Mucopolysaccharidosis type IVA (MPS IVA) was described in 1929 by Luis Morquio from Uruguay and James Brailsford from England, and was later found as an autosomal recessive lysosomal storage disease. MPS IVA is caused by mutations in the gene encoding the enzyme, N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Reduced GALNS activity results in impaired catabolism of two glycosaminoglycans (GAGs), chondroitin-6-sulfate (C6S) and keratan sulfate (KS). Clinical presentations of MPS IVA reflect a spectrum of progression from a severe ”classical” phenotype to a mild “attenuated” phenotype. More than 180 different mutations have been identified in the GALNS gene, which likely explains the phenotypic heterogeneity of the disorder.
Accumulation of C6S and KS manifests predominantly as short stature and skeletal dysplasia (dysostosis multiplex), including atlantoaxial instability and cervical cord compression. However, abnormalities in the visual, auditory, cardiovascular, and respiratory systems can also affect individuals with MPS IVA. Diagnosis is typically based on clinical examination, skeletal radiographs, urinary GAG, and enzymatic activity of GALNS in blood cells or fibroblasts. Deficiency of GALNS activity is a common assessment for the laboratory diagnosis of MPS IVA; however, with recently increased availability, gene sequencing for MPS IVA is often used to confirm enzyme results. As multiple clinical presentations are observed, diagnosis of MPS IVA may require multi-system considerations.
This review provides a history of defining MPS IVA and how the understanding of the disease manifestations has changed over time. A summary of the accumulated knowledge is presented, including information from the International Morquio Registry. The classical phenotype is contrasted with attenuated cases, which are now being recognized and diagnosed more frequently. Laboratory based diagnoses of MPS IVA are also discussed.
Mucopolysaccharidosis IVA; MPS IVA; Morquio A; GALNS; laboratory diagnosis
Characteristic cardiac valve abnormalities and left ventricular hypertrophy are present in untreated patients with mucopolysaccharidosis type VI (MPS VI). Cardiac ultrasound was performed to investigate these findings in subjects during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB, rhN-acetylgalactosamine 4-sulfatase, galsulfase, Naglazyme®). Studies were conducted in 54 subjects before ERT was begun and at specific intervals for up to 96 weeks of weekly infusions of rhASB at 1 mg/kg during phase 1/2, phase 2, and phase 3 trials of rhASB. At baseline, mitral and aortic valve obstruction was present and was significantly greater in those ≥12 years of age. Mild mitral and trace aortic regurgitation were present, the former being significantly greater in those <12 years. Left ventricular hypertrophy, with averaged z-scores ranging from 1.6–1.9 SD greater than normal, was present for ages both <12 and ≥12 years. After 96 weeks of ERT, ventricular septal hypertrophy regressed in those <12 years. For those ≥12 years, septal hypertrophy was unchanged, and aortic regurgitation increased statistically but not physiologically. Obstructive gradients across mitral and aortic valves remained unchanged. The results suggest that long-term ERT is effective in reducing intraventricular septal hypertrophy and preventing progression of cardiac valve abnormalities when administered to those <12 years of age.
Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked, recessive, lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase. It has multisystemic involvement, with manifestations in the brain, upper respiratory tract, heart, abdomen, joints and bones. Bone involvement leads to decreased growth velocity and short stature in nearly all patients. A therapeutic option for patients with MPS II is enzyme replacement therapy (ERT) with idursulfase (Elaprase®). We compared annual growth rates before and during ERT in 18 patients from Mainz, Germany, and Manchester, UK. Group 1 included nine patients who started ERT before 10 years of age; group 2 contained nine patients aged more than 10 years at the start of ERT. All patients had received weekly or biweekly ERT or placebo for 1 year, followed by ERT for more than 3 years. For patients in group 1, the mean (± SD) height increase was 14.6 ± 5.5 cm during 3 years of ERT. Only one patient in this group (who was below the 3rd percentile when starting ERT) deviated from the normal growth curve over this time. Patients in group 2 had a mean height increase of 8.1 ± 1.7 cm after 3 years of ERT compared with an increase of 1 cm in the year before ERT. ERT seems to have a positive influence on growth in patients with MPS II. Most benefit is seen in patients beginning ERT before the age of 10 years. This supports the recommendation that ERT should be started as early as possible in patients with MPS II.
