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Biomedical subjects

A Superti-Furga

Publications and source records attributed to A Superti-Furga.

At least 37 records · Page 2Linked to original sources
PubMed2001

PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification.

Inogranic pyrophosphate (PPi) inhibits hydroxyapatite deposition, and mice deficient in the PPi-generating nucleoside triphosphate pyrophosphohydrolase (NTPPPH) Plasma cell membrane glycoprotein-1 (PC-1) develop peri-articular and arterial calcification in early life. In idiopathic infantile arterial calcification (IIAC), hydroxyapatite deposition and smooth muscle cell (SMC) proliferation occur, sometimes associated with peri-articular calcification. Thus, we assessed PC-1 expression and PPi metabolism in a 25-month-old boy with IIAC and peri-articular calcifications. Plasma PC-1 was <1 ng/ml by enzyme-linked immunosorbent assay in the proband, but 10 to 30 ng/ml in unaffected family members and controls. PC-1 functioned to raise extracellular PPi in cultured aortic SMCs. However, PC-1 was sparse in temporal artery lesion SMCs in the proband, unlike the case for SMCs in atherosclerotic carotid artery lesions of unrelated adults. Proband plasma and explant-cultured dermal fibroblast NTPPPH and PPi were markedly decreased. The proband was heterozygous at the PC-1 locus, and sizes of PC-1 mRNA and polypeptide, and the PC-1 mRNA-coding region sequence were normal in proband fibroblasts. However, immunoreactive PC-1 protein was relatively sparse in proband fibroblasts. In conclusion, deficient extracellular PPi and a deficiency of PC-1 NTPPPH activity can be associated with human infantile arterial and peri-articular calcification, and may help explain the sharing of certain phenotypic features between some IIAC patients and PC-1-deficient mice.

Arteriosclerosis↗
PubMed2001

Hepatic carnitine palmitoyltransferase I deficiency: acylcarnitine profiles in blood spots are highly specific.

BACKGROUND: In carnitine palmitoyltransferase I (CPT-I) deficiency (MIM 255120), free carnitine can be increased with no pathologic acylcarnitine species detectable. As inclusion of CPT-I deficiency in high-risk and newborn screening could prevent potentially life-threatening complications, we tested whether CPT-I deficiency might be diagnosed by electrospray ionization-tandem mass spectrometry (ESI-MS/MS). METHODS: A 3.2-mm spot of whole blood dried on filter paper was extracted with 150 microL of methanol. After derivatization of carnitine and acylcarnitines to their butyl esters, the samples were analyzed by ESI-MS/MS with 37.5 pmol of L-[(2)H(3)]carnitine and 7.5 pmol of L-[(2)H(3)]palmitoylcarnitine as internal standards. RESULTS: In all dried-blood specimens from each of three patients with CPT-I deficiency, we found an invariably increased ratio of free carnitine to the sum of palmitoylcarnitine and stearoylcarnitine [C0/(C16 + C18)]. The ratio in patients was between 175 and 2000, or 5- to 60-fold higher than the ratio for the 99.9th centile of the normal newborn population in Bavaria (n = 177 842). No overlap with the values of children that were known to be supplemented with carnitine was detected [C0/(C16 + C18), 34 +/- 30; mean +/- SD; n = 27]. CONCLUSIONS: ESI-MS/MS provides a highly specific acylcarnitine profile from dried-blood samples. The ratio of free carnitine to the sum of palmitoylcarnitine and stearoylcarnitine [C0/(C16 + C18)] is highly specific for CPT-I deficiency and may allow presymptomatic diagnosis.

Biomarkers↗
PubMed2001

Molecular-pathogenetic classification of genetic disorders of the skeleton.

Genetic disorders of the skeleton (skeletal dysplasias and dysostoses) are a large and disparate group of diseases whose unifying features are malformation, disproportionate growth, and deformation of the skeleton or of individual bones or groups of bones. To cope with the large number of different disorders, the "Nosology and Classification of the Osteochondrodysplasias," based on clinical and radiographic features, has been designed and revised periodically. Biochemical and molecular features have been partially implemented in the Nosology, but the rapid accumulation of knowledge on genes and proteins cannot be easily merged into the clinical-radiographic classification. We present here, as a complement to the existing Nosology, a classification of genetic disorders of the skeleton based on the structure and function of the causative genes and proteins. This molecular-pathogenetic classification should be helpful in recognizing metabolic and signaling pathways relevant to skeletal development, in pointing out candidate genes and possible therapeutic targets, and more generally in bringing the clinic closer to the basic science laboratory and in promoting research in this field.

Bone Diseases, Developmental↗
PubMed2000

Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type.

