Recognition of alpha-mannosidosis in paediatric and adult patients: Presentation of a diagnostic algorithm from an international working group.

Alpha-mannosidosis is an ultra-rare progressive lysosomal storage disorder caused by deficiency of alpha-mannosidase. Timely diagnosis of the disease has the potential to influence patient outcomes as preventive therapies can be initiated at an early stage. However, no internationally-recognised algorithm is currently available for the diagnosis of the disease. With the aim of developing a diagnostic algorithm for alpha-mannosidosis an international panel of experts met to reach a consensus by applying the nominal group technique. Two proposals were developed for diagnostic algorithms of alpha-mannosidosis, one for patients ≤10 years of age and one for those >10 years of age. In younger patients, hearing impairment and/or speech delay are the cardinal symptoms that should prompt the clinician to look for additional symptoms that may provide further diagnostic clues. Older patients have different clinical presentations, and the presence of mental retardation and motor impairment progression and/or psychiatric manifestations should prompt the clinician to assess for other symptoms. In both younger and older patients, either additional metabolic monitoring or referral for testing is warranted upon suspicion of disease. Oligosaccharides in urine (historically performed) or serum were considered as an initial screening procedure, while enzymatic activity may also be considered as first choice in some centres. Molecular testing should be performed as a final confirmatory step. The developed algorithms can easily be applied in a variety of settings, and may help to favour early diagnosis of alpha mannosidosis and treatment.

Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.

The nutritional status and the height of the arch of the foot in preschool children.

AIM: Childhood obesity is an increasingly common problem. It is associated with poor posture especially with lower limb deformities. The study aimed at assessing the prevalence of overweight and obesity in preschoolers, the analysis also contained the relationship between the nutritional status and the foot arching. METHODS: One thousand two hundred ninety-four children at the age from 3 to 6 years took part in the study. The height and weight of the children were measured. From these measurements, the BMI and Cole Index values were calculated. The prevalence of overweight and obesity were estimated. The degree of foot arching was measured using a podoscope and categorised according to Clarke's angle (CA). Differences in CA between right and left foot were analysed across all groups according to age and gender. Secondly CA for both feet was compared between girls and boys from all age groups. Thirdly, CA was compared for the same gender but between different age groups. Finally, nutritional status and CA for the right and left foot were correlated. Basic descriptive statistics, the U Mann-Whitney test, a one-way ANOVA and the linear correlation study were used to verify the presence of trend. RESULTS: Twenty percent of boys and 15.7% of girls were found overweight, and 9.8% of both male and female subjects were found obese. The prevalence of overweight increased with age. The longitudinal arch of the foot was higher in girls. It increased with age. The height of the longitudinal arch of the foot was smaller in overweight and obese children. CONCLUSION: A substantial number of overweight and obese preschoolers took part in the study, in which a significant dependence between excessive body weight and flat feet was found. The preschool education programmes should include pro-health exercises combining aerobic training with exercises developing good body posture habits.

Non-paraganglioma tumors of the jugular foramen - Growth patterns, radiological presentation, differential diagnosis.

OBJECTIVE: Most common tumors of the jugular foramen are paragangliomas. However, other lesions, also malignant, may involve the jugular foramen and mimic radiographic presentation of paragangliomas. Therefore, a correct preoperative diagnosis is crucial for best treatment planning. This study analyzes imaging characteristics of non-paraganglioma neoplasms involving the jugular foramen, with attention given to features helpful in differential diagnosis. STUDY DESIGN: A retrospective chart search. SETTING: Teritary referral university centre. SUBJECTS AND METHODS: During the years 1997-2010, 11 cases of jugular foramen tumors other than paragangliomas, with available imaging studies, were identified. Histopathology revealed: 3 schwannomas, 1 malignant schwannoma, 2 meningiomas, 1 hemangiopericytoma, 1 ependymoma, 1 endolymphatic sac carcinoma (ELST) and 2 nasopharyngeal carcinoma metastases. CT, MRI and angiography were assessed to determine tumor growth directions, bone involvement, tumor morphology and vascular composition. RESULTS: Schwannomas were characterized by parapharyngeal space involvement, jugular foramen expansion, preservation of cortical margins, irregular contrast enhancement. Meningiomas presented diffuse bone infiltration, sclerotic changes, erosion of the cortical bone. Ependymoma showed diffuse skull base infiltration, permeative erosion, heterogeneity, abundant vascularization. Hemangiopericytoma radiologically imitated paraganglioma. ELST showed permeative/geographic bony destruction, heterogeneity, intratumoral bony fragments. Metastases were lytic, solid lesions characterized by circumferential growth, internal carotid artery encasement and stenosis. CONCLUSIONS: A combination of certain radiological features including tumor epicenter, growth vectors, skull base infiltration, bony changes and tumor morphology help establish correct preoperative diagnosis and differentiate less common jugular foramen tumors, from most common paragangliomas. Hemangiopericytoma may radiologically mimic paraganglioma.

