Search

Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by developmental delay and multiple malformations. Some of the patients have skin photosensitivity and therefore tend to avoid direct exposure to sunlight.SLOS patients typically have low concentrations of cholesterol and abnormally high concentrations of its precursor 7-dehydrocholesterol (7-DHC) in biological fluids and tissues. 7-DHC is also a precursor in the cutaneous synthesis of vitamin D. Sunlight exposure plays a major role in this pathway and reactions transforming 7-DHC into vitamin D and then into 25-hydroxyvitamin D are known not to be specifically regulated. The aim of this study was to evaluate vitamin D status in SLOS patients. We measured 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum concentrations and markers of calcium metabolism in five SLOS patients. Despite abnormally high concentrations of 7-DHC, circulating concentrations of vitamin D metabolites were not significantly different from appropriate controls matched for sex, age and season of blood collection. The analysis of historical serum samples stored in our laboratory from the same cases plus 10 other SLOS patients further supported these findings. Our data suggest that SLOS patients have a peculiar vitamin D metabolism that protects them from vitamin D intoxication. This appears to be due in most cases to decreased transformation of 7-DHC into 25-hydroxyvitamin D, perhaps depending on reduced sunlight exposure as a consequence of photosensitivity. Possible alternative mechanisms are discussed.

We report a father and son affected by spondylo-epi-metaphyseal dysplasia with multiple dislocations (Hall type), also called leptodactylic form. This family contributes to the delineation of the clinical and radiological phenotype of this rare condition.

Gaucher disease, the most common lysosomal storage disorder, is a heterogeneous multisystem condition. Patients with non-neuronopathic (type 1) Gaucher disease may suffer from hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life. Enzyme replacement therapy (ERT) with mannose-terminated glucocerebrosidase reverses or ameliorates many of the manifestations of type 1 Gaucher disease. However, the variable disease pattern and severity, and the uncertain manner of progression, render the decision to initiate ERT difficult. Thus, implementation of treatment and evaluation of the therapeutic response must be tailored to the individual patient. To obtain an evidence-based consensus on contemporary therapeutic goals, an international panel of physicians with extensive clinical experience in Gaucher disease met to review the extant literature on its treatment. The panel adopted an integrated system-based approach to arrive at a comprehensive guide to individualized management. Here we establish goals of treatment in Gaucher disease and propose a comprehensive schedule of monitoring of all relevant aspects to confirm the achievement, maintenance, and continuity of the therapeutic response.

For patients with type 1 Gaucher disease, challenges to patient care posed by clinical heterogeneity, variable progression rates, and potential permanent disability that can result from untreated or suboptimally treated hematologic, skeletal, and visceral organ involvement dictate a need for comprehensive, serial monitoring. An updated consensus on minimum recommendations for effective monitoring of all adult patients with type 1 Gaucher disease has been developed by the International Collaborative Gaucher Group (ICGG) Registry coordinators. These recommendations provide a schedule for comprehensive and reproducible evaluation and monitoring of all clinically relevant aspects of this disease. The initial assessment should include confirmation of deficiency of beta-glucocerebrosidase, genotyping, and a complete family medical history. Other assessments to be performed initially and at regular intervals include a complete physical examination, patient-reported quality of life using the SF-36 survey, and assessment of hematologic (hemoglobin and platelet count), visceral, and skeletal involvement, and biomarkers. Specific radiologic imaging techniques are recommended for evaluating visceral and skeletal pathology. All patients should undergo comprehensive regular assessment, the frequency of which depends on treatment status and whether therapeutic goals have been achieved. Additionally, reassessment should be performed whenever enzyme therapy dose is altered, or in case of significant clinical complication.

We present a case of recurrent pulmonary alveolar proteinosis after heart-lung transplantation in a child with lysinuric protein intolerance. The recurrence of the pulmonary disease provides further insight regarding the possible pathogenesis of pulmonary alveolar proteinosis and therapeutic options for this complication.

Objective: To investigate brain morphology and function in patients with glycogen storage disease type I (GSDI)., Study Design: Nineteen patients (13 females and 6 males, aged 0.9-22.6 years) and 38 sex- and age-matched controls entered the study. Neurological examinations, psychometric tests (IQ, tests of performance and verbal abilities), standard electroencephalogram (EEG), somatosensory (SEPs), visual (VEPs), and brain-stem auditory evoked potentials (BAEPs), and brain magnetic resonance imaging (MRI) were performed., Results: The results of tests of performance ability were lower in patients than in controls (P <.05). The prevalence of abnormal EEG findings (26.3% versus 2.6%), VEPs (38.4% versus 7.7%), SEPs (23.0% versus 0%), and BAEPs abnormalities (15.7% versus 0%) was higher in patients than in controls (P <.05). MRI pattern was altered in 57.1% of patients and was normal in all controls (P <.05). Both results of tests of performance ability and BAEPs abnormalities significantly correlated with the frequency of admissions for hypoglycemia, whereas EEG abnormalities correlated with dietary compliance (P <.05)., Conclusions: Brain damage, probably caused by recurrent severe hypoglycemia, may be present in patients with GSDI.

