Download Purple pigments: The pathophysiology of acute porphyric neuropathy

Clinical Neurophysiology 122 (2011) 2336–2344
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Clinical Neurophysiology
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Purple pigments: The pathophysiology of acute porphyric neuropathy
Cindy S.-Y. Lin a,⇑, Ming-Jen Lee b, Susanna B. Park c, Matthew C. Kiernan c
a
School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia
Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
c
Neuroscience Research Australia and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia
b
a r t i c l e
i n f o
Article history:
Accepted 8 July 2011
Available online 19 August 2011
Keywords:
Acute intermittent porphyria
Peripheral neuropathy
Haem
Porphyric neuropathy
h i g h l i g h t s
Acute intermittent porphyria (AIP) is the most common porphyria associated with neuropathy.
AIP neuropathy occurs due to mutation in the hydroxymethylbilane synthase gene (HMBS), although
90% of carriers of such mutations may remain asymptomatic.
The development of porphyric neuropathy appears related to energy failure due to lack of haem,
combined with direct neurotoxicity of porphyrin precursors, potentially leading to dysfunction of the
axonal membrane Na+/K+ ATPase.
a b s t r a c t
The porphyrias are inherited metabolic disorders arising from disturbance in the haem biosynthesis pathway. The neuropathy associated with acute intermittent porphyria (AIP) occurs due to mutation involving the enzyme porphobilinogen deaminase (PBGD) and is characterised by motor-predominant features.
Definitive diagnosis often encompasses a combination of biochemical, enzyme analysis and genetic testing, with clinical neurophysiological findings of a predominantly motor axonal neuropathy. Symptomatic
and supportive treatment are the mainstays during an acute attack. If administered early, intravenous
haemin may prevent progression of neuropathy. While the pathophysiology of AIP neuropathy remains
unclear, axonal dysfunction appears intrinsically linked to the effects of neural energy deficits acquired
through haem deficiency coupled to the neurotoxic effects of porphyrin precursors. The present review
will provide an overview of AIP neuropathy, including discussion of recent advances in understanding
developed through neurophysiological approaches that have further delineated the pathophysiology of
axonal degeneration.
Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights
reserved.
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.
Porphyric neuropathy and the haem biosynthetic pathway. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.
Historical background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical features of porphyric neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Genetics of AIP neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Precipitating triggers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical diagnosis of porphyric neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abbreviations: AIP, acute intermittent porphyria; ALA, d-aminolevulinic acid;
ALAS1, d-aminolevulinate synthase 1; CMAP, compound motor action potential;
GBS, Guillain–Barré syndrome; HMBS, hydroxymethylbilane synthase; PBG, porphobilinogen; PBGD, porphobilinogen deaminase; rAAV, recombinant adeno-associated virus vector.
⇑ Corresponding author. Address: School of Medical Sciences, University of New
South Wales, High Street, Randwick, Sydney, NSW 2052, Australia. Tel.: +61 2 9382
2413; fax: +61 2 9382 2437.
E-mail address: [email protected] (C.S.-Y. Lin).
1388-2457/$36.00 Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2011.07.036
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4.
5.
6.
C.S.-Y. Lin et al. / Clinical Neurophysiology 122 (2011) 2336–2344
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3.1.
Electrodiagnostic testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Specialised testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Mechanisms of neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Pathophysiology of AIP neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Treatment and management of AIP neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
Acute intermittent porphyria (AIP) is the most common of the
acute porphyrias, a group of metabolic disorders characterised by
dysfunction of the haem biosynthetic pathway. Porphyrins are
the main precursors of haem, critically important for respiration,
energy transfer and enzymatic catalysis, representing a major component of haemoglobin, catalases, peroxidases, cytochrome P-450
and other molecules. Neuropathy is a key feature of the porphyrias,
typically presenting as an acute, predominantly motor neuropathy
of the axonal type. The present review will address the clinical features of AIP neuropathy, including clinical assessment and medical
management, with a focus on the mechanisms that underlie the
development of axonal dysfunction in AIP patients.
1.1. Porphyric neuropathy and the haem biosynthetic pathway
Porphyric neuropathy arises due to deficiency in haem biosynthetic pathway enzymes (Fig. 1; Thunell, 2000; Foran and Ábel,
2003). Deficiency in the third enzyme in the pathway, porphobilinogen deaminase (PBGD), produces AIP. If the pathway is operating
normally, haem production is initiated through conversion of glycine and succinate coenzyme A to d-aminolevulinic acid (ALA), followed by dimerization into porphobilinogen (PBG; Thunell, 2000;
Foran and Ábel, 2003). However, in AIP patients, PBGD deficiency
induces acute episodes delineated by overproduction and accumulation of the porphyrin precursors ALA and PBG.