BACKGROUND: Ehlers-Danlos syndrome type IV, the vascular type, results from mutations in the gene for type III procollagen (COL3A1). Affected patients are at risk for arterial, bowel, and uterine rupture, but the timing of these events, their frequency, and the course of the disease are not well documented. METHODS: We reviewed the clinical and family histories of and medical and surgical complications in 220 index patients with biochemically confirmed Ehlers-Danlos syndrome type IV and 199 of their affected relatives. We identified the underlying COL3A1 mutation in 135 index patients. RESULTS: Complications were rare in childhood; 25 percent of the index patients had a first complication by the age of 20 years, and more than 80 percent had had at least one complication by the age of 40. The calculated median survival of the entire cohort was 48 years. Most deaths resulted from arterial rupture. Bowel rupture, which often involved the sigmoid colon, accounted for about a quarter of complications but rarely led to death. Complications of pregnancy led to death in 12 of the 81 women who became pregnant. The types of complications were not associated with specific mutations in COL3A1. CONCLUSIONS: Although most affected patients survive the first and second major complications, Ehlers-Danlos syndrome type IV results in premature death. The diagnosis should be considered in young people who come to medical attention because of uterine rupture during pregnancy or arterial or visceral rupture.

Adolescent↗
PubMed2000

Boy with syndactylies, macrocephaly, and severe skeletal dysplasia: not a new syndrome, but two dominant mutations (GLI3 E543X and COL2A1 G973R) in the same individual.

An unusual combination of syndactylies, macrocephaly, and severe skeletal dysplasia was observed in a newborn infant. A history of digital anomalies in the father and grandfather lead to the diagnosis of dominantly inherited Greig cephalopolysyndactyly syndrome (GCPS, MIM #175700). Having explained the digital findings and macrocephaly, the skeletal changes were thought to fit best congenital spondyloepiphyseal dysplasia (SEDC MIM #183900), a type II collagen disorder. Molecular analysis confirmed the presence of two dominant mutations in the propositus: a GLI3 mutation (E543X), which was present also in the father and grandfather, and a de novo COL2A1 mutation leading to a G973R substitution. Thus, this boy combined the syndactyly-macrocephaly phenotype of Greig cephalosyndactyly syndrome with a severe form of spondyloepiphyseal dysplasia caused by the structural defect in type II collagen. The diagnostic difficulties posed by the combination of two genetic disorders and the contribution of molecular diagnostics are well illustrated by this case.

Abnormalities, Multiple↗
PubMed2000

Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene.

Otospondylomegaepiphyseal dysplasia (OSMED) is an autosomal recessive skeletal dysplasia accompanied by severe hearing loss. The phenotype overlaps that of the autosomal dominant disorders-Stickler and Marshall syndromes-but can be distinguished by disproportionately short limbs, severe hearing loss, and lack of ocular involvement. In one family with OSMED, a homozygous Gly-->Arg substitution has been described in COL11A2, which codes for the alpha2 chain of type XI collagen. We report seven further families with OSMED. All affected individuals had a remarkably similar phenotype: profound sensorineural hearing loss, skeletal dysplasia with limb shortening and large epiphyses, cleft palate, an extremely flat face, hypoplasia of the mandible, a short nose with anteverted nares, and a flat nasal bridge. We screened affected individuals for mutations in COL11A2 and found different mutations in each family. Individuals from four families, including three with consanguineous parents, were homozygous for mutations. Individuals from three other families, in whom parents were nonconsanguineous, were compound heterozygous. Of the 10 identified mutations, 9 are predicted to cause premature termination of translation, and 1 is predicted to cause an in-frame deletion. We conclude that the OSMED phenotype is highly homogenous and results from homozygosity or compound heterozygosity for COL11A2 mutations, most of which are predicted to cause complete absence of alpha2(XI) chains.

Adult↗
PubMed1999

The painful hip: evaluation of criteria for clinical decision-making.

UNLABELLED: Children with a painful hip present a diagnostic challenge since clinical differentiation between septic arthritis, transient synovitis and Perthes disease may be difficult. Septic arthritis, a potentially life-threatening and debilitating medical emergency, requires early recognition for successful treatment, while transient synovitis and Perthes disease may be managed conservatively. An "ideal" single test for discrimination between these conditions is currently not available. We assessed the value of clinical examination and simple laboratory tests together with radiography and hip ultrasound in differentiating septic arthritis from transient synovitis and Perthes disease by analyzing the records of 89 children treated at our institution for hip pain. Ultrasound, radiographs, laboratory, clinical, and follow-up data were available for all the children. Diagnoses were made according to established criteria. Transient synovitis was present in 64 patients, septic arthritis in 8 (of whom 2 had additional osteomyelitis), and Perthes disease in 4. All children with septic arthritis had hip effusion shown by ultrasound and at least two of the following criteria: fever, elevation of erythrocyte sedimentation rate (ESR) and of C-reactive protein (CRP). None of the children without effusion on ultrasound or who lacked two or all criteria had septic arthritis. Radiographs had no significant impact on the decision-making in primary evaluation of acute hip pain. CONCLUSION: We conclude that investigation of painful hips in children, based on hip ultrasound, body temperature, ESR and CRP, may allow cases for hip joint aspiration to be selected efficiently and may reduce the number of radiographs and hospital admissions.

