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PORPHYRIA ^{1, 2}

General   Acute   Biochemistry   Genetics Unsafe drugs Acute Intermittent Porphyria Coproporphyria Variegate Porphyria δ-aminolevulinic acid dehydratase deficiency Also see: Tyrosinemia

From: Virginia King George III: Later years

Biochemistry: General

• Porphyrias
  • 7 syndromes
  • Result from partial deficiency of an enzyme in heme biosynthesis pathway
• Heme
  • Synthesised in every human cell
    • 85% is made in erythroid cells
    • Liver: 80% is used for the creation of different cytochromes
  • Biosynthesis regulated by 2 tissue specific δ-aminolaevulinic acid synthases (ALAS)
    • Liver
      • Heme represses synthesis of ALAS: Can be used to treat an acute porphyric attack
      • Many drugs, alcohol, steroids & other chemicals induce ALAS: Can provoke acute attack
    • Erythroid cells: Regulation is complex; Heme induces hemeoglobin synthesis
• Porphyrias general mechanism: Overproduction syndromes
  • Formation of toxic heme precursors
  • Overproduction is variable & associated with stimuli
• Porphyrins and porphyinogens are intermediates in heme synthesis: External link
• Porphyrins consist of four pyrrole rings joined by methene bridges: External link
• Porphyrinogens are more reduced than the corresponding porphyrins.
• Attacks
  • 4 types of porphyrias cause neurologic attacks
    • Acute intermittent porphyria
    • Hereditary coproporphyria
    • Variegate porphyria
    • Aminolevulinate dehydratase deficiency porphyria
  • All porphyrias produce elevated urine δ-amino-levulinic acid during attacks: External link
• Porphyrias can be divided into 2 subgroups: Hepatic & Erythropoietic
  • Category related to organ in which accumulation of porphyrins and their precursors appears
  • Hepatic
    • Aminolevulinate dehydratase deficiency porphyria
    • Acute intermittent porphyria
    • Porphyria cutanea tarda
    • Hereditary coproporphyria
    • Variegate porphyria
  • Erythropoietic
    • Congenital erythropoietic porphyria
    • Erythropoietic protoporphyria
  
  

Genetics: General

• Inheritance: Usually autosomal dominant with incomplete penetrance; Occasionally autosomal recessive
• Mutations
  • Most cause loss of function of the specific protein
  • Remaining enzyme levels usually sufficient to maintain patients' normal demand for heme
• Panethnic
• Prevalence varies from 0·5 to 10 per 100,000 in different populations.

Acute porphyrias: General

• Syndromes
  • Acute intermittent porphyria
  • Hereditary coproporphyria
  • Variegate porphyria
• General features
  • Attacks are clinically indistinguishable in 3 syndromes
  • Clinical manifestations arise after puberty
  • Attacks more frequent in women: Precipitated by menstrual cycle
  • Later onset: May be associated with hepatoma
• Attacks: Clinical features
  • Onset with with minor behavioral changes: Anxiety, Restlessness & Insomnia
  • Autonomic neuropathy
    • Gastrointestinal
      • Abdominal pain: Opiate treatment
      • Vomiting: Chlorpromazine treatment
      • Constipation: Lactulose treatment
    • Other pain: Back; Extremities
    • Vascular
      • Hypertension; Tachycardia
      • Treat with β-blockers
    • Arrhythmias
  • Motor-Sensory neuropathy
    • Weakness: May be diffuse; Respiratory involvement in some
    • Sensory loss: Distal
    • Tendon reflexes: Reduced
  • CNS: Rule out hyponatremia
    • Seizures
    • Confusion
  • General treatment
    • Heme arginate or Hematin
      • Dose: 3 mg/kg per day for 3–4 consecutive days
      • Side effects: Thrombophlebitis, Coagulopathy & Anaphylactic reactions
  • Also see: Acute intermittent porphyria
• Biochemistry
  • Induction of heme biosynthesis
  • Porphyrin precursors (δ-aminolaevulinic acid & porphobilinogen) excreted massively from liver
  • Precursors are neurotoxic & cause vascular injury
  • Urinary porphobilinogen increased during attack