Fabry disease (FD) is a lysosomal storage disorder associated with marked cerebrovascular disease. Conventional MRI shows an extensive load of white matter lesions (WMLs) which may already be present at an early stage in the disease.
Investigator independent and sensitive quantification of structural changes in the brain in clinically affected men and women with FD.
We performed a voxel based analysis of diffusion tensor images (DTI) in 25 patients with FD and 20 age matched normal controls.
DTI revealed significant increases in cerebral white matter mean diffusivity (MD) in patients with FD, which were pronounced in the periventricular white matter. Even the subgroup of patients without significant WMLs load (n = 18) showed increased diffusivity in the cerebral white matter. In gray matter areas, MD elevation was detected only in the posterior part of the thalamus, independent of the visible pulvinar alterations on T1 weighted images. Voxel based fractional anisotropy measurements did not differ significantly between patients and controls.
The present study demonstrates the clinical feasibility of voxel based analysis of DTI as a sensitive tool to quantify brain tissue alterations in FD. The pattern of increased brain tissue diffusivity is probably due to microangiopathic alterations, mainly affecting the long perforating arteries.
Fabry disease is a rare X linked lysosomal storage disorder resulting from deficiency of α‐galactosidase A activity. Although the severity of clinical features in male patients is well described, only recently have studies reported the high prevalence of disabling clinical features in heterozygous females.
This study sets out to examine the clinical features and natural history of Fabry disease in further detail in a large group of female patients.
Data were obtained from 303 females enrolled in the Fabry Outcome Survey. Pain was assessed using the Brief Pain Inventory, and health related quality of life (HRQoL) was assessed using the European Quality of Life Questionnaire. A modified version of the Mainz Severity Score Index was also applied. Data on left ventricular mass (LVM) index, mean ventricular wall thickness, and glomerular filtration rate (GFR) were used to assess cardiac and renal involvement.
The most commonly reported clinical features in females were neurological (77%) and cardiac (59%). A history of renal involvement was recorded in 40% of cases. Neurological features were the earliest to develop (mean age: 16 years), whereas cardiac (mean age: 33.5 years) and renal (mean age: 37.3 years) features developed later. LVM index increased exponentially with age. In addition, age was negatively correlated with estimated GFR and HRQoL.
Females with Fabry disease report important age related clinical features and clinical investigation demonstrates evidence of disease progression. This study highlights the importance of careful and longitudinal assessment of female heterozygote patients with Fabry disease.
Fabry disease; Fabry Outcome Survey; heterozygotes
Although current concepts of anterior femoroacetabular impingement predict damage in the labrum and the cartilage, the actual joint damage has not been verified by computer simulation. We retrospectively compared the intraoperative locations of labral and cartilage damage of 40 hips during surgical dislocation for cam or pincer type femoroacetabular impingement (Group I) with the locations of femoroacetabular impingement in 15 additional hips using computer simulation (Group II). We found no difference between the mean locations of the chondrolabral damage of Group I and the computed impingement zone of Group II. The standard deviation was larger for measures of articular damage from Group I in comparison to the computed values of Group II. The most severe hip damage occurred at the zone of highest probability of femoroacetabular impact, typically in the anterosuperior quadrant of the acetabulum for both cam and pincer type femoroacetabular impingements. However, the extent of joint damage along the acetabular rim was larger intraoperatively than that observed on the images of the 3-D joint simulations. We concluded femoroacetabular impingement mechanism contributes to early osteoarthritis including labral lesions.
