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J M Graham

Publications and source records attributed to J M Graham.

At least 55 records · Page 3Linked to original sources
PubMed1999

A data-driven approach to the study of heterogeneity in idiopathic Parkinson's disease: identification of three distinct subtypes.

Idiopathic Parkinson's disease (IPD) has been subclassified on the basis of predominant motor symptomatology, age at disease onset, depressive affect, and cognitive performance. However, subgroups are usually arbitrarily defined and not reliably based on qualitatively distinct neuropathology. We explored heterogeneity in IPD in a data-driven manner using comprehensive demographic, motor, mood, and cognitive information collected from 176 patients with IPD. Cluster analysis revealed three subgroups of patients at a disease duration of 5.6 years and two subgroups at 13.4 years. The subgroups may represent the clinical progression of three distinct subtypes of IPD. The "motor only" subtype was characterized by motor symptom progression in the absence of intellectual impairment. Equivalent motor symptom progression was shown by the "motor and cognitive" subtype which was accompanied by executive function deficits progressing to global cognitive impairment. The "rapid progression" subtype was characterized by an older age at disease onset and rapidly progressive motor and cognitive disability. There was no relationship between the motor and cognitive symptoms in any subtype of IPD. We conclude that the clinical heterogeneity of IPD is governed by distinct neuropathologic processes with independent etiologic influences.

Aged↗
PubMed1999

The spectrum of mutations in UBE3A causing Angelman syndrome.

Angelman syndrome (AS) is characterized by mental retardation, absence of speech, seizures and motor dysfunction. AS is caused by maternal deletions for chromosome 15q11-q13, paternal uniparental disomy (UPD), imprinting defects or loss-of-function mutations in the UBE3A locus which encodes E6-AP ubiquitin-protein ligase. The UBE3A gene is imprinted with paternal silencing in human brain and similar silencing of the Ube3a locus in Purkinje cells and hippocampal neurons in the mouse. We have sequenced the major coding exons for UBE3A in 56 index patients with a clinical diagnosis of AS and a normal DNA methylation pattern. The analysis identified disease-causing mutations in 17 of 56 patients (30%) including 13 truncating mutations, two missense mutations, one single amino acid deletion and one stop codon mutation predicting an elongated protein. Mutations were identified in six of eight families (75%) with more than one affected case, and in 11 of 47 isolated cases (23%); no mutation was found in one family with two siblings, one with a typical and one with an atypical phenotype. Mutations were de novo in nine of the 11 isolated cases. An amino acid polymorphism of threonine substituted for alanine at codon 178 was identified, and a 3 bp length polymorphism was found in the intron upstream of exon 8. In all informative cases, phenotypic expression was consistent with imprinting with a normal phenotype when a mutation was on the paternal chromosome and an AS phenotype when a mutation was on the maternal chromosome. Laboratory diagnosis and genetic counseling for AS are complex, and mutation analysis is valuable in clinically typical AS patients with a normal methylation analysis.

Angelman Syndrome↗
PubMed1999

PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome.

Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family ( P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family ( P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients ( P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR ( P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone ( P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.

Abnormalities, Multiple↗
PubMed1999

Williams-Beuren syndrome: an update and review for the primary physician.

Williams-Beuren syndrome is an autosomal dominant disorder resulting from a submicroscopic deletion of contiguous genes on the long arm of chromosome 7. It consists of a variety of hallmark physical features, which include distinctive facial characteristics, cardiac anomalies (of which the most common is supravalvular aortic stenosis), and occasional idiopathic hypercalcemia. The condition also includes a unique cognitive profile, with relative sparing of language and facial recognition skills against a background of mental retardation. This paper reviews the early history and clinical experience with this syndrome, how it unfolds from infancy through adulthood, and how it manifests in different organ systems. Evidence-based recommendations are then offered for the treatment of the specific developmental and medical issues that arise in patients with Williams syndrome.

Adolescent↗
PubMed1999

Direct measurement of cerebrospinal fluid pressure through the cochlea in a congenitally deaf child with Mondini dysplasia undergoing cochlear implantation.

