Testing for dominant ataxias should be included in the evaluation of infants with nonspecific progressive neurologic symptoms and retinitis pigmentosa, especially in cases with a positive family history for spinocerebellar ataxia.