Level of Evidence: Level II, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.
It is unknown whether nutritional deficiencies affect the morphology and function of structural cells, such as epithelial cells, and modify the susceptibility to viral infections. We developed an in vitro system of differentiated human bronchial epithelial cells (BEC) grown either under selenium adequate (Se+) or selenium deficient (Se-) conditions, to determine whether selenium deficiency impairs host defense responses at the level of the epithelium. Se- BECs had normal SOD activity, but decreased activity of the selenium-dependent enzyme GPX1. Interestingly, catalase activity was also decreased in Se- BECs. Both Se- and Se+ BECs differentiated into a mucociliary epithelium; however, Se- BEC demonstrated increased mucus production and increased Muc5AC mRNA levels. This effect was also seen in Se+ BEC treated with 3-aminotriazole, and inhibitor of catalase activity, suggesting an association between catalase activity and mucus production. Both Se- and Se+ were infected with influenza A/Bangkok/1/79 and examined 24 hours post-infection. Influenza-induced IL-6 production was greater while influenza-induced IP-10 production was lower in Se- BECs. In addition, influenza-induced apoptosis was greater in Se- BEC as compared to the Se+ BECs. These data demonstrate that selenium deficiency has a significant impact on the morphology and influenza-induced host defense responses in human airway epithelial cells.
Influenza; selenium; bronchial epithelial cells; in vitro
Background: Fabry disease is an X linked lysosomal storage disease caused by deficiency of the lysosomal enzyme α-galactosidase A. This leads to accumulation of globotriaosylceramide in nearly all tissues, including the blood vessels, kidney, myocardium, and nervous system. Symptoms often begin in childhood and include acroparaesthesia, with burning or tingling pain that spreads from the extremities to more proximal sites.
Aims: This study set out to evaluate pain and its influence on quality of life in patients with Fabry disease receiving enzyme replacement therapy (ERT) with agalsidase alfa.
Methods: Data were obtained from the Fabry Outcome Survey. Pain was measured using the Brief Pain Inventory (BPI), and health-related quality of life (HRQoL) was documented with the European Quality of Life Questionnaire (EQ-5D).
Results: The mean (SD) score for "pain at its worst" on the BPI prior to ERT was 5.1 (2.7). One year after commencement of ERT, this had improved by 0.5, and improved by a further 0.6 after 2 years (p<0.05). Similar statistically significant improvements were seen for "pain on average" and "pain now" after 2 years of ERT. The mean HRQoL utility score prior to ERT was 0.66 (0.32). After 12 months of treatment with agalsidase alfa, this had improved to 0.74 (0.26; p<0.05); this improvement was maintained after 2 years.
Conclusions: ERT with agalsidase alfa significantly reduces pain and improves quality of life in patients with Fabry disease.
Sialorrhoea is a socially disabling problem in bulbar
amyotrophic lateral sclerosis (ALS). Botulinum toxin A (BoNT/A) was injected into the salivary glands in five patients with bulbar ALS and
sialorrhoea. The effect of BoNT/A was measured by the number of paper
handkerchiefs used each day and by salivary gland scintigraphy. BoNT/A
ameliorated sialorrhoea and quality of life without major adverse
effects. BoNT/A may be a relatively safe and effective treatment for
sialorrhoea in selected patients.