Background and Objective: An international study on the frequency of the mutation 677C-T of the methylenetetrahydrofolate reductase (MTHFR) gene and its genotypes has been performed on a sample of consecutive liveborn infants around the world. In that study Spain participated through the ECEMC group. Here we present the distribution of the frequency of the T-allele by Spanish Regions (Autonomic Comunities)., Subjects and Method: The ECEMC collaborating physicians gathered blood samples from 15 consecutive liveborn infants in 67 hospitals from all over the country during the same months, specifying the ethnicity and sex of each infant. The frequency of the mutation was estimated through the percentage with its confidence interval. The *2 of homogeneity (k-1 degrees of freedom) was used to confirm that the frequencies were not statistically different across the country., Results: The frequency distribution of the TT genotype does not differ significantly between Spanish Regions., Conclusions: This seems to be the first nation-wide study on a homogeneous sample of individuals. The observed frequencies are in agreement with those observed in some published studies on specific Spanish geographic areas. The overall frequency is similar to that reported in Mediterranean countries.

Unlabelled: Gaucher disease is caused by defective activity of glucocerebrosidase. The resulting accumulation of glucocerebroside in the lysosomes of visceral macrophages in various tissue and organ compartments leads to multiple manifestations, including hepatosplenomegaly, anemia, thrombocytopenia, growth retardation and skeletal disease. The most prevalent form of Gaucher disease is the non-neuronopathic (type 1) variant, which lacks primary involvement of the central nervous system. Traditionally, this has been referred to as the 'adult type'; however, 66% of individuals with symptomatic non-neuronopathic Gaucher disease manifest in childhood. Onset in childhood is usually predictive of a severe, rapidly progressive phenotype and children with non-neuronopathic Gaucher disease are at high risk for morbid complications. Enzyme therapy with recombinant human glucocerebrosidase in childhood can restore health in reversible manifestations and prevent the development of irreversible symptoms. A heightened focus on pediatric Gaucher disease is therefore needed. Although some correlation has been found between genotype and phenotype, mutation analysis is of limited value in disease prognosis. Management of pediatric Gaucher disease should be underpinned by a thorough assessment of the phenotype at baseline with regular monitoring thereafter. Excluding neuronopathic disease is recommended as the first step. Subsequently, baseline evaluation should focus on staging of different storage tissues, particularly the bone the involvement of which results in the greatest long-term morbidity. These organ assessments are recommended because bone disease severity may not correlate with disease severity in other organs and vice versa. In addition, different organs may respond differently to therapy. Initial assessment of each organ system can enable setting of realistic and individualized goals., Conclusion: A thorough approach to baseline assessment will improve the understanding of childhood Gaucher disease, optimizing management to minimize impairment of growth and development and prevent irreversible symptoms.

Unlabelled: In individuals with non-neuronopathic Gaucher disease, childhood manifestations are usually predictive of a more severe phenotype. Although children with Gaucher disease are at risk of irreversible disease complications, early intervention with an optimal dose of enzyme therapy can prevent the development of complications and ensure adequate, potentially normal, development through childhood and adolescence. Very few, if any, children diagnosed by signs and symptoms should go untreated. Evidence suggests that disease severity, disease progression and treatment response in different organs where glucocerebroside accumulates are often non-uniform in affected individuals. Therefore, serial monitoring of the affected compartments is important. This should include a thorough physical examination at 6- to 12-monthly intervals. Neurological assessment should be performed to rule out neurological involvement and should be undertaken periodically thereafter in children who are considered to have risk factors for developing neuronopathic disease. Haematological and biochemical markers, such as haemoglobin, platelet counts and chitotriosidase levels, should be assessed every 3 months initially, but when clinical goals have been met through treatment with enzyme therapy, the frequency can be reduced to every 12 to 24 months. Careful monitoring of bone disease is vitally important, as the resulting sequelae are associated with the greatest level of morbidity. By combining various imaging modalities, the skeletal complications of non-neuronopathic Gaucher disease can be effectively monitored so that irreversible skeletal pathology is avoided and pain due to bone involvement is diminished or eliminated. Monitoring must include regular psychosocial, functional status and quality-of-life evaluation, as well as consistent assessment of therapeutic goal attainment and necessary dosage adjustments based on the patient's progress., Conclusion: Through comprehensive and serial monitoring, ultimately, a therapeutic dose of enzyme therapy that achieves sustained benefits can be found for each child with non-neuronpathic Gaucher disease.

Baraitser-Winter syndrome is a rare autosomal recessive disorder characterized by developmental delay, dysmorphic features, and multiple malformations also involving the brain. We report a further case and provide updated information about an unrelated girl reported in the original paper by Baraitser and Winter. Both of them presented with pachygyria and the latter case was recently found to have subcortical band heterotopia on high resolution brain MRI imaging. These two patients and a review of the previously reported cases indicate that a specific pattern of brain anomalies falling in the agyria-pachygyria-band spectrum is associated with this dysmorphic syndrome, which may be considered another example of syndromic neuronal migration defect.

We report on a 17-year-old male with severe pre- and postnatal growth retardation, craniosynostosis, distinctive facial features, acanthosis nigricans, deafness, mental retardation and progressive multi-organ involvement, particularly of the endocrine system, including hypothyroidism, hypogonadism, transitory hypoparathyroidism, and insulin resistance. In order to find a common mechanism explaining these multiple abnormalities, we searched for a possible defect in the signal transduction pathways from membrane to nucleus involving G-protein coupled receptors (GPCR). Adenylyl cyclase activity was evaluated by assaying c-AMP in the patient's cultured fibroblasts stimulated with several drugs and toxins acting on different effectors upstream of adenylyl cyclase. The preliminary results indicate a reduced cAMP accumulation in the patient, neither caused by constitutive activation of Gi nor inhibition of Gs signaling, and probably resulting from an alteration in the adenylyl cyclase system. The differential diagnosis with syndromes showing common clinical features with our patient is discussed., (Copyright 2003 Wiley-Liss, Inc.)

