Behavioural Aspects of Acute
Intermittent Porphyria
A. Luder, and N. Schoenfeld
Technion, Haifa and University of Tel-Aviv; Israel
4 Acute Porphyrias:
ALA dehydratase deficiency
AIP
Variegate
Hereditary coproporphyria
4 Chronic porphyrias:
Porphyria cutanea tarda PCT
Erythropoietic protophorphyria
Congenital erythropoietic
porphyria (Gunther’s)
Pseudoporphyria (porphyrinuria)
CATEGORY
Hepatic
Erythropoietic
TYPE
CLINICAL PRESENTATION
INHERITANCE
ALA dehydratase deficiency
Acute attacks
Autosomal recessive
Acute intermittent porphyria
Acute attacks
Autosomal dominant
Porphyria cutanea tarda
Skin disease
Usually acquired; a minority are
inherited (autosomal dominant)
Hereditary coproporphyria
Skin disease, acute attacks
Autosomal dominant
Variegate porphyria
Skin disease, acute attacks
Autosomal dominant
Congenital erythropoietic
porphyria
Skin disease
Autosomal recessive
Erythropoietic protoporphyria
Skin disease: specific
presentation with immediate
photosensitivity
Autosomal dominant: severe
forms have complex inheritance
Hydroxymethylbilane
Erythropoeitic
The Case of N.H.
• 14 year-old girl was referred for genetic evaluation by
Child Psychiatrist and Child Development Center in
because of severe pervasive developmental disorder
with autistic features, behavioural disturbance, and MR
• Only child of single pregnancy, unrelated healthy
parents of Indian Jewish (Cochin) descent
• Pregnancy after Pergonal therapy for infertility
• Pregnancy delivery and early life normal, BW 2.9 Kg
• Parents healthy, unrelated. Family history negative for
early death, retardation, chronic or psychiatric disease
The Case of N.H.
• Early psychomotor development normal
• Age 3 Otitis media and febrile disease
• Age 4 referred to developmental evaluation for
speech delay
• Seen by 2 geneticists who raised the possibility of
Rett syndrome
• “Metabolic work-up” at a major hospital – negative
• Treated with Favoxil (Fluvoxamine maleate; 5-HT
reuptake inhibitor; UWECO) Mellaril (Thioridazine;
phenothiazine; UWC) and Minirin (Desmopressin
acetate; vasopressin analogue; UWC)
** Drug use codes: University of Cape Town Porphyria Service
http://web.uct.ac.za/depts/porphyria/professional/prof%20index.htm
The Case of N.H.
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Age 14 re-investigated
Brain MRI: Mild cerebral atrophy R>L
CSF normal, neurotransmitters normal
Catecholamine excretion normal
OA: Increased urinary fumarate, 2-ketoglutarate
AA: Increased alanine and glutamate
Lactate/pyruvate, ammonia, carnitine, VLCFA,
transferrin isoforms – normal
• FRAXA and MeCP2: no abnormalities
• Muscle biopsy: PDHC, ETC enzymes and
histiochemistry normal
• Fibroblasts: normal fumarase activity
The Case of N.H.
• Age 16 no specific diagnosis
• Parents report severe behavioural deterioration before
menstruation – shrieking, violence, uncontrollable
agitation and crying
• Started on OC (Harmonet gestodene/ethinyloestradiol)
but with further deterioration including vomiting and
stuporous attacks requiring hospitilization
• On further questioning – NH dislikes sun exposure and
becomes very irritable
• NH’s mother – chronic constipation, pre-menstrual
pain, dislikes sun exposure (but no rashes)
• Porphyria suspected
The Case of N.H.
Aminolevulenic Porphobilinogen RBC PBGD ***
Acid
24 hr. excretion
24 hr. excretion* **
N.H. 1st.
N.H. 2nd.
4.3
4.7
1.7
2.5
15
13
O.H.
(mother)
5.4
3.0
17
Normal: * <5 mg/24hrs; ** <2 mg/24hrs; 25-45 nmol urop./ml/h
Studies by N. Schoenfeld, Beilinson Hospital, Petah Tiqwa, Israel
The Case of N.H.
• Is the diagnosis of AIP established?
• Lack of convincing biochemical evidence
• Enzyme levels at heterozygote levels – possible
overlap with normal individuals
• Dangerous to rely on metabolic/enzymatic evaluation
of an individual. Efforts should be made to:
– Repeat studies
– Study first-degree relatives
– Confirm with molecular studies
The Case of N.H.
Acute
Attacks
RBC PBGD,
% normal *
Urinary
ALA
mol/24h **
Urinary
PBG
mol/24h
***
Mutation
analysis
G532A
++
42
32.7
11.0
+/-
O.H.
(mother)
-
50
41.2
13.3
+/-
D.H.
(father)
-
90
nd.
nd.
-/-
N.H.
Normal:
* >70%
** <38
*** <8.8
Data: Minder EI, Schneider-Yin X, Zentrallabor, Staatspital Triemli, Zurich, Switzerland
The Case of N.H.
