Independent Registries Are Cost-Effective Tools to Provide Mandatory Postauthorization Surveillance for Orphan Medicinal Products.

OBJECTIVES: Orphan medicinal products (OMPs) often receive market authorization under conditions imposed by regulators for ongoing postauthorization surveillance (PAS) to answer questions that remain at the time of market entry. This surveillance may be provided through industry-funded registries (IFRs). Nevertheless, data in these registries may not be of sufficient quality to answer these questions and may not always be accessible for regulatory review. We propose that a mandatory independent registry is an efficient and cost-effective tool for PAS for OMPs. METHODS: Using data from the Canadian Fabry Disease Initiative, we reviewed costs per unique patient from sites participating in both the independent national registry and IFRs for Fabry disease and compared data completeness from the Canadian Fabry Disease Initiative to that in published documents from IFRs. RESULTS: The costs of data collection through the independent registry were 17% to 36% (depending on site) lower than costs to collect data in the IFRs, and completeness of data collected through the independent registry was higher than that through the IFRs. Data from the independent registry were reviewed annually to guide indications for publicly funded Fabry disease therapy. Even when enrollment ceased to be a requirement to receive therapy, 77% of patients continued to enroll in the registry, suggesting the structure was acceptable to patients. CONCLUSIONS: Independent registries are cost-effective and efficient tools and should be mandated by regulatory agencies as the preferred tool for PAS for OMPs. Countries with publicly funded health systems should consider investment in registry infrastructure for OMPs.

Exome Sequencing and the Management of Neurometabolic Disorders.

BACKGROUND: Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. METHODS: To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient's clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. RESULTS: We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). CONCLUSIONS: Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children's Hospital Foundation and others.).

Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study.

BACKGROUND: Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. METHODS: In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex. RESULTS: 387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (ß: -18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar. CONCLUSIONS: Treatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta.

Transplantation as disease modifying therapy in adults with inherited metabolic disorders.

Transplantation is an established disease modifying therapy in selected children with certain inherited metabolic diseases (IMDs). Transplantation of hematopoietic stem cells or solid organs can be used to partially correct the underlying metabolic defect, address life threatening disease manifestations (such as neutropenia) or correct organ failure caused by the disease process. Much less information is available on the use of transplantation in adults with IMDs. Transplantation is indicated for the same IMDs in adults as in children. Despite similar disease specific indications, the actual spectrum of diseases for which transplantation is used differs between these age groups and this is partly related to the natural history of disease. There are diseases (such as urea cycle defects and X-linked adrenoleukodystrophy) for which transplantation is recommended for selected symptomatic patients as a treatment strategy in both adults and children. In those diseases, the frequency with which transplantation is used in adults is lower than in children and this may be related in part to a reduced awareness of transplantation as a treatment strategy amongst adult clinicians as well as limited donor availability and allocation policies which may disadvantage adult patients with IMDs. Risks of transplantation and disease-specific prognostic factors influencing outcomes also differ with age. We review the use of transplantation as a disease modifying strategy in adults focusing on how this differs from use in children to highlight areas for future research.

Prolonged granulocyte colony stimulating factor use in glycogen storage disease type 1b associated with acute myeloid leukemia and with shortened telomere length.

Glycogen storage disease (GSD) type 1 is a rare autosomal recessive inherited condition. The 1b subtype comprises the minority of cases, with an estimated prevalence of 1 in 500,000 children. Patients with glycogen storage disease type 1b are often treated with granulocyte colony stimulating factor (G-CSF) for prolonged periods to improve symptoms of inflammatory bowel disease (IBD) and in the face of severe neutropenia to decrease risk of infection. Long-term G-CSF treatment may result in an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) possibly due to increased marrow stress resulting in telomere shortening. To our knowledge, there have been two published cases of AML in GSD type 1b patients following long-term G-CSF exposure. Here, we report two further cases of AML/MDS-related changes in patients GSD type 1b treated with G-CSF. One patient developed AML with complex karyotype after 20 years of G-CSF treatment. The second patient was found to have short telomeres after 10 years of G-CSF exposure, but no evidence of acute leukemia at present. The third patient developed AML/MDS after 25 years of G-CSF use, with short telomeres prior to bone marrow transplant. Together these cases suggest that GSD type 1b patients with prolonged G-CSF exposure may be at an increased risk of MDS/AML states associated with G-CSF-induced shortened telomeres. We recommend that any GSD1b patients with prolonged G-CSF should have routine telomere assessments with monitoring for MDS if telomere shortening is observed, and with particular attention warranted if there is unexplained loss of G-CSF responsiveness.