Osteoimmunology in mucopolysaccharidoses type I, II, VI and VII. Immunological regulation of the osteoarticular system in the course of metabolic inflammation.

BACKGROUND: Mucopolysaccharidoses (MPSs) are rare genetic diseases caused by a deficient activity of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. These metabolic blocks lead to the accumulation of GAGs in various organs and tissues, resulting in a multisystemic clinical picture. The pathological GAG accumulation begins a cascade of interrelated responses: metabolic, inflammatory and immunological with systemic effects. Metabolic inflammation, secondary to GAG storage, is a significant cause of osteoarticular symptoms in MPS disorders. OBJECTIVE AND METHOD: The aim of this review is to present recent progress in the understanding of the role of inflammatory and immune processes in the pathophysiology of osteoarticular symptoms in MPS disorders and potential therapeutic interventions based on published reports in MPS patients and studies in animal models. RESULTS AND CONCLUSIONS: The immune and skeletal systems have a number of shared regulatory molecules and many relationships between bone disorders and aberrant immune responses in MPS can be explained by osteoimmunology. The treatment options currently available are not sufficiently effective in the prevention, inhibition and treatment of osteoarticular symptoms in MPS disease. A lot can be learnt from interactions between skeletal and immune systems in autoimmune diseases such as rheumatoid arthritis (RA) and similarities between RA and MPS point to the possibility of using the experience with RA in the treatment of MPS in the future. The use of different anti-inflammatory drugs requires further study, but it seems to be an important direction for new therapeutic options for MPS patients.

Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single centre, randomised, multiple dose study.

BACKGROUND: Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly intravenous enzyme replacement therapy (ERT). We present the preliminary data after 12 months of treatment. METHODS: This is a phase I-II study to evaluate safety and efficacy of rhLAMAN. Ten patients (7-17 y) were treated. We investigated efficacy by testing motor function (6-minutes-Walk-Test (6-MWT), 3-min-Stair-Climb-Test (3-MSCT), The Bruininks-Oseretsky Test of Motor Proficiency (BOT2), cognitive function (Leiter-R), oligosaccharides in serum, urine and CSF and Tau- and GFA-protein in CSF. RESULTS: Oligosaccharides: S-, U- and CSF-oligosaccharides decreased 88.6% (CI -92.0 -85.2, p < 0.001), 54.1% (CI -69.5- -38.7, p < 0,001), and 25.7% (CI -44.3- -7.1, p < 0.05), respectively. Biomarkers: CSF-Tau- and GFA-protein decreased 15%, p < 0.009) and 32.5, p < 0.001 respectively. Motor function: Improvements in 3MSCT (31 steps (CI 6.8-40.5, p < 0.01) and in 6MWT (60.4 m (CI -8.9 -51.1, NS) were achieved. Cognitive function: Improvement in the total Equivalence Age of 4 months (0.34) was achieved in the Leiter R test (CI -0.2-0.8, NS). CONCLUSIONS: These data suggest that rhLAMAN may be an encouraging new treatment for patients with alpha-mannosidosis.The study is designed to continue for a total of 18 months. Longer-term follow-up of patients in this study and the future placebo-controlled phase 3 trial are needed to provide greater support for the findings in this study.

Peer assessment as a method for measuring harmful internet use.

