Porphyrias: a review and case report

1. Porphyrias: a review and case report

2. Anemia MCV=HCT/RBC 80-100 >100 <80 Sudden massive blood lose Marrow failure hemolysis Microcytic Megaloblastic anemia Spurious macrocytic anemia

3. Microcytic anemia Defect in hemoglobin synthesis 3-dimensional structure of hemoglobin. The four subunits are shown in red and yellow, and the heme groups in green.

4. Microcytic anemia Defect in hemoglobin sythesis Low or normal Iron binding capacity High High Iron Low or normal Defect in: Porphyrin synthesis Heme synthesis Globin synthesis Iron deficiency

5. Defect in: Porphyrin synthesis Heme synthesis Globin synthesis Hemoglobin electrophoresis Abnormal Normal Defect in: Porphyrin synthesis Heme synthesis Defect in: Globin synthesis Quantitative Both Qualitative Thalassemia Sickle-thal S,C,F,ect

6. Heme Non-erythroid Erythroid Haemoglobin Haemoproteins Electron transfer and energy trapping myoglobin Cytochromes Others

7. Porphyrins synthesis Mitochondrion Cytosol Spontaneous URO I COPRO I

8. Water-soluble Excreted in urine Water-soluble Excreted in urine Glycine ALA synthase + NH2-CH2-COOH D-ALA ALA dehydrase PBG deaminase PBG Hydroxymethylbilane

9. Water-soluble Excreted in urine Less water-soluble Excreted in urine/feces Hydroxymethylbilane URO III synthase Spontaneous URO I COPRO I URO III decarboxylase Uroporphyrinogen III Coproporphyrinogen III

10. Poor water-solubility Excreted in feces CORPO III COPRO oxidase Protoporphyrinogen IX PROTO oxidase Protoporphyrin IX Ferrochelatase Heme

11. Main Types of Porphyria Glycine +Succinyl CoA Acute Porphyrias ALAD Deficiency Porphyria ALA synthase Acute Intermittent Porphyria ALA (Neurological Porphyrias) Hereditary Coproporphyria ALA dehydrase Variegate Porphyria PBG PBG deaminase Hydroxymethylbilane (Unstable) Non-acute Porphyrias URO III synthase Spontaneous Porphyria Cutanea Tarda URO III URO I Erythropoietic Protoporphyria URO III decarboxylase (Cutaneous Porphyrias) Congenital Erythropietic Porphyria COPRO I COPRO III COPRO oxidase Secondary Porphyrias Lead Poisoning PROTO IX PROTO oxidase Iron Deficiency Protoporphyrin IX Coproporphyrinuria Ferrochelatase Heme

12. Main Types of Porphyria Tissue expression Inheritance ALAD Deficiency Porphyria Liver Autosomal recessive Acute Porphyrias Acute Intermittent Porphyria Autosomal dominant Liver (Neurological Porphyrias) Hereditary Coproporphyria Liver Autosomal dominant Variegate Porphyria Liver Autosomal dominant Non-acute Porphyrias Autosomal dominant Porphyria Cutanea Tarda Liver Erythropoietic Protoporphyria E , L Autosomal dominant (Cutaneous Porphyrias) Congenital Erythropietic Porphyria Erythroid cells Autosomal recessive Lead Poisoning Secondary Porphyrias Iron Deficiency Coproporphyrinuria

13. Glycine +Succinyl CoA Acute Porphyrias ALAD Deficiency Porphyria ALA synthase Acute Intermittent Porphyria urine ALA Hereditary Coproporphyria ALA dehydrase Variegate Porphyria PBG PBG deaminase Hydroxymethylbilane URO III synthase Spontaneous Non-acute Porphyrias Porphyria Cutanea Tarda URO III URO I Erythropoietic Protoporphyria URO III decarboxylase Congenital Erythropietic Porphyria COPRO I COPRO III COPRO oxidase Secondary Porphyrias Lead Poisoning PROTO IX PROTO oxidase Iron Deficiency Protoporphyrin IX Coproporphyrinuria Ferrochelatase Heme

14. urine urine urine Glycine +Succinyl CoA Acute Porphyrias ALAD Deficiency Porphyria ALA synthase Acute Intermittent Porphyria ALA Hereditary Coproporphyria ALA dehydrase Variegate Porphyria PBG PBG deaminase Hydroxymethylbilane URO III synthase Spontaneous Non-acute Porphyrias Porphyria Cutanea Tarda URO III URO I Erythropoietic Protoporphyria URO III decarboxylase Congenital Erythropietic Porphyria COPRO I COPRO III COPRO oxidase Secondary Porphyrias Lead Poisoning PROTO IX PROTO oxidase Iron Deficiency Protoporphyrin IX Coproporphyrinuria Ferrochelatase Heme