Acute Intermittent Porphyria

Genetics > 60 mutations Mutation locations Common sites: Exons 10, 12 & 14 (35% to 50%) None in exons 2 & 13 Mutations commonly unique to individual or very few families Mutation types: Missense 41%; Truncating 59% Porphobilinogen deaminase deficient mice Porphyric syndrome + Neuropathy Incomplete penetrance More frequently manifest in females (65%) than males (35%) Allelic disorder: Leukoencephalopathy, Childhood-onset, Recessive 3 HMBS protein Heme biosynthetic pathway Catalyzes condensation of 4 molecules of PBG to form hydroxymethylbilane Clinical features Acute attacks Onset: Post puberty to 5th decade Abdominal pain Usually 1st sign of attacks Precedes neuropathy Neuropathy 2 Frequency: 10% to 60% of patients Weakness May be severe, cause respiratory failure Proximal > Distal Symmetric or Asymmetric Arms > Legs Sensory Loss: Usually mild, distal, symmetric Pain syndrome: Diffuse, Proximal & Distal; Abdominal Tendon reflexes: Reduced Autonomic: Sympathetic & Parasympathetic involvement Course Precedes motor neuropathy Progressive Parasympathetic > Sympathetic Circulatory Tachycardia Blood pressure: High Vasospasm Urinary retention GI Constipation or Diarrhea Nausea & Vomiting Abdominal pain Temperature dysregulation Cranial nerve: Facial; Dysphagia CNS Mental status changes: Psychosis; depression; Dementia Seizures Course Duration: Days to Weeks Usually complete recovery Recurrence not uncommon Other: No photosensitivity Treatment Glucose, IV Givosiran Liver transplant Hematin: Suppresses symptoms of acute attack by 3 or 4 days Chlorpromazine: Abdominal pain & Psychotic disorders Meperidine: Pain Phenytoin: Probably least toxic anticonvulsant Unsafe drugs: Numerous Laboratory features Reduced porphobilinogen deaminase in erythrocytes EXCEPTION: Some mutations affect only non-erythroid tissues Urine: High PBG & ALA Normal fecal coproporphyrin & protoporphyrin between attacks Neuropathy CSF Often normal Occasional: Mild increase in protein or cells Nerve conduction studies CMAPs: Small No evidence of demyelination Sensory: Normal or small SNAPs EMG: Denervation; Some myopathic potentials Pathology Neuropathy: Predominantly axonal CNS: Patchy demyelination Tests Aminolevulinic acid: 24 hour urine Aminolevulinic acid dehydratase : Erythrocyte External link Porphobilinogen deaminase : Erythrocyte Urinary porphobilinogen: High in 88% between attacks HMBS variant: Leukoencephalopathy, Childhood onset (Spastic-Ataxia) 3 Epidemiology: 6 patients with survival to adulthood Genetics Mutations: Missense; Ala84Asp, Arg167Gln, Arg225Gln Inheritance: Recessive Clinical Onset ages: 4 to 22 years Spastic paraparesis: Legs > Arms Polyneuropathy: Sensory loss, Distal Ataxia Cognitive impairment: None or Mild Cataracts: Some patients Porphyric attacks: 1 patient Course: Slow progression Treatment: ? Regular carbohydrate-containing meals Laboratory NCV: SNAPs & CMAPs small amplitude Brain MRI Signal: Periventricular; White matter, deep & Thalami Cerebral & Cerebellar atrophy Urine: PBG & Porphyrin High History: King George III of England probably had porphyria

From: F Ford Distal Atrophy & Weakness: Child

Coproporphyria

• Clinical features
  • Attacks
  • Neuropathy
  • Skin photosensitivity
• Laboratory features
  • Reduced coproporphyinogen oxidase in erythrocytes
  • Elevated fecal coproporphyrin ± protoporphyrin between attacks
    

Variegate Porphyria

• PPOX location: Mitochondrial intermembrane space
• Clinical features
  • Acute attacks & Neuropathy
    • Features similar to Acute Intermittent porphyria
  • Skin photosensitivity
  • Frequent in South Africa due to a founder effect
• Laboratory features
  • Elevated fecal coproporphyrin & protoporphyrin between attacks
    

Porphyria, Acute hepatic

• Clinical features
  • Most cases with acute infantile hepatic disorder
  • Peripheral neuropathy not well described
  • Hemolysis: Some patients
• Laboratory features
  • Elevated fecal coproporphyrin & protoporphyrin between attacks
  • Normal porphobilinogen (elevated in other 3 neurologic types)
• Heterozygotes: Susceptible to lead intoxication