Pompe Disease: Diagnosis and Management. Evidence-Based Guidelines from a Canadian Expert Panel.

Pompe disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid alpha-glucosidase. Patients have skeletal muscle and respiratory weakness with or without cardiomyopathy. The objective of our review was to systematically evaluate the quality of evidence from the literature to formulate evidence-based guidelines for the diagnosis and management of patients with Pompe disease. The literature review was conducted using published literature, clinical trials, cohort studies and systematic reviews. Cardinal treatment decisions produced seven management guidelines and were assigned a GRADE classification based on the quality of evidence in the published literature. In addition, six recommendations were made based on best clinical practices but with insufficient data to form a guideline. Studying outcomes in rare diseases is challenging due to the small number of patients, but this is in particular the reason why we believe that informed treatment decisions need to consider the quality of the evidence.

Health economic evaluation of plasma oxysterol screening in the diagnosis of Niemann-Pick Type C disease among intellectually disabled using discrete event simulation.

BACKGROUND: Recently a less invasive method of screening and diagnosing Niemann-Pick C (NP-C) disease has emerged. This approach involves the use of a metabolic screening test (oxysterol assay) instead of the current practice of clinical assessment of patients suspected of NP-C (review of medical history, family history and clinical examination for the signs and symptoms). Our objective is to compare costs and outcomes of plasma oxysterol screening versus current practice in diagnosis of NP-C disease among intellectually disabled (ID) patients using decision-analytic methods. METHODS: A discrete event simulation model was conducted to follow ID patients through the diagnosis and treatment of NP-C, forecast the costs and effectiveness for a cohort of ID patients and compare the outcomes and costs in two different arms of the model: plasma oxysterol screening and routine diagnosis procedure (anno 2013) over 5 years of follow up. Data from published sources and clinical trials were used in simulation model. Unit costs and quality-adjusted life-years (QALYs) were discounted at a 3% annual rate in the base case analysis. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: The outcomes of the base case model showed that using plasma oxysterol screening for diagnosis of NP-C disease among ID patients is a dominant strategy. It would result in lower total cost and would slightly improve patients' quality of life. The average amount of cost saving was $3642 CAD and the incremental QALYs per each individual ID patient in oxysterol screening arm versus current practice of diagnosis NP-C was 0.0022 QALYs. Results of sensitivity analysis demonstrated robustness of the outcomes over the wide range of changes in model inputs. CONCLUSION: Whilst acknowledging the limitations of this study, we conclude that screening ID children and adolescents with oxysterol tests compared to current practice for the diagnosis of NP-C is a dominant strategy with clinical and economic benefits. The less costly, more sensitive and specific oxysterol test has potential to save costs to the healthcare system while improving patients' quality of life and may be considered as a routine tool in the NP-C diagnosis armamentarium for ID. Further research is needed to elucidate its effectiveness in patients presenting characteristics other than ID in childhood and adolescence.

Phenylketonuria Scientific Review Conference: state of the science and future research needs.

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 µmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 µmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

Performance of serum and dried blood spot acylcarnitine profiles for detection of fatty acid ß-oxidation disorders in adult patients with rhabdomyolysis.