The purpose of this prospective, randomized, double-blind study was to determine the anesthetic efficacy of a buffered lidocaine with epinephrine solution compared to a combination buffered lidocaine with epinephrine plus hyaluronidase solution in inferior alveolar nerve blocks. Thirty subjects randomly received an inferior alveolar nerve block using 1 of the 2 solutions at 2 separate appointments using a repeated-measures design. Mandibular anterior and posterior teeth were blindly pulp tested at 4-minute cycles for 60 minutes postinjection. No response from the subject to the maximum output (80 reading) of the pulp tester was used as the criterion for pulpal anesthesia. Anesthesia was considered successful when 2 consecutive readings of 80 were obtained. A postoperative survey was used to measure pain and trismus. The results demonstrated 100% of the subjects had profound lip numbness with both solutions for inferior alveolar nerve blocks. The anesthetic success rates for individual teeth ranged from 20 to 80%. There were no significant differences (P > .05) between the 2 solutions. However, the combination lidocaine/hyaluronidase solution resulted in a significant increase in postoperative pain and trismus. It was concluded that adding hyaluronidase to a buffered lidocaine solution with epinephrine did not statistically increase the incidence of pulpal anesthesia in inferior alveolar nerve blocks and, because of its potential tissue damaging effect, it should not be added to local anesthetic solutions for inferior alveolar nerve blocks.
Mucopolysaccharidosis type IIIB (MPS IIIB or Sanfilippo B disease) is an autosomal recessive storage disorder caused by deficiency of the lysosomal enzyme α-N-acetylglucosaminidase. Mutation screening was performed on a group of 22 patients using a combination of SSCP/heteroduplex analysis of amplified genomic fragments and direct sequencing of cDNA fragments. Twenty-one different mutations were identified, 18 of them novel. Together they account for 82% of the disease alleles. The mutation spectrum consists of two small insertions, two small deletions, three nonsense mutations, and 14 different missense mutations, one of them (M1L) affecting the initiation codon. The vast genetic heterogeneity seen in this disorder is reflected by the fact that only three of the mutations were identified in more than one patient.
Keywords: mucopolysaccharidosis type IIIB; Sanfilippo B disease; mutation screening; α-N-acetylglucosaminidase
The purpose of this prospective, randomized, double-blind study was to measure the degree of anesthesia obtained with a labial infiltration of either 2% lidocaine with 1:50,000 or 2% lidocaine with 1:100,000 epinephrine in mandibular anterior teeth. Another objective was to measure the degree of anesthesia obtained with a lingual infiltration of 2% lidocaine with 1:100,000 epinephrine in mandibular anterior teeth. Through use of a repeated-measures design, 40 subjects randomly received a labial infiltration at the lateral incisor apex of either 1.8 mL of 2% lidocaine with 1:100,000 epinephrine or 1.8 mL of 2% lidocaine with 1:50,000 epinephrine at 2 separate appointments. An additional 40 subjects received a lingual infiltration at the lateral incisor apex of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine. The mandibular anterior teeth were blindly pulp tested at 4-minute cycles for 60 minutes postinjection. No response from the subject to the maximum output (80 reading) of the pulp tester was used as the criterion for pulpal anesthesia. Anesthesia was considered successful when 2 consecutive 80 readings were obtained. For the 3 infiltrations, success rates for the lateral incisor ranged from 43 to 50%. Adjacent teeth had success rates of 27 to 63%. There was no significant difference (P > 0.05) in success between the labial infiltration of 2% lidocaine with 1:100,000 epinephrine and 2% lidocaine with 1:50,000 epinephrine or the lingual infiltration of 2% lidocaine with 1:100,000 epinephrine when compared with the labial infiltration of 2% lidocaine with 1:100,000 epinephrine. Duration of pulpal anesthesia declined steadily for all solutions over the 60 minutes. In conclusion, the success rate of 43-50% and declining duration of pulpal anesthesia over an hour indicates that a labial infiltration of 1.8 mL of either 2% lidocaine with 1:100,000 epinephrine or 1: 50,000 epinephrine or a lingual infiltration of 2% lidocaine with 1:100,000 epinephrine over the lateral incisor apex cannot be recommended clinically to provide profound pulpal anesthesia.