Lowry-Wood syndrome (LWS) is a rare condition characterized by multiple epiphyseal dysplasia (MED), microcephaly, and congenital nystagmus. A variable degree of mental retardation can also be present. It is probably inherited as an autosomal recessive trait. We report a new case of MED and microcephaly, without other additional features, suggesting a mild form of LWS. Molecular analysis of the cartilage oligomeric matrix protein (COMP) gene was performed and failed to find mutations., (Copyright 2003 Wiley-Liss, Inc.)

X-linked chondrodysplasia punctata (CDPX1), due to mutations of the arylsulfatase E (ARSE) gene, is a congenital disorder characterized by abnormalities in cartilage and bone development. We performed mutational analysis of the ARSE gene in a series of 16 male patients, and we found mutations in 12 subjects. Clinical variability was observed among the patients, including severe presentations with early lethality in one of them, and symptoms such as cataract and respiratory distress. This indicates that the clinical spectrum of CDPX1, commonly considered a relatively mild form of chondrodysplasia punctata, is wider than previously reported. Different types of mutations were found among the patients examined. Three missense mutations (I80N, T481M, P578S) were expressed in Cos7 cells to study the effects on arylsulfatase E catalytic activity. These mutations caused impaired enzymatic activity suggesting that they are responsible for the disease. Two nonsense mutations, W581X in four patients and R540X in one, were found. One patient showed an insertion (T616ins). In three patients we found deletions of the ARSE gene: in one the deletion involved only the 3' end of the gene, while in two the ARSE gene was completely deleted., (Copyright 2002 Wiley-Liss, Inc.)

Aim of this study was to confirm the initial results of a clinical trial on the treatment of Fabry's disease carried out in 13 Italian Nephrology Units. Fabry's disease is a rare, X-linked inherited disease, characterized by a-galactosidase (a-GAL) deficiency, a lysosomial enzymatic activity that results in the accumulation of neutral glycosphingolipids in the endothelial cells of the whole body, and causes painful crises, acroparesthesiae, angiokeratomas, corneal and lens dystrophy, and progressive damage to kidneys, heart and central nervous system, as well as potentially leading to death. The present availability of the recombinant form of a-GAL allows us to prevent or stop the long-term complications of this disease. A clinical trial, generously supported by Genzyme, was started on February 2001. In this trial 20 patients affected by Fabry's disease were periodically treated with agalsidase-beta, the commercial form of the enzyme. The initial results of the trial have indicated that the drug is capable of reducing both the number and intensity of painful crises, improving the patient's sensation of well-being, thus suggesting that this therapeutic approach might theoretically increase life expectancy in these patients.

N-Butyldeoxynojirimycin (NB-DNJ, miglustat 'Zavesca') is an orally active iminosugar which inhibits the biosynthesis of macromolecular substrates that accumulate pathologically in glycosphingolipidoses. Clinical trials of NB-DNJ in patients with Gaucher's disease demonstrate the therapeutic potential of such substrate inhibitors in the glycolipid storage disorders. However, macrophage-targetted enzyme replacement using intravenous mannose-terminated human glucocerebrosidase (imiglucerase, Cerezyme) is highly effective in ameliorating many of the manifestations of Gaucher's disease and is a treatment in widespread use. Given that imiglucerase and miglustat are now both licensed for the treatment of Gaucher's disease, there is a need to review their therapeutic status. Here the treatment of type 1 (non-neuronopathic) Gaucher disease is evaluated with particular reference to the emerging role of oral N-butyldeoxynojirimycin (miglustat) as a substrate-reducing agent. This position statement represents the consensus viewpoint of an independent international advisory council to the European Working Group on Gaucher Disease.

Background: Epidemiological studies about atopic dermatitis (AD) almost exclusively relate to childhood disease with little mention of adult-onset disease. In clinical practice, however, patients who have AD and in whom the onset of disease occurs in adult life are sometimes seen., Objective: Because the subjects with a chronic and recalcitrant eczema are frequently patch tested, the aim of this study was to evaluate the prevalence of adult-onset AD in a patch test population and the differences existing between the early- and adult-onset subsets., Methods: This retrospective analysis was performed on 502 adults (458 males, 44 females) affected by eczematous dermatitis, consecutively examined in the Department of Dermatology of the Italian Navy Hospital in Taranto. In this department, all the eczematous subjects are routinely submitted to the following tests: standard series (GIRDCA or SIDAPA with integrative haptens), prick test with environmental aeroallergens and common food allergens and dosage of total serum IgE. If it is required, additional series of patch tests are also applied. Many patients are also submitted to the atopy patch test (APT) with whole bodies of house dust mites at a concentration of 20%. In the AD patients, diagnosed according to the criteria of Hanifin and Rajka, the ages of onset were subdivided into the following categories: infancy (0-3 years); childhood (4-11 years); adolescence (> or =12 years). We arbitrarily also used the age of 18 years as the cut-off mark to allocate the patients to the adult-onset group (AOG) and defined as early-onset group (EOG) the cases encompassed in the aforesaid categories (i.e. onset < or =17 years)., Results: 8.8% of all eczemas were adult-onset ADs. 28 (5.6% of all eczemas) adult-onset ADs were 'sole' ADs, while 22 cases (3.2% of all eczemas) were adult-onset ADs in which a contact sensitization was detected. The mean SCORAD indexes, according to the age-of-onset groups, decreased when the age of onset increased. No statistical difference was detected between the EOG and AOG with regard to true contact sensitization, clinically relevant or non-relevant contact sensitization, prevalence of 'pure' AD and 'mixed' AD, and outcome of the APT. The hands were the most frequently affected site in the AOG., Conclusion: A small but significant number of patch-test-negative eczematous cases could be adult-onset ADs and, in this instance, the other two allergological tests (i.e. prick tests and dosage of total serum IgE) and an accurate evaluation according to stated clinical criteria should be performed. However, other studies on large series of patients are required to confirm our observation., (Copyright 2003 S. Karger AG, Basel)

