The effect of galsulfase enzyme replacement therapy on the growth of patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome).

Mucopolysaccharidosis (MPS) VI is an autosomal recessive lysosomal storage disorder arising from deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B) and subsequent intracellular accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin-4-sulfate. Manifestations are multi-systemic and include skeletal abnormalities such as dysostosis multiplex and short stature. Reference height-for-age growth charts for treatment-naïve MPS VI patients have been published for both the slowly and rapidly progressing populations. Categorization of disease progression for these charts was based on urinary GAG (uGAG) level; high (>200µg/mg creatinine) levels identified subjects as rapidly progressing. Height data for 141 patients who began galsulfase treatment by the age of 18years were collected and stratified by baseline uGAG level and age at ERT initiation in 3-year increments. The reference MPS VI growth charts were used to calculate change in Z-score from pre-treatment baseline to last follow-up. Among patients with high baseline uGAG levels, galsulfase ERT was associated with an increase in Z-score for those beginning treatment at 0-3, >3-6, >6-9, >9-12, and >12-15years of age (p<0.05). Increases in Z-score were not detected for patients who began treatment between 15 and 18years of age, nor for patients with low (≤200µg/mg creatinine) baseline uGAG levels, regardless of age at treatment initiation. The largest positive deviation from untreated reference populations was seen in the high uGAG excretion groups who began treatment by 6years of age, suggesting an age- and severity-dependent impact of galsulfase ERT on growth.

Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA.

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.

Intellectual and neurological functioning in Morquio syndrome (MPS IVa).

Mucopolysaccharidosis type IVa (MPS IVa, Morquio syndrome OMIM #253000) is a lysosomal storage disease caused by deficiency in N-acetylgalactosamine-6-sulfatase (GALNS, EC 3.1.6.4; encoded by GALNS gene at 16q24.3). Unlike other MPS disorders involving excessive heparan and dermatan sulfate, Morquio syndrome has not been associated with neurological involvement nor with intellectual impairment as this disorder of keratan sulfate has been described as a purely visceral and skeletal disorder. Neurocognitive assessment was undertaken of MPS IVa patients with age appropriate intellectual tests as well as a Child Behaviour Checklist as part of clinical follow up. Available neuroimaging studies (MRI and MR spectroscopy) were reviewed. Whilst more than half of the overall IQ scores fell in the average range, scores for 3/8 children fell below average. A number of behavioural problems were highlighted, including anxiety/depression, attention and somatic complaints. Subtle neuroimaging abnormalities were demonstrated in over half of the children. These findings present a challenge to existing assumptions about the nature of Morquio A syndrome. A hypothesis regarding the potential role of calcium signalling is explored.

Expert recommendations for the laboratory diagnosis of MPS VI.

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). This enzyme is required for the degradation of dermatan sulfate. In its absence, dermatan sulfate accumulates in cells and is excreted in large quantities in urine. Specific therapeutic intervention is available; however, accurate and timely diagnosis is crucial for maximal benefit. To better understand the current practices for diagnosis and to establish diagnostic guidelines, an international MPS VI laboratory diagnostics scientific summit was held in February of 2011 in Miami, Florida. The various steps in the diagnosis of MPS VI were discussed including urinary glycosaminoglycan (uGAG) analysis, enzyme activity analysis, and molecular analysis. The following conclusions were reached. Dilute urine samples pose a significant problem for uGAG analysis and MPS VI patients can be missed by quantitative uGAG testing alone as dermatan sulfate may not always be excreted in large quantities. Enzyme activity analysis is universally acknowledged as a key component of diagnosis; however, several caveats must be considered and the appropriate use of reference enzymes is essential. Molecular analysis supports enzyme activity test results and is essential for carrier testing, subsequent genetic counseling, and prenatal testing. Overall the expert panel recommends caution in the use of uGAG screening alone to rule out or confirm the diagnosis of MPS VI and acknowledges enzyme activity analysis as a critical component of diagnosis. Measurement of another sulfatase enzyme to exclude multiple sulfatase deficiency was recommended prior to the initiation of therapy. When feasible, the use of molecular testing as part of the diagnosis is encouraged. A diagnostic algorithm for MPS VI is provided.

