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J E Wraith

Publications and source records attributed to J E Wraith.

At least 19 recordsLinked to original sources
PubMed2006

The natural history of Niemann-Pick disease type C in the UK.

Niemann-Pick disease type C (NPC) is an autosomal recessive, neurovisceral lipid storage disorder. Mutations in two genes (NPC1 and NPC2) produce indistinguishable clinical phenotypes by biochemical mechanisms that have not yet been entirely clarified. The wide spectrum of clinical presentations of NPC includes hepatic and pulmonary disease as well as a range of neuropsychiatric disorders. Late-onset disease has been increasingly recognized as the biochemical diagnosis of NPC has been more widely applied in adult neurology clinics. The clinical presentation and follow-up of 94 patients with NPC is described, 58 of whom were still alive at the time this report was prepared. The age at diagnosis ranged from the prenatal period (with hydrops fetalis) up to 51 years. This review of NPC patients in the UK confirms the phenotypic variability of this inherited lipid storage disorder reported elsewhere. Although a non-neuronopathic variant has been described, most patients in this series who survived childhood inevitably suffered neurological and in some cases neuropsychiatric deterioration. While symptomatic treatment, such as anticholinergic and antiepileptic drugs, can alleviate some aspects of the disease, there is a clear need to develop a specific treatment for this progressively debilitating neurodegenerative disorder.

Adolescent↗
PubMed2006

Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease.

BACKGROUND: Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid alpha-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease. METHODS: Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n = 9) or 40 mg/kg (n = 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment. RESULTS: All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity. CONCLUSIONS: Recombinant human acid alpha-glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid alpha-glucosidase in which patients were older.

Dose-Response Relationship, Drug↗
PubMed2006

Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome.

Hurler syndrome (MPS 1H) is the severe form of mucopolysaccharidosis type 1 (MPS 1). Haematopoietic cell transplantation (HCT) is the treatment of choice, but carries a high incidence of graft failure and morbidity. The use of enzyme replacement therapy (ERT) might improve the clinical signs and symptoms before HCT, resulting in less transplantation-related complications. Moreover, clearance of glycosaminoglycans (GAG's) from the bone marrow might improve engraftment. Twenty-two patients with MPS 1H received one or more HCT procedures in combination with ERT. One patient with severe cardiomyopathy improved significantly after ERT. All children were in a relatively good clinical condition before HCT. Of patients 59, 82 and 86% were alive and engrafted after one, two and three HCT procedures, respectively. Two patients died after repetitive HCT. No serious ERT-infusion-related toxicity occurred. ERT with HCT was well tolerated. Neither a positive nor a negative effect on the number of patients who are alive and engrafted after receiving ERT before HCT as compared to a historic cohort was noted. However, patients in a poor clinical condition before HCT might benefit from ERT.

Child, Preschool↗
PubMed2005

Marrow stromal cells from patients affected by MPS I differentially support haematopoietic progenitor cell development.

Bone marrow transplantation is the therapy of choice in patients affected by MPS I (Hurler syndrome), but a high incidence of rejection limits the success of this treatment. The deficiency of alpha-L-iduronidase (EC 1.2.3.76), one of the enzymes responsible for the degradation of glycosaminoglycans, results in accumulation of heparan and dermatan sulphate in these patients. Heparan sulphate and dermatan sulphate are known to be important components of the bone marrow microenvironment and critical for haematopoietic cell development. In this study we compared the ability of marrow stromal cells from MPS I patients and healthy donors to support normal haematopoiesis in Dexter-type long term culture. We found an inverse stroma/supernatant ratio in the number of clonogenic progenitors, particularly the colony-forming unit granulocyte-machrophage in MPS I cultures when compared to normal controls. No alteration in the adhesion of haematopoietic cells to the stroma of MPS I patients was found, suggesting that the altered distribution in the number of clonogenic progenitors is probably the result of an accelerated process of differentiation and maturation. The use of alpha-L-iduronidase gene-corrected marrow stromal cells re-established normal haematopoiesis in culture, suggesting that correction of the bone marrow microenvironment with competent enzyme prior to transplantation might help establishment of donor haematopoiesis.

Adolescent↗
PubMed2005

Sleep disturbance in Sanfilippo syndrome: a parental questionnaire study.