Background: No reports on the frequency of X-linked ichthyosis (XLI) in the Italian general population and few surveys on the frequency of XLI in large communities in the world are available., Objective: The aim of this study was the assessment of the frequency of XLI in a large representative sample of the Italian male population., Subjects and Methods: This study involved young men who enlisted as conscripts in the Italian Navy from January 1998 through February 2002, examined, prior to enlistment, at the Draft Council's Medical Unit of the Italian Navy in Taranto, Italy, to evaluate their psychophysical fitness. All the patients with an ichthyosiform condition were referred to the Department of Dermatology of the Navy Hospital, underwent a thorough dermatological examination and completed a questionnaire regarding their personal and familial history. Pertinent results of the other clinical investigations were recorded and the final diagnosis was formulated on the basis of all these data., Results: From January 1998 through February 2002, of 75,653 young men examined, 15 cases of XLI were diagnosed, with a frequency of 1:5,043 or 1.98 per 10,000 (95% confidence interval based on the Poisson distribution 1.01-2.90). Four out of 15 cases (26.6%) showed corneal opacities. No other significant associated pathological change was observed., Conclusions: As this study is a survey involving a large male sample, homogeneous with reference to age, race and country of origin (southern Italy), the frequency of XLI could be estimated at about 1.98 per 10,000 males. These data are roughly in agreement with estimates from other European surveys., (Copyright 2003 S. Karger AG, Basel)

We report the clinical, biochemical, and molecular characterization of a patient with a novel defect of cholesterol biosynthesis. This patient presented with a complex phenotype, including multiple congenital anomalies, mental retardation, and liver disease. In the patient's plasma and cells, we found increased levels of lathosterol. The biosynthesis of cholesterol in the patient's fibroblasts was defective, showing a block in the conversion of lathosterol into 7-dehydrocholesterol. The activity of 3beta-hydroxysteroid-Delta(5)-desaturase (SC5D), the enzyme involved in this reaction, was deficient in the patient's fibroblasts. Sequence analysis of the SC5D gene in the patient's DNA, showing the presence of two missense mutations (R29Q and G211D), confirmed that the patient is affected by a novel defect of cholesterol biosynthesis.

Background: The most frequently employed diagnostic criteria of atopic dermatitis (AD) can be fulfilled in the absence of elevated total circulating IgE or specific IgE to food allergens or environmental aeroallergens and/or in the absence of personal or familial history of atopy as well. Therefore a distinction between 'extrinsic' or 'allergic' and 'intrinsic' or 'non-allergic' AD has been suggested. Recently, a patch test with environmental aeroallergens, named atopy patch test (APT), has been proposed for use in the study of AD. OBJECTIVE The aim of this study was to investigate the reactivity to APT in patients with 'extrinsic' and 'intrinsic' AD., Patients, Materials and Methods: Two groups of adult male subjects with AD were examined consecutively in our department (Department of Dermatology, Italian Navy Main Hospital, Taranto, Italy) andpatch tested with whole bodies of house dust mites (HDM) at a concentration of 20% in petrolatum (Dermatophagoides pteronyssinus 50%, D. farinae 50%). The groups included: (i) 95 patients affected by the adult clinical form of 'extrinsic' AD; (ii) 12 patients affected by the adult clinical form of 'intrinsic' AD; and (iii) a control group of 49 adult healthy male subjects with a negative anamnesis for eczema and atopy and negative skin prick test to aeroallergens/food allergens and/or normal level of total circulating IgE, also patch tested with the same allergen. The statistical differences were calculated by chi2 test and 95% confidence intervals (CI) were provided., Results: The APT was positive in 47.4% (CI: 37-57%) of'extrinsic'AD, in 66.6% (CI: 41-93%) of'intrinsic' AD and in 12.2% (CI: 3-21%) of healthy subjects. The differences between the two AD subgroups and the control group were statistically significant (P < 0.001)., Conclusions: APT positivity is more frequent in both 'extrinsic' and 'intrinsic' AD than in unaffected subjects. Other studies are needed to confirm our data and to explain why the APT is positive in the 'intrinsic' form.

Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) and type V (HSAN-V) are autosomal recessive genetic disorders, both characterized by a lack of pain sensation. We report a girl with clinical and neurophysiological findings consistent with a diagnosis of HSAN-V. We sequenced her TRKA gene, encoding a receptor tyrosine kinase for nerve growth factor and responsible for HSAN-IV, but we could not detect any mutation. These data indicate that a gene (or genes) other than TRKA is probably responsible for HSAN-V in some patients.