The classification of the porphyrias is based on historical and
clinical factors. Originally, porphyria was divided into congenital,
acute idiopathic, acute toxic and chronic forms (Günther, 1911).
Subsequently, the divisions were revised to acute, cutaneous, hepatic and erythropoietic to better reflect the clinical and biochemical features (Watson et al., 1951; With, 1980). The classification
into ‘acute’ versus ‘cutaneous’ was determined on the basis of
the major clinical manifestations of the porphyrias, as either acute
neurovisceral episodes or cutaneous manifestations (Anderson
et al., 2005). However, the use of the term ‘acute’ may be somewhat misleading, as the symptoms of the acute porphyrias are often chronic and long-lasting (Anderson et al., 2005).
Fig. 1. Mechanisms of porphyric neuropathy and the haem biosynthetic pathway. Haem biosynthetic pathway demonstrating the eight enzymes involved in haem
production, with the associated forms of porphyria indicated. The third enzyme porphobilinogen deaminase (PBGD), which is associated with AIP, is highlighted. Inset: the
two major hypothesised mechanisms of porphyric neuropathy are depicted as follows: (1) reduction in the available haem leading to diminished energy capacity which may
produce dysfunction of the energy dependent Na+/K+ ATPase and (2) direct neurotoxicity of accumulated porphyrin precursors including ALA and PBG.
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Present understanding suggests that there are four acute hepatic porphyrias with nervous system involvement – AIP, variegate
porphyria, hereditary coproporphyria and ALAD-deficiency porphyria (Stewart and Hensley, 1981; Mercelis et al., 1990; Barohn
et al., 1994; Kauppinen, 2005). As AIP remains the most common
and typically most severe of all the acute hepatic porphyrias
(Anderson et al., 2001; Badminton and Elder, 2002), AIP-related
neuropathy will form the focus of the present review.
1.2. Historical background
The term porphyria originally derives from the ancient Greek
word porphura (purple pigment), first utilised by the German
chemist Hoppe-Seyler in 1871 in the context of porphyrin molecules (Hoppe-Seyler, 1871; Watson, 1966). Hoppe-Seyler used
the term ‘hematoporphyrin’ (blood-purple) to describe the purple-red pigment isolated from hematin (Watson, 1966; Reuben,
2006) which was later identified in the urine of patients suffering
from a peculiar spectrum of neurovisceral symptoms subsequently
established to be porphyric neuropathy (Baumstark, 1874).
While AIP was only formally described in 1937, AIP has been
retrospectively implicated as a diagnosis for several notable historical figures, including members of the British Royal Family. King
George III (1738–1820) suffered from a debilitating episodic illness
with at least five acute exacerbations of abdominal pain, discoloured urine, walking difficulties and psychiatric disturbance. Based
on this spectrum of symptoms, Macalpine and Hunter (1966) proposed that King George suffered from AIP, although this was later
revised to variegate porphyria (Macalpine et al., 1968). The family
history of the houses of Stuart, Hanover and Prussia were traced,
with evidence suggesting that Mary, Queens of Scots may have suffered from porphyria which persisted in the Royal Family for 13
generations across 400 years (Macalpine et al., 1968). In addition,
it has been proposed that Vincent van Gogh suffered from AIP, with
six major episodes of psychiatric disturbance, gastrointestinal distress and potentially weakness, which may have been precipitated
by his lifestyle of extensive absinthe use, poor nutrition and the
use of camphor as a treatment for insomnia (Arnold, 2004).
2. Clinical features of porphyric neuropathy
Acute porphyrias are characterised by abrupt, episodic neurovisceral attacks involving severe abdominal pain, peripheral neuropathy and psychiatric disturbance (Table 1; Elder et al., 1997;
Anderson et al., 2005; Herrick and McColl, 2005). Abdominal pain,
the most frequent symptom in patients with AIP, is typically diffuse, and is often accompanied by other gastrointestinal symptoms
including nausea, vomiting, abdominal distension and constipation
(Anderson et al., 2005). These symptoms, combined with tachycardia, cardiac arrhythmia, and systemic arterial hypertension, are
thought to be mediated via autonomic dysfunction (Ridley, 1969;
Laiwah et al., 1985; Stewart, 2003; Albers and Fink, 2004).
In addition to autonomic dysfunction, central nervous system
involvement may be a major feature of the acute porphyric attack.
Psychiatric manifestations include anxiety, insomnia, depression,
confusion, agitation and hallucinations (Crimlisk, 1997; Thunell,
2010). In contrast, psychosis is relatively uncommon as a presenting symptom, but may develop as a prominent symptom during
the attack (Hift and Meissner, 2005; Thunell, 2010).