AIMS: To determine the incidence, manifestations, and best management of sleep disturbance in Sanfilippo syndrome (mucopolysaccharidosis (MPS) type III). METHODS: Families were ascertained through the MPS societies of Australasia, the UK, and the USA. Questionnaires were sent by mail and were answered anonymously. Identical questions regarding sleep disturbance were asked about unaffected siblings to provide control data. Sleep disturbance was quantified by a total sleep disturbance score. RESULTS: A total of 141 responses were received; 91.5% of children with Sanfilippo syndrome had sleep disturbance and this was significantly higher than for their unaffected sibs; 77.5% of parents had used medication for this problem, with melatonin and antihistamines being most commonly used. Melatonin and benzodiazepines were reported as the most efficacious. Many different environmental modifications had been employed for this problem and some parents reported success with behavioural therapies. CONCLUSIONS: Sleep disturbance is common, severe, and difficult to manage in Sanfilippo syndrome. Based on the parental responses and its safety profile, melatonin is the first line drug that should be tried. Behavioural therapy should be tried in all with Sanfilippo syndrome and sleep disturbance.

Adolescent↗
PubMed2004

Juvenile Sandhoff disease--nine new cases and a review of the literature.

Juvenile Sandhoff disease (McKusick 268800) is a rare lysosomal storage disorder with only 12 cases recorded in the literature. This condition is also referred to as the subacute form of hexosaminidase deficiency. We describe 9 new cases of Pakistani origin and compare these with the other published cases. Ataxia and speech abnormalities were the commonest presentation. Constipation and urinary incontinence were frequent and may be due to autonomic neuropathy. Cherry-red spot was not noted in any of our cases. Increased lower limb reflexes were the commonest physical finding. Significant delay in diagnosis may be due to the nonspecific presentation of this condition. Diagnosis was on the basis of hexosaminidase deficiency. Residual enzyme activity did not correlate with the clinical picture. Emerging therapies make early diagnosis of this disorder important.

Child↗
PubMed2004

Lactic acidosis and developmental delay due to deficiency of E3 binding protein (protein X) of the pyruvate dehydrogenase complex.

Pyruvate dehydrogenase deficiency is an important cause of primary lactic acidosis. Most cases occur as a result of mutations in the gene for the E1 alpha subunit of the complex, with a small number resulting from mutations in genes for other components, most commonly the E3 and E3-binding protein subunits. We describe pyruvate dehydrogenase E3-binding protein deficiency in two siblings in each of two unrelated families from Kuwait. The index patient in each family had reduced pyruvate dehydrogenase activity in cultured fibroblasts and no detectable immunoreactive E3-binding protein. Both were homozygous for nonsense mutations in the E3-binding protein gene, one involving the codon for glutamine 266, the other the codon for tryptophan 5.

Acidosis, Lactic↗
PubMed2003

Hearing loss due to mannosidosis and otitis media with effusion. A case report and review of audiological assessments in children with otitis media with effusion.

A case of a child with mannosidosis and bilateral otitis media with effusion (OME) is reported here along with some discussion of relevant literature to emphasize the need for age appropriate audiometric assessment before and after insertion of grommets for glue ear (OME). There is a need for multidisciplinary teamwork in the management of children with hearing loss. If OME is treated surgically, age-appropriate hearing assessment is required before and after insertion of grommets. The need for audiological assessments will be relevant even if children had passed the newborn hearing screening test.

Audiometry↗
PubMed2002

Niemann-Pick disease type C in adults.

Although it is often perceived as a paediatric disorder, significant numbers of patients with Niemann-Pick disease type C present for the first time in adult life or survive into adult life. The presentation in these patients differs from that seen in the classical juvenile form of the disease. Adult patients are often referred to clinicians with psychosis or other major psychiatric problems. The dystonia with preserved intellectual functioning can be mistaken for other basal ganglia disorders such as Wilson disease. The presence of vertical gaze palsy is an important clinical clue and, in the presence of a modest increase in plasma chitotriosidase activity, can be very helpful in the differential diagnosis. The diagnosis should be confirmed in suspected cases by filipin staining of cultured fibroblasts, as well as cholesterol esterification studies and DNA mutation analysis.

Adolescent↗
PubMed2002

Sleep disturbance in mucopolysaccharidosis type III (Sanfilippo syndrome): a survey of managing clinicians.