OBJECTIVE: Perilymph/cerebrospinal fluid (CSF) "gushers" may occur at cochleostomy during cochlear implant surgery, particularly in patients with congenital cochlear duct malformation in which CSF in the internal auditory meatus is in direct communication with the perilymphatic space in the cochlea. The object of the study was to measure the pressure and flow of a CSF gusher at cochleostomy. STUDY DESIGN: The design was a preoperative pressure measurement. SETTING: The setting was a multidisciplinary cochlear implant program. PATIENT: A 4-year-old girl with bilateral Mondini deformity undergoing cochlear implantation was studied. INTERVENTION: A size 23 FG intravenous cannula was inserted into the cochlea and connected to a pediatric drip set to form an improvised manometer. MAIN OUTCOME MEASURE: Intracochlear fluid pressure was measured at 14 cm H2O, equivalent to the normal CSF pressure that would be recorded in a child of this age at lumbar puncture. An indirect measurement of the likely size of the CSF/perilymph defect was made. RESULTS: This technique may allow better assessment of the risk of postoperative CSF leakage and meningitis. CONCLUSION: This simple technique of measuring the pressure in a perilymph gusher can be used to assess the need for careful sealing of the cochleostomy, to measure the reduction in pressure produced by head elevation or a spinal drain, and to assess the probable size of a defect in the lamina cribrosa.

Cerebrospinal Fluid Pressure↗
PubMed1999

Syndromes associated with immunodeficiency.

Immunodeficiency often has a genetic basis. Immune defects are the predominant manifestation in primary immunodeficiency disorders, and immune defects may also be associated with a number of other recognizable syndromes. There are 45 recognized primary immunodeficiency disorders, but immunodeficiency has been reported in 105 other syndromes. Abnormalities associated with these syndromes include growth deficiency (19 syndromes with disproportionate or proportionate short stature); specific organ system dysfunction (39 with gastrointestinal, dermatologic, or neurologic abnormalities); inborn errors of metabolism (17); miscellaneous anomalies (17); and chromosome anomalies (13). In most of these disorders, immunodeficiency is present in only a portion of the patients. However, in 49 syndromes, immunodeficiency is present in the vast majority. We review the clinical manifestations of each syndrome and delineate the associated immune defects. For most, the underlying mechanism linking the immune defect and other anomalies is unclear. Recognition of these conditions involving both the immune and other organ systems may facilitate accurate diagnosis and management, as well as yield information regarding genes critical for the development of the involved systems.

Chromosome Aberrations↗
PubMed1998

FG syndrome: report of three new families with linkage to Xq12-q22.1.

FG syndrome is a rare X-linked recessive form of mental retardation, first described by Opitz and Kaveggia in 1974 in five related males with mental retardation, disproportionately large heads, imperforate anus, and congenital hypotonia. Partial agenesis of the corpus callosum was noted in at least one of the initial cases and has been seen in a number of subsequently-reported cases. The associated congenital hypotonia with joint hyperlaxity tends to progress to contractures with spasticity and unsteady gait in later life. The presence of subtle facial abnormalities and the characteristic behavior in midchildhood facilitate diagnosis at this age, particularly when there are other affected male relatives in the maternal family. Recently, Briault et al. [1997] mapped a gene for FG syndrome to the Xq12-q21.31 region. We describe three additional families (six additional patients) with FG syndrome on whom we have conducted linkage analysis. Our findings support the localization of a gene for the FG syndrome in Xq12-q21. In addition, we have noted skewed X-inactivation in carrier females, as well as new associated findings in affected males of sagittal craniosynostosis and split hand malformation.

Abnormalities, Multiple↗
PubMed1998

Syndrome of coronal craniosynostosis with brachydactyly and carpal/tarsal coalition due to Pro250Arg mutation in FGFR3 gene.

Recently, a unique Pro250Arg point mutation in fibroblast growth factor receptor 3 (FGFR3) was reported in 61 individuals with coronal craniosynostosis from 20 unrelated families [Muenke et al. (1997): Am J Hum Genet 60:555-564]. The discovery of this apparently common mutation has resulted in the definition of a recognizable syndrome, through analysis of subtle clinical findings in families who were previously thought to have a variety of other craniosynostosis syndromes. Previous diagnoses in some of these families have included Jackson-Weiss, Saethre-Chotzen, and Pfeiffer syndromes, as well as Adelaide-type craniosynostosis and brachydactyly-craniosynostosis syndrome [Adès et al. (1994): Am J Med Genet 51:121-130; von Gernet et al. (1996): Am J Med Genet 63:177-184; Reardon et al. (1997): J Med Genet 34:632-636; Bellus et al. (1996): Nat Genet 14:174-176; Hollaway et al. (1995): Hum Mol Genet 4:681-683; Glass et al. (1994): Clin Dysmorphol 3:215-223]. There appears to be a need to further delineate the phenotype associated with this common mutation in FGFR3. We compare the clinical characteristics of previously reported cases of this unique Pro250Arg mutation with those of two additional families and suggest that this syndrome with a unique mutational basis be designated coronal craniosynostosis with brachydactyly and carpal/tarsal coalition due to Pro250Arg mutation in FGFR3 gene, to emphasize the distinctive findings which may be present even in the absence of coronal craniosynostosis.