Dietary practices in glutaric aciduria type 1 over 16 years.

BACKGROUND: In glutaric aciduria type 1 (GA1), dietary treatment with emergency management (EM) is essential to prevent encephalopathic crisis (EC). In the present study, dietary practices were examined in a single UK centre without access to newborn screening. METHODS: Twenty GA1 patients (11 males, median age: 10.2 years, range 2.2-24.1 years) were evaluated. Nine presented without EC (median diagnosis age: 1.1 years, range 4 days to 8 years) and 11 with EC (median diagnosis age 10 months, range 6 months to 1.7 years). Dietary treatment, neurological outcome, anthropometry and biochemical/haematological markers were assessed. RESULTS: Diet treatment varied according to age of diagnosis and symptom severity. Four of six pre-encephalopathic children diagnosed before 2 years of age were treated with carnitine, protein restriction (medium l.2 g kg day(-1)) and lysine-free/low tryptophan protein substitute (PS) (medium dose: 1.6 g kg day(-1)). EM consisted of natural protein cessation and glucose polymer with PS delivered via an enteral feeding tube. Older children (>3 years) without EC were given carnitine and protein restriction, and seven of nine EC patients had PS via an enteral feeding tube. Clinical deterioration occurred in two patients without EC; one taking PS and protein restriction (with a second untreatable pathology) and one after protein restriction only. In patients presenting with EC, four died and one had some improvement in movement, with the rest remaining stable but with severe disability. Patients taking PS had better nutritional markers [serum vitamin B(12) (P < 0.001), albumin (P < 0.001), haemoglobin (P < 0.001) and essential plasma amino acids]. CONCLUSIONS: Early diagnosis of GA1 before EC is essential because PS and protein restriction with meticulous EM prevents EC. PS also improves nutritional status irrespective of clinical condition.

MPS VII - Extending the classical phenotype.

Mucopolysaccharidosis VII (or Sly syndrome) is an autosomal recessive disorder characterised by a deficiency in the enzyme Beta-glucuronidase (GUSB). Partial degradation of glycosaminoglycans (GAGs); chondroitin sulfate (CS), dermatan sulfate (DS) and heparan sulfate (HS) results in the accumulation of these fragments in the lysosomes of many tissues, eventually leading to multisystem damage. In some cases, early diagnosis on clinical grounds alone can be difficult due to the extreme variability of the clinical presentation and disease progression. We present a case report of a 31-year-old male patient diagnosed with MPS VII at the age of 28, who multiple specialists saw without suspecting the diagnosis due to the unusual presentation. The patient presented with a history of developmental delay, scoliosis, kyphosis, corneal clouding, abnormal gait, short stature, hearing impairment, slightly coarse facial features and progressive deterioration of fine motor skills since childhood. The patient had inguinal hernia repair at around 12 months, bilateral hearing impairment with a left bone-anchored hearing aid, and spinal surgery. During spinal surveillance MPS VII was suspected by a spinal surgeon with interest in MPS, and the diagnosis confirmed with a deficiency in beta-glucuronidase in leucocytes and marginally elevated urinary GAGs. Next-generation sequencing identified two mutations in the GUSB gene (OMIM 611499), c.526C > T p.(Leu176Phe) and c.1820G > C p.(Gly607Ala). Although the patient exhibited features of the severe form of non-classical manifestations, his metabolic condition has remained reasonably stable, surviving into adulthood with only symptomatic treatment. We present the ever-expanding phenotypic spectrum of this ultra-rare disease.

Loss of NPC1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance.