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Diagnosis: Acute Intermittent Porphyria
Family member affected
No other pathology discovered
Unusual phenotype
N.H. Treatment
• Treatment of behavioural problem difficult
because of drug intolerance
• High carbohydrate diet
• Avoidance of stress, sun, infections
• “Correct” drug therapy
• Acute attacks – Haem iv, iv fluids and
glucose, analgesics, psychiatric management
N.H. Treatment
• Currently managed with decapeptyl (triptorelin; GnRH
analogue) for menstrual aggravation
• Aggression and agitation treated with small doses of
haldol (haloperidol; butyrophenone) 0.5 mg/d
• ?ECT - Little experience in acute porphyria (beware
of barbiturate anaesthetic agents)
Onset of Catatonia
• Recent onset of hypokinesis and “freezing” during
initiation and performance of daily activities
• Differential diagnosis:
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Adult autistic complication
Schizophrenia
Severe depression
Parkinsonism
• Managed with reduction in does of haldol and
introduction of amantidine
• Started on Zyprexa olanzapine, (serotonin 5-HT2
and dopamine D2 receptor antagonist) *
*Taylor, Francis. International Journal of Psychiatry in Clinical Practice 2003; 7:67-69
AIP
• Acute intermittent porphyria occurs in all
races
• The symptoms of acute intermittent
porphyria rarely occur before puberty.
An attack may last for several days or
longer and often requires hospitalization
• PBG, uroprophryin, and 5-ALA
accumulate in the plasma and the urine
Terminology
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AIP
Hydroxymethylbilane synthase deficiency
Intermittent acute porphyria syndrome
PBGD deficiency
Porphobilinogen deaminase deficiency
Porphyria, Swedish type
Pyrroloporphyria
Swedish genetic porphyria
Swedish porphyria
UPS deficiency
Uroporphyrinogen I synthase deficiency
AIP
• 1-5 cases per 100,000 (US) 60-100 per
100,000 Sweden
• AD but female:male ratio 1.5-2.1:1
• Most cases become symptomatic 18-40
years. Presentation before puberty or
after 40 is unusual
Presentation
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Colicky abdominal pain 95%
Pyschiatric symptoms – depression, hysteria
Peripheral neuropathy 66%
Long symptom-free periods are characteristic
Skin manifestations are absent
(MR and pre-pubertal PDD have not been
previously described in the literature)
Abdominal Pain
• The abdominal pain is severe and lasts for
several days. Pain of short duration (<1 d) or
chronic abdominal pain is not observed in AIP
• The pain often is severe, epigastric and
colicky in nature
• Patients often are free of pain between
attacks
• Constipation is common and can be very
severe
• Frequently, nausea and vomiting are present
Neurovisceral and Autonomic
Involvement
• Nausea, constipation, colicky abdominal pain,
vomiting, urinary and fluid retention,
hypertension, tachycardia, increased
sweating and intermittent fever
Peripheral Nerve Involvement
• Peripheral neuropathy, weakness and aching in
muscles and joints, unsteady gait, poor coordination,
numbness/ tingling of arms and legs
• Guillain-Barré syndrome classic or assymetric
• Tendon reflexes maybe reduced normal or brisk
Sensory Syndrome
• Neuropathic pain syndrome: Diffuse, Proximal &
Distal; Abdominal
• Sensory loss: Usually mild, distal, symmetric
• Usually patients have concurrent neurologic or
abdominal symptoms
CNS Involvement
• Seizures, mental status changes, cortical
blindness,coma, delirium, depression,
headaches, difficulty concentrating,
personality changes
Physical Signs
• From 30-80% of patients have tachycardia
• Fever can be present in some patients
• Hypertension is observed in half of patients
and may persist between attacks
Neurological Signs
• Motor neuropathy, more predominant in the lower
limbs
• Areflexia frequent
• Any nerve can be involved, including cranial
neuropathies
• Cortical blindness
• Neurological symptoms affecting the central,
peripheral and/or autonomic nervous systems:
Precipitating Factors
• An inherited deficiency of PBGD is necessary
but not sufficient to cause clinical disease in
AIP
• On average, out of 100 patients with the
genetic defect, perhaps 10-20 secrete excess
porphyrin precursors and only 1-2 have
symptoms
• Precipitating factors can induce cytochrome
P450 and ALAS1 and thereby increase the
demand for haem synthesis
Precipitators
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Fasting, ketoacidosis
Stress, surgery
Hormonal
Drugs barbiturates, oral contraceptives and
estrogens, sulfa drugs, cocaine, griseofulvin
(Fulvicin), chloroquine phosphate (Aralen),
methyldopa (Aldomet),
Diet and dieting
Alcohol smoking
Acute infections
Unknown
Psychiatric Aspects
• Diagnosis is based on a high index of suspicion
and appropriate investigation
• Consistently higher rates of porphyria have been
found in psychiatric patients (up to 0.3%)
• Some psychotropic drugs have been safely used
in the treatment of AIP, but many others (eg.
