Whilst best known for forming an essential component of haemoglobin, haem is found in several other proteins throughout the body – namely myoglobin, catalase, peroxidase and hepatic and pulmonary cytochromes. The clinical manifestations of the porphyrias are not due to a lack of haem synthesis which remains sufficient in most disorders, but due to the build up of porphyrins which are toxic too some tissues when they become too concentrated.
8 distinct porphyrias have been described to date. The clinical phenotype depends on which enzyme in the haem synthesis pathway is affected. Based on symptomatology, the porphyrias can be broadly classed into 3 main groups. Neurovisceral porphyrias, most commonly AIP which consists of acute attacks, precipiated by drugs of…. A photocutaneous group with 2 main patterns of symptoms. EPP with….but with minimal external signs, other than some erythema OR And finally a third group which display a mixture of both neurovisceral and photocutaneous symptoms. As clinical features alone are not sufficiently specific either to con firm a diagnosis or to distinguish between the various forms, correct interpretation of the appropri-ate biochemical investigations is essential for accurately diagnosing and managing the porphyrias, It is a cutaneous porphyria similar to EPP that is not included on this now outdated diagram, known as X linked dominant protoprophyria, that shall be the focus of this case report.
Ok, so that’s a brief overview of porphyrias in general, but what about the newly discovered photocutaneous porphyria x-linked dominant PP that is the subject of the case that I shall present? This diagram here, believe it or not, is a simplified version of the haem synthesis pathway and the pathology. To start with the pathway in normal physiology (click), in the erythroid bone marrow cells, glycine and succinly coA are combined by the enzyme ALA-synthase 2, which is the rate limiting step of the pathway in mitochondria. A number of intermediate reactions occur in the cell cytoplasm (as was shown on the previous diagram), before an intermediate molecule know as PP IX is combined with iron by ferrochelatase enzyme to produce Haem. In EPP, the vast majority of patients have a form caused by the coinheritance of 2 affected FECH alleles, resulting in much decreased FECH activity with a subsequent backlog and increase of PP IX. The accumulation of PP IX spills out into other tissues, namely the skin and liver. This explains the symptoms of EPP which are lifelong, acute, painful photosensitivity often described as a burning sensation on sun exposure. As I mentioned this tends to occur without obvipus external signs other than erythema and oedema in some. Accumulation in the liver can result in progressive liver damage, with 10-20% of cases demonstrating biochemical evidence of damage, which presents as severe liver disease in 2% and requires lifelong LF monitoring in all patients. Treatment is aimed at photoprotection and several agents such as beta carotene or UVB therapy have been used to try and prevent phototolerance, but evidence remains somewhat limited. 4 years ago, a previously unrecognised form of porphyria was discovered that presents in a similar manner to EPP. It is inherited in an X-linked dominant manner, an a number of disticnt mutations have been identified. They all result in a gain of function the ALA synthase 2 gene and therefore a build up PP IX. It is this build up in PP IX which explains the identical symptomatology of XLDPP so again acute, painful photosensitivity and liver dysfunction. As with all the porphyrias, XLDPP can be distinguished biochemically with a much higher levels of PP IX within the erythrocytes themselves and a greater proportion of this is bound to zinc. Management thus far has been based on similar strategies to EPP, but again evidence is unfortunately lacking.
So what is the significance of this and why is it important to consider this topic? Liver (mention how many fams/individuals in the study) Implications: may account for much of the “EPP” where no FECH mutation is found. Important to entertain this diagnosis in anyone presenting with such symptoms where the inheritance appears to follow an X-linked pattern. In terms of benefits as an SSC project it has also given me the chance revise the concept of X-linked disease and appreciate the importance of biochemical tests amongst metabolic disease.
The family history was interesting: The patient’s mother (who accompanied her to the consultation) reported identical symptoms, and explained that her own father and (deceased) grandmother had also been affected. It would be unusual for EPP to span so many generations with its traditionally low penetrance. X-linked conditions display an absence of father to son transmission and while, there has only been one chance for this to happen in this pedigree (here), its absence does fall in line with X-linked inheritance. On specific questioning, there was no known family history of any liver disease.
A provisional diagnosis of EPP was made before referral to the local porphyria service. In order to evaluate the disease biochemically and reach a diagnosis, the following investigations were carried out: There was a raised level of erythrocyte total porphyrin which is seen in both XLDPP and EPP as protoprphyin IX rises in the erythrocytes. A further screen showed this to display increased zinc chelation which is characteristic of XLDPP specifically. The spectroscopy peak suggested incresed protoporphyin IX so again suggested either XLDPP or EPP. Her liver Fx at this stage was normal. Faecal porphyrin was raised and urine porphyrine:creatinine ratio was normal and this again fits as PP IX is strictly hydrophobic. Finally sequencing of the ALAS2 gene, the one which is affected in XLDPP, confirmed this diagnosis by finding a recognised deletion that cause a gain in function of the enzyme. This revealed a diagnosis of XLDPP.
Following diagnosis, the condition was fully explain to the patient and her symptomatic mother and grandfather. They were explained how the disease occurs and that management, as for EPP, is based around sun avoidance. All were prescribed a reflectant sunscreen formulated to protect against visible light. It is light in the visible spectrum and long wavelength UVA which is thought to cause the induce the changes in PP IX in the skin which result in the production of free radicals and reactive oxygen species and cause the painful photosensitivity. Subsequently typical sunscreens and also windows which surprisingly enough don’t protect against visible light….also don’t protect against XLDPP. Unsurprisingly these zinc and titanium oxide based screens are fairly thick stuff, so there is documented evidence of patient disfication with). Hopefully she will gain some relief through the course of narrow band UVB therapy she has been prescribed for this coming summer. UVB is outside of the wavelength range which induces these phototoxic changes in PP IX and it is thought that it improves photolerance by increasing the melanin content and thickening the stratum corneum and underlying epidermis. This provides a barrier of protection (click), effectively by producing a tan and helps dampen down the downstream changes in the protoporphyin molecule that cause the photosensitivity. A referral to the hepatology team was also made to establish a monitoring strategy for protoporphyin induced liver disease.