In Npc1 null mice, a model for Niemann Pick Disease Type C1, it has been reported that hepatocyte insulin receptor function is significantly impaired, consistent with growing evidence that membrane fluidity and microdomain structure have an important role in insulin signal transduction. However, whether insulin receptor function is also compromised in human Niemann Pick disease Type C1 is unclear. We now report a girl who developed progressive dementia, ataxia and opthalmoplegia from 9 years old, followed by severe acanthosis nigricans, hirsutism and acne at 11 years old. She was diagnosed with Niemann Pick Disease type C1 (OMIM#257220) based on positive filipin staining and reduced cholesterol-esterifying activity in dermal fibroblasts, and homozygosity for the p.Ile1061Thr NPC1 mutation. Further analysis revealed her also to be heterozygous for a novel trinucleotide deletion (c.3659 + 1_3659 + 3delGTG) at the end of exon 20 of INSR, encoding the insulin receptor, leading to deletion of Trp1193 in the intracellular tyrosine kinase domain. INSR mRNA and protein levels were normal in dermal fibroblasts, consistent with a primary signal transduction defect in the mutant receptor. Although the proband was significantly more insulin resistant than her father, who carried the INSR mutation but was only heterozygous for the NPC1 variant, their respective degrees of IR were very similar to those previously reported in a father-daughter pair with the closely related p.Trp1193Leu INSR mutation. This suggests that loss of NPC1 function, with attendant changes in membrane cholesterol composition, does not significantly modify the IR phenotype, even in the context of severely impaired INSR function.

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) as a cause of liver disease in infants in the UK.

Citrin deficiency is a disorder with two phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and adult-onset type II citrullinaemia (CTLN2). NICCD presents in the first few weeks of life with prolonged cholestasis and metabolic abnormalities including aminoacidaemia (notably citrulline, tyrosine, threonine, arginine and methionine) and galactosuria. Symptoms resolve within the first year of life, thus making a diagnosis difficult after this time. Although patients subsequently remain generally healthy, some may develop more severe symptoms of CTLN2, characterized by neurological changes, one or more decades later. To date more than 400 cases have been reported, almost all from East Asia (mainly Japan). Here we describe the first two cases of NICCD in infants from the UK, one of caucasian origin and one of Pakistani origin. Both showed typical clinical and biochemical changes with a diagnosis confirmed by the presence of previously unreported mutations in the SLC25A13 gene. The presence of citrin deficiency in other ethnic groups means that NICCD needs to be considered in the diagnosis of any neonate with an unexplained cholestasis. We discuss both the difficulties in diagnosing these patients in populations where very few DNA mutations have been identified and the problems faced in the management of these patients. These findings also raise the possibility of adults with CTLN2 in whom a diagnosis has yet to be made.

Mortality and cause of death in mucopolysaccharidosis type II-a historical review based on data from the Hunter Outcome Survey (HOS).

Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a progressive, multisystemic disease caused by a deficiency of iduronate-2-sulfatase. Patients with the severe form of the disease have cognitive impairment and typically die in the second decade of life. Patients with the less severe form do not experience significant cognitive involvement and may survive until the fifth or sixth decade of life. We studied the relationship of both severity of MPS II and the time period in which patients died with age at death in 129 patients for whom data were entered retrospectively into HOS (Hunter Outcome Survey), the only large-scale, multinational observational study of patients with MPS II. Median age at death was significantly lower in patients with cognitive involvement compared with those without cognitive involvement (11.7 versus 14.1 years; p = 0.024). These data indicate that cognitive involvement is indicative of more severe disease and lower life expectancy in patients with MPS II. Median age at death was significantly lower in patients who died in or before 1985 compared with those who died after 1985 (11.3 versus 14.1 years; p alpha 0.001). The difference in age at death between patients dying in or before, relative to after, the selected cut-off date of 1985 may reflect improvements in patient identification, care and management over the past two decades. Data from patients who died after 1985 could serve as a control in analyses of the effects of enzyme replacement therapy with idursulfase on mortality in patients with MPS II.

Transition of patients with mucopolysaccharidosis from paediatric to adult care.

