Search PubMed⌕ Search

Biomedical subjects

John M Graham

Publications and source records attributed to John M Graham.

At least 37 records · Page 2Linked to original sources
PubMed2005

Fragile X syndrome: an update and review for the primary pediatrician.

Fragile X syndrome (FXS) is the most common inherited cause of mental retardation. Since the initial identification of the responsible gene more than a decade ago, substantial progress has been made in both the clinical aspects of the disorder and its mechanistic basis; hence, it is important for primary care physicians to be familiar with these advances when providing anticipatory guidance. Timely diagnosis allows children to receive early intervention services and families to receive genetic counseling. Here the current state of knowledge is reviewed and a framework is provided for early recognition and diagnosis, along with counseling and treatment implications for the children and family members.

Adolescent↗
PubMed2004

MICRO syndrome: an entity distinct from COFS syndrome.

Children born with the findings of microcephaly, cataracts and microcornea can result not only from a prenatal viral infection, but also from an autosomal recessive Mendelian disorders. We present three pairs of affected siblings with MICRO syndrome, who were born with congenital microcephaly, microcornea, and cataracts. MICRO syndrome is an autosomal recessive syndrome consisting of congenital microcephaly, cortical dysplasia, microcornea, cataracts, optic atrophy, severe mental retardation, hypotonic diplegia, and hypogenitalism. At birth, MICRO syndrome resembles Cerebro-Oculo-Facio-Skeletal (COFS) syndrome, but it differs in the lack of the rapidly progressive neurologic features leading to severe brain atrophy with calcifications. Patients with MICRO syndrome manifest frontal cortical dysplasia, hypoplasia of the corpus callosum, cortical blindness with optic atrophy, profound mental retardation, and progressive joint contractures with growth failure. COFS syndrome shares also many clinical and cellular similarities with Cockayne syndrome (CS), and cultured cells in both conditions demonstrate hypersensitivity to ultraviolet (UV) radiation due to impaired nucleotide excision repair (NER). NER studies in cultured fibroblasts from MICRO patients give normal results, so MICRO syndrome should be considered in children with features resembling COFS syndrome and CS, but who have normal NER. MICRO should be distinguished from other similar clinical disorders with normal NER by the presence of significant visual impairment and cortical blindness despite early surgery for congenital cataracts, frontal polymicrogyria, thin corpus callosum, and cortical atrophy by MRI.

Abnormalities, Multiple↗
PubMed2004

Molar tooth sign of the midbrain-hindbrain junction: occurrence in multiple distinct syndromes.

The Molar Tooth Sign (MTS) is defined by an abnormally deep interpeduncular fossa; elongated, thick, and mal-oriented superior cerebellar peduncles; and absent or hypoplastic cerebellar vermis that together give the appearance of a "molar tooth" on axial brain MRI through the junction of the midbrain and hindbrain (isthmus region). It was first described in Joubert syndrome (JS) where it is present in the vast majority of patients with this diagnosis. We previously showed that the MTS is a component of several other syndromes, including Dekaban-Arima (DAS), Senior-Löken, and COACH (cerebellar vermis hypoplasia (CVH), oligophrenia, ataxia, coloboma, and hepatic fibrosis). Here we present evidence that the MTS is seen together with polymicrogyria, Váradi-Papp syndrome (Orofaciodigital VI (OFD VI)), and a new syndrome with encephalocele and cortical renal cysts. We also present a new patient with COACH syndrome plus the MTS. We propose that the MTS is found in multiple distinct clinical syndromes that may share common developmental mechanisms. Proper classification of patients with these variants of the MTS will be essential for localization and identification of mutant genes.

Abnormalities, Multiple↗
PubMed2004

Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis.

The filamins are cytoplasmic proteins that regulate the structure and activity of the cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and protein trafficking pathways are organized (reviewed in refs. 1,2). We identified mutations in the gene encoding filamin B in four human skeletal disorders. We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721). We found that filamin B is expressed in human growth plate chondrocytes and in the developing vertebral bodies in the mouse. These data indicate an unexpected role in vertebral segmentation, joint formation and endochondral ossification for this ubiquitously expressed cytoskeletal protein.