A patient with a multiple congenital anomalies/mental retardation (MCA/MR) syndrome had an unbalanced translocation (3;5)(q26.1;p14), causing partial 5p monosomy and partial 3q trisomy. The phenotype observed in this patient results from the combination of those described in the isolated dup(3q) and del(5p) syndromes. Some clinical features of this patient are shared by the Smith-Lemli-Opitz syndrome (SLOS), a well-known MCA/MR syndrome due to the deficiency of 7-dehydrocholesterol reductase (DHCR7). We review the previously reported cases of chromosomal anomalies with clinical features suggesting SLOS., (Copyright 2002 Wiley-Liss, Inc.)

Purpose: To assess whether interactions of common alleles of two folate genes contribute to spina bifida risk., Methods: Case-control study, comparing 203 children with spina bifida to 583 controls., Results: Homozygosity for the 677C-T allele of 5,10-methylenetetrahydrofolate reductase (MTHFR) alone was associated with an odds ratio for spina bifida of 1.57 (95% confidence interval [CI], 1.02-2.38). For the 844ins68 allele of cystathionine-beta-synthase alone, the odds ratio was 0.83 (95% CI, 0.39-1.64). For the joint genotype, the odds ratio was 3.69 (95% CI, 1.04-13.50)., Conclusions: Interactions between common alleles of folate genes might contribute to the risk for spina bifida.

We report on a girl with a trisomy 1q42-q44 due to an inverted duplication of this region, associated with a terminal deletion of the long arm of the rearranged chromosome 1. Both the large duplication (more than 30 cM) and the small deletion were detected by FISH. Complete karyotype was: (46,XX, inv dup(1)(q44q42).ish(dup del 1)(q44q42)(D1S446x2, D1S423x2, tel1q-). The phenotype of the patient is characterized by macrocephaly with prominent forehead, downslanting palpebral fissures, micrognathia, and psychomotor retardation. All these clinical features are the same as observed for the typical trisomy 1q42-qter syndrome. The phenotypic effects of the inversion and the terminal deletion of 1q in addition to the trisomy are discussed here., (Copyright 2001 Wiley-Liss, Inc.)

Congenital insensitivity to pain with anhidrosis is an autosomal recessive hereditary disorder characterized by recurrent episodic fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. The human TRKA gene (NTRK1), located on chromosome 1q21-q22 encodes the receptor tyrosine kinase for nerve growth factor. We reported that TRKA is the gene responsible for CIPA and we developed a comprehensive strategy to screen for TRKA mutations and polymorphisms, as based on the gene's structure and organization. Here we report eight novel mutations detected as either a homozygous or heterozygous state in nine CIPA families from five countries. Mendelian inheritance of the mutations was confirmed in seven families for which samples from either parent were available. However, non-mendelian inheritance seems likely for the family when only samples from the mother and siblings, (but not from the father) were available. A paternal uniparental disomy for chromosome 1 is likely to be the cause of reduction to homozygosity of the TRKA gene mutation in this family. Interestingly, a Hispanic patient from the USA has two autosomal genetic disorders, CIPA and pyruvate kinase deficiency, whose genetic loci are both mapped to a closely linked chromosomal region. A splice mutation and a missense mutation were detected in the TRKA and PKLR genes from the homozygous proband, respectively. Thus, concomitant occurrence of two disorders is ascribed to a combination of two separate mutant genes, not a contiguous gene syndrome. This finding suggests a mechanism responsible for two autosomal genetic disorders in one patient. All these data further support findings that TRKA defects can cause CIPA in various ethnic groups. This will aid in diagnosis and genetic counseling of this painless but severe genetic disorder., (Copyright 2001 Wiley-Liss, Inc.)

Background: Severe hyperhomocysteinemia due to cystathionine beta-synthase deficiency (CbetaSD) is associated with early atherothrombotic vascular disease. Homocysteine may exert its effects by promoting oxidative damage. In the present study, we investigated whether in vivo formation of 8-iso-prostaglandin (PG) F(2alpha), a platelet-active product of arachidonic acid peroxidation, is enhanced in CbetaSD and whether it correlates with in vivo platelet activation, as reflected by thromboxane (TX) metabolite excretion., Methods and Results: Urine and blood samples were obtained from patients with homozygous CbetaSD (n=13) and age-matched healthy subjects. Urinary 8-iso-PGF(2alpha) excretion was significantly higher in CbetaSD patients than in control subjects (640+/-384 versus 213+/-43 pg/mg creatinine; P=0.0015) and correlated with plasma homocysteine (rho=0.398, P=0.0076). Similarly, urinary 11-dehydro-TXB(2) excretion was enhanced in CbetaSD (1166+/-415 versus 324+/-72 pg/mg creatinine; P=0.0015) and correlated with urinary 8-iso-PGF(2alpha) (rho=0.362, P=0.0153). Vitamin E supplementation (600 mg/d for 2 weeks) was associated with a statistically significant increase in its plasma levels (from 16.6+/-4.6 to 40.4+/-8.7 micromol/L, P=0.0002) and with reductions in 8-iso-PGF(2alpha) (from 790+/-159 to 559+/-111 pg/mg creatinine, P=0.018) and 11-dehydro-TXB(2) (from 1273+/-383 to 913+/-336 pg/mg creatinine, P=0.028). A statistically significant inverse correlation was found between urinary 8-iso-PGF(2alpha) and plasma vitamin E levels (rho=-0.745, P=0.0135)., Conclusions: The results of the present study suggest that enhanced peroxidation of arachidonic acid to form bioactive F(2)-isoprostanes may represent an important mechanism linking hyperhomocysteinemia and platelet activation in CbetaSD patients. Moreover, they provide a rationale for dose-finding studies of vitamin E supplementation in this setting.

