Fair Funding Decisions: Consistency of the Time Horizons Used in the Calculation of Quality-Adjusted Life Years for Therapies for Very Rare Diseases by the National Institute for Health and Care Excellence in England.

The National Institute for Health and Care Excellence (NICE) in England uses quality-adjusted life years (QALYs) to assess the cost-effectiveness of treatments. A QALY is a measure that combines the size of the clinical benefit of a treatment with the time the patient benefits from it, i.e., the time horizon. We wanted to know how consistently QALY gains are calculated at NICE. Therefore, we have analysed information on the time horizons used for the QALY calculations of the concluded evaluations conducted under the Highly Specialised Technologies programme for treatments of very rare diseases at NICE. For treatments with final guidance published by December 2023 (n = 29), a time horizon of median 97.5 years (range: 35 to 125 years) was used to calculate the QALY gains. For most QALY calculations, the accepted time horizon was longer than either the expected treatment duration or the estimated life expectancy. In contrast, for the only technology with a final negative funding decision, i.e., afamelanotide for treating the lifelong chronic disease erythropoietic protoporphyria, a time horizon that was shorter than the expected treatment duration was used. The fairness and consistency of the evaluation process of treatments for very rare diseases at NICE should be reviewed.

The Telltale Botox: Botulinum Toxin Injection by an Expert Hand as an Intracranial Aneurysm Detector.

Complications in aesthetic medicine can be considered a consequence of the inexperience of the performing physician, but in some cases, they can unveil far more serious conditions, hitherto silent. We present a case of a 48-year-old patient who, following botulinum toxin type A (Botox) injection for treatment of forehead wrinkles, returned to our attention 12 days later for a discrete, newly onset right eyelid ptosis. This ptosis was a telltale sign of the presence of an intracranial aneurysm closely related with the oculomotor nerve. The lack of compensatory action by the frontalis muscle in maintaining the eyelid in position allowed us to highlight the extrinsic compression deficit of the oculomotor nerve. Subsequently, the patient underwent endovascular treatment of the aneurysm, leading to complete resolution of the case.

NUP85 as a Neurodevelopmental Gene: From Podocyte to Neuron.

Pathogenic gene variants encoding nuclear pore complex (NPC) proteins were previously implicated in the pathogenesis of steroid-resistant nephrotic syndrome (SRNS). The NUP85 gene, encoding nucleoporin, is related to a very rare form of SRNS with limited genotype-phenotype information. We identified an Italian boy affected with an SRNS associated with severe neurodevelopmental impairment characterized by microcephaly, axial hypotonia, lack of achievement of motor milestones, and refractory seizures with an associated hypsarrhythmic pattern on electroencephalography. Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum and a simplified gyration of the cerebral cortex. Since the age of 3 years, the boy was followed up at our Pediatric Nephrology Department for an SRNS, with a focal segmental glomerulosclerosis at renal biopsy. The boy died 32 months after SRNS onset, and a Whole-Exome Sequencing analysis revealed a novel compound heterozygous variant in NUP85 (NM_024844.5): 611T>A (p.Val204Glu), c.1904T>G (p.Leu635Arg), inherited from the father and mother, respectively. We delineated the clinical phenotypes of NUP85-related disorders, reviewed the affected individuals so far reported in the literature, and overall expanded both the phenotypic and the molecular spectrum associated with this ultra-rare genetic condition. Our study suggests a potential occurrence of severe neurological phenotypes as part of the NUP85-related clinical spectrum and highlights an important involvement of nucleoporin in brain developmental processes and neurological function.

The real-world effectiveness of intravenous brivaracetam as a second-line treatment in status epilepticus.

PURPOSE: Status epilepticus (SE) is defined by abnormally prolonged seizures that may lead to brain damage and death. Our aim was to evaluate the efficacy and tolerability (effectiveness) of intravenous brivaracetam (BRV) as a second-line treatment. METHODS: Twenty-one patients (median age 68 years ± 17.28) were prospectively recruited between June 2019 and December 2022. Patients were treated with BRV (50-200 mg) as a second-line add-on therapy for SE. We evaluated the response of SE to the administration of BRV in terms of SE termination and recurrence of epileptic seizures at 6, 12, and 24 h, also monitoring safety. The first-line therapy was represented by intravenous benzodiazepines (mainly diazepam). RESULTS: Almost a quarter of patients had generalized seizures, whereas the vast majority (76.2%) presented focal seizures. In 52.4% of patients, the underlying cause was cerebrovascular. Fourteen (66.7%) patients displayed a good early response in the subsequent 6 h. At 12 and 24 h, 8 (38%) and 11 (52.4%) patients, respectively, did not present seizures. CONCLUSION: The present study highlights the potential of BRV when used as an early add-on therapy in SE, further confirming its good safety profile.