Codon, Terminator↗
PubMed2004

Clinical and behavioral features of patients with Borjeson-Forssman-Lehmann syndrome with mutations in PHF6.

OBJECTIVE: To describe clinical and behavioral features of 10 men from 2 families with Borjeson-Forssman-Lehmann syndrome (BFLS) and missense mutations in the PHF6 zinc-finger transcription factor gene. STUDY DESIGN: BFLS behavioral features were compared with other age-matched men with other syndromes and similar intellectual functioning through the use of standardized questionnaires: the Child Behavior Checklist, the Vineland Adaptive Behavior Scales, and the Reiss Personality Profile. Participants included 10 with BFLS, 10 with Prader-Willi syndrome, and 23 with Klinefelter syndrome variants (13 with 48,XXYY, 4 with 48,XXXY, and 6 with 49,XXXXY). RESULTS: Contrary to initial reports, our men with BFLS had no microcephaly, seizures, or short stature. They manifested deep-set eyes with large ears, coarse facial features, small external genitalia, gynecomastia, and obesity. Family A had mild to moderate mental retardation, whereas family B was more severely affected. On Vineland Adaptive Behavior Scales, men with BFLS had higher daily living and social skills than communicative skills. Men with BFLS also had lower internalizing and externalizing symptoms and appeared more social and helpful than men with Prader-Willi syndrome or Klinefelter syndrome variant. CONCLUSIONS: Men with BFLS from 2 families with mutations in the PHF6 gene manifested distinctive clinical features and a low risk for maladaptive behaviors.

Abnormalities, Multiple↗
PubMed2003

Iodixanol density gradient preparation in university of wisconsin solution for porcine islet purification.

Generally, prior to the purification of isolated pancreatic islets, the collagenase-digested tissue is incubated in the University of Wisconsin solution (UWS; approximately 320 mOsm) for osmotic stabilization to preserve or improve the density differences between islets and acinar fragments. The adverse effects arising from the subsequent pelleting and resuspension of the islets in a second, different (often highly hyperosmotic) purification solution are avoided in the protocol described here; preparation of the purification medium is simply achieved by mixing the UWS preincubated islets with a second UWS containing the inert impermeant iodixanol. Flotation of the islets isolated from juvenile porcine pancreases through this mildly hypertonic (approximately 380 mOsm) gradient of iodixanol-UWS achieves a much higher recovery of islets of an improved viability than the customary method using a Ficoll gradient. The method has been extended to human islet purification.

Animals↗
PubMed2003

A new X-linked syndrome with agenesis of the corpus callosum, mental retardation, coloboma, micrognathia, and a mutation in the Alpha 4 gene at Xq13.

We describe two brothers with a unique pattern of malformations that includes coloboma (iris, optic nerve), high forehead, severe retrognathia, mental retardation, and agenesis of the corpus callosum (ACC). Both boys have low-set cupped ears with sensorineural hearing loss, normal phallus, pectus excavatum, scoliosis, and short stature. One brother had choanal atresia and cardiac defects consisting of ventricular septal defect (VSD) and patent ductus arteriosus (PDA) which resolved spontaneously. Differential diagnosis between a number of clinical entities was considered, however, because ACC and the distinctive facial features were reminiscent of FG syndrome, DNA was analyzed for markers linked to the FGS1 locus at Xq13-q21. Notably, the brothers were concordant for markers spanning this presumed FG region, and in both we have identified adjacent alterations (-57delT and T-55A) in the Alpha 4 gene located within this interval. Alpha 4 is a regulatory subunit of the major cellular phosphatase, PP2A, that has recently been shown to interact with MID1, the product of the gene mutated in X-linked Opitz GBBB syndrome. The double nucleotide change identified in this family was not observed in 410 control chromosomes, suggesting that it may be a pathogenetic change. Altered expression of Alpha 4, through either a change in translational efficiency, mRNA stability or splicing, could explain the clinical phenotype in these boys and the phenotypic overlap with Opitz GBBB syndrome.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Johnson-McMillin syndrome, a neuroectodermal syndrome with conductive hearing loss and microtia: report of a new case.