In addition to psychiatric symptoms, encephalopathy and seizures may also develop in patients with acute porphyria. Encephalopathy, resulting in altered consciousness, somnolence or coma
may present, with abnormalities on magnetic resonance imaging
demonstrating cortical lesions similar to those described in poster-
Table 1
Neurological manifestations of acute intermittent porphyria.
Symptoms of AIP
Relative prevalence in AIP patients
Central nervous system manifestations
Seizures/convulsions
Psychosis
Depression
Anxiety
Coma
Low to moderate (5–30%)
Moderate (10–58%)
Low (13%)
Moderate (26%)
Low (2–10%)
Autonomic neuropathy
Abdominal pain
Tachycardia
Hypertension
Constipation
Nausea/vomiting
Very high (85–100%)
High (30–85%)
High (36–74%)
High (28–84%)
High (43–88%)
Peripheral neuropathy
Weakness/paresis
Sensory changes
Pain (other areas)
Respiratory paresis
High (20–68%)
Moderate (7–38%)
High (20–70%)
Moderate (9–20%)
Other features
Discoloured urine
Hyponatraemia
High (70–90%)
Moderate (25–39%)
References: Bylesjö et al. (1996), Elder et al. (1997), De Siervi et al. (1999), Foran and
Ábel (2004), Anderson et al. (2005), Hift and Meissner (2005), Kauppinen (2005),
Millward et al. (2005), Bylesjö et al. (2009), Ventura et al. (2009).
ior reversible encephalopathy (Utz et al., 2001; Maramattom et al.,
2005; Gürses et al., 2008).
Seizures may occur in up to 5% of patients with AIP, often triggered by an identified cause such as hyponatremia or inappropriate medications (Bylesjö et al., 1996; Hift and Meissner, 2005).
Hyponatremia occurs in up to 30% of patients and may be due to
excessive gastrointestinal loss or inappropriate antidiuretic hormone secretion (Ludwig and Goldberg, 1963; Anderson et al.,
2005).
Porphyric peripheral neuropathy has been classified as a predominantly motor axonal neuropathy (Albers et al., 1978; Albers
and Fink, 2004), beginning with muscle pain and weakness that
may further progress over a 2 week period to tetraplegia or death,
if treatment is not initiated (Ridley, 1969; Puy et al., 2010). Patients
may require ventilation due to paresis of the respiratory and bulbar
muscles (Albers et al., 1978). Typically, abdominal pain precedes
the development of neuropathy by days to weeks (Ridley, 1969).
Motor neuropathy is usually symmetrical and begins proximally
in the upper extremities, and less commonly may be associated
with cranial nerve involvement (Ridley, 1969; Simon and Herkes,
2011). Neuropathy occurs in 20–68% of patients during the course
of an acute attack (Albers et al., 1978; Albers and Fink, 2004),
although the pattern of motor involvement may be quite variable
between patients and even in the same patient between different
attacks (Ridley, 1969).
Sensory neuropathy is less common but may occur, manifested
by neuropathic pain and distal paraesthesiae, especially in the lower limbs or alternatively in a ‘‘bathing suit’’ proximal distribution
(Ridley, 1969; Albers et al., 1978; Elder et al., 1997; Solinas and
Vajda, 2008). During acute attacks, abdominal pain may be associated with transient sensory symptoms including paraesthesia,
hypothesia and pain (Solinas and Vajda, 2008).
2.1. Genetics of AIP neuropathy
AIP neuropathy occurs due to mutations in the hydroxymethylbilane synthase gene (HMBS), which produces a partial
deficiency of the third enzyme in the haem pathway, porphobilinogen deaminase (PBGD). However, only a percentage of HMBS gene
mutation carriers will become symptomatic, as penetrance is
C.S.-Y. Lin et al. / Clinical Neurophysiology 122 (2011) 2336–2344
incomplete (Andersson et al., 2000). Inheritance is typically autosomal dominant and the prevalence of HMBS gene mutations
may be as high as 1 per 500 (Mustajoki et al., 1992a), however
the prevalence of manifest AIP is only 1–2 per 100,000 (Badminton
and Elder, 2002).
The HMBS gene (Genbank Accession Number: M95623) is located at chromosome 11q23.3 (Meisler et al., 1980; Wang et al.,
1981; Grandchamp et al., 1987; Chretien et al., 1988). The first
mutation in the HMBS gene associated with AIP was reported in
1989 (Grandchamp et al., 1989) and to date, over 300 different
mutations have been identified (Hrdinka et al., 2006). Missense
mutations are the most common (Whatley et al., 2009), and the
majority of mutations introduce a premature stop codon, rendering
a loss of function in PBGD enzyme activity (Mgone et al., 1993; Lee
et al., 1995; Puy et al., 1997; Yang et al., 2008).