Mitochondrial DNA Copy Number Drives the Penetrance of Acute Intermittent Porphyria.

No published study has investigated the mitochondrial count in patients suffering from acute intermittent porphyria (AIP). In order to determine whether mitochondrial content can influence the pathogenesis of porphyria, we measured the mitochondrial DNA (mtDNA) copy number in the peripheral blood cells of 34 patients and 37 healthy individuals. We found that all AIP patients had a low number of mitochondria, likely as a result of a protective mechanism against an inherited heme synthesis deficiency. Furthermore, we identified a close correlation between disease penetrance and decreases in the mitochondrial content and serum levels of PERM1, a marker of mitochondrial biogenesis. In a healthy individual, mitochondrial count is usually modulated to fit its ability to respond to various environmental stressors and bioenergetic demands. In AIP patients, coincidentally, the phenotype only manifests in response to endogenous and exogenous triggers factors. Therefore, these new findings suggest that a deficiency in mitochondrial proliferation could affect the individual responsiveness to stimuli, providing a new explanation for the variability in the clinical manifestations of porphyria. However, the metabolic and/or genetic factors responsible for this impairment remain to be identified. In conclusion, both mtDNA copy number per cell and mitochondrial biogenesis seem to play a role in either inhibiting or promoting disease expression. They could serve as two novel biomarkers for porphyria.

Quality-Adjusted Life Years in Erythropoietic Protoporphyria and Other Rare Diseases: A Patient-Initiated EQ-5D Feasibility Study.

Erythropoietic protoporphyria (EPP) is an ultra-rare inborn error of metabolism characterised by painful phototoxic burn injuries after short exposure times to visible light. Patients with EPP are highly adapted to their condition which makes the quantification of their health-related quality of life (QoL) challenging. In the presented patient-initiated feasibility study, we describe a new approach to assess treatment benefits in EPP by measuring QoL with the generic EQ-5D instrument in five patients under long-term (≥two years) treatment with afamelanotide, the first approved therapy for EPP. For the study, we selected patients with EPP who in addition were affected by an involuntary treatment interruption (caused by a temporary reimbursement suspension) because we hypothesized that individuals who had previously unlearned their adaptation are better able to assess their life without treatment than treatment-naïve patients. QoL under treatment was comparable to the age-matched population norm, and retrospective results for a treatment interruption and phototoxic reaction time point were comparable to the QoL of patients with chronic neuropathic pain and acute burn injuries, respectively. The results were accepted by the National Institute for Health and Care Excellence in England for their evaluation of the cost-effectiveness of afamelanotide, i.e., the calculation of quality-adjusted life years.

Paraneoplastic neurological syndromes of the central nervous system: a single institution 7-year case series.

BACKGROUND: Paraneoplastic neurological syndromes (PNSs) are nonmetastatic complications of malignancy, defined by the presence of onconeural antibodies (ONAs). ONAs may be found in 60% of patients with central nervous system (CNS) involvement, and they are directed against intraneuronal antigens or channels, receptors or associated proteins located at the synaptic or extra-synaptic neuronal cell membrane. Given its rare incidence, there are few epidemiological case series on CNS-PNS. We aim to discuss the variability of CNS-PNSs etiology, clinical features, management and outcome, highlighting the importance of early recognition and appropriate treatment, leading to significant reduction of mortality and morbidity. METHODS: We retrospectively reviewed our 7-years single-center experience, and specifically discussed the underlying etiology, parenchymal CNS involvement, and the acute treatment response. Only cases fulfilling PNS Euronetwork criteria for definitive PNS were included. RESULTS: A total of 26 probable PNSs cases involving CNS were identified. We reported medical records of eleven (42.3%) illustrative cases, meeting the criteria of definite PNS and presenting variable clinical spectrum and different radiological appearances. Our series has a relative paucity of the most common syndromes and larger portion of clinical diagnosis with ONAs. Well-characterized ONAs had been detected in CSF of six patients. CONCLUSIONS: Our case series supports the utmost importance of early recognition of CNS-PNSs. Screening for occult malignancies should not be limited to patients with classical CNS syndrome. Empiric immunomodulatory therapy may be considered before the diagnostic evaluation is completed, in order to prevent unfavorable outcome. Late presentations should not discourage initiation of treatment.