Harmful Internet use (HIU) describes unintended use of the Internet. It could be both self-harm and harming others. Our research goal is to develop a more accurate method for measuring HIU by this novel peer assessment. As such, it may become, with our call for more research, a paradigm shift supplementing every rating scale or other type of Internet use assessment. In addition to classic statistical analysis, structural equations have been employed. Results indicate that the true positive rate (TPR) is substantially higher than assessed in other studies.•Peer assessment improvement.•AUC for ROC was computed to establish cut-off points for the used scale.•Results obtained by the Structural Equation model indicate that parental care has a moderate influence on subjects' attempts to fight HIU.

Audiological and radiological study of eight polish patients with alpha-mannosidosis.

Alpha-mannosidase catalyze lysosomal cleaving of mannose residues from glycoproteins. The enzyme is encoded by the MAN2B1 gene. Biallelic pathogenic variants cause enzymatic deficiency, which clinically results in alpha-mannosidosis (AM), an autosomal recessively inherited condition. Typical features observed in AM patients include intellectual disability, loss of speech, dysmorphic features, progressive motor problems, ataxia, hearing impairment and recurrent otitis. The cause of the latter is mainly attributed to immunodeficiency. The aim of our study was to demonstrate the otolaryngologic and hearing outcomes in patients with AM. The study group consisted of 8 AM patients: 6 males and 2 females, aged 2.5-37 yrs. The clinical course, dysmorphic ENT features, hearing status and the HRCT scans of the temporal bones were analyzed. MS Excel for Windows and Statistica software package were used for the comparison of interaural audiometric loss, mean hearing loss and mean hearing threshold for each patient's audiometric frequency tested. We identified ENT dysmorphic features in all of our AM patients, while the hearing loss was detected in 6 out of our 8 patients. For those cases, the onset of deafness was noted in the first decade of life, this impairment was sensorineural, of cochlear origin, bilateral, of a moderate degree (mean loss 62.76 dB; median 60 dB, standard deviation 12.5 dB), symmetrical and stable. The shape of the audiometric curves of our patients can be described as slightly sloping towards the higher tested frequencies, with a marked improvement at 4 kHz. The radiological examination revealed normal structures of the ears, with the exception of one case where a persistent otitis generated a cochlear gap. We therefore concluded that the hearing loss in our AM patients derived from cochlear impairment unrelated with recurrent otitis.

Enzyme replacement therapy for mucopolysaccharidosis II from 3 months of age: a 3-year follow-up.

AIM: We present a 3-year follow-up of a boy with mucopolysaccharidosis type II (MPS II) who had idursulfase therapy initiated at the age of 3 months and compare his clinical course to his healthy twin brother. METHODS: Detailed anthropometric features, ultrasound studies of liver and spleen volumes, echocardiography and audiological examinations, psychological tests, joint range of motion (ROM) and skeletal radiographs were monitored. RESULTS: After 3 years of treatment, the patient has not developed any clinical manifestations of MPS II. He did not develop coarse facial features, joint disease, or organomegaly, and his cardiac function remained normal. There were no pronounced signs of dysostosis multiplex on radiographs. The only difference when compared with his healthy twin brother was lower IQ (Termann-Merrill 98 vs. 118) and mild deformity of one vertebrae. CONCLUSION: Our study suggests that early initiation of enzyme replacement therapy may significantly slow or prevent the development of irreversible disease manifestations and therefore modify the natural history of MPS II.

Transformative effect of a Humanitarian Program for individuals affected by rare diseases: building support systems and creating local expertise.

Rare diseases affect > 400 million people globally with a disproportionate burden falling on children, resulting in high morbidity and mortality rates. Affected individuals in some under-resourced countries have limited access to expert care or treatments; moreover, they suffer long diagnostic journeys during which debilitating and life-threatening complications occur. Lysosomal storage disorders (LSD) are prototype rare diseases due, in the main, to inherited deficiencies of lysosomal enzymes/transporters that affect up to 1 in 5000 newborns. Recognizing the need to provide treatment access to people with LSDs everywhere, a collaborative partnership was pioneered and set up 30 years ago. Partnering with local authorities, non-government organizations across six continents, local as well as international experts, a robust, sustainable Humanitarian Program emerged that now represents the most enduring charitable access program for LSD treatment. Here we present the history, process, lasting beneficial effect of the program to develop healthcare systems and infrastructures, and the lessons learned from addressing major unmet needs for LSDs.