While many of the 300 mutations in HMBS identified to date
have been unique, there are a number of clusters worldwide related to a ‘founder’ effect. In Sweden, the most common mutation
is W198X, a base substitution which results in a premature stop
codon which occurs in 50% of all patients with AIP in Sweden
(Floderus et al., 2002). This mutation is associated with increased
penetrance, increased severity of acute neurovisceral crises and
lasting disability (Andersson et al., 2000). However, other mutations (R167W and R225G) demonstrate reduced penetrance, lower
recurrence rate and milder acute attacks, associated with lower
excretion of porphyrin precursors suggesting that the mutations
produce greater residual PBGD enzyme activity (von und zu Fraunberg et al., 2005).
2.2. Precipitating triggers
As up to 90% of AIP heterozygotes remain asymptomatic
throughout life, the role of environmental triggers in producing
acute porphyric neuropathy are very important. Porphyric neuropathy may be precipitated by many environmental triggers
including medications, illness, starvation, vomiting, stress and hormonal fluctuations (Ridley, 1969; Kauppinen and Mustajoki, 1992;
Hift and Meissner, 2005). Any factor which increases the requirements for hepatic haem synthesis and induces ALAS1 activity
may produce an attack in susceptible individuals (Fig. 2). When
ALAS1 activity increases, the deficient PBGD enzyme becomes the
rate limiting enzyme of the pathway and leads to accumulation
of porphyrin precursors and induction of an acute neurovisceral
attack.
Drug metabolism requires the cytochrome P-450 pathway and
thus depletes the available haem pool, leading to ALAS1 induction.
The association between porphyric neuropathy and medications
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has long been identified (Waldenstrom, 1937; Rimington, 1963).
The development and widespread usage of barbiturates starting
from the early 1900s produced an increase in the number of severe
porphyric attacks with a high mortality rate (Waldenstrom, 1937;
Goldberg, 1959; Ridley, 1969; Thunell et al., 2000). Fortunately,
recognition of the role of drugs in precipitating an acute attack
has assisted in reducing the number and severity of attacks in more
recent times. There is an extensive list of medications and drugs
which are contraindicated in patients with AIP, which includes barbiturates, progesterone, sulphonamide antibiotics and many antiepileptic drugs (Thunell et al., 2007; American Porphyria
Foundation, 2010).
3. Clinical diagnosis of porphyric neuropathy
It is critical to reach a diagnosis of acute porphyric neuropathy
expeditiously, as delayed treatment may result in permanent neurological deficit or death. Since variable clinical manifestations and
misdiagnoses are common, the diagnosis should remain a consideration across complex neuropsychiatric, cardiovascular, toxic
and gastroenterological presentations (Table 1). To compound
these diagnostic difficulties, no single sign or symptom is universal
for the AIP presentation and there remain up to 10% of patients
who may not display any of the most common features (Anderson
et al., 2005).
3.1. Electrodiagnostic testing
Nerve conduction findings in porphyric neuropathy typically
demonstrate reductions in compound motor action potential
(CMAP) amplitude with relative preservation of conduction velocities (Maytham and Eales, 1971; Flügel and Druschky, 1977; Albers
et al., 1978; Defanti et al., 1985). Sensory nerve conduction abnormalities have been identified in some patients with AIP neuropathy, although to a lesser extent than motor axons (Flügel and
Druschky, 1977; Albers et al., 1978). Electromyography may establish evidence of widespread fibrillation potentials consistent with
denervation, particularly in proximal muscles (Flügel and Druschky, 1977; Albers et al., 1978; Albers and Fink, 2004). Sequential
assessment during acute episodes may demonstrate progressive
reductions in CMAP amplitude, associated with worsening of paresis (Albers et al., 1978). Electromyography may demonstrate polyphasic motor unit potentials with increased amplitude and
duration, indicating the presence of chronic denervation and reinnervation (Albers et al., 1978).
The combination of CMAP reduction with preserved conduction
velocities and features of denervation suggest that porphyria is pri-
Fig. 2. Development of an acute porphyric neurovisceral attack. The initial enzyme in the haem biosynthesis pathway, ALAS1, is controlled by a negative feedback mechanism
by the level of available haem. When the level of available haem is reduced, ALAS1 activity is induced leading to accumulation of porphyrin precursors. Different
environmental triggers are depicted involved in the development of an acute porphyric attack.