Trabecular bone score, bone marrow fat and vertebral fractures in cushing syndrome.

OBJECTIVE: Prediction of fragility fractures in Cushing syndrome (CS) is a challenge since dual energy X-ray absorptiometry (DXA) measurement of bone mineral density (BMD) does not capture all the alterations in bone microstructure induced by glucocorticoid excess. In this study we investigated the relationship between trabecular bone score (TBS), bone marrow fat (BMF) and vertebral fractures (VFs) in endogenous CS. DESIGN: Cross-sectional. METHODS: Thirty subjects (7 M and 23 F, mean age 44.8 ± 13.4 yrs, range: 25-71) with active hypercortisolism were evaluated for VFs by quantitative morphometry, BMD and TBS by lumbar spine DXA and BMF by single-voxel magnetic resonance spectroscopy of vertebral body of L3. RESULTS: Subjects with VFs (17 cases; 56.7%) had higher BMF (P = 0.014) and lower BMD T-score (P = 0.012) and TBS (P = 0.004) as compared to those without VFs. Prevalence of VFs resulted to be significantly higher in individuals with impaired TBS as compared to those with normal TBS (77.8% vs. 25.0%; P = 0.008). Among patients with VFs, only 6 (35.3%) had either osteoporosis or "low BMD for age". In logistic regression analysis, impaired TBS maintained the significant association with VFs [odds ratio (OR) 6.60, 95% C.I. 1.07-40.61; P = 0.042] independently of BMF (OR 1.03, 95% C.I. 0.99-1.08; P = 0.152). CONCLUSIONS: TBS might be more accurate than BMF in identifying subjects with active CS and skeletal fragility at risk of VFs. SIGNIFICANCE STATEMENT: Excess in glucocorticoids is associated with alterations in bone remodeling and metabolism, leading to fragility fractures regardless of bone mineral density, making more challenging for the clinician the identification of high-risk population and the definition of preventing strategies. In this context, instrumental parameters suggestive of bone quality alterations and predictive of increased fracture risk are needed. In this study, we found CS patients to have bone quality alterations as indicated by the decreased trabecular bone score and increased bone marrow fat, as measured by DEXA and MRI respectively. Both parameters were associated with high risk of VFs, and were inversely correlated, although TBS seems to be more accurate than BMF in fractures prediction in this clinical setting.

Minimally Invasive Surgery of Deep-Seated Brain Lesions Using Tubular Retractors and Navigated Transcranial Magnetic Stimulation-Based Diffusion Tensor Imaging Tractography Guidance: The Minefield Paradigm.

BACKGROUND: Surgical treatment of deep-seated brain lesions is a major challenge for neurosurgeons. Recently, tubular retractors have been used to help neurosurgeons in achieving the targeting and resection of deep lesions. OBJECTIVE: To describe a novel surgical approach based on the combination of tubular retractors and preoperative mapping by navigated transcranial magnetic stimulation (nTMS) and nTMS-based diffusion tensor imaging (DTI) tractography for the safe resection of deep-seated lesions. METHODS: Ten consecutive patients affected by deep-seated brain lesions close to eloquent motor/language/visual pathways underwent preoperative nTMS mapping of motor/language cortical areas and nTMS-based DTI tractography of adjacent eloquent white matter tracts, including optic radiations. The nTMS-based information was used to plan the optimal surgical trajectory and to guide the insertion of tubular retractors within the brain parenchyma without causing injury to the eloquent cortical and subcortical structures. After surgery, all patients underwent a new nTMS-based DTI tractography of fascicles close to the tumor to verify their structural integrity. RESULTS: Gross total resection was achieved in 8 cases, subtotal resection in 1 case, and a biopsy in 1 case. No new postoperative deficits were observed, except in 1 case where a visual field defect due to injury to the optic radiations occurred. Postoperative nTMS-based DTI tractography showed the integrity of the subcortical fascicles crossed by tubular retractors trajectory in 9 cases. CONCLUSION: The novel strategy combining tubular retractors with functional nTMS-based preoperative mapping enables a safe microsurgical resection of deep-seated lesions through the preservation of eloquent cortical areas and subcortical fascicles, thus reducing the risk of new permanent deficits.