In 1983, Johnson et al. described 16 related individuals with alopecia, anosmia or hyposmia, conductive hearing loss, microtia and/or atresia of the external auditory canal, and hypogonadotrophic hypogonadism inherited in an autosomal dominant pattern. Other less constant manifestations included facial asymmetry, mental retardation, congenital heart defect, cleft palate, and choanal stenosis. An isolated case was reported later (Johnston et al. [1987: Am J Med Genet 26: 925-927]) and thereafter an affected mother and son (Hennekam and Holtus [1993: Am J Med Genet 47: 714-716]). We describe an additional unrelated female patient with features resembling those of the previously reported cases. She presented with intrauterine growth deficiency, microcephaly, alopecia, bilateral microtia with canal atresia, conductive hearing loss, partial left facial palsy, posterior cleft palate, left choanal stenosis, tetralogy of Fallot, developmental delay, and right thumb polydactyly. Because the phenotypic abnormalities in this syndrome affect the brain, facial structures, ectoderm and its derivatives, outflow tract of the heart, and Rathke's pouch derivatives, this has suggested to previous authors etiologic involvement of the ectoderm and neuroectoderm of the first and second branchial arches, Rathke's pouch, and the diencephalon. Microtia with conductive hearing loss differentiates the condition from other ectodermal dysplasias. In the initial report, females appeared somewhat less affected than males, and there was male-to-male transmission. The mother of our patient manifests subtle features, which suggest she may be a mildly affected female. Additionally, there is a family history of early-onset alopecia in the maternal grandfather's relatives.

Abnormalities, Multiple↗
PubMed2003

van den Ende-Gupta syndrome of blepharophimosis, arachnodactyly, and congenital contractures: clinical delineation and recurrence in brothers.

We describe two Hispanic brothers born to unrelated parents with van den Ende-Gupta syndrome (VDEGS), a distinctive combination of characteristic dysmorphic features, skeletal abnormalities, and cerebellar hyperplasia. This syndrome was previously delineated by van den Ende et al. [1992: Am J Med Genet 42:467-469] and Gupta et al. [1995: J Med Genet 32:809-812], with additional reports by Phadke et al. [1998: Am J Med Genet 77:16-18] and Bistritzer et al. [1993: Clin Genet 44:15-19]. This is the fifth report of VDEGS, which is characterized by blepharophimosis, narrow nose with hypoplastic alae nasi, hypoplastic maxilla, everted lower lip, slender and elongated hands and feet, arachnodactyly, self-limiting joint contractures, and distinctive skeletal findings. This report of affected siblings, and a previous report of double second cousins born to consanguineous parents [Bistritzer et al. [1993: Clin Genet 44:15-19]], suggests autosomal recessive inheritance. This brings to eight, the total number of reported cases, derived from six families, three of which are consanguineous. It is important to distinguish VDEGS from Marden-Walker syndrome (MWS) since both syndromes include blepharophimosis, arachnodactyly, and congenital contractures. Both syndromes are inherited in an autosomal recessive fashion, but VDEGS lacks severe mental retardation, serious brain malformations, microcephaly, failure to thrive, and severe joint limitation, which are consistently present in MWS. Of particular importance, MWS may be associated with cerebellar malformations such as Dandy-Walker malformation, while the brothers reported herein with VDEGS both demonstrated distinctive cerebellar enlargement, a new finding for this disorder. While, congenital contractures with arachnodactyly are features commonly seen in several other delineated syndromes, such as congenital contractural arachnodactyly (CCA) syndrome, characteristic facial features (blepharophimosis, narrow nose with ocular hypertelorism, prominent ears, and everted lower lip), distinguish VDEGS from other syndromes associated with CCA, including CCA.

Blepharophimosis↗
PubMed2003

Toward a genetic etiology of CHARGE syndrome: I. A systematic scan for submicroscopic deletions.