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marily an axonal neuropathy, with greater dysfunction in motor
nerves, as opposed to a myopathy (Maytham and Eales, 1971; Flügel and Druschky, 1977; Albers et al., 1978; Defanti et al., 1985; Lin
et al., 2008). In support, studies of muscle tissue in patients with
AIP have identified neurogenic changes, including a severe loss of
nerve fibres, with limited evidence of muscle change (Cavanagh
and Mellick, 1965; Yamada et al., 1984). In addition, pathological
studies have revealed degeneration primarily affecting nerves,
both motor and sensory (Cavanagh and Mellick, 1965; Yamada
et al., 1984). However, it is accepted that these electrophysiological
findings remain non-specific and that accurate diagnosis of porphyric neuropathy can only be made in conjunction with biochemical, enzymatic and genetic assays.
With early and appropriate treatment, the neurophysiological
features of neuropathy may resolve, with evidence of increased
CMAP amplitudes and reduction in fibrillation potentials (Kuo
et al., 2007). However, neuropathy may be persistent and patients
may only demonstrate partial improvement following a severe
acute attack (Flügel and Druschky, 1977). Subtle nerve conduction
abnormalities may be identified in patients with AIP, without clinical manifestations, particularly slowed conduction velocity of ulnar and median nerves (Mustajoki and Seppălăinen, 1975;
Kochar et al., 2000), potentially reflecting subclinical neuropathy
in patients between acute attacks.
Onset and progression of porphyric neuropathy may appear
similar to Guillain–Barré syndrome (GBS), leading to overlap in
diagnosis (Table 2; Elder et al., 1997; Albers and Fink, 2004). The
characteristic electrodiagnostic findings in early demyelinating
GBS include absent H reflexes, abnormal CSAP amplitudes and absent or prolonged F waves (Gordon and Wilbourn, 2001). Subsequent signs include marked slowing of nerve conduction and
conduction block, characteristic of a demyelinating neuropathy
(Dhand, 2006). In contrast, ankle reflexes may be preserved in
AIP despite loss of other deep tendon reflexes, which may assist
in differentiating porphyric neuropathy from demyelinating GBS
(Flügel and Druschky, 1977).
Similarly, from a clinical neurophysiological perspective H-reflexes may be preserved in early electrodiagnostic studies, without
prolongation of F-waves. Such findings would be considered generally atypical for demyelinating GBS (Kochar et al., 2000; Gordon
and Wilbourn, 2001; Lin et al., 2008), although normal nerve conduction studies may occur in up to 13% of patients with early GBS
(Hadden et al., 1998; Hughes and Cornblath, 2005). However, the
axonal variant of GBS may also involve preservation of reflexes
and similar electrodiagnostic features to AIP neuropathy (Hadden
and Hughes, 2003). Serial electrodiagnostic studies and biochemical analyses may be required to definitively distinguish axonal GBS
from AIP neuropathy (Hiraga et al., 2005; Kokubun et al., 2010).
3.2. Specialised testing
Prompt diagnosis of AIP neuropathy may be achieved through a
combination of biochemical, enzymatic and genetic assays, in addition to electrodiagnostic studies (Table 3; Hift and Meissner, 2005).
Table 2
Typical electrodiagnostic findings in motor studies in porphyric neuropathy compared to demyelinating Guillain–Barré syndrome.
Porphyric neuropathy
Guillain–Barré syndrome
Reduced amplitudes
Preservation of H reflexes
Relative preservation of F waves
Minor conduction slowing
Preserved distal latency
No conduction block
Reduced amplitudes
Delayed/absent H reflex
Delayed/absent F waves
Significant conduction slowing
Prolonged distal latency
Conduction block
Table 3
General clinical and diagnostic features of AIP.
Gene
Gene locus
Inheritance mode
Hydroxymethylbilane synthase (HMBS)
11q23.3
Autosomal dominant (low penetrance)
Enzyme deficiency
Enzyme deficiency level
Porphobilinogen deaminase (PBGD)
50%
Biochemical testing
Urine
Faeces
Plasma
Highly " ALA, PBG and porphyrins
Normal to mildly " porphyrins
Normal to mildly " porphyrins
Notes: Rapid urinary PBG screening remains the first-line diagnostic test for acute
porphyric neuropathy. Second-line biochemical tests such as faecal and plasma
porphyrin levels may help to differentiate types of acute porphyria. Between porphyric episodes, PBGD enzyme assays and genetic analysis may also be useful to
identify AIP patients.
Acute porphyric neuropathy is biochemically characterised by
overproduction and tissue accumulation of the porphyrin precursors d-aminolevulinic acid (ALA) and porphobilinogen (PBG). During an acute attack, urine PBG levels may be elevated more than
10 times normal levels (Thunell, 2010) and PBG levels may reach
twice that of ALA (Floderus et al., 2002).