Prevalence, clinical features, and radiological pattern of artery of Percheron infarction: a challenging diagnosis.

PURPOSE: Occlusion of artery of Percheron (AOP), a rare variant of paramedian branches of posterior cerebral artery, results in a characteristic pattern of ischemic lesions in bilateral paramedian thalami with or without midbrain and anterior thalami involvement. AIM: To evaluate the prevalence, the clinical, and the imaging features of AOP infarction in a single comprehensive stroke center experience. METHODS: We retrospectively search in our stroke center database, patients with ischemic lesions in the AOP distribution. We collected clinical features and time between hospital admission and diagnosis. Imaging findings were categorized following a pre-selected classification. RESULTS: Of 2830 ischemic stroke admitted in our center, we identified 15 patients with AOP infarction (0.53%). Clinical manifestations were variable, but oculomotor disturbances, particularly vertical gaze palsy, were the most observed, followed by consciousness impairment, varying from drowsiness to coma. The most frequent imaging pattern was bilateral paramedian thalamic infarction with midbrain infarction, and the V-sign was recognized in 6 cases from this group. In 8 patients a fetal origin of the PCA was observed. The average time from first hospital admission to diagnosis was 28.09 h. CONCLUSIONS: The prevalence of AOP infarction in our center was 0.53%. Diagnosis of AOP infarction can be challenging and should be suspected in case of sudden altered consciousness.

Three-Dimensional Constructive Interference in Steady State (3D CISS) Imaging and Clinical Applications in Brain Pathology.

Three-dimensional constructive interference in steady state (3D CISS) is a steady-state gradient-echo sequence in magnetic resonance imaging (MRI) that has been used in an increasing number of applications in the study of brain disease in recent years. Owing to the very high spatial resolution, the strong hyperintensity of the cerebrospinal fluid signal and the high contrast-to-noise ratio, 3D CISS can be employed in a wide range of scenarios, ranging from the traditional study of cranial nerves, the ventricular system, the subarachnoid cisterns and related pathology to more recently discussed applications, such as the fundamental role it can assume in the setting of acute ischemic stroke, vascular malformations, infections and several brain tumors. In this review, after briefly summarizing its fundamental physical principles, we examine in detail the various applications of 3D CISS in brain imaging, providing numerous representative cases, so as to help radiologists improve its use in imaging protocols in daily clinical practice.

Associated Effect of SLC40A1 and TMPRSS6 Polymorphisms on Iron Overload.

Mutations in the ferroportin (FPN) gene SLC40A1 alter iron recycling and cause disturbances in iron homeostasis. The variants of TMPRSS6 contribute to the development of iron deficiencies. In this study, we determined the role of FPN and TMPRSS6 gene polymorphisms in the modulation of iron homeostasis based on biochemical parameters. PCR analysis and sequencing were performed to determine the single nucleotide polymorphisms (SNPs) SLC40A1 c.44−24G>C (rs1439816), SLC40A1 c.663T>C (rs2304704), and TMPRSS6 c.2207T>C (rs855791). Hemoglobin concentration and iron status were determined by standard procedures. We studied 79 iron-loaded individuals for SLC40A1 polymorphisms. Interestingly, 35/79 individuals with SLC40A1 SNPs also carried a TMPRSS6 c.2207T>C polymorphism. The biochemical values of the iron overloaded individuals were compared to those of the individuals carrying TMPRSS6 SNPs and the healthy individuals (wild-type group). The ferritin concentration, transferrin saturation % (TS%), and hemoglobin concentration were significantly higher in the participants with FPN SNPs than in the other three groups. The ferritin concentration and TS% were higher in participants with both SLC40A1 and TMPRSS6 SNPs than in the TMPRSS6 and wild-type groups, while hemoglobin concentration was significantly higher than that in the TMPRSS6 SNP group only. The participants with TMPRSS6 SNPs had significantly lower ferritin concentration, TS%, and hemoglobin concentration than all the other groups. SLC40A1 and TMPRSS6 SNPs might act in the opposite direction, preventing the development of severe iron overload, and the modulation of the iron status by TMPRSS6 SNPs might provide protection.