To determine whether a repeated intraosseous (IO) injection would increase or prolong pulpal anesthesia, we measured the degree of anesthesia obtained by a repeated IO injection given 30 min following a combination inferior alveolar nerve block/intraosseous injection (IAN/IO) in mandibular second premolars and in first and second molars. Using a repeated-measures design, we randomly assigned 38 subjects to receive two combinations of injections at two separate appointments. The combinations were an IAN/IO injection followed approximately 30 min later by another IO injection of 0.9 ml of 2% lidocaine with 1:100,000 epinephrine and a combination IAN/IO injection followed approximately 30 min later by a mock IO injection. The second premolar, first molar, and second molar were blindly tested with an Analytic Technology pulp tester at 2-min cycles for 120 min postinjection. Anesthesia was considered successful when two consecutive readings of 80 were obtained. One hundred percent of the subjects had lip numbness with IAN/IO and with IAN/IO plus repeated IO techniques. Rates of anesthetic success for the IAN/IO and for the IAN/IO plus repeated IO injection, respectively, were 100% and 97% for the second premolar, 95% and 95% for the first molar, and 87% and 87% for the second molar. The repeated IO injection increased pulpal anesthesia for approximately 14 min in the second premolar and for 6 min in the first molar, but no statistically significant differences (P > 0.05) were shown. In conclusion, the repeated IO injection of 0.9 ml of 2% lidocaine with 1:100,000 epinephrine given 30 min following a combination IAN/IO injection did not significantly increase pulpal anesthesia in mandibular second premolars or in first and second molars.
PRINTS is a database of protein family 'fingerprints' offering a diagnostic resource for newly-determined sequences. By contrast with PROSITE, which uses single consensus expressions to characterise particular families, PRINTS exploits groups of motifs to build characteristic signatures. These signatures offer improved diagnostic reliability by virtue of the mutual context provided by motif neighbours. To date, 800 fingerprints have been constructed and stored in PRINTS. The current version, 17.0, encodes approximately 4500 motifs, covering a range of globular and membrane proteins, modular polypeptides, and so on. The database is accessible via the UCL Bioinformatics World Wide Web (WWW) Server at http://www. biochem.ucl.ac.uk/bsm/dbbrowser/ . We have recently enhanced the usefulness of PRINTS by making available new, intuitive search software. This allows both individual query sequence and bulk data submission, permitting easy analysis of single sequences or complete genomes. Preliminary results indicate that use of the PRINTS system is able to assign additional functions not found by other methods, and hence offers a useful adjunct to current genome analysis protocols.
The purpose of this study was to investigate the ability of low-dose fentanyl to produce analgesia when administered via the periodontal ligament injection in teeth with symptomatic, inflamed pulps. All subjects presented for emergency treatment with moderate to severe pain and had a posterior tooth with a clinical diagnosis of irreversible pulpitis. Twenty subjects randomly received either 10 micrograms fentanyl citrate or saline placebo via the periodontal ligament injection in a double-blind manner. The subjects rated their pain prior to injection and rated pain intensity and pain half gone for 59 min postinjection. Low-dose fentanyl delivered via the periodontal ligament injection in inflamed teeth provided significantly greater analgesia than the saline placebo (P < 0.05). Since the dose of fentanyl used was less than the dose required to provide analgesia by a central mechanism, the results of this study may be consistent with a peripheral opioid mechanism of action.
The PRINTS database of protein family 'fingerprints' is a diagnostic resource that complements the PROSITE dictionary of sites and patterns. Unlike regular expressions, fingerprints exploit groups of conserved motifs within sequence alignments to build characteristic signatures of family membership. Thus fingerprints inherently offer improved diagnostic reliability by virtue of the mutual context provided by motif neighbours. To date, 600 fingerprints have been constructed and stored in PRINTS, representing a 50% increase in the size of the database in the last year. The current version, 13.0, encodes approximately 3000 motifs, covering a range of globular and membrane proteins, modular polypeptides, and so on. The database is accessible via UCL's Bioinformatics World Wide Web (WWW) server at http://www.biochem.ucl.ac.uk/bsm/dbbrowser / . We describe here progress with the database, its Web interface, and a recent exciting development: the integration of a novel colour alignment editor (http://www.biochem.ucl.ac.uk/bsm/dbbrowser++ +/CINEMA ), which allows visualisation and interactive manipulation of PRINTS alignments over the Internet.
