Explore the vast range of titles available.

Background Aceruloplasminemia is a rare genetic iron overload disorder, characterized by progressive neurological manifestations. The effects of iron chelation on neurological outcomes have only been described in case studies, and are inconsistent. Aggregated case reports were analyzed to help delineate the disease-modifying potential of treatment. Methods Data on clinical manifestations, treatment and neurological outcomes of treatment were collected from three neurologically symptomatic Dutch patients, who received deferiprone with phlebotomy as a new therapeutic approach, and combined with other published cases. Neurological outcomes of treatment were compared between patients starting treatment when neurologically symptomatic and patients without neurological manifestations. Results Therapeutic approaches for aceruloplasminemia have been described in 48 patients worldwide, including our three patients. Initiation of treatment in a presymptomatic stage of the disease delayed the estimated onset of neurological manifestations by 10 years (median age 61 years, SE 5.0 vs. median age 51 years, SE 0.6, p  = 0.001). Although in 11/20 neurologically symptomatic patients neurological manifestations remained stable or improved during treatment, these patients were treated significantly shorter than patients who deteriorated neurologically (median 6 months vs. median 43 months, p  = 0.016). Combined iron chelation therapy with deferiprone and phlebotomy for up to 34 months could be safely performed in our patients without symptomatic anemia (2/3), but did not prevent further neurological deterioration. Conclusions Early initiation of iron chelation therapy seems to postpone the onset of neurological manifestations in aceruloplasminemia. Publication bias and significant differences in duration of treatment should be considered when interpreting reported treatment outcomes in neurologically symptomatic patients. Based on theoretical grounds and the observed long-term safety and tolerability in our study, we recommend iron chelation therapy with deferiprone in combination with phlebotomy for aceruloplasminemia patients without symptomatic anemia.

Introduction A small proportion of patients with acute intermittent porphyria (AIP) suffer from recurrent porphyric attacks, with a severely diminished quality of life. In this retrospective case-control study, the burden of disease is quantified and compared among three AIP patient subgroups: cases with recurrent attacks, cases with one or occasional attacks and asymptomatic carriers. Methods Data from patient records and questionnaires were collected in patients between 1960 and 2016 at the Erasmus Medical Center, Rotterdam, the Netherlands. We collected symptoms related to porphyria, porphyria related complications, attack frequency, hospitalisation frequency, hospitalisation days related to acute porphyric attacks, frequency of heme infusions and medical healthcare costs based on hospitalisations and heme therapy. Results In total 11 recurrent AIP cases, 24 symptomatic AIP cases and 53 AIP carriers as controls were included. All recurrent patients reported porphyria related symptoms, such as pain, neurological and/or psychiatric disorders, and nearly all developed complications, such as hypertension and chronic kidney disease. In the recurrent cases group, the median lifelong number of hospitalisation days related to porphyric attacks was 82 days per patient (range 10–374), and they spent a median of 346 days (range 34–945) at a day-care facility for prophylactic heme therapy; total follow-up time was 243 person-years (PYRS). In the symptomatic non-recurrent group the median lifelong number of hospitalisation days related to porphyric attacks was 7 days per patient (range 1–78), total follow-up time was 528 PYRS. The calculated total medical healthcare cost for recurrent cases group was €5.8 million versus €0.3 million for the symptomatic cases group.

Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disease, causing lifelong painful phototoxic reactions, minimal sunlight exposure, and vitamin D deficiency. Previous studies reported a high osteoporosis prevalence in EPP patients. To identify those at risk for low bone mineral density (BMD) and assess which factors, including treatment with cholecalciferol and afamelanotide, improve BMD in EPP. A longitudinal ambispective single-center cohort study. Data from patient files and two-time questionnaires from adult patients with EPP who underwent at least one dual-energy x-ray absorptiometry (DXA) scan between 2012 and 2023 were used. BMD is low in EPP patients, with 82.7% of the 139 patients having a Z-score below 0 SD at baseline. Low BMD classified as osteopenia was found in 39.5%, and osteoporosis in 15.3%. There were 50 osteoporosis-related fractures in 34.2% of patients. Aging (odds ratio [OR] 1.08; CI, 1.03-1.12), persistent vitamin D deficiency (OR 1.11; 95% CI, 1.00-1.23) and a low body mass index (OR 0.91; 95% CI, 0.82-0.99) increased the odds of low BMD. Patients with a vitamin D deficiency (OR 5.51; 95% CI, 1.69-17.92) and no cholecalciferol at baseline (OR 0.22; 95% CI, 0.04-1.34) had the highest odds of improving their BMD. Afamelanotide did not improve BMD. 25-hydroxyvitamin D (25(OH)D) status plays a crucial role in both preventing low BMD and improving BMD. EPP is a natural model for lack of sunlight exposure and vitamin D deficiency, underlining the importance of lifelong adequate vitamin D status for bone health in the general population.