Adolescent↗
PubMed1999

Homozygosity for a novel DTDST mutation in a child with a 'broad bone-platyspondylic' variant of diastrophic dysplasia.

Atypical or variant forms of well-known chondrodysplasias may pose diagnostic problems. We report on a girl with clinical features suggesting diastrophic dysplasia but with unusual radiographic features including severe platyspondyly, wide metaphyses, and fibular overgrowth, which are partially reminiscent of metatropic dysplasia. The diagnosis was clarified by molecular analysis of the DTDST gene, which revealed homozygosity for a previously undescribed mutation leading to a Q454P substitution in the 10th transmembrane domain of the DTDST sulfate transporter. Molecular analysis may be of particular value in such atypical cases.

Anion Transport Proteins↗
PubMed1999

Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia.

Members of the CCN (for CTGF, cyr61/cef10, nov) gene family encode cysteine-rich secreted proteins with roles in cell growth and differentiation. Cell-specific and tissue-specific differences in the expression and function of different CCN family members suggest they have non-redundant roles. Using a positional-candidate approach, we found that mutations in the CCN family member WISP3 are associated with the autosomal recessive skeletal disorder progressive pseudorheumatoid dysplasia (PPD; MIM 208230). PPD is an autosomal recessive disorder that may be initially misdiagnosed as juvenile rheumatoid arthritis. Its population incidence has been estimated at 1 per million in the United Kingdom, but it is likely to be higher in the Middle East and Gulf States. Affected individuals are asymptomatic in early childhood. Signs and symptoms of disease typically develop between three and eight years of age. Clinically and radiographically, patients experience continued cartilage loss and destructive bone changes as they age, in several instances necessitating joint replacement surgery by the third decade of life. Extraskeletal manifestations have not been reported in PPD. Cartilage appears to be the primary affected tissue, and in one patient, a biopsy of the iliac crest revealed abnormal nests of chondrocytes and loss of normal cell columnar organization in growth zones. We have identified nine different WISP3 mutations in unrelated, affected individuals, indicating that the gene is essential for normal post-natal skeletal growth and cartilage homeostasis.

Adolescent↗
PubMed1999

Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.

Greig cephalopolysyndactyly syndrome, characterized by craniofacial and limb anomalies (GCPS; MIM 175700), previously has been demonstrated to be associated with translocations as well as point mutations affecting one allele of the zinc finger gene GLI3. In addition to GCPS, Pallister-Hall syndrome (PHS; MIM 146510) and post-axial polydactyly type A (PAP-A; MIM 174200), two other disorders of human development, are caused by GLI3 mutations. In order to gain more insight into the mutational spectrum associated with a single phenotype, we report here the extension of the GLI3 mutation analysis to 24 new GCPS cases. We report the identification of 15 novel mutations present in one of the patient's GLI3 alleles. The mutations map throughout the coding gene regions. The majority are truncating mutations (nine of 15) that engender prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. Two missense and two splicing mutations mapping within the zinc finger motifs presumably also interfere with DNA binding. The five mutations identified within the protein regions C-terminal to the zinc fingers putatively affect additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to two adjacent independent domains (TA(1)and TA(2)) in the C-terminal third of GLI3. Since these are the only functional domains affected by three C-terminally truncating mutations, we postulate that GCPS may be due either to haploinsufficiency resulting from the complete loss of one gene copy or to functional haploinsufficiency related to compromised properties of this transcription factor such as DNA binding and transactivation.

Animals↗
PubMed1999

Determination of bone markers in pycnodysostosis: effects of cathepsin K deficiency on bone matrix degradation.

Pycnodysostosis (Pycno) is an autosomal recessive osteosclerotic skeletal dysplasia that is caused by the markedly deficient activity of cathepsin K. This lysosomal cysteine protease has substantial collagenase activity, is present at high levels in osteoclasts, and is secreted into the subosteoclastic space where bone matrix is degraded. In vitro studies revealed that mutant cathepsin K proteins causing Pycno did not degrade type I collagen, the protein that constitutes 95% of organic bone matrix. To determine the in vivo effects of cathepsin K mutations on bone metabolism in general and osteoclast-mediated bone resorption specifically, several bone metabolism markers were assayed in serum and urine from seven Pycno patients. Two markers of bone synthesis, type I collagen carboxy-terminal propeptide and osteocalcin, were normal in all Pycno patients. Tartrate-resistent acid phosphatase, an osteoclast marker, was also normal in these patients. Two markers that detect type I collagen telopeptide cross-links from the N and C termini, NTX and CTX, respectively, were low in Pycno. A third marker which detects a more proximal portion of the C terminus of type I collagen in serum, ICTP, was elevated in Pycno, a seemingly paradoxical result. The finding of decreased osteoclast-mediated type I collagen degradation as well as the use of alternative collagen cleavage sites by other proteases, and the accumulation of larger C-terminal fragments containing the ICTP epitope, established a unique biochemical phenotype for Pycno.