Cholelithiasis is considered uncommon in infancy, childhood, and adolescence. We performed a prospective, controlled study showing that children with Down's syndrome have a significantly higher prevalence of cholelithiasis (4.7%) compared with controls (0.2%). Clinicians should be aware of the risk of gallstones in children with Down's syndrome.

Background: A multicenter research study of Down syndrome patients was carried out to estimate the prevalence of celiac disease in patients with Down syndrome and to show clinical characteristics and laboratory data of Down syndrome patients., Methods: The authors studied 1,202 Down syndrome patients. Fifty-five celiac disease patients (group 1) were compared with 55 immunoglobulin A antigliadin-positive antiendomysium antibodies-negative patients (group 2) and with 57 immunoglobulin A antigliadin-negative antiendomysium antibodies-negative patients (group 3)., Results: Celiac disease was diagnosed in 55 of 1,202 Down syndrome patients (4.6%). In group 1, weight and height percentiles were shifted to the left, whereas these parameters were normally distributed in groups 2 and 3. In celiac patients, diarrhea, vomiting, failure to thrive, anorexia, constipation, and abdominal distension were higher than in the other two groups. Low levels of hemoglobinemia, serum iron, and calcium were observed more frequently in group 1. The diagnosis of celiac disease was made after a mean period of 3.8 years from the initiation of symptoms. Sixty-nine percent of patients showed a classic presentation, 11% had atypical symptoms, and 20% had silent celiac disease. Autoimmune disorders were more frequent (30.9%) in group 1 than in the other two groups examined (15%; P < 0.05)., Conclusions: This study reconfirms a high prevalence of celiac disease in Down syndrome. However, the diagnostic delay, the detection of atypical symptoms or silent form in one third of the cases, and the increased incidence of autoimmune disorders suggest the need for the screening of celiac disease in all Down syndrome patients.

Molecular analysis of 289 chromosomes has been performed in a cohort of phenylketonuria (PKU) patients whose ancestors lived in five Italian regions, Calabria, Campania, Piemonte, Puglia/Basilicata and Sicilia. Phenylalaninehydroxylase (PAH) gene mutations and minihaplotypes (combinations of PAH gene STR and VNTR systems) have been determined for 78.5 and 64%, respectively, of the chromosomes studied. 21 different minihaplotypes and 24 PKU mutations were found. Heterogeneity tests carried out for the frequencies of mutations and minihaplotypes show that the distribution of eight mutations and four minihaplotypes is statistically heterogeneous in the five Italian regions. Although the evolutionary rate of microsatellites or the age of these mutations is difficult to estimate with accuracy, our findings taken together show a genetic stratification of the Italian population. These results rule out allelic homogeneity of PKU at the molecular level between regions of Italy, yet minihaplotype data may be of practical use for a multistep approach to PAH gene genotyping., (Copyright 2001 S. Karger AG, Basel)

In lysinuric protein intolerance (LPI), impaired transport of cationic amino acids in kidney and intestine is due to mutations of the SLC7A7 gene. To assess the functional consequences of the LPI defect in nonepithelial cells, we have characterized cationic amino acid (CAA) transport in human fibroblasts obtained from LPI patients and a normal subject. In both cell types the bidirectional fluxes of arginine are due to the additive contributions of two Na(+)-independent, transstimulated transport systems. One of these mechanisms, inhibited by N-ethylmaleimide (NEM) and sensitive to the membrane potential, is identifiable with system y(+). The NEM- and potential-insensitive component, suppressed by L-leucine only in the presence of Na(+), is mostly due to the activity of system y(+)L. The inward and outward activities of the two systems are comparable in control and LPI fibroblasts. Both cell types express SLC7A1 (CAT1) and SLC7A2 (CAT2B and CAT2A) as well as SLC7A6 (y+LAT2) and SLC7A7 (y+LAT1). We conclude that LPI fibroblasts exhibit normal CAA transport through system y(+)L, probably referable to the activity of SLC7A6/y+LAT2.

We report on a male patient with bilateral upper limb amelia, facial clefts, and bilateral renal hypoplasia. We compare the clinical findings in our patient with those of the other three similar cases reported. This is the first long-surviving patient described with this association of malformations., (Copyright 2000 Wiley-Liss, Inc.)

Beckwith-Wiedeman syndrome (BWS) and Klippel-Trenaunay-Weber syndrome (KTWS) are different human disorders characterized, among other features, by tissue overgrowth. Deregulation of one or more imprinted genes located at chromosome 11p15.5, of which insulin-like growth factor 2 (IGF2) is the most likely candidate, is believed to cause BWS, whereas the etiology of KTWS is completely obscure. We report a case of BWS and a case of KTWS in a single family. The probands, sons of two sisters, showed relaxation of the maternal IGF2 imprinting, although they inherited different 11p15.5 alleles from their mothers and did not show any chromosome rearrangement. The patient with BWS also displayed hypomethylation at KvDMR1, a maternally methylated CpG island within an intron of the KvLQT1 gene. The unaffected brother of the BWS proband shared the same maternal and paternal 11p15.5 haplotype with his brother, but the KvDMR1 locus was normally methylated. Methylation of the H19 gene was normal in both the BWS and KTWS probands. Linkage between the insulin-like growth factor 2 receptor (IGF2R) gene and the tissue overgrowth was also excluded. These results raise the possibility that a defective modifier or regulatory gene unlinked to 11p15.5 caused a spectrum of epigenetic alterations in the germ line or early development of both cousins, ranging from the relaxation of IGF2 imprinting in the KTWS proband to disruption of both the imprinted expression of IGF2 and the imprinted methylation of KvDMR1 in the BWS proband. Analysis of these data also indicates that loss of IGF2 imprinting is not necessarily linked to alteration of methylation at the KvDMR1 or H19 loci and supports the notion that IGF2 overexpression is involved in the etiology of the tissue hypertrophy observed in different overgrowth disorders, including KTWS.

Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive disorder, is characterized by insensitivity to pain, self-mutilating behaviour, anhidrosis and recurrent hyperpyrexia. It is a hereditary sensory and autonomic neuropathy, also classified as HSAN, due to a defect of the receptor for nerve growth factor. CIPA is the first human genetic disorder caused by a defect in the neurotrophin signal transduction system. This is the first clinical report of CIPA patients characterized on molecular grounds. The clinical phenotypes of our patients show that CIPA is characterized by a multisystem involvement besides the nervous system, including bone fracture with slow healing, immunologic abnormalities, such as low response to specific stimuli, chronic inflammatory state ending in systemic amyloidosis. The molecular characterization allows a better understanding of most of the clinical features.

Lysinuric protein intolerance (LPI) is a rare autosomal recessive defect of cationic amino acid transport caused by mutations in the SLC7A7 gene. We report the genomic structure of the gene and the results of the mutational analysis in Italian, Tunisian, and Japanese patients. The SLC7A7 gene consists of 10 exons; sequences of all of the exon-intron boundaries are reported here. All of the mutant alleles were characterized and eight novel mutations were detected, including two missense mutations, 242A-->C (M1L) and 1399C-->A (S386R); a nonsense mutation 967G-->A (W242X); two splice mutations IVS3 +1G-->A and IVS6 +1G-->T; a single-base insertion, 786insT; and two 4-bp deletions, 455delCTCT and 1425delTTCT. In addition, a previously reported mutation, 1625insATCA, was found in one patient. It is noteworthy that 242A-->C causes the change of Met1 to Leu, a rare mutational event previously found in a few inherited conditions. We failed to establish a genotype/phenotype correlation. In fact, both intrafamilial and interfamilial phenotypic variability were observed in homozygotes for the same mutation. The DNA-based tests are now easily accessible for molecular diagnosis, genetic counseling, and prenatal diagnosis of LPI.

Background: It is difficult to carry out studies on the prevalence of tinea pedis in the community. Some studies are performed on selected groups of subjects, exposed to the same risk factors, i.e. schoolchildren, public bathers, athletes and military men., Objective: The aim of this work was to detect in a sample of military men the prevalence of tinea pedis and the awareness of their condition, and to relate the infection to risk factors of the group as well., Methods: 410 male Italian navy cadets in an Italian navy petty officers school were clinically examined and mycological cultures were performed, employing the skin scrapings obtained from suspected lesions., Results: Dermatophytes were isolated from toe clefts in 10 subjects, giving a point prevalence of 2.4% (95% confidence interval 1.3-4.4%). The isolated dermatophytes were Trichophyton mentagrophytes (70%), Trichophyton rubrum (20%) and Epidermophyton floccosum (10%). None of the subjects was aware of his disease. No significant association was observed between tinea pedis and risk factors (i.e. hyperhidrosis and habits)., Conclusion: The prevalence in our sample was lower than that observed in previous studies on military men. That can be attributed to the general amelioration of hygienic conditions and strengthening of preventive habits. Therefore the prevalence of tinea pedis in Italian sailors seems to be reduced but still rather relevant. That is important because these subjects are a reservoir of ringworm infection., (Copyright 2000 S. Karger AG, Basel)

Using a bioinformatic approach, we have identified a new transcript, SLC7A8, mapping to 14q11.2, within the lysinuric protein intolerance (LPI) critical region. This gene is highly expressed in skeletal muscle, intestine, kidney, and placenta and encodes a predicted protein of 535 amino acids, homologous to the amino acid permease CD98 light chain and cationic amino acid transporters. RNA in situ hybridization data on mouse embryos confirm the expression in kidney and intestine and, interestingly, reveal that SLC7A8 is also highly expressed in eye, in retinal pigmented epithelium, and in tooth buds at day 16.5 of gestation. Mutational analysis excluded any direct involvement of the SLC7A8 gene product in LPI disease. The homology data and the expression pattern are in agreement with the hypothesis that SLC7A8 represents a novel light chain interacting with the 4F2 heavy chain in the multimeric complex mediating neutral and/or cationic amino acid transport and cystine/glutamate exchange., (Copyright 1999 Academic Press.)

Geleophysic dysplasia (MIM *231050) is a rare autosomal recessive disorder, characterized by short stature with short limbs, brachydactyly, joint contractures, and a good-natured facial appearance. Infiltration of liver and cardiac leaflets has been reported in some patients. Based on the clinical picture and the detection of lysosome-like inclusions in hepatocytes, tracheal mucosa, chondrocytes, and skin fibroblasts, the underlying cause of the conditions is considered to be a generalized lysosomal storage defect. We report on a new case born to consanguineous parents, first observed at age 8 months, and for whom a 7-year follow-up is available., (Copyright 1999 Wiley-Liss, Inc.)