Magnetic Resonance Angiography and Cisternography fused images in acute ischemic stroke may save time during endovascular procedure revealing vessel anatomy.

Background and purpose: Endovascular treatment (EVT) is a time-dependent procedure that aims to remove the arterial blood flow obstruction in brain vessels in acute ischemic stroke. In our center, the MRI patient selection protocol in acute ischemic stroke is performed with DWI, FLAIR, MR angiography (MRA) and MR cisternography (MRC) sequences. MRA and MRC are promptly and automatically fused in order to have a clear detection of vessel anatomy, before and during EVT.Our study aim is to evaluate if the fusion process between MRA and MRC could be considered time-safe and could influence EVT duration or outcome. Materials and methods: 45 patients were retrospectively selected for the study and divided into 2 groups according to the presence of MRC sequence fused with MRA (Group 1) or not (Group 2 - controls). Results: MRA and MRC fusion was able to depict vessel anatomy in all subjects of Group 1 (22 patients, 12 females; age 75.59 years ± 10.87). Group 1 presented EVT time reduction (p < 0.05; p = 0.040) (51.59 min ± 30.94) when compared to Group 2 (23 patients, 13 females; age 75.04 years ± 12.12) (71.96 min ± 34.55) of 20.37 min average. No differences between groups were detected evaluating: NIHSS at admission (p = 0.49) and discharge (p = 0.67), pre-stroke mRS (p = 0.89), mRS at 90 days (p = 0.62), ASPECT (p = 0.98) and ASPECT-DWI scores (p = 0.93), time from symptom onset to groin puncture (p = 0.80), thromboaspiration vs combined technique (p = 0.67), EVT success (p = 0.63). Conclusion: Fusion of MRA and MRC is a safe and promising technique in promptly revealing vascular anatomy beyond vessel obstruction, and can play a role in EVT duration reduction.

Heme Biosynthetic Gene Expression Analysis With dPCR in Erythropoietic Protoporphyria Patients.

Background: The heme biosynthesis (HB) involves eight subsequent enzymatic steps. Erythropoietic protoporphyria (EPP) is caused by loss-of-function mutations in the ferrochelatase (FECH) gene, which in the last HB step inserts ferrous iron into protoporphyrin IX (PPIX) to form heme. Aim and method: The aim of this work was to for the first time analyze the mRNA expression of all HB genes in peripheral blood samples of patients with EPP having the same genotype FECH c.[215dupT]; [315-48T > C] as compared to healthy controls by highly sensitive and specific digital PCR assays (dPCR). Results: We confirmed a decreased FECH mRNA expression in patients with EPP. Further, we found increased ALAS2 and decreased ALAS1, CPOX, PPOX and HMBS mRNA expression in patients with EPP compared to healthy controls. ALAS2 correlated with FECH mRNA expression (EPP: r = 0.63, p = 0.03 and controls: r = 0.68, p = 0.02) and blood parameters like PPIX (EPP: r = 0.58 p = 0.06). Conclusion: Our method is the first that accurately quantifies HB mRNA from blood samples with potential applications in the monitoring of treatment effects of mRNA modifying therapies in vivo, or investigation of the HB pathway and its regulation. However, our findings should be studied in separated blood cell fractions and on the enzymatic level.

Muscle MRI in McArdle Disease: A European Multicenter Observational Study.