For a suspected acute porphyric attack, initial investigations
should include assessment of urinary PBG, which may exceed
880 lmol/d (normal 018 lmol/d) (Table 3; Thunell et al., 2000;
Anderson et al., 2005; Aarsand et al., 2006; Puy et al., 2010). Rapid
urinary PBG screening remains the first-line diagnostic test for
acute porphyric neuropathy, so that treatment can be promptly
commenced in an acute crisis. Urinary ALA levels are also often increased during an acute attack of AIP (Puy et al., 2010). Elevation of
ALA in the absence of changes in PBG levels may assist in diagnosing the extremely rare ALAD-deficiency porphyria (Doss et al.,
1986) or lead neuropathy (Bergdahl et al., 1997) in conjunction
with further confirmatory testing.
Further biochemical analyses can be completed as second-line
tests to differentiate between different types of acute porphyria,
including assessment of faecal and plasma porphyrin levels
(Anderson et al., 2005). In patients with AIP, faecal porphyrin
levels are typically only slightly elevated, in contrast to hereditary coproporphyria and variegate porphyria (Foran and Ábel,
2003). Similarly, plasma porphyrin levels may be mildly elevated
in patients with AIP neuropathy, but are extremely high and
produce characteristic plasma fluorescence peaks in patients
with variegate porphyria (Anderson et al., 2005; Whatley et al.,
2009).
Between acute attacks, the level of ALA and PBG in AIP patients
may be within the normal reference range. Enzyme activity measurement as well as genetic testing are recommended to help confirm the type of acute porphyria and to enable identification of
asymptomatic genetic carriers. In asymptomatic AIP patients, genetic analysis has a sensitivity of 98% (Kauppinen and von und
zu Fraunberg, 2002; Whatley et al., 2009; Thunell, 2010). Genetic
detection of AIP carriers is essential to enable early counselling,
to assist in avoiding precipitating factors and to prevent acute neurovisceral attacks. Erythrocyte PBGD enzyme assays may also be
useful in identifying dysfunction in patients where a mutation cannot be identified (Whatley et al., 2009). Assessment of erythrocyte
PBGD enzyme activity has established that enzyme activity is most
commonly reduced by 50% in AIP (Meyer et al., 1972; Thunell,
2010). However, while enzymatic testing has high sensitivity
(100%), it is not very specific (<50%), as PBGD activity may be affected by other conditions (Whatley et al., 2009). In addition,
5% of HMBS mutations result in a deficiency of the hepatic enzyme but preservation of PBGD activity in erythrocytes (Mustajoki,
1981; Nordmann and Puy, 2002).
C.S.-Y. Lin et al. / Clinical Neurophysiology 122 (2011) 2336–2344
4. Mechanisms of neurotoxicity
While there are two main hypotheses regarding mechanisms of
neurotoxicity in porphyric neuropathy, consensus is building that
both mechanisms may contribute to the development of nerve
dysfunction (Fig. 1). While pathologically porphyric neuropathy
is characterised by severe motor nerve denervation and chromolysis of anterior horn cells with relative sparing of sensory pathways
(Gibson and Goldberg, 1956; Cavanagh and Mellick, 1965; Sweeney et al., 1970; Egger et al., 2006), the initial development of acute
porphyric neuropathy may be functional rather than structural.
The two major proposed mechanisms of porphyric neuropathy appear related to reduction in available haem producing diminished
energy capacity with dysfunction of the energy dependent Na+/K+
ATPase and secondly, direct neurotoxicity of accumulated porphyrin precursors including ALA and PBG.
Pathological studies have demonstrated evidence of widespread
peripheral nerve axonal degeneration, suggestive of a ‘dying-back’
Wallerian degenerative process (Cavanagh and Mellick, 1965;
Sweeney et al., 1970; Yamada et al., 1984). Findings at autopsy
have demonstrated widespread chromatolysis of anterior horn
cells, most likely subsequent to this peripheral axonal damage
(Gibson and Goldberg, 1956; Hierons, 1957; Cavanagh and Mellick,
1965; Sweeney et al., 1970; Yamada et al., 1984). Muscle biopsy
has revealed primarily neurogenic changes, including a severe loss
of nerve fibres with evidence of muscle denervation atrophy only
prominent in a few muscles (Cavanagh and Mellick, 1965; Yamada
et al., 1984) Although the most severe abnormalities were evident
in motor fibres, sensory fibres were also affected (Cavanagh and
Mellick, 1965; Yamada et al., 1984).
