Recommendations for patient screening in ultra-rare inherited metabolic diseases: what have we learned from Niemann-Pick disease type C?

BACKGROUND: Rare and ultra-rare diseases (URDs) are often chronic and life-threatening conditions that have a profound impact on sufferers and their families, but many are notoriously difficult to detect. Niemann-Pick disease type C (NP-C) serves to illustrate the challenges, benefits and pitfalls associated with screening for ultra-rare inborn errors of metabolism (IEMs). A comprehensive, non-systematic review of published information from NP-C screening studies was conducted, focusing on diagnostic methods and study designs that have been employed to date. As a key part of this analysis, data from both successful studies (where cases were positively identified) and unsuccessful studies (where the chosen approach failed to identify any cases) were included alongside information from our own experiences gained from the planning and execution of screening for NP-C. On this basis, best-practice recommendations for ultra-rare IEM screening are provided. Twenty-six published screening studies were identified and categorised according to study design into four groups: 1) prospective patient cohort and family-based secondary screenings (18 studies); 2) analyses of archived 'biobank' materials (one study); 3) medical chart review and bioinformatics data mining (five studies); and 4) newborn screening (two studies). NPC1/NPC2 sequencing was the most common primary screening method (Sanger sequencing in eight studies and next-generation sequencing [gene panel or exome sequencing] in five studies), followed by biomarker analyses (usually oxysterols) and clinical surveillance. CONCLUSIONS: Historically, screening for NP-C has been based on single-patient studies, small case series, and targeted cohorts, but the emergence of new diagnostic methods over the last 5-10 years has provided opportunities to screen for NP-C on a larger scale. Combining clinical, biomarker and genetic diagnostic methods represents the most effective way to identify NP-C cases, while reducing the likelihood of misdiagnosis. Our recommendations are intended as a guide for planning screening protocols for ultra-rare IEMs in general.

Mortality in patients with Sanfilippo syndrome.

BACKGROUND: Sanfilippo syndrome (mucopolysaccharidosis type III; MPS III) is an inherited monogenic lysosomal storage disorder divided into subtypes A, B, C and D. Each subtype is characterized by deficiency of a different enzyme participating in metabolism of heparan sulphate. The resultant accumulation of this substrate in bodily tissues causes various malfunctions of organs, ultimately leading to premature death. Eighty-four, 24 and 5 death certificates of patients with Sanfilippo syndrome types A, B and C, respectively, were obtained from the Society of Mucopolysaccharide Diseases (UK) to better understand the natural course of these conditions, covering the years 1977-2007. RESULTS: In Sanfilippo syndrome type A mean age at death (± standard deviation) was 15.22 ± 4.22 years, 18.91 ± 7.33 years for patients with Sanfilippo syndrome type B and 23.43 ± 9.47 years in Sanfilippo syndrome type C. Patients with Sanfilippo syndrome type A showed significant increase in longevity over the period of observation (p = 0.012). Survival rates of patients with Sanfilippo syndrome type B did not show a statistically significant improvement (p = 0.134). In Sanfilippo syndrome types A and B, pneumonia was identified as the leading cause of death. CONCLUSIONS: The analysis of 113 death certificates of patients with Sanfilippo syndrome in the UK has demonstrated that the longevity has improved significantly in patients with Sanfilippo syndrome type A over a last few decades. The numbers of patients with Sanfilippo syndrome types B and C were too small to identify any significant trend changes for these groups. Respiratory tract infections, notably pneumonia, remain the leading cause of mortality in Sanfilippo syndrome types A and B. The extended lifespans of patients with Sanfilippo syndrome type A were achieved despite the lack of therapies to target the primary insult or pathophysiology of the disease. However, the mean age at death of these patients remains low when compared with the general population. Therefore, there is an urgent need for effective disease-specific therapies to be developed so that the quality of life and survival of patients with Sanfilippo syndrome can be improved.

Lipid profile in adult patients with Fabry disease - Ten-year follow up.

