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A Case Report: X-linked Dominant Protoporphyria
Matthew SeagerACS iSSC
ObjectivesIntroductionPorphyriasClassificationErythropoetic and X-linked dominant protoporphyrias (EPP & XLDPP)Why is this topic important?
Case report – XLDPP
Conclusions and learning points
Introduction - PorphyriasHeterogeneous group of inherited metabolic
disorders of the haem biosynthesis pathwayDue 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 ofNeuro – neuropathy, seizures, psychiatric
Visceral – colic, abdominal pain, vomiting
Photocutaneous:
•Painful bullous eruptions and/or scarring – PCT/CEP•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
lifeThe initial study (Whatley et al 2008) found:
17% clinically overt liver disease c.f. 2% EPPClose to 100% penetrance c.f EPP and other
porphyriasX-linked
Revise X-linked disease & importance of biochem tests!!
Implications for genetic counselling
Case report - XLDPP18 year old ♀PC – “Burning” photosensitivityHPC:
Lifelong. Occurs “within minutes” of sun exposureNo rash, erythema or swellingSkin feels and appears normal in between episodesWorse during summer monthsSunscreen – partial protection. Windows – none!
PMH & DH - NAD EPP??
Case report - XLDPPFH:
Case report - XLDPPInvestigation Result Reference Comment
Bloods
Erythrocyte total porphyrin (μmol/L)
60.6 0.4-1.7 suggests XLDPP/EPP
Erythrocyte porphyrin screen
Increased zinc & free PP IX
N/A Suggests XLDPP
Fluorescence emission spectroscopy (nm)
Peak 633 630-634in XLDPP/EPP
Suggests XLDPP/EPP
LFT Within normal ranges
Suggests lack of liver pathology
Faecal Total porphyrin (nmol/g dry weight)
459 10-200 suggests XLDPP
Urine Porphyrin:creatinine ratio (nmol/mmol)
16 <40 Normal in XLDPP/EPP
Genetic ALAS2 sequencing c.1706_1709 delAGTG
N/A Recognised GoF XLDPP deletion
Case report - XLDPPManagement plan:
Advised RE: sun avoidanceReflectant sunscreen vs visible lightNarrow band UVB 3-4/week for summer 2012Hepatology referral to establish monitoring
Adapted from Timonen 2009
XLDPP (& EPP) – Future hopeAfamelanotide (α-MSH analog):
Preliminary results - RCT 100 EPP patients promising Bone marrow transplantation
Harms et al 2009
ConclusionsXLDPP 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
Learning pointsDisability & disadvantage:
Great impact of “benign” pathology
Consultation & procedural skills:Witnessed genetic counselling of family
Evidence based medicine:Looked at evidence first hand
Thanks for listening.
References 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;
375(9718):924-37. 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, Finland
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.