Female Hunter syndrome caused by a single mutation and familial XCI skewing: implications for other X-linked disorders.

Familial X-chromosome inactivation (XCI) skewing was investigated in a family in which a female mucopolysaccharidosis type II (MPS II) (Hunter syndrome, an X-linked genetic disease) occurred. Among eight related females aged under 60 years from three generations who were tested, four revealed a non-random pattern of XCI. Detailed genetic analysis failed to find mutations in genes that were previously reported as important for the XCI process. Haplotype analysis excluded linkage of non-random XCI with genes localized on the X-chromosome. We propose that analysis of the XCI pattern should be taken into consideration when assessing risk factors for X-linked recessive genetic disorders.

Molecular and clinical consequences of novel mutations in the arylsulfatase A gene.

Metachromatic leukodystrophy (MLD), a severe neurodegenerative metabolic disorder, is caused by deficient activity of arylsulfatase A (ARSA; EC 3.1.6.8), which leads to a progressive demyelinating process in central and peripheral nervous systems. In this study, a DNA sequence analysis was performed on six Polish patients with different types of MLD. Six novel mutations were identified: one nonsense (p.R114X), three missense (p.G122C, p.G293C, p.C493F) and two frameshift mutations (g.445_446dupG and g.2590_2591dupC). Substitutions p.G293C and p.C493F and duplication g.445_446dupG caused a severe reduction of enzyme activity in transient transfection experiments on mammalian cells (less than 1% of wild-type (WT) ARSA activity). Duplication 2590_2591dupC preserved low-residual ARSA activity (10% of WT ARSA). In summary, the novel MLD-causing mutations in the exons 2, 5 and even in 8 of the ARSA gene described here can be classified as severe type 0, leading in homozygosity to the late infantile form MLD. Growth retardation, delayed motor development, gait disturbances, tonic-clonic seizures and non-epileptic muscle spasms were the first onset symptoms in patients with late infantile form of MLD. In individual with juvenile type MLD gait disturbances evidenced the onset of the disease, while in a patient with late juvenile MLD, difficulties at school were displayed.

Management of neuronopathic Gaucher disease: revised recommendations.

The original guidelines drawn up for the management of the neuronopathic forms of Gaucher disease were felt to be in need of revision; in particular, the role of high-dose enzyme replacement therapy (120 IU/kg of body weight every 2 weeks) in stabilizing neurological disease. The existing published evidence was analysed; it was concluded that it did not support the role of high-dose ERT, although this might be required to treat severe visceral disease.

The identification of discontinuous epitope in the human cystatin C - Monoclonal antibody HCC3 complex.

Human cystatin C (hCC) is a cysteine proteinase inhibitor involved in pathophysiological processes of dimerization and amyloid formation. These processes are directly associated with a number of neurodegenerative disorders such as Alzheimer disease or hereditary cystatin C amyloid angiopathy (HCCAA). One of the ideas on how to prevent amyloid formation is to use immunotherapy. HCC3 is one of a group of antibodies binding to hCC and reducing the in vitro formation of cystatin C dimers. Therefore, identification of the binding sites in the hCC-HCC3 complex may facilitate a search of effective drugs against HCCAA as well as understanding the mechanisms of neurodegenerative disorders. In this work we present epitope identification of the hCC-HCC3 complex using methods such as affinity chromatography, epitope excision and extraction MS approach, enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry (HDX MS). Comprehensive analysis of the obtained results allowed us to identify the epitope sequence with the key fragment covering hCC L1 loop and two potential epitopic fragments - α-helical part, hCC (17-28) and ß4 strand in C-terminal part of hCC. The presence of the L1 loop in the epitope sequence accounts for the significant reduction of hCC dimer formation in the presence of HCC3 antibody. SIGNIFICANCE OF THE STUDY: Deciphering the mechanism of the cystatin C aggregation process and detailed analysis of the interactions between hCC, or its pathogenic variant, and monoclonal antibodies, potentially constituting aggregation inhibitors, might be of great value as there still is a complete lack of any kind of efficient therapy for young people with the pathogenic mutation of hCC.

