Porphyria

• Group of inherited disorders caused by heme synthesis

• 3 forms of porphyria that are associated with peripheral neuropathy as wells as CNS abnormalities:

  • AIP

  • HCP

  • VP

• Other forms of porphyria including X-linded sideroblastic anemia, ALAD-deficient porphyria, congenital erythropoietic porphyria, erythropoietic porphyria, except porphyria cutanea tarda have the potential to result in a neuropathy.

Porphyria are a group of metabolic disorders arising from a defect in the heme biosynthetic pathway.  Clnical presentation is diverse and neuropathies, and an acute intermittent porphyria (AIP).   AIP is an autosomal dominant disease due to deficiency of hydroxmethylbilane synthase (encoded by HMBS gene).  Most, if not at all, peripheral neuropathy is described have concomitant involvement of the large nerve fibers, suggesting that he does not appear SFN.  However, autonomic neuropathy was responsible for variety of symptoms during the acute attack and the majority of patients with AIP.  Manifest with autonomic dysfunction without large fiber peripheral neuropathy or focal CNS impairment.

Clinical features:  The acute neurological features are similar, however, a photosensitive rash is seen with HCP and VP but not seen in AIP.  Attacks of porphyria can be triggered by certain drugs (usually those metabolized by the P450 system), hormonal changes (pregnancy, and luteal phase of the menstrual cycle), and dietary restrictions. 

An acute attack of porphyria is often heralded by acute abdominal pain.  Later patients may develop agitation, hallucinations, or seizures.  Several day later, back and leg pain followed by weakness can occur and may mimic GBS.  Motor involvement is usually asymmetric, proximal, or distal and affects arms or leg preferentially.  CN are also affected, leading to facial weakness and dysphagia. Sensory impairment may be difficult to determine if the patient is encephalopathic.  Muscle stretch reflexes are often reduced.  Autonomic dysfunction manifested by signs of sympathetic overactivity (pupillary dilatation, tachycardia, and HTN) is common.  Constipation, urinary retention, and incontinence can also be seen.  Recovery is usually good, provided treatment is instituted rapidly to prevent excessive amounts of axonal damage. 

Laboratory features: 

• CSF protein is normal or mildly elevated.

• LFTs and hematology are usually normal.

• Some patients are hyponatremic (SIADH).

• Urine may appear brownish in color secondary to high concentrations of porphyrin metabolites.

• Urine and stool are checked for accumulating intermediary precursor of heme:

  • delta-aminulevulinic acid - ALAD deficient porphyria

  • prophobilinogen - AIP

  • uroporphobilinogen

  • coproporphyrinogen - HCP

  • protoporphyrinogen - VP

• The specific lowered enzyme activities can be also measure in erythrocytes and leukocytes.

• EDX:

  • Sensory NCS usually demonstrate normal NCV and DL but amplitudes may be slightly reduced though not to the same degree as CMAPs are reduced.

  • Motor NCV are mildly reduced or normal and DL are normal or slightly prolonged. 

  • The primary abnormality on NCS is the marked reduction of CMAP amplitudes.

  • nEMG demonstrates primarily a reduced recruitment, fibrillation potentials, and positive sharp waves. 

• Histopathology:

  • Axonal degeneration in apparent nerve biopsies. 

• Molecular Genetics and Pathogenesis:

  • Porphyrias are AD.

  • AIP is associated with porphobilinogen deaminase deficiency

  • HCP is caused by defects in coproporphyrin oxidase

  • VP is associated with protoporphyrinogen oxidase

  • AIP the most common acute hepatic porphyrias.  It is caused by a mutation in hydroxymethylbilane synthase, the second step in the pathway that produces heme.  Lack of heme induces upregulation of the first enzyme of the first enzyme in the pathway, ALS synthase 1 (ALAS1), in an attempt to ramp up heme production.  The futile overactivity of ALSA1 leads to a buildup of two upstream intermediates including delta-aminolevulinic acid (ALA), which is believed to be the most important neurotoxic species.  Clinical symptoms of AIP include a motor-predominant neuropathy, arrhythmia, and intense abdominal pain, likely from bowel stasis.  The inability to detoxify various drugs in the liver may have secondary toxic effects on the nervous system.  

• Treatment:

  • IV glucose started at a rate of 10-20 g/h.  If there is no improvement in 24 hours, then IV hematin at 2-5 mg/kg/d for 3-14 days should be given.

  • Hematin dose can be infused over a 30-60 minute period.

  • Avoid drugs that can precipitate the acute porphyric attack.

    • Avoid barbiturates

  • Givosiran interfering RNA binds to the messenger RNA of ALAS1, triggering its degradation by the cellular defense machinery, reducing enzyme production and thus ALA build-up.