Abnormalities, Multiple↗
PubMed1998

Dissection of hepatic receptor-mediated endocytic pathways using self-generated gradients of iodixanol (Optiprep).

Iodixanol is a new, nonionic, iodinated density gradient medium which has an advantage over other similar media in that it rapidly forms self-generated gradients in vertical or near-vertical rotors. Endocytosis of 99mTc-labeled neogalactosyl albumin (99mTc-NGA), a synthetic ligand for the asialoglycoprotein receptor, was studied by administering the ligand as a short pulse to perfused rat livers operating under single-pass conditions. Intracellular processing was arrested at various times after the pulse and the resultant homogenate cleared of nuclei and heavy mitochondria by centrifugation at 3000 g for 10 min. After adjustment to 12.5% (w/v) iodixanol, the 3000 g supernatants were centrifuged at 350,000 g for 60 min to form the gradients in which early, clathrin-containing vesicles, low-density endosomes, and lysosomes were well-resolved. 99mTc-NGA bound to the sinusoidal membrane could be partially resolved from clathrin-containing vesicles by inclusion of 1 mM CaCl2 in the homogenization and gradient buffers. Two populations of early clathrin-containing vesicles could be resolved by rate-zonal centrifugation in preformed iodixanol gradients. Thus, iodixanol is an excellent density gradient medium for the rapid and efficient resolution of endosome compartments.

Albumins↗
PubMed1998

Teratogen update: gestational effects of maternal hyperthermia due to febrile illnesses and resultant patterns of defects in humans.

This review has covered the pertinent literature concerning the teratogenic effects of hyperthermia in man and experimental animals. This is the first teratogen that was initially discovered in animals and then subsequently found to be a cause for concern in humans when similar patterns of defects were observed. Hyperthermia is a physical agent with a dose-response curve for abortions and malformations, but these effects can be mitigated in some circumstances by the heat shock response (HSR). We have reviewed the known functions of HSR and provided some insight into why embryos have some protection following an initial dose of heat, if it is sufficient to initiate the response. Thus, by reviewing the effects of hyperthermia in experimental animals, as well as malformative and protective mechanisms of teratogenesis, we have attempted to understand the effects of human hyperthermia teratogenesis.

Animals↗
PubMed1998

Cumming syndrome: report of two additional cases.

We present two unrelated cases with a similar pattern of multiple congenital anomalies including limb shortening, long bone angulation, and cervical lymphocele. We believe these cases to represent additional examples of a syndrome first described by Cumming et al. (1986), and by Urioste et al. (1991) and Ming et al. (1997).

Abnormalities, Multiple↗
PubMed1998

Radiological malformations of the ear in Pendred syndrome.

Pendred syndrome comprises the association of severe congenital sensorineural deafness with thyroid pathology. Although it is the commonest form of syndromic hearing loss, the primary genetic defect remains unknown. The variable clinical presentation allied to the difficulty in securing the diagnosis have resulted in relatively poor documentation of the radiological features of this syndrome. We now present data on 40 patients, all complying with strict diagnostic criteria for the disorder, and describe our experience of the prevalence of specific malformations of the inner ear as well as comparing the relative merits of computed tomography (CT) and magnetic resonance imaging (MRI) in the investigation of this inherited condition. Deficiency of the interscalar septum in the distal coils of the cochlea (Mondini deformity) was found to be a common but probably not a constant feature of Pendred syndrome. However, enlargement of the endolymphatic sac and duct in association with a large vestibular aqueduct was present in all 20 patients examined by MRI. We conclude that thin section high resolution MRI on a T2 protocol in the axial and sagittal planes is the imaging investigation of choice.

Cochlea↗
PubMed1998

Mutation analysis of UBE3A in Angelman syndrome patients.

Angelman syndrome (AS) is caused by chromosome 15q11-q13 deletions of maternal origin, by paternal uniparental disomy (UPD) 15, by imprinting defects, and by mutations in the UBE3A gene. UBE3A encodes a ubiquitin-protein ligase and shows brain-specific imprinting. Here we describe UBE3A coding-region mutations detected by SSCP analysis in 13 AS individuals or families. Two identical de novo 5-bp duplications in exon 16 were found. Among the other 11 unique mutations, 8 were small deletions or insertions predicted to cause frameshifts, 1 was a mutation to a stop codon, 1 was a missense mutation, and 1 was predicted to cause insertion of an isoleucine in the hect domain of the UBE3A protein, which functions in E2 binding and ubiquitin transfer. Eight of the cases were familial, and five were sporadic. In two familial cases and one sporadic case, mosaicism for UBE3A mutations was detected: in the mother of three AS sons, in the maternal grandfather of two AS first cousins, and in the mother of an AS daughter. The frequencies with which we detected mutations were 5 (14%) of 35 in sporadic cases and 8 (80%) of 10 in familial cases.