15. urine urine urine urine Urine feces Glycine +Succinyl CoA Acute Porphyrias ALAD Deficiency Porphyria ALA synthase Acute Intermittent Porphyria ALA Hereditary Coproporphyria ALA dehydrase Variegate Porphyria PBG PBG deaminase Hydroxymethylbilane URO III synthase Spontaneous Non-acute Porphyrias Porphyria Cutanea Tarda URO III URO I Erythropoietic Protoporphyria URO III decarboxylase Congenital Erythropietic Porphyria COPRO I COPRO III COPRO oxidase Secondary Porphyrias Lead Poisoning PROTO IX PROTO oxidase Iron Deficiency Protoporphyrin IX Coproporphyrinuria Ferrochelatase Heme

16. urine Urine feces urine urine urine feces Glycine +Succinyl CoA Acute Porphyrias ALAD Deficiency Porphyria ALA synthase Acute Intermittent Porphyria ALA Hereditary Coproporphyria ALA dehydrase Variegate Porphyria PBG PBG deaminase Hydroxymethylbilane URO III synthase Spontaneous Non-acute Porphyrias Porphyria Cutanea Tarda URO III URO I Erythropoietic Protoporphyria URO III decarboxylase Congenital Erythropietic Porphyria COPRO I COPRO III COPRO oxidase Secondary Porphyrias Lead Poisoning PROTO IX PROTO oxidase Iron Deficiency Protoporphyrin IX Coproporphyrinuria Ferrochelatase Heme

17. Urine Feces Urine Glycine +Succinyl CoA Acute Porphyrias ALAD Deficiency Porphyria ALA synthase Acute Intermittent Porphyria ALA Hereditary Coproporphyria ALA dehydrase Variegate Porphyria PBG PBG deaminase Hydroxymethylbilane URO III synthase Spontaneous Non-acute Porphyrias Congenital Erythropietic Porphyria URO III URO I Porphyria Cutanea Tarda URO III decarboxylase Erythropoietic Protoporphyria COPRO I COPRO III COPRO oxidase Secondary Porphyrias Lead Poisoning PROTO IX PROTO oxidase Iron Deficiency Protoporphyrin IX Coproporphyrinuria Ferrochelatase Heme

18. Urine Feces urine Urine Glycine +Succinyl CoA Acute Porphyrias ALAD Deficiency Porphyria ALA synthase Acute Intermittent Porphyria ALA Hereditary Coproporphyria ALA dehydrase Variegate Porphyria PBG PBG deaminase Hydroxymethylbilane URO III synthase Spontaneous Non-acute Porphyrias Congenital Erythropietic Porphyria URO III URO I Porphyria Cutanea Tarda URO III decarboxylase Erythropoietic Protoporphyria COPRO I COPRO III COPRO oxidase Secondary Porphyrias Lead Poisoning PROTO IX PROTO oxidase Iron Deficiency Protoporphyrin IX Coproporphyrinuria Ferrochelatase Heme

19. Feces Feces Glycine +Succinyl CoA Acute Porphyrias ALAD Deficiency Porphyria ALA synthase Acute Intermittent Porphyria ALA Hereditary Coproporphyria ALA dehydrase Variegate Porphyria PBG PBG deaminase Hydroxymethylbilane URO III synthase Spontaneous Non-acute Porphyrias Congenital Erythropietic Porphyria URO III URO I Porphyria Cutanea Tarda URO III decarboxylase Erythropoietic Protoporphyria COPRO I COPRO III COPRO oxidase Secondary Porphyrias Lead Poisoning PROTO IX PROTO oxidase Iron Deficiency Protoporphyrin IX Coproporphyrinuria Ferrochelatase Heme

20. urine Feces Feces Urine Feces Glycine +Succinyl CoA Acute Porphyrias ALAD Deficiency Porphyria ALA synthase Acute Intermittent Porphyria ALA Hereditary Coproporphyria ALA dehydrase Variegate Porphyria PBG PBG deaminase Hydroxymethylbilane URO III synthase Spontaneous Non-acute Porphyrias Congenital Erythropietic Porphyria URO III URO I Porphyria Cutanea Tarda URO III decarboxylase Erythropoietic Protoporphyria COPRO I COPRO III COPRO oxidase Secondary Porphyrias Lead Poisoning PROTO IX PROTO oxidase Iron Deficiency Protoporphyrin IX Coproporphyrinuria Ferrochelatase Heme Zn-protoporphyrin

21. Glycine +Succinyl CoA Acute Porphyrias ALAD Deficiency Porphyria ALA synthase Acute Intermittent Porphyria ALA Hereditary Coproporphyria ALA dehydrase Variegate Porphyria PBG PBG deaminase Hydroxymethylbilane URO III synthase Spontaneous Non-acute Porphyrias Congenital Erythropietic Porphyria URO III URO I Porphyria Cutanea Tarda URO III decarboxylase Erythropoietic Protoporphyria COPRO I COPRO III COPRO oxidase Secondary Porphyrias Lead Poisoning PROTO IX PROTO oxidase Iron Deficiency Protoporphyrin IX Coproporphyrinuria Ferrochelatase Heme Zn-protoporphyrin

22. Sunnybrook Health Sciences Center Sampling Guide Notes: At time of acute attack: 1. Collect a random urine sample first (50 ml with no preservatives), before attempting to collect a 24-h sample. 2. Request "Porphyrin Precursors" (ALA & PBG) instead of "Porphyrins" screen and quantitation. The Laboratory will have to adjust pH to 4-6 for "Porphyrin Precursors", but pH 8-10 for "Porphyrins". - The commonest problem causing confusion! 3. All sample containers should be covered with tin foil to shield off from light.