Mucopolysaccharidoses (MPS) are rare disorders associated with enzyme deficiencies, resulting in glycosaminoglycan (GAG) accumulation in multiple organ systems. As patients increasingly survive to adulthood, the need for a smooth transition into adult care is essential. Using case studies, we outline strategies and highlight the challenges of transition, illustrating practical solutions that may be used to optimise the transition process for patients with MPS disorders. Seven MPS case studies were provided by four European inherited metabolic disease centres; six of these patients transferred to an adult care setting and the final patient remained under paediatric care. Of the patients who transferred, age at the start of transition ranged between 14 and 18 years (age at transfer ranged from 16 to 19 years). While there were some shared features of transition strategies, they varied in duration, the healthcare professionals involved and the management of adult patients with MPS. Challenges included complex symptoms, patients' unwillingness to attend appointments with unfamiliar team members and attachment to paediatricians. Challenges were resolved by starting transition at an early age, educating patients and families, and providing regular communication with and reassurance to the patient and family. Sufficient time should be provided to allow patients to understand their responsibilities in the adult care setting while feeling assured of continued support from healthcare professionals. The involvement of a coordinated multidisciplinary team with expertise in MPS is also key. Overall, transition strategies must be comprehensive and individualised to patients' needs.

Long-term compliance with a novel vitamin and mineral supplement in older people with PKU.

BACKGROUND: The long-term efficacy of vitamin and mineral preparations in dietary-treated adult patients with phenylketonuria (PKU) is unreported. AIM: In an open, intervention trial, the acceptability, safety and impact on biochemical and haematological micronutrient status of a new vitamin and mineral tablet (Phlexy Vits, SHS International) was investigated. METHODS: Fifteen subjects with PKU (median age 21 years, range 8-33 years) on low-phenylalanine diet from two PKU centres were recruited. No vitamins or minerals were added to their protein substitute and for 12 months they took their full daily requirements of vitamin and minerals from Phlexy Vits (5 tablets/daily). All but two subjects had taken alternative vitamin and mineral supplements before the trial. Fasting bloods were taken at baseline (week -2 and at week 0), 4 and 12 months for a range of biochemical and nutritional measurements. RESULTS: By 4 months, serum vitamin B(12) (p = 0.003), serum manganese (p=0.03) and plasma (p=0.03) and red blood cell (p=0.004) glutathionine peroxidase (GSHPx) all significantly increased but remained within normal reference ranges. By 12 months, serum vitamin B(12) (p<0.05) and plasma GSHPx (p<0.05) remained increased. The Phlexy Vits tablets scored better than conventional vitamin and mineral supplements for overall acceptability (p<0.05), and ease of swallowing (p=0.1) at 4 months, although swallowing score deteriorated by 12 months (p<0.05). There was a small but significant deterioration in compliance with taking the vitamin and mineral supplements between 4 and 12 months (p<0.05). CONCLUSION: In the long term, these comprehensive vitamin and mineral tablets appeared acceptable and improved biochemical nutritional status, although there were long-term compliance and swallowing issues.

Does maternal knowledge and parent education affect blood phenylalanine control in phenylketonuria?

BACKGROUND: Metabolic control in phenylketonuria (PKU) may be influenced by parental ability because dietary treatment involves complex food choices. This is an observational study to compare maternal carer (MC) knowledge and parental education with phenylalanine concentrations in children with PKU. METHODS: Children (n = 46; 26 boys) aged 1-10 years (median age 6 years) on dietary treatment were recruited. Their median lifetime and median phenylalanine concentrations in the year prior to study were estimated. MC completed a questionnaire to assess dietary knowledge. RESULTS: Overall maternal knowledge on most aspects of diet was good and there was a correlation between annual median blood phenylalanine concentrations, but at the age of 5-6 years of age only, and higher maternal carer scores on PKU knowledge (r = -0.646; P < 0.0001). Three of only four children (12%) with median phenylalanine concentrations above 500 micromol L(-1) in the year prior to study had both parents leave school without educational qualifications. Children who had median phenylalanine concentrations (n = 3; 7%) over the recommended ranges at 3 years of age or earlier continued to have poor control. CONCLUSIONS: Blood phenylalanine control within the first 3 years of age, poor parental educational achievement at school level, and unsatisfactory maternal dietary knowledge may all influence longer-term blood phenylalanine control in children.