Non-invasive measures of brain iron content would be of great benefit in neurodegeneration with brain iron accumulation (NBIA) to serve as a biomarker for disease progression and evaluation of iron chelation therapy. Although magnetic resonance imaging (MRI) provides several quantitative measures of brain iron content, none of these have been validated for patients with a severely increased cerebral iron burden. We aimed to validate R2* as a quantitative measure of brain iron content in aceruloplasminemia, the most severely iron-loaded NBIA phenotype. Tissue samples from 50 gray- and white matter regions of a postmortem aceruloplasminemia brain and control subject were scanned at 1.5 T to obtain R2*, and biochemically analyzed with inductively coupled plasma mass spectrometry. For gray matter samples of the aceruloplasminemia brain, sample R2* values were compared with postmortem in situ MRI data that had been obtained from the same subject at 3 T – in situ R2*. Relationships between R2* and tissue iron concentration were determined by linear regression analyses. Median iron concentrations throughout the whole aceruloplasminemia brain were 10 to 15 times higher than in the control subject, and R2* was linearly associated with iron concentration. For gray matter samples of the aceruloplasminemia subject with an iron concentration up to 1000 mg/kg, 91% of variation in R2* could be explained by iron, and in situ R2* at 3 T and sample R2* at 1.5 T were highly correlated. For white matter regions of the aceruloplasminemia brain, 85% of variation in R2* could be explained by iron. R2* is highly sensitive to variations in iron concentration in the severely iron-loaded brain, and might be used as a non-invasive measure of brain iron content in aceruloplasminemia and potentially other NBIA disorders.

BackgroundPeutz–Jeghers syndrome (PJS) is associated with an increased cancer risk. As the determination of optimal surveillance strategies is hampered by wide ranges in cancer risk estimates and lack of data on cancer-related mortality, we assessed cancer risks and mortality in a large cohort of patients with PJS.MethodsDutch PJS patients were included in this cohort study. Patients were followed prospectively between January 1995 and July 2009, and clinical data from the period before 1995 were collected retrospectively. Data were obtained by interview and chart review. Cumulative cancer risks were calculated by Kaplan–Meier analysis and relative cancer and mortality risks by Poisson regression analysis.ResultsWe included 133 PJS patients (48% males) from 54 families, contributing 5004 person-years of follow-up. 49 cancers were diagnosed in 42 patients (32%), including 25 gastrointestinal (GI) cancers. The median age at first cancer diagnosis was 45 years. The cumulative cancer risk was 20% at age 40 (GI cancer 12%), increasing to 76% at age 70 (GI cancer 51%). Cumulative cancer risks were higher for females than for males (p=0.005). The relative cancer risk was higher in PJS patients than in the general population (HR 8.96; 95% CI 6.46 to 12.42), and higher among female (HR 20.40; 95% CI 13.43 to 30.99) than among male patients (HR 4.76; 95% CI 2.82 to 8.04). 42 patients had died at a median age of 45 years, including 28 cancer-related deaths (67%). Mortality was increased in our cohort compared to the general population (HR 3.50; 95% CI 2.57 to 4.75).ConclusionsPJS patients carry high cancer risks, leading to increased mortality. The malignancies occur particularly in the GI tract and develop at young age. These results justify surveillance in order to detect malignancies in an early phase to improve outcome.

The simultaneous dysfunction of two enzymes within the heme biosynthetic pathway in a single patient is rare. Not more than 15 cases have been reported. A woman with a transient episode of severe photosensitivity showed a biochemical porphyrin profile suggestive of hereditary coproporphyria (HCP), whereas some of her relatives had a profile that was suggestive of variegate porphyria (VP). HCP and VP result from a partial enzymatic deficiency of coproporphyrinogen oxidase (CPOX) and protoporphyrinogen oxidase (PPOX), respectively. DNA analysis in the index patient revealed mutations in both theCPOX andPPOX genes, designated as c.557-15C>G and c.1289dupT, respectively. TheCPOX mutation leads to a cryptic splice site resulting in retention of 14 nucleotides from intron 1 in the mRNA transcript. Both mutations encode null alleles and were associated with nonsense-mediated mRNA decay. Given the digenic inheritance of these null mutations, coupled with the fact that both HCP and VP can manifest with life-threatening acute neurovisceral attacks, the unusual aspect of this case is a relatively mild clinical phenotype restricted to dermal photosensitivity.

This article considers the case of a 22-year-old female with congenital disorder of glycosylation type Ib and a history of congenital hepatic fibrosis, portal hypertension and esophageal varices, who presented with edema, diarrhea, hypoalbuminemia and pancytopenia. Protein-losing enteropathy was diagnosed. As previous mannose therapy was associated with diarrhea and abdominal pain, albumin was infused followed by intravenous and subcutaneous therapy with unfractionated heparin. Background A 22-year-old female presented with edema, diarrhea, hypoalbuminemia and pancytopenia. She had previously been diagnosed with congenital disorder of glycosylation type Ib, and had a history of congenital hepatic fibrosis, portal hypertension and esophageal varices. In the past she had refused mannose therapy because of associated diarrhea and abdominal pain. Investigations Laboratory examinations, abdominal ultrasonography, bacterial and viral cultures of blood, urine and stools, double-balloon enteroscopy and fecal excretion test using 51 Cr-labeled albumin. Diagnosis Protein-losing enteropathy. Management Infusion of albumin followed by intravenous and subcutaneous therapy with unfractionated heparin.

Due to a typesetting error the wrong figure 2 was used.