Direct neurotoxicity of porphyrin precursors such as ALA has
been proposed as a mechanism leading to axonal damage. ALA
has been demonstrated to be neurotoxic to cells of the nervous system (Moore, 1990; Helson et al., 1993). In addition, ALA promotes
free radial generation, leading to oxidative stress and DNA damage
(Moore, 1990; Monteiro et al., 1991; Helson et al., 1993; Onuki
et al., 2004). Administration of ALA in animal models produced
DNA damage, mitochondrial damage and oxidative stress (Demasi
et al., 1996; Onuki et al., 2004). ALA levels are significantly increased during porphyric attacks and may also be elevated in several conditions producing porphyric-like neuropathy, particularly
acute lead poisoning and hereditary tyrosinaemia (Egger et al.,
2006).
However, ALA alone is not sufficient to produce an acute porphyric attack. ALA levels during an attack do not closely correlate
with clinical status (Gorchein and Webber, 1987) and administration of ALA to healthy controls does not produce symptoms of porphyria (Dowdle et al., 1968; Mustajoki et al., 1992b), indicating
that other factors are important in the pathogenesis and development of acute porphyric neuropathy.
An alternate hypothesis suggests that energy deficits due to reduced haem availability are important in the development of porphyric neuropathy (Meyer et al., 1998; Sassa, 2006). As haem is an
essential component of the mitochondrial electron transport chain,
deficits in haem production may lead to energy distribution failure,
adversely affecting neural function and axonal transport (Sengupta
et al., 2005; Chernova et al., 2006). Haemoproteins and detoxification enzymes rely on haem for appropriate function. Haem deficits
may affect the ability of mitochondrial systems to successfully protect against oxidative damage, leading to increased production of
reactive oxygen species (Meyer et al., 1998; Ferrer et al., 2010).
Cytochrome P450, a hepatic enzyme involved in detoxification of
drugs, is reliant on haem availability, which may lead to impairment of drug detoxification during porphyric attacks (Anderson
et al., 1976; Thunell et al., 2000; Lavandera et al., 2007).
2341
The recent development of genetic animal models of AIP has
provided further insight into the development of neuropathy
(Lindberg et al., 1996). Utilising gene targeting, a PBGD-deficient
mouse model has been developed which demonstrated several
typical features of AIP neuropathy, including 70% decreased PBGD
enzyme activity, increased ALA and PBG levels and phenobarbitalinduced acute porphyric attacks (Lindberg et al., 1996). PBGD-deficient mice develop progressive motor neuropathy, with prominent
axonal degeneration, reduction in CMAP amplitudes and deficits in
motor function (Lindberg et al., 1996, 1999). The mechanisms
underlying the development of neuropathy in PBGD-deficient mice
have not been completely clarified. While raised ALA or PBG levels
are not necessary to produce neuropathy (Lindberg et al., 1999),
relative haem deficiency affecting haemoprotein synthesis in the
liver and brain has been found to contribute to nervous system
dysfunction in vivo (Meyer et al., 2005).
4.1. Pathophysiology of AIP neuropathy
Evidence for abnormalities in axonal function in porphyric patients between episodes has recently been provided through specialised nerve excitability techniques (Kiernan et al., 2000, 2001;
Burke et al., 2001; Krishnan et al., 2009) that have assessed axonal
ion channel function and membrane potential in patients with AIP,
and in asymptomatic mutation carriers (Lin et al., 2008). While
nerve excitability (and thereby resting membrane potential) was
normal in asymptomatic mutation carriers, AIP patients who had
previously suffered acute porphyric neuropathy demonstrated altered excitability (Fig. 3). Mathematical modelling of these changes
was consistent with a reduction in the hyperpolarisation-activated
cation conductance (IH) by 30% (Lin et al., 2008). These axonal
membrane abnormalities were only evident in AIP patients who
had previously experienced an acute porphyric attack, presumably
as a consequence of metabolic crises. These findings suggested that
reductions in inward rectification may occur in patients with AIP
between acute exacerbations, perhaps reflecting subclinical dysfunction in axonal metabolism. Of critical relevance, previous studies have linked alterations in IH as an early manifestation of
hypoxia and impaired cellular metabolism (Duchen, 1990; Zhang
et al., 2006).
Separately, during an acute episode of porphyric neuropathy,
excitability findings were consistent with axonal membrane depolarisation, which subsequently normalised following treatment
(Lin et al., 2008). Depolarisation of the axonal membrane may be
induced by impairment of axonal Na+/K+ pump function (Kaji and
Sumner, 1989; Kiernan and Bostock, 2000), which is dependent
on energy availability to power ion exchange. The pump is electrogenic and contributes 15 mV to membrane potential (Morita et al.,
1993). Membrane depolarisation and impaired Na+/K+ pump function have been identified in animal models of porphyria (Becker
et al., 1971, 1975; Russell et al., 1983), and develop potentially as
a consequence of exposure to neurotoxic porphyrin precursors,
such as ALA (Becker et al., 1971, 1975) or via derangement of energy supply.