Prospective treatment in carnitine-acylcarnitine translocase deficiency.

Carnitine-acylcarnitine translocase (CACT) deficiency is a rare disorder that results in long-chain fatty acids being unavailable for mitochondrial beta-oxidation and ketogenesis. It can present in the neonatal period or infancy with a severe clinical form, typically with convulsions, hypothermia, encephalopathy, cardiomyopathy and liver dysfunction, or with a milder phenotype with episodes of hypoglycaemia and hyperammonaemia during intercurrent illness. Investigations show hypoketonaemia, intermittent dicarboxyluria and hypocarnitinaemia with grossly elevated acylcarnitines. Enzyme assay or DNA analysis confirms the diagnosis. The severe phenotype results in severe disability or death. The less severe phenotype can also cause significant disability secondary to hypoglycaemia and/or hyperammonaemia at presentation. We report the outcome of two siblings with CACT deficiency. The index patient presented at the age of 2 months during a respiratory illness with hypoglycaemia, hyperammonaemia and cardiorespiratory collapse. Acylcarnitine profiles showed decreased free carnitine but striking elevations of long-chain acylcarnitines. Urine organic acids showed dicarboxylic aciduria. Fatty acid oxidation studies showed reduced oleate and myristate oxidation. His acylcarnitine profile normalized after he was started on a medium-chain triglyceride (MCT) low-fat diet and carnitine supplementation. Low CACT activity on enzyme assay confirmed the diagnosis. He has resulting profound developmental delay and epilepsy. The sibling was prospectively treated with a low-fat MCT diet and carnitine supplementation. Acylcarnitine profile at birth also showed elevated long-chain acylcarnitines. Fatty acid oxidation studies confirmed the diagnosis. To date he has normal development and has not had any significant periods of hypoglycaemia or hyperammonaemia.

Evaluation of impact of anti-idursulfase antibodies during long-term idursulfase enzyme replacement therapy in mucopolysaccharidosis II patients.

OBJECTIVES: This 109-week, nonrandomized, observational study of mucopolysaccharidosis II (MPS II) patients already enrolled in the Hunter Outcome Survey (HOS) (NCT00882921), assessed the long-term immunogenicity of idursulfase, and examined the effect of idursulfase-specific antibody generation on treatment safety (via infusion-related adverse events [IRAEs]) and pharmacodynamics (via urinary glycosaminoglycans [uGAGs]). METHODS: Male patients ≥ 5 years, enrolled in HOS regardless of idursulfase treatment status were eligible. Blood/urine samples for anti-idursulfase antibody testing and uGAG measurement were collected every 12 weeks. RESULTS: Due to difficulties in enrolling treatment-naïve patients, data collection was limited to 26 enrolled patients of 100 planned patients (aged 5.1-35.5 years) all of whom were non-naïve to treatment. Fifteen (58%) patients completed the study. There were 11/26 (42%) seropositive patients at baseline (Ab +), and 2/26 (8%) others developed intermittent seropositivity by Week 13. A total of 9/26 patients (35%) had ≥ 1 sample positive for neutralizing antibodies. Baseline uGAG levels were low due to prior idursulfase treatment and did not change appreciably thereafter. Ab + patients had persistently higher uGAG levels at entry and throughout the study than Ab - patients. Nine of 26 (34%) patients reported IRAEs. Ab + patients appeared to have a higher risk of developing IRAEs than Ab - patients. However, the relative risk was not statistically significant and decreased after adjustment for age. CONCLUSIONS: 50% of study patients developed idursulfase antibodies. Notably Ab + patients had persistently higher average uGAG levels. A clear association between IRAEs and antibodies was not established.

Breast feeding in IMD.

