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Diagnosis and management of porphyria

BMJ 2000; 320 doi: (Published 17 June 2000) Cite this as: BMJ 2000;320:1647

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Neuropsychiatric disorders in porphria and methylmalonic acidosis

Patients with prophyria and methylmalonic acidosis, be it secondary
to an enzyme defect or an impairment in adenosylcorbalamin synthesis, a
cobalt deficiency, or a B12 deficiency, may suffer from a wide range of
neuropsychiatric disorders including depression, self mutilation and
suicide. The common metabolic denominator appears to be an energy deficit
caused by disorders in the metabolism of succinyl CoA.

Succinyl CoA is one of the intermediate metabolic products in the
Krebs cycle being synthesised from alpha ketoglutarate and metabolised
into malate and thence oxalacetate. Succinyl Co A is also the substrate
for porphyrin and haem synthesis which competes with the Krebs cycle for
succinyl CoA. Succinyl Co A accumulates in tissues that are deprived of
their blood supply because metabolism within the Krebs cycle is
inhibited. Resynthesis of ATP by oxidative phosphorylation is, therefore,
also impaired creating an energy deficit. Succinyl CoA may also
accumulate in porhyrria because of the interruption in that metabolic
pathway. An accumulation of succinyl CoA in porphyria may, in accordance
with the law of mass action, inhibit the synthesis of succinyl CoA from
alpha ketoglutarate and thus also inhibit ATP resyntheis by oxidative
phosphorylation and create an energy defict. An accumulation of succinyl
CoA should also inhibit synthesis of succinyl CoA from methylmalonyl CoA
which is catalysed by the apoenzyme methylmalonyl CoA mutase. The co-
enzyme that converts this inactive apoenzyme into an active holoenzyme is
adenosylcobalamin. Adenosylcobalamin is synthesised from the
uroporphyrogen III generated in porhyrrin metabolism. Acting as a coenzyme
for this reaction is one of the two known actions of cobalamin (B12) in
humans, the other being a co-enzyme for the apoenzyme methionine synthase
which catalyses the conversion of homocysteine into methionine.

Methylmalonyl CoA is synthesised from methionine and other amino
acids, that being synthesised from methionine being though the
intermediate product homocysteine. Methylmalonyl CoA is also synthesised
by beta oxidation from odd chain fatty acids, an important source of
metabolic fuel in stress during which catecholamines and especially
cortisol mobilise fatty acids. The commonest forms of stress capable of
increasing the availability of methylmalonyl CoA are severe exercise,
anaerobiosis, and the release of cytokines (1,2). Methylmalonyl-CoA
mutase is also expressed in ischaemia presumably as part of a feed back
response to the accompanying impairment of succinyl CoA utilisation in the
Krebs cycle in ischaemia (3). In which case the Krebs cycle would be
primed to metabolise the accumulating methylmalonyl CoA substrate nupon
the resumption of oxidative phosphorylation.

The synthesis of succinyl CoA from methylmalonyl CoA is impaired when
the activity of the apoenzyme methylmalonyl CoA mutase is impaired
because of a gene mutation or because of a deficiency in its obligatory co
-enzyme adenosylcobalamin. The impairment cause by a deficiency in
adenosylcobalamin is most commonly caused by an inadequacy of B12 intake,
an impairment of B12 absorption because of the failure of gastric mucosa
to secrete intrinsic factor, and because of a failure to be resynthesised
from uroprophyrogen III. The latter must also occur in porphyria for the
synthesis of uroporphyrogen II is blocked.

It has been postulated that the neuropsychiatric disorders seen in
methylmalonic acidosis in humans may be due to a toxic effect of
methylmalonic acid per se. This hypothesis is based upon the finding that
a dose-related cell death was produced by injecting methylmalonic acid
into the basal ganglia of adult rat brain (3). This hypothesis does not
appear to be applicable in man for methylmalonic acidosis is benign when
accompanied by a renal tubular acidosis which compensates for the
metabolic acidosis present (4). In other words the problem appears to lie
in the acidosis rather than the accumulation of methylmalonyl CoA. Given
the importance of succinyl CoA in the efficient running of the Krebs cycle
and resynthesis of ATP by oxidative phosphorylation the most likely cause
of this acidosis is unreversed ATP hydrolysis (5,6). The appearance of
the neuropsychiatric disorders appear, therefore, to be due to the many
consequences of a cerebral energy deficit as previously proposed