CHARGE syndrome is a distinctive subgroup within the more heterogeneous group of patients with CHARGE association. While significant progress has been made in the clinical delineation of this syndrome, the molecular basis of the disorder remains unknown. Based on the complex phenotype, some overlap with DiGeorge/velocardiofacial syndrome (DGS/VCFS), and its estimated population incidence, we hypothesized that CHARGE syndrome could be caused by an unidentified genomic microdeletion. In order to address this hypothesis, we carried out a genome-wide screen for loss of expected heterozygosity using 811 microsatellite markers in ten CHARGE syndrome subjects and their unaffected parents. Eight markers gave results suggestive of failure to inherit one parental allele. These loci were tested with fluorescence in situ hybridization (FISH), but none showed evidence of deletion. This screen sets upper limits on the length of a CHARGE-related microdeletion, should that be the genetic mechanism underlying the phenotype.

Alleles↗
PubMed2003

Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families.

CDMP-1, a cartilage-specific member of the TGFss superfamily of secreted signaling molecules, plays a key role in chondrogenesis, growth and patterning of the developing vertebrate skeleton. Homozygous CDMP-1 mutations cause Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia and DuPan syndrome in humans, as well as brachypodism in mice, while heterozygous mutations cause brachydactyly type C (BDC). We present clinical and radiographic data from three unrelated families in which 12 members share the same heterozygous CDMP-1 mutation, an insertion (insG206), resulting in a frameshift predicted to cause functional haploinsufficiency. Although eight mutation carriers display BDC, four have normal hands and feet, confirming nonpenetrance of BDC with CDMP-1 mutations. In addition, several carriers have other skeletal abnormalities, including severe bilateral vertical talus (in two), developmental hip dysplasia (in one), and short stature (in two, who are otherwise unaffected). Premature vertebral end-plate disease was observed in four mutation carriers and was associated with spondylolysis and spondylolisthesis in three of these. Axial skeletal involvement has not been previously reported in association with CDMP-1 mutations. This finding is consistent with CDMP-1 expression in human hypertrophic chondrocytes, which are present in the ring epiphyses of vertebral end plates. Phenotypic variation in BDC has previously been attributed either to locus heterogeneity or to the varied functional effects of different CDMP-1 mutations. The remarkable range of phenotypes caused by this identical CDMP-1 mutation in these families emphasizes the crucial role of genetic background, stochastic variation and/or environmental factors in modifying the observed phenotype. Our findings illustrate that nonpenetrance for the typical features of BDC can be appreciable and that atypical skeletal features that have been reported in some patients with BDC (i.e., clubfoot, short stature, spondylolysis) may also result from CDMP-1 mutation.

Bone Diseases↗
PubMed2003

Syndromic immunodeficiencies: genetic syndromes associated with immune abnormalities.

In syndromic immunodeficiencies, clinical features not directly associated with the immune defect are prominent. Patients may present with either infectious complications or extra-immune medical issues. In addition to the immunologic abnormality, a wide range of organ systems may be affected. Patients may present with disturbances in skeletal, neurologic, dermatologic, or gastrointestinal function or development. These conditions can be caused by developmental abnormalities, chromosomal aberrations, metabolic disorders, or teratogens. For a number of these conditions, recent advances have resulted in an enhanced understanding of their genetic basis. The finding of immune deficits in a number of defined syndromes with congenital anomalies suggests that an underlying genetic syndrome should be considered in those patients in whom a significant non-immune feature is present.

Animals↗
PubMed2003

Graham Fraser Memorial Lecture 2002. From frogs' legs to pieds-noirs and beyond: some aspects of cochlear implantation.