Breast feeding has proven benefits for many infants with inherited metabolic disorders (IMDs) but, with the exception of phenylketonuria, there are few reports in other conditions. A questionnaire, completed by dietitians and clinicians from 27 IMD centres from 15 countries (caring for a total of over 8000 patients with IMDs on diet) identified breast feeding experience in IMD. Successful, demand breast feeding (in combination with an infant amino acid formula free of precursor amino acids) was reported in 17 infants with MSUD, 14 with tyrosinaemia type I, and 5 with homocystinuria. Eighty-nine per cent were still breast fed at 16 weeks. Fewer infants with organic acidaemias were demand breast fed (7 with propionic acidaemia; 6 with methylmalonic acidaemia and 13 with isovaleric acidaemia) (usually preceded by complementary feeds of a protein-free infant formula or infant amino acid formula free of precursor amino acids). Only 12 infants with urea cycle disorders were given demand breast feeds, but this was unsuccessful beyond 8 days in CPS deficiency. Further work is needed in developing guidelines for feeding and for clinical and biochemical monitoring for breast-fed infants with IMDs.

'Ready to drink' protein substitute is easier is for people with phenylketonuria.

UNLABELLED: In phenylketonuria (PKU), compliance with taking protein substitute is an issue in teenage and older patients. A 'ready to drink' protein substitute may overcome many of the practical issues associated with its administration. OBJECTIVE: To investigate the efficacy of a liquid protein substitute in a 6-week, three-part, randomized, crossover, controlled study. METHODS: 27 subjects (15 female; 12 male) with PKU with a median age of 30 years (range 8-49 years) were recruited. One subject withdrew from the study. Their median daily dose of protein equivalent was 60 g (range 45-75 g). In parts 1 and 2, subjects were randomized to either a liquid or a powder protein substitute with the same nutritional composition per unit (each 130 ml liquid pouch or 25 g powder sachet contained 15 g protein equivalent). In part 3, subjects chose liquid, powder or a combination of both. Weekly blood phenylalanine (Phe) concentrations were estimated, and during weeks 2, 4 and 6 subjects completed a daily questionnaire on administration issues. RESULTS: All but one of 26 subjects chose the liquid in part 3 as either their sole (69%, n = 18) or partial source (28%, n = 7) of protein substitute. Blood Phe concentrations were significantly better on the liquid (p = 0.03). With the liquid protein substitute, subjects were less self-consciousness (p = 0.003) and found it easier to take away from home (p = 0.001). Overall, the liquid was easier (p < 0.0001), more convenient (p = 0.002) and resulted in less wastage of protein substitute (p = 0.001). CONCLUSION: Liquid protein substitute was popular and efficacious, reduced self-consciousness and overall improved compliance of teenagers and adults with PKU.

Development of a suspicion index to aid diagnosis of Niemann-Pick disease type C.

OBJECTIVES: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive lysosomal lipid storage disorder that is invariably fatal. NP-C diagnosis can be delayed for years due to heterogeneous presentation; adult-onset NP-C can be particularly difficult to diagnose. We developed a Suspicion Index tool, ranking specific symptoms within and across domains, including family members who have NP-C, to provide a risk prediction score to identify patients who should undergo testing for NP-C. METHODS: A retrospective chart review was performed in 5 centers in Europe and 2 in Australia (n = 216). Three patient types were selected: classic or variant filipin staining NP-C cases (n = 71), NP-C noncases (confirmed negative by filipin staining; n = 64), or controls with at least 1 characteristic symptom of NP-C (n = 81). NP-C signs and symptoms were categorized into visceral, neurologic, or psychiatric domains. Logistic regression was performed on individual signs and symptoms within and across domains, and regression coefficients were used to develop prediction scores for NP-C. Internal validation was performed with the bootstrap resampling method. RESULTS: The Suspicion Index tool has good discriminatory performance with cutpoints for grading suspicion of NP-C. Neonatal jaundice/cholestasis, splenomegaly, vertical supranuclear gaze palsy, cataplexy, and cognitive decline/dementia were strong predictors of NP-C, as well as symptoms occurring in multiple domains in individual patients, and also parents/siblings or cousins with NP-C. CONCLUSIONS: The Suspicion Index tool is a screening tool that can help identify patients who may warrant further investigation for NP-C. A score ≥70 indicates that patients should be referred for testing for NP-C.