Impact of high-volume, intermediate-volume and low-volume bowel preparation on colonoscopy quality and patient satisfaction: An observational study.

Background: Although optimal bowel preparation is essential for high-quality screening colonoscopy, documentation of preparation quality, patient satisfaction and adherence is scarce. Aim: The aim of this article is to compare low-volume (LV, 300 ml sodium picosulfate), intermediate-volume (IV, 2 l polyethylene glycol, PEG + ascorbic acid and sodium ascorbate), and high-volume (HV, 4 l PEG) purgatives. Results: A total of 5000 individuals (50.5% women) were enrolled between March 2015 and July 2017 (LV:IV:HV = 3.61:1.54:1). Overall sex- and age-adjusted adenoma detection rate was 25.4% (LV 23.8%, IV 25.4%, HV 29.8%), median age was 59.6 years, and cleansing was successful in 96.8%. Success rates of bowel cleansing were highest with HV (97.6%), followed by LV (97.2%) and IV (95.3%) with OR 2.04 (CI 95% 1.20-3.45, p = 0.008) and OR 1.79 (CI 95% 1.27-2.50, p = 0.001), respectively, compared to IV. A total of 93.5% of the LV group would use the same purgative in the future, 73.2% of IV and 69.4% of HV. A total of 84.4% would prefer overnight preparation, 12.1% same-day preparation. Conclusion: All purgatives investigated showed good bowel cleansing quality results, patient satisfaction and compliance. Improvement in patient information might lead to even higher participation rates in screening colonoscopy since one in five patients stated that bowel preparation worried him or her most prior to colonoscopy.

D-ribose therapy in four Polish patients with adenylosuccinate lyase deficiency: absence of positive effect.

Deficiency of adenylosuccinate lyase (ADSL) (OMIM 103050) is an autosomal recessive disorder of the purine de novo synthesis pathway and purine nucleotide cycle, diagnosed so far in approximately 50 patients. The clinical presentation is characterized by severe neurological involvement including hypotonia, seizures, developmental delay and autistic features. Epilepsy in ADSL deficiency is frequent and occurs in approximately two-thirds of patients, beginning either early in the neonatal period or after the first year of life. At present there is no treatment of proven clinical efficacy. Despite of the increasing number of ADSL-deficient patients reported, there are only a few communications of therapeutic considerations or efforts. Among them only two showed some beneficial effects in ADSL-deficient patients. D-ribose, a simple and relatively cheap therapy, has been associated with improvement of behaviour and progressive reduction of the seizure frequency in one 13-year-old patient with ADSL deficiency. In this study we have re-examined D-ribose treatment in four ADSL-deficient patients. Assessments consisted of biochemical markers and neurological outcome. The 12-month trial of D-ribose failed to show any clinical benefit in ADSL patients with both milder and severe phenotype. D-ribose administration was accompanied by neither reduction in seizure frequency nor growth enhancement. Additionally, patients with milder type II presented the first seizure after 4 and 8 months of the D-ribose treatment. Therefore, we could not confirm a positive effect of D-ribose as previously reported.

Hypoxanthine-guanine phosphoribosylotransferase deficiency--the spectrum of Polish mutations.

Hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC 2.4.2.8) deficiency (OMIM 308000) is an inborn error of purine metabolism. The defect causes three overlapping clinical syndromes: Lesch-Nyhan disease (LND; OMIM 300322), HPRT-related hyperuricaemia with neurologic dysfunction (HRND) and hyperuricaemia alone (HRH; OMIM 300322). During the period 1977-2007, 18 patients belonging to 12 Polish families and one Latvian family with HPRT deficiency have been identified. The majority of patients had a typical LND phenotype, three patients were classified as HRH and one patient as an intermediate phenotype (HRND). Genetic analysis revealed 12 different HPRT1 mutations, five of them being unique. In two typical Lesch-Nyhan families a novel single-base substitution, c.220T>G (p.Phe74Val), and a deletion of seven nucleotides, c.395_401del7 (p.Ile132LysfsX3), were found. Another novel single-base substitution, c.295T>G (p.Phe99Val), was identified in a patient with severe partial deficiency of HPRT with neurological dysfunction. In patients belonging to the HRH group, two transitions were detected: c.481G>A (p.Ala161Thr) and c.526C>T (p.Pro176Ser). Other mutations identified in Polish patients, c.131A>G (p.Asp44Gly), c.222C>A (p.Phe74Leu), c.385-1G>A (p.Asn129_Glu134del), c.482C>A (p.Ala161Glu), c.508C>T (p.Arg170Ter) and c.569G>A (p.Gly190Glu), have been reported previously in unrelated patients and are located within one of the clusters of hot spots of the HPRT1 gene (exons 3, 7 and 8). Patients with partial phenotypes presented mutations predicted to permit some degree of residual enzyme function (single-base substitutions). All mutations, except c.508C>T (p.Arg170Ter), were found in single families only, indicating the lack of any common mutation causing HPRT deficiency in Poland.

Management of non-neuronopathic Gaucher disease with special reference to pregnancy, splenectomy, bisphosphonate therapy, use of biomarkers and bone disease monitoring.

Enzyme replacement was introduced as treatment for non-neuronopathic Gaucher disease more than 15 years ago. To ensure the best use of this costly ultra-orphan agent, a systematic disease management approach has been proposed by an international panel; this includes the development, by consensus, of achievable treatment goals. Here we critically review these goals and monitoring guidelines and incorporate emerging experience of the disease in the therapeutic era, as well as contemporary clinical research. This review makes recommendations related specifically to the management of pregnancy; the appropriate use of splenectomy and bisphosphonate treatment; the relevance of biochemical markers to disease monitoring; and the use of semi-quantitative methods for assessing bone marrow infiltration. In addition, we identify key areas for development, including the requirement for a validated index of disease severity; the need to correlate widely used biomarkers with long-term disease outcomes, and the desirability of establishing agreed standards for monitoring of bone disease particularly in infants and children with Gaucher disease.

Holistic Long-Term Care Over Elderly Kidney Transplant Recipients.

Kidney transplantation is an optimal method of renal replacement therapy in patients with phase V chronic kidney disease. Elderly patients (older than 60 years) with a kidney transplant create a significant and constantly growing pool of patients with this type of organ transplantation. In this group of patients, long-term care should be particularly stringent and vigilant. Apart from typical conditions associated with chronic kidney disease and possible post-transplant complications as well as side effects of immunosuppressive treatment, the patient also experiences changes and limitations associated with the progress of age and diseases typical for old age, characterized by a higher risk of infection, and changed pharmacokinetics/pharmacodynamics. Undoubtedly, patients should remain under the medical care of qualified transplantologists, but constant cooperation with a general practitioner and geriatrician would be of added value. Study results show that although most of the elderly kidney recipients have constant contact with their general practitioners, and almost half of them use private care, contribution of the geriatrician to the transplant care system is unsatisfactory, and elderly kidney recipients would expect more extensive outpatient care.

Outcome of type III Gaucher disease on enzyme replacement therapy: review of 55 cases.

The European Task Force for Neuronopathic Gaucher Disease (NGD) met in 2006 to review its 2001 guidelines. Fifty-five patients from five European countries were reviewed; 29 were male and 26 female. The majority of the patients were homozygous for the L444P mutation. All had been on enzyme replacement therapy (ERT). However, there was considerable variation in the dose of ERT, as well as an uneven distribution of risk factors. Thus, the oldest patients were on the lowest doses, and several had had a total splenectomy, while the youngest patients had a high proportion of compound heterozygosity and were on the highest doses, and very few had had a splenectomy. This heterogeneity rendered analysis very difficult. However, some observations were possible. The older patients appeared to remain relatively stable despite a low dose of ERT. In the younger patients, there was no clear effect of high-dose ERT. However, the period of follow-up was too short in many patients to draw valid conclusions. These data will be used to draw up revised guidelines.