As I mentioned the treatment of XLDPP and EPP remains largely unsatisfactory due to the lack of proven efficacy and in the case of the reflectant sunscreen - the distressing psychological side effects. Luckily there is some hope for more satisfactory treatments. Afamelanotide, an analog of alpha-MSH, has been shown to improve phototolerance and patient reported self-exposure to sunlight when given subcutaneously every 60 days. Here we have a graph, taken from the initial results of a study in the NEJM that shows that 5 patients who were treated with afamelanotide were able to tolerate exposure of the dorsum of the hand to articial light for increasing lengths of time as treatment progressed. As with UVB therapy, the likely photoprotective mechanism is via increased melanin synthesis. Fortuntately, these results have been replicated on a much larger scale in a more with more robust evidence, in the form of an ongoing RCT of 100 patients. Preliminary results from the stage III trial have also shown EPP patients receiving afamelanotide exprerience photosens less often and the pain is less severe. This has lead the Italian health service, somewhat prematurely before the trial is complete!, to authorise the treatment for EPP. So far afamelantoide appears to be safe and does not appear to drive the potential for malignant melanoma, and may even protect against it. One final interesting point relates to a case report pubished about 10 years ago. A 47 year old woman with a 25 year history of undiagnosed painful, acute photosensitivity underwent a BM transplant for CML.During workup before her BM she was diagnosed with EPP and following Tx, her symptoms resolved entirely. It is highly unlikely that the risks of BMT are justified in conditions like EPP and XLDPP that can be managed conservatively (albeit unsatisfactorily), but BMT has now been used in sufferers of EPP with particularly bad liver dysfx requiring transplantation. This aims to cure the genetic metabolic abnormality and prevent the same damage from the porphyria occurring again in the new liver. This may prove particularly useful in the setting on XLDPP if it does become apparent that there is in fact an increased risk of liver disease in this form of porphyria.
Mx largely similar to EPP as similar biochem profile – distinction important due to genetic counselling difference and potential increased LD
A Case Report: X-linked Dominant Protoporphyria
A Case Report: X-linked
Erythropoetic and X-linked dominant
protoporphyrias (EPP & XLDPP)
Why is this topic important?
Case report – XLDPP
Conclusions and learning points
Introduction - Porphyrias
Heterogeneous group of inherited metabolic disorders of
the haem biosynthesis pathway
Due to abnormalities of the haem synthesis enzymes and
accumulation of haem precursors & porphyrins
Majority of haem synthesis occurs in haematopoietic
marrow cells (also liver parenchymal cells)
Toxic effects of porphyrins/precursors symptoms
Porphyrias - Classification
Adapted from Thadani et al 2000
Neurovisceral (“Acute porphyrias”):
•Acute attacks of
Neuro – neuropathy, seizures, psychiatric
Visceral – colic, abdominal pain, vomitingPhotocutaneous:
•Painful bullous eruptions and/or scarring –
•Acute, painful photosensitivity without
external signs – EPPMixed:
Neurological & photocutaneous features
EPP & XLDPP
Adapted from Puy et al 2010
EPP – Painful photosensitivity
& liver dysfunction
XLDPP – Painful photosensitivity
& liver dysfunction
Why is this topic important?
Rare (EPP 1:75,000-200,000) but great impact on life
The initial study (Whatley et al 2008) found:
17% clinically overt liver disease c.f. 2% EPP
Close to 100% penetrance c.f EPP and other porphyrias
Revise X-linked disease & importance of biochem tests!!
Implications for genetic counselling
Case report - XLDPP
18 year old ♀
PC – “Burning” photosensitivity
Lifelong. Occurs “within minutes” of sun exposure
No rash, erythema or swelling
Skin feels and appears normal in between episodes
Worse during summer months
Sunscreen – partial protection. Windows – none!
PMH & DH - NAD EPP??
XLDPP and EPP are photocutaneous porphyrias
Pathophysiological similarities disorders
present/managed almost identically
Lack of evidence for definitive management and current
regimens fairly unsatisfactory
Further research: treatment and prognosis
Disability & disadvantage:
Great impact of “benign” pathology
Consultation & procedural skills:
Witnessed genetic counselling of family
Evidence based medicine:
Looked at evidence first hand
Thadani H, Deacon A, Peters T. Diagnosis and management of
porphyria. BMJ 2000; 320(7250):1647-51.
Puy H, Gouya L, Deybach JC. Porphyrias. Lancet 2010;
Whatley SD, Ducamp S, Gouya L, et al C-terminal deletions in the
ALAS2 gene lead to gain of function and cause X-linked dominant
protoporphyria without anemia or iron overload. Am J Hum
Genet 2008; 83(3):408-14.
Timonen K. Cutaneous porphyrias. Clinical and histopathological
study. Academic Dissertation 2009. Department of Medicine
Division of Dermatology and Allergology University of Helsinki,
Harms J, Lautenschlager S, Minder CE, Minder EI. An alpha-
melanocyte-stimulating hormone analogue in erythropoietic
protoporphyria. N Engl J Med 2009; 360(3):306-7.