Results from these approaches, in conjunction with the findings
from clinical excitability studies, suggest that energy deficits may
play a central role in the aetiology of acute porphyric neuropathy.
Nervous system cells have high metabolic demands and appropriate
energy availability is required to ensure neuronal function (Sengupta et al., 2005). Haem-containing enzymes and proteins are necessary for mitochondrial electron transport and to protect against
oxidative damage (Meyer et al., 1998). However, it is likely that multiple factors contribute to the development of porphyric neuropathy, especially given the involvement of numerous environmental
triggers in addition to haem deficiency and ALA neurotoxicity.
2342
C.S.-Y. Lin et al. / Clinical Neurophysiology 122 (2011) 2336–2344
Fig. 3. Modulation of axonal excitability in patients with AIP. (A) Differences in axonal excitability recordings (current–threshold relationship) between AIP patients who had
previously experienced acute attacks (blue circles) and normal controls (red circles), demonstrating the difference in inward rectification in the AIP patients. (B) Mathematical
modelling of excitability recordings, with the standard model shown in grey and a model with 27% reduced inwardly rectifying conductance in black, depicting the same
change as AIP patients. Data reproduced from Lin et al. (2008) with permission. (C) Flow diagram of the potential mechanisms underlying the development of nerve
excitability changes in patients with AIP. In patients who had previously experienced acute attacks but did not have clinical evidence of neuropathy, axonal excitability
recordings demonstrated reduced inward rectification (IH), suggestive of a subclinical change in axonal metabolism. However, in separate studies during acute porphyric
neuropathy, recordings suggested axonal depolarisation, possibly due to reduced Na+/K+ pump function. (For interpretation of the references to colour in this figure legend,
the reader is referred to the web version of this article).
5. Treatment and management of AIP neuropathy
6. Conclusion
The general treatment of AIP is focused on the prevention of
acute crises and the supportive management of symptoms during
an acute attack. As soon as an acute porphyric attack is diagnosed,
symptomatic treatment should be instituted (Thunell et al., 2000).
Specific caution must be used to ensure that symptomatic treatments do not exacerbate porphyria and fluid balance must be carefully monitored to avoid the development of hyponatraemia,
which may induce seizures (Anderson et al., 2005; Puy et al., 2010).
Intravenous haemin was introduced in 1971 as an effective disease-specific therapy for acute porphyria (Bonkovsky et al., 1971).
Haemin or haem arginate acts to restore the available haem pool in
the liver and to inhibit ALAS1 activity. Treatment effectively reduces ALA and PBG levels during an acute attack, and prompts clinical recovery from neuropathy (Herrick et al., 1989; Mustajoki and
Nordmann, 1993; Anderson et al., 2005; Hift and Meissner, 2005).
Early administration of haemin or haem arginate treatment may
result in shorter hospitalisation times and improved resolution of
neuropathic symptoms (Mustajoki and Nordmann, 1993; Muthane
et al., 1993; Lin et al., 2008). Treatment may produce dramatic
recovery even in patients with severe tetraparesis (Diot et al.,
2007), although recovery is not always complete (Hift and
Meissner, 2005).
Future directions for treatment of porphyric neuropathy include
utilising adenoviral vectors (Johansson et al., 2004), targeted plasmids (Unzu et al., 2010a) or recombinant adeno-associated virus
vectors (rAAV) with liver-specific enhancers and promoters to
introduce the HMBS gene specifically to hepatocytes (Unzu et al.,
2010b; Yasuda et al., 2010). Importantly, such approaches in
mouse models appear to be neuroprotective, preventing loss of axons and accordingly neurophysiological abnormalities and producing improved neurological function (Unzu et al., 2010b; Yasuda
et al., 2010).
Porphyric neuropathy remains a prominent and disabling consequence of AIP. While improved diagnosis, patient education
and prompt treatment during acute episodes have led to a reduced
occurrence of severe porphyric neuropathy, there still remains a
lack of understanding about the exact mechanism contributing to
the development of nerve dysfunction. While standard neurophysiological assessment reveals a predominantly motor axonal
neuropathy, recent excitability studies have provided novel insights suggesting that axonal dysfunction relates to energy dysfunction, particularly in relation to axonal Na+/K+ pump function
and inward rectification. Importantly, energy deficits related to a
lack of haem availability and direct neurotoxicity of porphyrin precursors may be important in the development of neuropathy. Neuroprotection before these deficits develop may seem the best
strategy for future treatment directions, to further reduce the
severity and prevalence of acute porphyric neuropathy.
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