Acid Phosphatase↗
PubMed1999

Ehlers-Danlos syndrome type VII: clinical features and molecular defects.

We evaluated the clinical features, molecular defects, and problems associated with the management of two patients who had type-VII Ehlers-Danlos syndrome and reviewed the cases of eighteen patients with this condition who had been reported on previously. The typical clinical features associated with this syndrome include bilateral congenital dislocation of the hip; severe generalized hypermobility of the joints; multiple dislocations of joints other than the hip; muscular hypotonia; and hyperelasticity, fragility, and a doughy texture of the skin. Collagen and DNA analyses demonstrated that both of our patients had type-VIIB Ehlers-Danlos syndrome, which is caused by heterozygous new mutations of the COL1A2 gene that encodes the proalpha2(I) chain of type-I procollagen. The obligatory GT dinucleotide at the splice donor site of intron 6 was altered in both of our patients: one patient (Case 1) had an A substitution of the G nucleotide, and the other patient (Case 2) had a C substitution of the T nucleotide. Abnormal splicing resulted in the loss of the exon 6-encoded N-telopeptide, which includes the N-proteinase cleavage site. Despite multiple operative procedures, one of our patients, who was thirty-seven years old at the time of the most recent follow-up, continued to have persistent subluxation of the right hip and osteoarthritis of the left hip. Closed reduction of the dislocated hips, regardless of the type of immobilization used, was unsuccessful in all twenty patients. The results of open reduction were improved when capsulorrhaphy was combined with iliac or femoral osteotomy, or both.

Adult↗
PubMed1999

Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation.

We have observed over 25 different mutations in the diastrophic dysplasia sulphate transporter gene (DTDST) in association with the recessive disorders achondrogenesis 1B, atelosteogenesis 2, and diastrophic dysplasia. The c862t (R279W) transition is the most common mutation in non-Finnish patients, but in these disorders it is usually combined with other DTDST mutations. We had not seen a case of homozygosity for c862t (R279W) until we analysed DNA from a 36 year old male with tall-normal stature (180 cm) who asked for genetic counselling for suspected multiple epiphyseal dysplasia. He was treated for club foot and hip dysplasia at birth. Skeletal changes consistent with multiple epiphyseal dysplasia, with the peculiar finding of a double layered patella, were recognised during childhood. Cleft palate, swelling of the ear pinna, and hitch hiker thumb were absent. He was found to be homozygous, and both healthy parents heterozygous, for the R279W mutation in DTDST, and his fibroblasts showed a sulphate incorporation defect typical of DTDST disorders. Counselling was given for a recessive disorder, thereby considerably reducing the probability of affected offspring. Multiple epiphyseal dysplasia is more frequently caused by dominant mutations in the COMP (EDM1, McKusick 132400) and COL9A2 genes (EDM2, McKusick 600204). A few other patients and families with features similar to our proband have been described previously and considered to have autosomal recessive MED (EDM4, McKusick 226900). This observation confirms the existence of this entity and assigns it to the phenotypic spectrum associated with mutations at the DTDST locus.

Adult↗
PubMed1998

Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1.

Atelosteogenesis type 1 (AO1) is a rare lethal chondrodysplasia characterized by incomplete ossification of cartilage anlagen. Histologically, the cartilage contains irregular clusters that occasionally include giant chondrocytes. Pulmonary hypoplasia is a characteristic finding that has been presumed to be the cause of neonatal lethality. We report on a male fetus with AO1 and document the early ultrasonographic/ radiologic progression of this disorder from 15 weeks gestation until delivery at 41 weeks. While the radiological findings we describe are typical of AO1 by the lack of proximal and middle phalangeal ossification, the complete radiological picture showed considerable overlap with boomerang dysplasia. Although pulmonary hypoplasia was present, it was moderate and considered unlikely to be the sole cause of death. Detailed neonatal and postmortem examination showed severe subglottic hypoplasia and tracheomalacia. The tracheal walls were supported by thin and pliable cartilaginous plates that allowed luminal collapse with minimal pressure. The marked luminal narrowing, tracheomalacia, and temporal proximity of extubation to demise support tracheal collapse as a major contributor to the death in AO1. The detailed description of this patient should contribute to earlier diagnosis of this condition; anticipation of the poor prognosis in AO1 is essential for appropriate genetic counseling of the parents and for determining postnatal treatment options.

Abnormalities, Multiple↗