BACKGROUND: Fabry disease, an X-linked genetic condition, results from alpha-galactosidase deficiency and increased accumulation of glycosphingolipids in cardiovascular tissues. Clinical manifestation includes vasculature associated complications. Hyperlipidaemia is one of the cardiovascular risk factors however it has never been well defined in Fabry disease. Enzyme Replacement Therapy (ERT) is available but its effect on serum cholesterol is unknown. The aim of this project was to assess the influence of long-term ERT on lipid profile in a large cohort of adult patients with Fabry disease. METHODS: This was a retrospective analysis of lipid profile results. Patients with Fabry disease were on ERT for 10 years, were not treated with statins and had no severe renal impairment. All patients had lipid profile measured before ERT was commenced and 6, 12, 24, 36, 48, 60, 120 months later. Statistical analysis included ANOVA, Student t-test and descriptive statistics. RESULTS: Among 72 patients, 40 were females (median age 45; range 29-75), 32 males (median age 46; range 20-69). There was no significant difference in total cholesterol or HDL-cholesterol measured at baseline before ERT was commenced and 6, 12, 24, 36, 48, 60 and 120 months after ERT was commenced in 72 patients (ANOVA; P = 0.673 and P = 0.883, respectively). Female patients on ERT had higher mean HDL-cholesterol as compared to female patients with Fabry disease who were asymptomatic and not treated (P ≥ 0.05). Total cholesterol between treated and non-treated female patients was comparable. Female patients on ERT have higher total cholesterol and HDL-cholesterol when compared to lipid results in male patients on ERT. Total cholesterol/HDL-cholesterol ratio was low in female and male patients on ERT over 10 years. CONCLUSION: Adult patients with Fabry disease have remarkably elevated HDL-cholesterol and as a result, elevated total cholesterol. It is possible that elevated HDL-cholesterol has a cardioprotective effect in patients with this condition. Long term ERT does not have a significant impact on lipid profile in female and male population with Fabry disease.

The factors affecting lipid profile in adult patients with Mucopolysaccharidosis.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of rare inherited disorders characterized by abnormal accumulation of glycosaminoglycans (GAGs) within the myocytes and coronary arteries. Little is known about hyperlipidaemia as a potential cardiovascular risk factor in these patients. Baseline cholesterol data in adults are scarce. Therefore, the aim of this study was to analyse factors affecting lipid profile in different types of MPSs to determine if abnormalities in lipid profile contribute to the overall risk of cardiovascular disease. METHODS: Adult patients (above the age of 16) with MPS type I, II, III, IV and VI attending clinics in two Inherited Metabolic Disorders centres were included. Their lipid profile, lipoprotein (a), HbA1c, Glucose Tolerance Test (GTT), BMI and treatment type were extracted. Analysis included descriptive statistics and Student t-test. RESULTS: Eighty two patients with five MPS types (I, II, III, IV and VI) were included in the study; 29 were females (35%) and 53 were males (65%). BMI above 25 kg/m2 in all MPS types indicated that some patients were overweight for their height. Only one patient post-HSCT had diabetes. In 3 cases insulin was analysed during GTT and showed no insulin resistance despite raised BMI. Mean total cholesterol and LDL-cholesterol were below 5 mmol/L and 3 mmol/L, respectively, in five individual MPS types. Lipoprotein (a) was available for 6 MPS IV patients and was not significantly raised. CONCLUSIONS: MPS disorders are not associated with significant hypercholesterolaemia or diabetes mellitus despite increased BMI. Total cholesterol and LDL-cholesterol were within the targets for primary prevention for non-MPS population. Lipoprotein (a) is not a useful marker of cardiovascular disease in a small group of adult MPS IV patients irrespectively of treatment option. Whether long-term cardiovascular risk is dependent on lipid profile, diabetes, obesity or GAGs deposition within the organ system remains unanswered.

Niemann-Pick type C disease - the tip of the iceberg? A review of neuropsychiatric presentation, diagnosis and treatment.

Niemann-Pick type C (NP-C) disease is a rare neurodegenerative lysosomal storage disorder. It is highly heterogeneous, and there is limited awareness of a substantial subgroup that has an attenuated adolescent/adult-onset disease. In these patients psychiatric features, often a psychosis, may dominate the initial impression, although often there is an associated ataxia and cognitive impairment. Typically, patients experience a substantial diagnostic delay. In this review we highlight the importance of early recognition and discuss the pathophysiology, neuropsychiatric presentation and recent changes in the investigation and work-up of these patients, and treatment options.

A systematic review of the prevalence of Morquio A syndrome: challenges for study reporting in rare diseases.