BACKGROUND: Plasma/serum and dried blood spot (DBS) acylcarnitine profiles (ACPs) are key to the diagnosis of mitochondrial fatty acid ß-oxidation disorders (FAODs). Despite their significant clinical applications, limited published data exists to compare their sensitivities and specificities. We retrospectively evaluated these two methods in adult patients with a history of rhabdomyolysis; investigated for an underlying FAOD. METHODS: A retrospective study was completed for adult patients (investigated between 2003 and 2011) meeting the inclusion criteria of a history of recurrent rhabdomyolysis or one episode of rhabdomyolysis with a history of exercise intolerance. All subjects underwent investigations for an underlying FAOD including DBS and serum ACP analysis concurrently collected during a symptom-free period, and skin biopsy for cultured fibroblast fatty acid oxidation studies or enzyme activity measurement, as indicated, with or without molecular confirmation. Their medical records were reviewed, and the performance of the two methods were compared. RESULTS: Seven out of 31 subjects (22.6 %) were diagnosed with an underlying FAOD. Long chain acylcarnitines were more markedly elevated in serum samples from confirmed CPTII cases (n = 4) as compared to matched DBS profiles. The sensitivity and specificity of DBS ACP was 71.4 % (95 % CI, 0.30-0.95) and 100 % (95 % CI, 0.79-1.00), respectively, compared to a sensitivity of 100 % (95 % CI, 0.56-1.00) and a specificity of 94.7 % (95 % CI, 0.72-1.00) for serum ACP. CONCLUSION: FAODs appear to be a common cause of recurrent rhabdomyolysis or rhabdomyolysis with a history of exercise induced myalgia. At least historically, FAODs maybe underdiagnosed in adults with rhabdomyolysis. This study suggests that serum ACP might be more sensitive than DBS ACP for detection of an underlying FAOD in adults with rhabdomyolysis while asymptomatic.

Phenotypic variability of Krabbe disease across the lifespan.

Krabbe disease (galactocerebrosidase deficiency) is an inherited leukodystrophy that results in severe neurological defects due to altered myelination. Classically, disease onset is within the first year of life. Juvenile and adult-onset cases may have less classic presentations, making diagnosis difficult and often delayed. Here, we review the literature to demonstrate the hetereogeneity of presenting symptoms across all age groups. We also discuss diagnostic approach, emphasizing variation in biochemical, functional, and genetic results among Krabbe phenotypes. Better understanding of the various Krabbe disease phenotypes is critical to facilitate timely diagnosis and appropriate treatment of this clinically heterogeneous disorder. Variabilité phénotypique dans la maladie de Krabbe au cours de la vie du patient. La maladie de Krabbe (déficit en galactocérébrosidase) est une leukodystrophie héréditaire qui donne lieu à des déficits neurologiques sévères dus à un trouble de la myélinisation. Chez les cas dont la présentation est classique, la maladie débute au cours de la première année de vie. Si la maladie commence chez un adolescent ou un adulte, le mode de présentation peut-etre moins classique, ce qui rend le diagnostic difficile et souvent tardif. Nous analysons les articles traitant du sujet pour démontrer l'hétérogénéité des symptômes au moment de la première consultation et ceci dans tous les groupes d'âge. Nous discutons également de l'approche diagnostique en mettant l'emphase sur la variation des résultats biochimiques, fonctionnels et génétiques des différents phénotypes dans la maladie de Krabbe. Une meilleure compréhension des différents phénotypes est cruciale pour faciliter un diagnostic précoce et un traitement approprié de cette maladie dont le mode de présentation clinique est hétérogène.

Response to "Canadians Need Improved Access to Drugs for Rare Diseases, Not More Denial".

The comments provided by Rawson and Adams (2023) miss the mark of our articles (Sirrs et al. 2023a, 2023b). We agree that the patient perspective is critical and that patients with "rare diseases have a right to healthcare and have huge unmet needs …" (p. 7). However, we challenge Rawson and Adams' (2023) thesis that keeping drug prices higher in Canada than in most other countries would solve the problem of access to therapies for rare diseases that have no available treatment.

Impact of hematopoietic stem cell transplantation in glycogen storage disease type Ib: A single-subject research design using 13C-glucose breath test.