24. Porphyrin assays provided through HICL Bio-Rad Column HPLC

25. Enzymatic Spectrophometric Screening ICP-MS

26. CASE A boy, average hematologic parameters over the subsequent 3 years were as follows: Mean corpuscular volume (MCV), 67 fL → microcytic Iron studies were unremarkable → Defect in: Porphyrin synthesis Heme synthesis Globin synthesis Hemoglobin (Hb) level, 70.0 g/L; Mean corpuscular hemoglobin level, consistently < 20 pg; Reticulocyte counts ranged from 3.6% to 6.7%;

27. A physical examination revealed scars on the face, hands, and forearms. → photosensitive bullous dermatosis The diapers exhibited brilliant pink fluorescence when illuminated with long-range ultraviolet light. → Photosensitive porphyrin rings Fluorescent red cells were detected using a microscope fitted with a 405 nm light source. → CEP or EP A 50-mL urine sample contained 2003 ug uroporphyrin (normal, trace); 92% of this was uro-I. → CEP Erythrocyte UROS activity was 21% of the normal mean. Collectively, these findings confirmed the diagnosis of CEP.

28. Erythrocyte UROS activity was normal in both parents, an unexpected finding as obligate carriers (heterozygotes) for UROS mutations generally have half-normal enzymatic activity. UROS was sequenced, and no mutations or deletions were found in the child or the parents. A GATA1 point mutation was found in the child at codon 216, changing arginine to tryptophan (R216W), as well as on 1 of the 2 GATA1 alleles of his mother and maternal grandmother. GATA1 gene, at Xp11.23, encodes a transcription factor, GATA binding factor 1 (GATA-1), that is critical for normal erythropoiesis, globin gene expression, and megakaryocyte development. GATA-1 also regulates expression of UROS in developing erythrocytes.

29. General Symptomology:__Abdominal pain___Abdominal tenderness___Loss of appetite___Nausea___Vomiting___Constipation___Carbohydrate craving___Breast secretions___Diarrhea___Partial ileus [Intestinal blockage]___Abdominal distention___Dysuria [Painful Urination]___Bladder Dysfunction___Urinary Retention___Amenorrhea [Lack of menses]Physical Findings of Acute Attack__Red or dark urine___Tachycardia [Pulse] >100___Labile hypertension >90 diastolic [blood pressure]___Fever [Pyrexia]___Profused sweating___Edema [Retention of fluids] [Swelling]___Postural Hypotension [Low Blood Pressure]___Hypertrichosis [excessive body hair growth]___Hyperpigmentation [skin coloring]

30. Neurological Symptoms of Acute Attack[Peripheral manifestations]___Peripheral neuropathy___Muscle weakness___Paresis . paralysis___Sensory disorde___Respiratory paralysis___Foot drop___Wrist drop___Abnormal Gait___Pain:  Arms, legs, hips and/or lower back___Loss of sensation___Dyesthesia                ___Numbness                ___Tingling               ___Burning Sensation___Bulbar paresis                ___Tongue paralization                ___Mouth paralization                ___Throat paralization [Cerebral manifestations]___Behavorial change___Anxiety___Irritability___Delirium___Depression___Confusion___Hallucination___Insomnia___ANS [altered neurological state]___Restlessness___Sensory loss___Seizure___Depressed or absent tendon reflexes___Cranial nerve involvement

31. Hematology/Blood Chemistry___Hyponatremia [Below normal sodium level] <130___Increased Bun [Urea Nitrogen]___Increased AST [Aspartate Aminotransferase]___Elevated Alkaline Phosphatase [Liver panel test]___Increased ALT [Aspartate Aminotransferase]___Hypokalemia [Below normal potassium level]___Leukocytosis [Abnormal increase in WBC] > 10,000___Increased ESR >22___Hypochloremia < 90 [A decrease in the chloride level]___Anemia [Iron deficiency]Cutaneous manifestations___Skin photosensitivity___Blistering___Severe Tissue Scarring___Increased Hair growth___Pigmentation Darkening___Thickening of skin___Severe Itching Special lab studies___Decreased blood volume___EEG abnormalities___Electromyographic abnormalities___Muscle denervation___Decreased nerve conduction velocity___Abnormal CSF___Increased fibrillation potential