barbiturates, phenothiazenes, benzodiazepines,
serotonin uptake anatagonists) may precipitate
attacks and are forbidden or problematic
• Little information about the safety of newer
psychotropic drugs
Psychiatric Involvement
• The relationship between acute intermittent porphyria
and psychiatric symptoms is complex. Porphyria may
present with only psychiatric symptoms
• Porphyria may mimic a wide variety of psychiatric
conditions, and, conversely, psychiatric symptoms may
manifest secondary to the porphyria
• Well described:
• Psychosis similar to schizophrenia
• Histrionic personality disorder which may not receive much
attention
• Not described:
• Pervasive developmental disorder
• Mental retardation
• Complex behavioural and personality disorder in childhood
Psychiatric Symptomology
• Patients without acute attacks may have chronic, mild
non-specific complaints but be at risk for acute crises
in the future
• Affective symptoms: Emotional lability, insomnia,
grandiose delusions, conduct disorder with disruptive
behavior, impulsive behavior, aggression, encopresis,
hyperactivity
• Neurotic symptoms: Anxiety (26%) *, restlessness,
agitation, depression (13%) *, hysteria, phobias,
conversion disorder, chronic fatigue syndrome and
somatization disorder
* Millward, Kelly, King, Peters Journal Inherited Metabolic Disease 2005;28:1099-107
Psychiatric Symptomology
• Suicide and attempted suicide
• Pseudo-PMT syndrome
• Organic disorders, delirium, and altered
consciousness ranging from somnolence to coma
•This condition may have inspired the vampire and werewolf legends
•Poe's Roderick Usher ("Fall of the House of...") was perhaps based on
someone with acute intermittent porphyria (JAMA 261: 863, 1989)
•UMKC's Loretta Loftus et. al. suggests porphyria as the cause of
Vincent VanGogh's craziness (Br. Med. J. 303: 1589, 1991)
Flourescent teeth
Red-stained teeth
King George III Syndrome
• Nervous trembling, altered
consciousness, intractable pain,
and terrible insomnia
• Possible trigger factor – erratic
eating habits
• Late onset – after 50 years
Neurotoxicity Mechanisms
• Most current thinking focuses on accumulations of toxic
metabolites.
• Delta-amino levulinic acid (DALA) and porphobilinogen
(PBG) are neurotoxins that produce cerebral dysfunction
and damage (confusion, "psychiatric disease"), autonomic
neuropathy (constipation, urinary retention, tachycardia,
hypertension) and severe (sometimes chronic) abdominal
pain – mechanisms unclear
• DALA may be a false transmitter for GABA. It also blocks
one of ATP-ases (perhaps a sodium pump).
• Another hypothesis – unsaturation of hepatic tryptophan
pyrrolase secondary to liver haem deficiency leads to
altered tryptophan delivery to CNS – increased tryptophan
excretion
• Other theories – vasospasm, reduced NOS activity,
impaired GTP formation, PLP deficiency
Genetics
• Porphobilinogen deaminase deficiency PBGD
• EC 2.5.1.61, Chromosome 11q24.1-q24.2, AD
• Alternative name: Hydroxymethylbilane synthase
HMBS
Genetics
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More than 60 mutations described
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 with neuropathy
Diagnosis
• Urine PBG and DALA will be increased during acute
episodes AIP (also variegate porphyria and
coproporphyria.)
• Urine rich in PBG turns reddish-purple (uroporphyrin)
on long exposure to bright light (toilet, ward station,
lab). "Porphyria" means "purple"
• Levels can be normal between attacks
• Urine "dipstick" test for urobilinogen should record
PBG but in practice unreliable because PBG is very
unstable
• Since not every acute porphyrin is AIP, foecal
porphyrin and RBC PBGD activity should also be
evaluated together with plasma flourescence scan
Correct Collection of
Specimens
• Use light-proof bottle (wrap it in aluminum
foil.)
• Urine should be alkalinized and refrigerated.
• High pressure liquid chromatography to
screen for DALA and PBG – 24 hour
excretion
Definitive Diagnosis
• The definitive test is to measure monopyrrole
porphobilinogen deaminase (uroporphyrinogen I
synthetase) in RBCs
• Some overlap with normal individuals is seen
• Determination of mutation in PBGD gene
• Family member studies
Porphyria – An Imitator
• This diagnosis should be entertained in the
following situations:
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unexplained leukocytosis
unexplained neuropathy
aetiologically obscure neurosis or psychosis
'idiopathic' seizure disorder
unexplained abdominal pain
susceptibility to stress
?unexplained PDD, MR or behavioural
disturbance in childhood?
Pitfalls
• Some patients exhibit no hard physical findings, and
the patients get dismissed for years as "functional",
“malingerers”, "mentally ill", or "drug seekers“
• The screening tests are often done on samples that
have been handled improperly, resulting in falsenegative results
• Diagnostic criteria are poorly-defined. Mild versions
are surely common and are missed by the standard
enzyme "normal ranges“
• Identification of a biochemical or genetic anomaly is
not in itself and indicator of clinical disease
• Is there another co-existing condition?
Treatment Dilemmas
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Safe and unsafe drugs, UWC, UWECO drugs
Side effects v. progression of disease
Drug interactions
Better modalities for follow-up needed
Achbara Bridge, near Safed, Israel