Angelman Syndrome↗
PubMed1998

Olanzapine in the treatment of hallucinosis in idiopathic Parkinson's disease: a cautionary note.

BACKGROUND: Hallucinosis is a dopaminergic dose limiting complication of the treatment of idiopathic Parkinson's disease. Typical neuroleptic medications cannot be used for suppressing hallucinosis because the extrapyramidal side effects worsen parkinsonian motor control. Olanzapine is a novel atypical antipsychotic drug with few reported extrapyramidal side effects which may be more suitable for controlling hallucinosis in these patients. METHODS: Olanzapine was given to five patients with idiopathic Parkinson's disease and the dosage was titrated until a clinically meaningful reduction in hallucinosis was achieved. The commercially available 5 mg, 7.5 mg and 10 mg tablets were used. RESULTS: After an initial 9 days of treatment, hallucinosis frequency was significantly reduced, an effect which was maintained with continued treatment. However, during this early phase of treatment, parkinsonian motor disability increased, which resulted in two of the patients discontinuing medication. CONCLUSIONS: Olanzapine is effective in the suppression of hallucinosis in patients with idiopathic Parkinson's disease but the currently available dose increments may result in an unacceptable exacerbation of motor disability.

Aged↗
PubMed1998

CHARGE association: an update and review for the primary pediatrician.

CHARGE association is a nonrandom pattern of congenital anomalies that occurs together more frequently than one would expect on the basis of chance. This common multiple anomaly condition has an estimated prevalence of 1:10,000. The number of children diagnosed with CHARGE association is increasing, owing presumably to greater awareness of this condition and advances in the care of complex, chronically ill children, resulting in improved survival and outcome. This review of CHARGE association presents diagnostic criteria that may define a concise, recognizable syndrome with a single pathogenetic basis. This review also summarizes our current understanding of the management for this complex and chronic multiple congenital anomaly condition and discusses the pathogenetic basis for this condition.

Abnormalities, Multiple↗
PubMed1998

Cervical teratoma: prenatal diagnosis and long-term follow-up.

Cervical teratomas are rare tumours which are the result of abnormal prenatal development. They are usually detected at birth, but can occasionally remain silent until adulthood. Obstruction of the airway is the major challenge in the neonatal period. Prenatal diagnosis allows for early consultation with paediatric surgical specialists, so that the time and place of delivery can be addressed, and planning for resuscitative efforts can be organized in advance. If the airway is quickly stabilized and resection of the tumour is not delayed, the prognosis is good. Cervical teratomas in neonates are usually benign; however, malignant transformation and metastasis can occur as a rare event, influencing long-term survival and prognosis. We present two cases of neonatal cervical teratoma detected prenatally by ultrasound. In one case, termination of the pregnancy was elected. In the other case, the child was delivered at 36 weeks' gestation, an airway was secured, and subtotal resection of the tumour was performed. No developmental or neurological deficit has been detected on long-term follow-up at 5 years of age. We present a review of the literature, with attention to outcome and potential for malignancy in neonatal cervical teratomas, in order to provide help in decision-making, once prenatal diagnosis is made.

Adult↗
PubMed1997

Evaluation of mental retardation: recommendations of a Consensus Conference: American College of Medical Genetics.

A Consensus Conference utilizing available literature and expert opinion sponsored by the American College of Medical Genetics in October 1995 evaluated the rational approach to the individual with mental retardation. Although no uniform protocol replaces individual clinician judgement, the consensus recommendations were as follows: 1. The individual with mental retardation, the family, and medical care providers benefit from a focused clinical and laboratory evaluation aimed at establishing causation and in providing counseling, prognosis, recurrence risks, and guidelines for management. 2. Essential elements of the evaluation include a three-generation pedigree: pre-, peri-, and post-natal history, complete physical examination focused on the presence of minor anomalies, neurologic examination, and assessment of the behavioral phenotype. 3. Selective laboratory testing should, in most patients, include a banded karyotype. Fragile X testing should be strongly considered in both males and females with unexplained mental retardation, especially in the presence of a positive family history, a consistent physical and behavioral phenotype and absence of major structural abnormalities. Metabolic testing should be initialed in the presence of suggestive clinical and physical findings. Neuroimaging should be considered in patients without a known diagnosis especially in the presence of neurologic symptoms, cranial contour abnormalities, microcephaly, or macrocephaly. In most situations MRI is the testing modality of choice. 4. Sequential evaluation of the patient, occasionally over several years, is often necessary for diagnosis, allowing for delineation of the physical and behavioral phenotype, a logical approach to ancillary testing and appropriate prognostic and reproductive counseling.

Diagnosis, Differential↗