PRINTS is a compendium of protein motif 'fingerprints' derived from the OWL composite sequence database. Fingerprints are groups of motifs within sequence alignments whose conserved nature allows them to be used as signatures of family membership. To date, 400 fingerprints have been constructed and stored in Prints, the size of which has doubled in the last year. The current version, 9.0, encodes approximately 2000 motifs, covering a range of globular and membrane proteins, modular polypeptides, and so on. Fingerprints inherently offer improved diagnostic reliability over single motif methods by virtue of the mutual context provided by motif neighbours. PRINTS thus provides a useful adjunct to the widely used PROSITE dictionary of patterns. The database is now accessible via the Database Browser on the UCL Bioinformatics server at http://www.biochem.ucl.ac.uk/bsm/dbbrowser .
Actinobacillus pleuropneumoniae serotype reference strains and 204 A. pleuropneumoniae field strains representing all 12 serotypes and both biovars 1 and 2, obtained from laboratories from various countries worldwide, were analyzed for the presence of the toxin genes apxIC, apxIA, apxIB, apxID, apxIIC, apxIIA, apxIIIC, apxIIIA, apxIIIB, and apxIIID by DNA-DNA hybridization with specific gene probes. Expression of the toxins ApxI, ApxII, and ApxIII was assessed by immunoblot analysis with monoclonal antibodies. The results show that the patterns of apx genes and those of the expressed Apx toxins in biovar 1 field strains are the same as those of the genes and toxins of corresponding serotype reference strain. We found only three strains which had certain apx genes missing compared with the genes in their serotype reference strains. Analysis of the expression of the three toxins showed that nearly all strains expressed their apx genes and produced the same Apx toxins as their serotype reference strain. We found only one strain that did not produce ApxI, although it contained the apxICABD genes, and one strain which did not express ApxII but which contained apxIICA. Several field strains which initially showed that their serotype did not correspond to the apx gene profile of the reference strain and which had an unexpected virulence for the given serotype revealed that their initial serotyping was erroneous. We show that the apx gene profiles are inherent to a given serotype. The method cannot differentiate between all 12 serotypes. However, it allowed us to distinguish five groups of toxin gene patterns which showed pathological, toxicological, and epidemiological significance. None of the biovar 2 strains contained apxIII genes. The apxI and apxII genes in the biovar 2 strains, however, were the same as those found in the serotype reference strains of biovar 1.
A clinical recovery score (CRS) assessing recovery after general anesthesia was compared with the Digit-Symbol Substitution Test (DSST), Trieger Test (TT), a patient-completed visual analogue scale for alertness (VAS), and an independent observer's evaluation of recovery. The CRS included ratings of the following parameters: activity, respiration, circulation, consciousness, ambulation, color, and nausea and vomiting. Forty patients requiring the removal of three or four third molars participated in the study. All patients received the same general anesthetic technique. Each patient was evaluated by the five methods preoperatively, on admission to the recovery room, and at 15-min intervals until discharge. The four recovery tests (CRS, DSST, TT, VAS) were evaluated using chi 2 analysis to determine if there was any overall difference among the tests using the observer's determination of home readiness as the standard for discharge. The CRS was significantly more in agreement with the observer's determination than were the paper and pencil tests. The recovery tests were also evaluated with regard to instances of early dismissal or prolonged retention of the patient, again using the observer's determination as the "gold standard." The CRS was the only recovery test devoid of early dismissals. We conclude that the CRS provides a valid, simple measure of recovery that can be readily used in offices providing outpatient anesthesia and in studies measuring clinical recovery from anesthesia or sedation.