Background: Glycogen storage disease type Ib (GSD Ib) is an autosomal recessively inherited deficiency of the glucose-6-phosphate translocase (G6PT). Clinical features include a combination of a metabolic phenotype (fasting hypoglycemia, lactic acidosis, hepatomegaly) and a hematologic phenotype with neutropenia and neutrophil dysfunction. Dietary treatment involves provision of starches such as uncooked cornstarch (UCCS) and Glycosade® to provide prolonged enteral supply of glucose. Granulocyte colony-stimulating factor (G-CSF) is the treatment of choice for neutropenia. Because long-term stimulation of hematopoiesis with G-CSF causes serious complications such as splenomegaly, hypersplenism, and osteopenia; hematopoietic stem cell transplantation (HSCT) has been considered in some patients with GSD Ib to correct neutropenia and avoid G-CSF related adverse effects. Whether HSCT also has an effect on the metabolic phenotype and utilization of carbohydrate sources has not been determined. Objective: Our objective was to measure the utilization of starch in a patient with GSD Ib before and after HSCT using the minimally invasive 13C-glucose breath test (13C-GBT). Design: A case of GSD Ib (18y; female) underwent 13C-GBT four times: UCCS (pre-HSCT), UCCS (3, 5 months post-HSCT) and Glycosade® (6 months post-HSCT) with a dose of 80 g administered via nasogastric tube after a 4 h fast according to our patient's fasting tolerance. Breath samples were collected at baseline and every 30 min for 240 min. Rate of CO2 production was measured at 120 min using indirect calorimetry. Finger-prick blood glucose was measured using a glucometer hourly to test hypoglycemia (glucose <4 mmol/L). Biochemical and clinical data were obtained from the medical records as a post-hoc chart review. Results: UCCS utilization was significantly higher in GSD Ib pre-HSCT, which reduced and stabilized 5 months post-HSCT. UCCS and Glycosade® utilizations were low and not different at 5 and 6 months post-HSCT. Blood glucose concentrations were not significantly different at any time point. Conclusions: Findings show that HSCT stabilized UCCS utilization, as reflected by lower and stable glucose oxidation. The results also illustrate the application of 13C-GBT to examine glucose metabolism in response to various carbohydrate sources after other treatment modalities like HSCT in GSD Ib.

Expensive Drugs for Rare Diseases in Canada: Time for Action Everywhere and by Everyone.

Expensive drugs for rare diseases pose unique economic, evidentiary and ethical challenges, and these will continue to escalate unless steps are taken urgently to address these challenges. We propose concrete actions that all stakeholders (federal and provincial/territorial governments, patients, healthcare providers, the public and drug manufacturers) could take now as a first step toward enhancing sustainability in the use of innovative (albeit expensive) therapies within our publicly funded healthcare system.

Expensive Drugs for Rare Diseases in Canada: What Value and at What Cost?

There has been explosive growth in the market for expensive drugs for rare diseases (EDRDs). Traditional standards of evidence are not achievable for rare diseases, so lower standards are applied. The price of these drugs is extremely high. This combination of lower standards and higher prices make EDRDs attractive to manufacturers. Legislation designed to incentivize drug development for rare diseases contains loopholes that drive prices up worldwide. Canada compounds those problems with a complex network of agencies that impede communication between those providing market authorization and those purchasing drugs. Drug pricing is not related to metrics like investment or value, but rather willingness to pay. Without high-quality evidence to assess value, we inadvertently prioritize patients with rare diseases over those with common diseases, creating conflict among ethical principles such as social utility, justice and the rule of rescue. Lack of transparency over what is being funded and for whom makes it hard to mitigate challenges through effective policy development. We review the evidentiary, economic and ethical issues around EDRDs and ways to move forward, including enhanced transparency and the development of high-quality evidence to ensure that we do not pay for drugs that do not work.

Emphysema in an adult with galactosialidosis linked to a defect in primary elastic fiber assembly.