As neuropsychiatric disorders do not occur with a folic acid
deficiency and an impairment of ATP resynthesis does not appear to be
caused by a folic acid deficiency it would seem that the neuropsychiatric
disorders associated with megaloblastic anaemia may be due to an energy
deficit as previously proposed (7-10). The anemia is caused by a folate
deficiency which in the case of patients with a B12 deficiency is
functional due to the “folate trap”(11). . How then might neuropsychiatric
disorders arise in patients with dysfunction of methionine synthase or the
mutant MTHFR gene? By impairing the salvage of adenine nucleotides in
anaerobiosis? In which cases the neuropsychiatric disturbances in these
disorders would be confined to those patients who for other reasons, such
as cytokine release or mitochondrial toxins, have an impairment of
mitochondrial oxidative phosphorylation. It is also possible, as
previously suggested, that gene mutations might also be the product an
impairment of mitochondrial oxidative phosphorylation for mutant
mitochondrial DNA increases with ageing (12).

The proposal that neuropsychiatric disorders and other organ
dysfunctions are all the product of an energy deficit holds in all the
circumstances in which I have considered it including prophyria,
methylmalonic acidosis, B12 deficiency, cobalt deficiency, schizophrenia,
hypothyroidism and hypothermia (13).

For those whose biochemistry is as rusty as mine enzymes a proteins which
catalyse biochemical reactions increasing their rate in the order of a
million times. Enzymes which need co-factors to work are called
apoenzymes and when combined with their cofactor are called holenzymes.

Most enzymes follow Michaelis-Menten kinetics. The rate of the
biochemical reaction depends upon the kinetic constant for the enzyme and
the concentration of both substrate and enzyme present the rate increasing
to plateau as the concentration of either substrate or enzyme are
increased. The rate at which holoenzymes are formed also increases to a
plateau as the concentration of apoenzyme and co-factor are increased.
The rate at which a catalysed biochemical reaction proceeds also depends,
in accordance with the law of mass action, upon not only upon the
concentration of the reactants but also upon the concentration of the
products. Thus the rate at which the holoenzyme-substrate forms succinyl
CoA, for example, increases as the concentration of succinyl CoA formed
decreases and decrease to a halt as it increases.

My accounting of the biochemical adaptations that change mitochondrial
permeability was not completely accurate, specifically in regards to the
effects of omega-3-fatty acids (13). For a more accurate accounting of
the adaptations see the source (14).

1. Coppack SW. Pro-inflammatory cytokines and adipose tissue.
Proc Nutr Soc. 2001 Aug;60(3):349-56. Review.

2. Bishop NC, Gleeson M, Nicholas CW, Ali A. Influence of carbohydrate
supplementation on plasma cytokine and neutrophil degranulation responses
to high intensity intermittent exercise.
Int J Sport Nutr Exerc Metab. 2002 Jun;12(2):145-56.

3. Narasimhan P, Sklar R, Murrell M, Swanson RA, Sharp FR. Methylmalonyl-
CoA mutase induction by cerebral ischemia and neurotoxicity of the
mitochondrial toxin methylmalonic acid.
J Neurosci. 1996 Nov 15;16(22):7336-46

4. Dudley J, Allen J, Tizard J, McGraw M. Benign methylmalonic acidemia in
a sibship with distal renal tubular acidosis.
Pediatr Nephrol. 1998 Sep;12(7):564-6.

5. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid-
base balance.
Br J Anaesth. 1995 May;74(5):591-606. Review.

6. Fiddian-Green RG. Monitoring of tissue pH: the critical measurement.
Chest. 1999 Dec;116(6):1839-41.

7. Delirium: a cerebral energy deficit?
Richard G Fiddian-Green, 23 Sep 2002

8. Psychiatric aspects: an energy deficit?
Richard G Fiddian-Green, 3 Oct 2002

9. Dual Effect of energy deficit on hippocampal neurogenesis
Richard G Fiddian-Green, 28 Oct 2002

10. Re: Preventing closed minds Richard G Fiddian-Green, 2 Dec 2002

11. Fiddian-Green RG. Rapid responses to: Homocysteine and cardiovascular
disease: evidence on causality from a meta-analysis David S Wald, Malcolm
Law, and Joan K Morris BMJ 2002; 325: 1202-1206

12. Iatrogenic diseases with a common cause? Richard G Fiddian-Green, 25 Oct 2002

13. Madness, hyperhomocysteinemia, metabolic rate and body temperature
Richard G Fiddian-Green, 6 Jan

14. Hochachka PA, Somero GW. Biochemical adaptation. Oxford University
Press, New York, NY, 2002.

Competing interests:  
None declared

Competing interests: No competing interests

19 January 2003
Richard G Fiddian-Green