Lysinuric protein intolerance (LPI) is a rare autosomal recessive defect of cationic amino acid transport (CAA), relatively common in Finland and Italy. After weaning, LPI patients present poor feeding, vomiting and failure to thrive. A severe pulmonary complication and episodes of metabolic imbalance may lead to death. Prenatal diagnosis has not been available due to lack of either biochemical or molecular markers to be used in the fetal period. The LPI locus has recently been assigned to chromosome 14q12, very close to the T-cell receptor alpha-chain (TCRA) locus. We carried out a prenatal diagnosis for LPI by linkage analysis in one LPI Italian family after CVS. For the haplotype analysis 11 DNA markers from the LPI critical region were used (D14S742, D14S50, D14S283, five TCRA intragenic polymorphic sites, D14S990, MYH7 and D14S80). It was concluded that the haplotype analysis indicated that the fetus was healthy as he had inherited the two wild alleles of the LPI locus. After birth, the clearances of CAA were measured and found to be in the normal range, thus confirming the result of the prenatal diagnosis. The prenatal diagnosis of LPI can now be offered to families affected by LPI., (Copyright 1999 John Wiley & Sons, Ltd.)

The molecular mechanism of the fragile X syndrome is based on the expansion of an unstable CGG repeat in the 5' untranslated region of the FMR1 gene in most patients. This expansion is associated with an abnormal DNA methylation leading to the absence of production of FMR1 protein (FMRP). Such expansion apparently predisposes the repeat and flanking regions to further instability that may lead to mosaic conditions with a full mutation and a premutation or, rarely, with normal or reduced alleles that can sometimes be transcriptionally active. In this study we describe eight unrelated fragile X patients who are mosaic for both a full mutation and an allele of normal (four cases) or reduced size (four cases). Sequencing analysis of the deletion breakpoints in 6 patients demonstrated an internal deletion confined to the CGG repeat in four of them, which represents the most likely explanation for the regression of the full mutation to a normal sized allele. In two patients with a reduced allele, the deletion encompassed the entire CGG repeat and part of the flanking regions. Analysis of FMRP by Western blot was performed in one of the mosaics with a normal sized allele and in three of those with a reduced allele. In the first patient's lymphocytes FMRP was detected, whereas in the three other patients the deletion is likely to impair transcription as no FMRP was present in their lymphocytes., (Copyright 1999 Wiley-Liss, Inc.)

Congenital insensitivity to pain with anhidrosis (CIPA) is characterized by recurrent episodes of unexplained fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. Human TRKA encodes a high-affinity tyrosine kinase receptor for nerve growth factor (NGF), a member of the neurotrophin family that induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. We have recently demonstrated that TRKA is responsible for CIPA by identifying three mutations in a region encoding the intracellular tyrosine kinase domain of TRKA in one Ecuadorian and three Japanese families. We have developed a comprehensive strategy to screen for TRKA mutations, on the basis of the gene's structure and organization. Here we report 11 novel mutations, in seven affected families. These are six missense mutations, two frameshift mutations, one nonsense mutation, and two splice-site mutations. Mendelian inheritance of the mutations is confirmed in six families for which parent samples are available. Two mutations are linked, on the same chromosome, to Arg85Ser and to His598Tyr;Gly607Val, hence, they probably represent double and triple mutations. The mutations are distributed in an extracellular domain, involved in NGF binding, as well as the intracellular signal-transduction domain. These data suggest that TRKA defects cause CIPA in various ethnic groups.

Lysinuric protein intolerance (LPI, MIM 222700) is an autosomal recessive multisystem disorder found mainly in Finland and Italy. On a normal diet, LPI patients present poor feeding, vomiting, diarrhoea, episodes of hyperammoniaemic coma and failure to thrive. Hepatosplenomegaly, osteoporosis and a life-threatening pulmonary involvement (alveolar proteinosis) are also seen. LPI is caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in kidney and intestine. Metabolic derangement is characterized by increased renal excretion of CAA, reduced CAA absorption from intestine and orotic aciduria. The gene causing LPI was assigned using linkage analysis to chromosome 14q11.2 near the T-cell receptor alpha/delta chains locus, and a critical region has been defined. We have identified two new transcripts (SLC7A8 and SLC7A7) homologous to amino acid transporters, highly expressed in kidney and mapping in the LPI critical region. Mutational analysis of both transcripts revealed that SLC7A7 (for solute carrier family 7, member 7) is mutated in LPI. In five Italian patients, we found either an insertion or deletion in the coding sequence, which provides evidence of a causative role of SLC7A7 in LPI. Furthermore, we detected a splice acceptor change resulting in a frameshift and premature translation termination in four unrelated Finnish patients. This mutation may represent the founder LPI allele in Finland.

The major cause of homocystinuria is mutation of the gene encoding the enzyme cystathionine beta-synthase (CBS). Deficiency of CBS activity results in elevated levels of homocysteine as well as methionine in plasma and urine and decreased levels of cystathionine and cysteine. Ninety-two different disease-associated mutations have been identified in the CBS gene in 310 examined homocystinuric alleles in more than a dozen laboratories around the world. Most of these mutations are missense, and the vast majority of these are private mutations. The two most frequently encountered of these mutations are the pyridoxine-responsive I278T and the pyridoxine-nonresponsive G307S. Mutations due to deaminations of methylcytosines represent 53% of all point substitutions in the coding region of the CBS gene.