BACKGROUND: Morquio A (MPS IVA) is a rare disease characterised by a deficiency of N-acetylgalactosamine-6 sulfatase (GALNS) and presenting with short stature, abnormal gait, cervical spine instability and shortened lifespan. PURPOSE: To prepare a systematic review of the prevalence of Morquio A in multiple countries and suggest recommendations for reporting rare diseases. METHODS: Medline, Medline In-Process, Medline Daily Update, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database and PROSPERO were searched from inception to October 2013 to identify relevant information on the epidemiology of Morquio A. Forty Patient Organisation Representatives (POR) and Key Opinion Leaders (KOL) across 24 countries were contacted for data. Observational studies were included and case reports were excluded. Searches were performed without date or language restriction. Two researchers independently screened and extracted data. Quality of study reporting was assessed using a checklist adapted from STROBE (STrengthening the Reporting of OBservational studies in Epidemiology). Point or birth prevalence was stratified according to diagnostic method and discussed narratively. RESULTS: In total 9,074 records were retrieved from searching and 25 studies were included for data extraction. Twenty out of 40 KOL and POR responded (50%) and 9 provided data (23%). Point prevalence of Morquio A was 1 per 926,000 in Australia, 1 per 1,872,000 in Malaysia and 1 per 599,000 in UK and Morquio (unclassified) was 1 per 323, 000 in Denmark. Birth prevalence of Morquio A (using recommended diagnostic methods) ranged from 1 per 71,000 in UAE to 1 per 500,000 in Japan. All results were compromised by poor study reporting and internal validity. CONCLUSIONS: The review highlighted that there is a misunderstanding of the definitions for prevalence and incidence in the field; that studies were poorly reported (diagnostic methods and patient characteristics) and that no suitable quality assessment tool exists. Overestimation and underestimation of prevalence data can occur. Bespoke reporting guidelines and a quality assessment tool specifically for prevalence of rare diseases are recommended.

Gastrointestinal disturbances and their management in miglustat-treated patients.

Miglustat (Zavesca®) is approved for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy is unsuitable, and for the treatment of progressive neurological manifestations in adult and paediatric patients with Niemann-Pick disease type C (NP-C). Gastrointestinal disturbances such as diarrhoea, flatulence and abdominal pain/discomfort have consistently been reported as the most frequent adverse events associated with miglustat during clinical trials and in real-world clinical practice settings. These adverse events are generally mild or moderate in severity, occurring mostly during the initial weeks of therapy. The mechanism underlying these gastrointestinal disturbances is the inhibition by miglustat of intestinal disaccharidase enzymes (mainly sucrase and maltase), leading to sub-optimal hydrolysis of carbohydrates and subsequent osmotic diarrhoea and altered colonic fermentation. Transient decreases in body weight, which are often observed during initial miglustat therapy, are considered likely due to gastrointestinal carbohydrate malabsorption and associated negative caloric balance. While most cases of diarrhoea resolve spontaneously during continued miglustat therapy, diarrhoea also responds well to anti-propulsive medications such as loperamide. Dietary modifications such as reduced consumption of dietary sucrose, maltose and lactose have been shown to improve the gastrointestinal tolerability of miglustat and reduce the magnitude of any changes in body weight, particularly if initiated at or before the start of therapy. Miglustat dose escalation at treatment initiation may also reduce gastrointestinal disturbances. This article discusses these aspects in detail, and provides practical recommendations on how to optimize the gastrointestinal tolerability of miglustat.

Inborn errors of metabolism for the diagnostic radiologist.

Inherited metabolic disorders are becoming more important with the increasing availability of diagnostic methods and therapies for these conditions. The radiologist has become an important link in making the diagnosis or collaborating with the specialist centre to diagnose these disorders and monitor effects of therapy. The modes of presentation, disease-specific groups, classic radiological features and investigations are explored in this article to try and give the general radiologist some crucial background knowledge. The following presentations are covered: acute intoxication, hypoglycaemia, developmental delay and storage features. Specific groups of disorders covered are the abnormalities of intermediary metabolism, disorders of fatty acid oxidation and ketogenesis, mitochondrial disorders, lysosomal storage disorders, and, briefly, other groups such as peroxisomal disorders, disorders of glycosylation, and creatine synthesis disorders. New advances and the demands for monitoring are also briefly explored.