Behavioural Aspects of Acute Behavioural Aspects of Acute Intermittent PorphyriaIntermittent Porphyria

A. Luder, and N. SchoenfeldTechnion, Haifa and University of Tel-Aviv; Israel

4 Acute Porphyrias4 Acute Porphyrias:

ALA dehydratase deficiency

AIP

Variegate

Hereditary coproporphyria

4 Chronic porphyrias4 Chronic porphyrias:

Porphyria cutanea tarda PCT

Erythropoietic protophorphyria

Congenital erythropoietic porphyria (Gunther’s)

Pseudoporphyria (porphyrinuria)

CATEGORYCATEGORY TYPETYPE CLINICALCLINICAL PRESENTATIONPRESENTATION INHERITANCEINHERITANCE

Hepatic 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

Erythropoietic 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.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.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.The Case of N.H.• 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.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.The Case of N.H.Aminolevulenic Acid 24 hr. excretion*

Porphobilinogen 24 hr. excretion **

RBC PBGD ***

N.H. 1st.N.H. 2nd.

4.34.7

1.72.5

1513

O.H. (mother)

5.43.017

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.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.The Case of N.H.Acute

AttacksRBC PBGD, % normal *

Urinary ALA

mol/24h **

Urinary PBG

mol/24h ***

Mutation analysis G532A

N.H.++4232.711.0+/-

O.H. (mother)

-5041.213.3+/-

D.H. (father)

-90nd.nd.-/-

Normal: * >70% ** <38 *** <8.8Data: Minder EI, Schneider-Yin X, Zentrallabor, Staatspital Triemli, Zurich, Switzerland

The Case of N.H.The Case of N.H.

• Diagnosis: Acute Intermittent Porphyria• Family member affected• No other pathology discovered• Unusual phenotype

N.H. TreatmentN.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. TreatmentN.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 CatatoniaOnset of Catatonia• Recent onset of hypokinesis and “freezing” during initiation

and performance of daily activities• Differential diagnosis:

– 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

AIPAIP

• 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

TerminologyTerminology• 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

AIPAIP

• 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

PresentationPresentation

• 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 PainAbdominal 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 Neurovisceral and Autonomic InvolvementInvolvement

• Nausea, constipation, colicky abdominal pain, vomiting, urinary and fluid retention, hypertension, tachycardia, increased sweating and intermittent fever

Peripheral Nerve InvolvementPeripheral 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 SyndromeSensory Syndrome

• Neuropathic pain syndrome: Diffuse, Proximal & Distal; Abdominal

• Sensory loss: Usually mild, distal, symmetric• Usually patients have concurrent neurologic or

abdominal symptoms

CNS InvolvementCNS Involvement• Seizures, mental status changes, cortical

blindness,coma, delirium, depression, headaches, difficulty concentrating, personality changes

Physical SignsPhysical 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 SignsNeurological 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 FactorsPrecipitating 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

PrecipitatorsPrecipitators• 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 AspectsPsychiatric 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 InvolvementPsychiatric 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 SymptomologyPsychiatric 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 SymptomologyPsychiatric 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 SyndromeKing George III Syndrome• Nervous trembling, altered

consciousness, intractable pain, and terrible insomnia

• Possible trigger factor – erratic eating habits

• Late onset – after 50 years

Neurotoxicity MechanismsNeurotoxicity 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

GeneticsGenetics• Porphobilinogen deaminase deficiency PBGD• EC 2.5.1.61, Chromosome 11q24.1-q24.2, AD• Alternative name: Hydroxymethylbilane synthase

HMBS

GeneticsGenetics

• 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

DiagnosisDiagnosis• 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 Correct Collection of SpecimensSpecimens

• 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 DiagnosisDefinitive 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 ImitatorPorphyria – An Imitator

• This diagnosis should be entertained in the following situations: • 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?

PitfallsPitfalls• 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 false-negative 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 DilemmasTreatment Dilemmas

• 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