Galactosialidosis is a lysosomal storage disorder caused by loss of function of protective protein cathepsin A, which leads to secondary deficiencies of ß-galactosidase and neuraminidase-1. Emphysema has not been previously reported as a possible complication of this disorder, but we now describe this condition in a 41-year-old, non-smoking male. Our patient did not display deficiency in α-1-antitrypsin, the most common cause of emphysema in non-smokers, which brings about disseminated elastolysis. We therefore hypothesized that loss of cathepsin A activity was responsible because of previously published evidence showing it is prerequisite for normal elastogenesis. We now present experimental evidence to support this theory by demonstrating impaired primary elastogenesis in cultures of dermal fibroblasts from our patient. The obtained data further endorse our previous finding that functional integrity of the cell surface-targeted molecular complex of cathepsin A, neuraminidase-1 and the elastin-binding protein (spliced variant of ß-galactosidase) is prerequisite for the normal assembly of elastic fibers. Importantly, we also found that elastic fiber production was increased after exposure either to losartan, spironolactone, or dexamethasone. Of immediate clinical relevance, our data suggest that surviving patients with galactosialidosis should have periodic assessment of their pulmonary function. We also encourage further experimental exploration of therapeutic potential of the afore-mentioned elastogenesis-stimulating drugs for the alleviation of pathological processes in galactosialidosis that could be mechanistically linked to impaired deposition of elastic fibers.

A co-occurrence of osteogenesis imperfecta type VI and cystinosis.

Osteogenesis imperfecta type VI (OI type VI) is a rare autosomal recessive disorder caused by mutations in the SERPINF1 gene that encodes pigment epithelium-derived factor (PEDF). Cystinosis is an autosomal recessive lysosomal transport disorder caused by mutations in the CTNS gene. Both SERPINF1 and CTNS are located on chromosome 17p13.3. We describe an individual presenting with both OI type VI and cystinosis. The patient was diagnosed with cystinosis at the age of 11 months and OI type VI on bone biopsy at the age of 8 years. He has sustained over 30 fractures during his lifetime, and at the age of 19 years entered end-stage renal disease and subsequent renal transplant. An Affymetrix 6.0 array was used to look for areas of loss of heterozygosity on chromosome 17. Sequencing of the SERPINF1 and CTNS genes was performed, followed by quantitative PCR and Western blot of PEDF to characterize the identified mutation. A 6.58 Mb region of homozygosity was identified on the Affymetrix 6.0 array, encompassing both the SERPINF1 and CTNS genes. Sequencing of the genes identified homozygosity for a known pathogenic CTNS mutation and for a novel in-frame duplication in SERPINF1. Skin fibroblasts produced a markedly reduced amount of SERPINF1 transcript and PEDF protein. This patient has the concurrent phenotype of two rare recessive diseases, cystinosis and OI type VI. We identified for the first time an in-frame duplication in SERPINF1 that is responsible for the OI type VI phenotype in this patient.

Variability of phenotype in two sisters with pyridoxine dependent epilepsy.

BACKGROUND: Pyridoxine dependent epilepsy (PDE) is characterized by neonatal epileptic encepahalopathy responsive to pharmacological doses of vitamin B6. Recently an autosomal recessive deficiency in Antiquitin (ALDH7A1), a gene involved in the catabolism of lysine has been identified as the underlying cause. CASE REPORT: In 21 and 23 year-old sisters, who had presented with neonatal / early infantile onset seizures, PDE was confirmed by elevated urinary alpha aminoadipic- 6- semialdehyde (α-AASA) excretion and compound heterozygosity for two known ALDH7A1 missense mutations. Although epilepsy was well controlled upon treatment with pyridoxine, thiamine, phenytoin and carbamazepine since early infancy, both had developmental delay with prominent speech delay as children. As adults, despite the same genetic background and early treatment with pyridoxine, their degree of intellectual disability (ID) differed widely. While the older sister's cognitive functions were in the moderate ID range and she was not able to live unattended, the younger sister had only mild ID and was able to live independently. CONCLUSION: Although seizures are a defining feature of PDE, other disease manifestations can vary widely even within the same family. Adult neurologists should be aware that the diagnosis of PDE can be delayed and PDE should be considered in the differential diagnosis of adults with seizure disorders dating from childhood.