Sanfilippo syndrome (mucopolysaccharidosis type III) is the commonest mucoploysaccharidosis. It causes neurodegeneration with often profound sleep and behavioral disturbance. Management of the sleep disturbance is difficult and inconsistent. In this study, we surveyed clinicians with particular expertise in the management of individuals with mucopolysaccharidoses. We found that sleep problems are almost universal in this patient population and that no one treatment is consistently viewed as beneficial. Among the clinicians surveyed, melatonin is reported as the medication most likely to be of benefit. Benzodiazepines, chloral hydrate, antihistamines and antipsychotic agents are overall reported as less efficacious. The major side-effect of the medications as a group was reported to be daytime somnolence. Based on this study, recommendations are given regarding the approach to sleep disturbance in Sanfilippo syndrome.

Behavior Therapy↗
PubMed2002

Lysosomal disorders.

Although most lysosomal storage disorders present in infancy or early childhood with a progressive condition often associated with dysmorphism, considerable genetic heterogeneity exists resulting in a range of illnesses that can include a dramatic neonatal presentation. Whilst some conditions present with a characteristic neonatal phenotype (e.g. Niemann-Pick disease type C), the remainder present in a nonspecific way often with non-immune hydrops fetalis. Diagnosis can be helped by appropriate radiological studies and, in some patients, evidence of the storage phenomena can be seen in peripheral blood smears or bone marrow aspirates. Unfortunately, for the majority of affected patients no effective, curative, treatment is possible. New developments in therapy including enzyme replacement therapy and substrate deprivation may improve prognosis in some disorders. It is important to establish an accurate diagnosis, as prenatal testing can then be offered in future pregnancies.

Abnormalities, Multiple↗
PubMed2002

Cardiovascular changes in children with mucopolysaccharide disorders.

UNLABELLED: The aims of this study were to evaluate cardiac involvement, assess risk factors and mortality, and define the outcome of cardiac abnormalities with age in the different types of mucopolysaccharidoses (MPS). The echocardiograms of 99 patients with MPS, aged 1-24 y (median age 10.3 y) were reviewed between 1978 and 2000. Mitral regurgitation (MR) was detected in 29 patients (29%). MR was more frequent in types IH [n = 11 (38%)], II [n = 10 (24%)] and III [n = 4 (20%)]. Sixteen patients (16%) developed aortic regurgitation (AR), seen mostly in types II [n = 9 (56%)] and IV [n = 4 (24%)]. AR and/or MR was detected in 37 patients and 8 had both abnormalities of borderline significance (odds ratio 2.95, 95% confidence interval 1.0-8.85, p = 0.05). Of 99 patients, 47 had a normal study on their first echocardiogram, whereas only 7 had a normal study on subsequent echocardiograms. Fifty-four (54%) had a single echocardiogram. Of these, 27 (50%) were abnormal and 27 normal. Forty-five patients had more than one echocardiogram, of which 25 (56%) were abnormal and 20 normal. In 13/20 (65%) a cardiac abnormality developed on a subsequent echocardiogram which was statistically significant (p = 0.002). Overall mitral and aortic valve abnormalities showed a positive association with age. Univariate analysis of risk factors showed that increasing age, MPS I and ejection fraction were significant risk factors for death. However, left ventricular hypertrophy, mitral valve abnormalities and type II MPS were not significant risk factors for death, with borderline significance for aortic valve abnormalities. CONCLUSION: This study demonstrates the evaluation of ventricular function, which is a significant risk factor for death, along with increasing age and MPS I, and outlines the borderline significance of aortic valve abnormalities, which has not been mentioned in previous studies. It also shows that mitral valve lesions, commonly seen in MPS, were not a significant risk factor for death. The results emphasize the importance of performing serial echocardiograms in patients with MPS to assess ventricular function and the progression of cardiac abnormalities with age.

Adolescent↗
PubMed2002

Facial appearance in glycogen storage disease type III.

Amylo-1,6-glucosidase deficiency (glycogen storage disease type III) is associated with hypoglycaemia, hepatomegaly, raised transaminases and in most cases skeletal myopathy and cardiomyopathy. The disorder has not been considered to cause dysmorphism. We report consistent facial features in seven patients with GSD type III consisting of midface hypoplasia with a depressed nasal bridge and a broad upturned nasal tip, indistinct philtral pillars, and bow-shaped lips with a thin vermillon border. Younger patients had in addition deepset eyes. Several children had clinical problems such as persistent otitis media or recurrent sinusitis. The underlying aetiology of these features is unknown but the similarity in all our patient suggests that there is a facial phenotype for this disorder.

Body Height↗