BACKGROUND AND OBJECTIVES: Glycogen storage disease type V (GSDV) or McArdle disease is a muscle glycogenosis that classically manifests with exercise intolerance and exercise-induced muscle pain. Muscle weakness and wasting may occur but is typically mild and described as located around the shoulder-girdle in elderly patients. Paraspinal muscle involvement has received little attention in the literature. The present study aimed to quantify fat-replacement of paraspinal, shoulder and lower limb muscles by magnetic resonance imaging in a European cohort of GSDV patients. METHODS: This observational study included patients with verified GSDV and healthy controls (HC). Whole-body MR-images and clinical data were collected. The degree of muscle fat-replacement was evaluated on T1-weighted images with the semi-quantitative visual Mercuri-scale, and on Dixon-images where individual muscle fat fractions (FF) were quantitatively calculated. RESULTS: MR-images and clinical data from a total of 57 GSDV patients (age 44.3±15.2 years) from five European centers were assessed and compared to findings in 30 HC (age 42.4±14.8 years). Patients with GSDV had significantly more fat-replacement of theparaspinal muscles compared to HC on all levels investigated detected both by the Mercuri and the Dixon methods (Dixon, paraspinal composite-FF (GSDV vs HC), at the cervical-: 31.3±13.1 vs 15.4±7.8; thoracic-: 34.5±19.0 vs 16.9±8.6 and lumbar-level: 43.9±19.6 vs 21.8±10.2 (p<0.0001)). Patients with GSDV also had significantly more fat-replacement of the shoulder muscles (evaluated by the Mercuri-scale), along with significantly, but numerically less, fat-replacement of thigh- and calf muscles compared to HC (Dixon, lower limb composite-FF (GSDV vs HC) at the thigh-: 12.0±5.6 vs 8.8±2.7 and calf-level: 13.1±6.7 vs 9.1±2.9 (p≤0.05)). DISCUSSION: The primary findings are that patients with GSDV exhibit severe fat-replacement of the paraspinal muscles, which can have important implications for the future management of patients with GSDV, and also significant fat-replacement of shoulder-girdle muscles as previously described. The clinical relevance of the discrete increases in lower limb FF is uncertain. The changes were found to be age-related in both groups, but an accelerated effect was found in GSDV, probably due to continuous muscle damage.

Cisternostomy for malignant middle cerebral artery infarction: proposed pathophysiological mechanisms and preliminary results.

BACKGROUND: The ischaemic stroke of the territory of the middle cerebral artery represents an event burdened by high mortality and severe morbidity. The proposed medical treatments do not always prove effective. Decompressive craniectomy allows the ischaemic tissue to shift through the surgical defect rather than to the unaffected regions of the brain, thus avoiding secondary damage due to increased intracranial pressure. In this study, we propose a novel treatment for these patients characterised by surgical fenestration of the cisterns of the skull base. METHODS: We have treated 16 patients affected by malignant middle cerebral artery ischaemia and treated with cisternostomy between August 2018 and December 2019. The clinical history, neurological examination findings and neuroradiological studies (brain CT, CT angiography, MRI) were performed to diagnose stroke. Clinical examination was recorded on admission and preoperatively using the Glasgow Coma Scale and the National Institutes of Health Stroke Scale. RESULTS: The study included 16 patients, 10 males and 6 females. The mean age at surgery was 60.1 years (range 19-73). Surgical procedure was performed in all patients. The patients underwent immediate postoperative CT scan and were in the early hours evaluated in sedation window. In total, we recorded two deaths (12.5%). A functional outcome between mRS 0-3, defined as favourable, was observed in 9 (64.2%) patients 9 months after discharge. A functional outcome between mRS 4-6, defined as poor, was observed in 5 (35.7%) patients 9 months after discharge. CONCLUSIONS: The obtained clinical results appear, however, substantially overlapping to decompressive craniectomy. Cisternostomy results in a favourable functional outcome after 9 months. This proposed technique permits that the patient no longer should be undergone cranioplasty thus avoiding the possible complications related to this procedure. The results are certainly interesting but higher case numbers are needed to reach definitive conclusions.

Endothelial Dysfunction in Acute Hepatic Porphyrias.

Background Acute hepatic porphyrias (AHPs) are a group of rare diseases caused by dysfunctions in the pathway of heme biosynthesis. Although acute neurovisceral attacks are the most dramatic manifestations, patients are at risk of developing long-term complications, several of which are of a vascular nature. The accumulation of non-porphyrin heme precursors is deemed to cause most clinical symptoms. Aim We measured the serum levels of endothelin-1 (ET-1) and nitric oxide (NO) to assess the presence of endothelial dysfunction (ED) in patients with AHPs. Forty-six patients were classified, according to their clinical phenotype, as symptomatic (AP-SP), asymptomatic with biochemical alterations (AP-BA), and asymptomatic without biochemical alterations (AP-AC). Results Even excluding those under hemin treatment, AP-SP patients had the lowest NO and highest ET-1 levels, whereas no significant differences were found between AP-BA and AP-AC patients. AP-SP patients had significantly more often abnormal levels of ED markers. Patients with the highest heme precursor urinary levels had the greatest alterations in ED markers, although no significant correlation was detected. Conclusions ED is more closely related to the clinical phenotype of AHPs than to their classical biochemical alterations. Some still undefined disease modifiers may possibly determine the clinical picture of AHPs through an effect on endothelial functions.