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.