The 2002 Graham Fraser Memorial Lecture deals first with the French origins of cochlear implantation in Paris in the 1950s and the role of André Djourno and Charles Eyriès. Following this work in Paris Dr William House in Los Angeles continued work on cochlear implants and, subsequently, experimental implant programmes were started in California, Paris, Vienna and Melbourne. The next section of this lecture covers the experimental work of Galvani in establishing the role of electricity in physiology. The results of his first experiments were published in 1791, the year that Mondini produced the first account of a cochlear malformation in a congenitally deaf child. At around the same time sign language for congenitally deaf children was being developed for the first time in Paris by Epée and the first disputes occurred between oralists and those who promoted signing for the education of congenitally deaf children. In a present day cochlear implant programme good results from implanting congenitally deaf children at an early age and implanting adults who have become profoundly deaf are now taken for granted. We do have much to learn, however, from more complex implant candidates and some examples of such candidates are presented. Lastly, looking to the future, the use of PET scanning to try and gain information about how the brain handles the information provided to it by a cochlear implant is described.

Cochlear Implantation↗
PubMed2003

Rapid separation of LDL subclasses by iodixanol gradient ultracentrifugation.

BACKGROUND: A predominance of small, dense LDL (sdLDL) confers in excess of a threefold increase in coronary heart disease (CHD) risk. The conventional method for the detection of sdLDL, salt density gradient ultracentrifugation (DGUC) has been superseded by more rapid techniques. This report presents novel methodology for the separation of sdLDL by a combination of iodixanol density gradient centrifugation and digital photography. METHODS: LDL subclasses were separated in 3 h from prestained plasma on a self-forming density gradient of iodixanol. LDL subclass profiles were generated by digital photography and gel-scan software. Plasma samples from 106 normo- and dyslipidemic individuals were used to optimize the gradient for the resolution of LDL heterogeneity. A subgroup of 47 LDL profiles were then compared with LDL subclasses separated by salt DGUC. RESULTS: The peak density of the predominant LDL band correlated significantly with the relative abundance (as a percentage) of sdLDL as resolved by salt DGUC (P <0.001). As shown previously, LDL isolated at a lighter density in iodixanol compared with salt gradients. A predominance of sdLDL corresponded to a peak density on iodixanol of 1.028 kg/L. This density and the area under the LDL profile lying above this density were sensitive and specific markers for the prediction of a predominance of sdLDL (P <0.001) and showed predictable associations with plasma triglycerides (r = 0.59; P <0.001) and HDL (r = -0.4; P <0.001). CONCLUSIONS: This simple method for the detection of sdLDL can differentiate a predominance of sdLDL, is highly reproducible, and can be used preparatively to isolate sdLDL.

Centrifugation, Density Gradient↗
PubMed2002

Spectrum of dolichospondylic dysplasia: two new patients with distinctive findings.

Dolichospondylic dysplasia (DD) is a rare skeletal dysplasia primarily characterized by tall vertebral bodies and disproportionate short stature. Radiographic manifestations include tall vertebral bodies and gracile bones of the hands. Patients usually have eye and ear findings in addition to borderline mental retardation; however, tall vertebral bodies and slender tubular bones are also seen in the 3-M syndrome. Patients with the 3-M syndrome have a characteristic face with a triangular shape, frontal bossing, a flattened malar region, full eyebrows, a short nose with a bulbous tip, upturned nares, and full lips. We present two unrelated patients who share a distinct phenotype and have tall vertebral bodies, overtubulation of long bones, and short tubular bones of the hands and feet. We discuss the overlapping and distinguishing features between DD and the 3-M syndrome. Patient 1 was a 13-year-old female, and patient 2 was an unrelated adult female. These patients had normocephaly and short stature. They shared a common phenotype consisting of mild malar hypoplasia, a narrowed nasal body with a fleshy tip, full lips, and normal intelligence. In addition, they showed mild hand and foot abnormalities. These two patients lack many of the typical clinical features of both DD and the 3-M syndrome. They share a common phenotype and likely represent a distinct disorder. The spectrum of disorders with tall vertebral bodies as a key feature may include different entities that may be further defined with the characterization of the molecular defect(s).

Abnormalities, Multiple↗
PubMed2002

The mutational spectrum of brachydactyly type C.

Growth/differentiation factor-5 (GDF5), also known as cartilage-derived morphogenetic protein-1 (CDMP-1), is a secreted signaling molecule that participates in skeletal morphogenesis. Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC). Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12. We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier. Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro. These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5.

Animals↗