Clinical Diagnosis

Terms that need to be defined when considering diagnostic criteria for hydroxymethylbilane synthase (HMBS) deficiency

In modern nomenclature, HMBS deficiency is alternatively referred to as:

• HMBS deficiency without clinical or biochemical manifestations

• HMBS deficiency with biochemical manifestations only (i.e., increased porphobilinogen (PBG) excretion)

• HMBS deficiency with clinical and biochemical manifestations (i.e., acute intermittent porphyria [AIP])

In an older but often still used nomenclature, HMBS deficiency is referred to as:

• Symptomatic acute intermittent porphyria (AIP) (i.e., clinically expressed)
  
  or

• Latent AIP (i.e., no clinical features in an individual with an HMBS disease-causing mutation).

Note: In this GeneReview, the term acute intermittent porphyria (AIP) refers to HMBS deficiency with clinical and biochemical manifestations.

AIP is suspected in individuals with the following:

• Symptoms of an acute attack. Between 90% and 95% of individuals with AIP exhibit abdominal pain and tachycardia, the most common features; however, no single clinical symptom is exclusively characteristic of AIP.

• A red or red-brownish tint to the urine, the color of which varies from the color of dilute strawberry sap to port wine and is enhanced by exposure to air and light. This color reflects increased urinary concentrations of the porphyrin precursor porphobilinogen (PBG) and the porphyrins formed from it.

• A family history consistent with autosomal dominant inheritance

Definitive diagnosis of:

• HMBS deficiency with clinical and biochemical manifestations relies on presence of clinical manifestations, red- or red-brown urine, and increased urinary excretion of PBG.

• HMBS deficiency without biochemical manifestations relies primarily on molecular genetic testing.

Testing

Molecular Genetic Testing

Gene. HMBS (previously designated as PBGD) is the only gene in which mutation is known to cause HMBS deficiency.

Clinical testing

• Sequence analysis identifies mutations in 98% or more of individuals with HMBS deficiency [Kauppinen & von und zu Fraunberg 2002].

Table 2. Summary of Molecular Genetic Testing Used in Hydroxymethylbilane Synthase (HMBS) Deficiency

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency 1	Test Availability
HMBS	Sequence analysis	Sequence variants 2	>98% 1	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Refers to the detection of an HMBS mutation and not the presence of clinically expressed AIP

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

• During an acute attack that includes neurovisceral symptoms, measurement of urinary concentration of PBG is highly sensitive and specific and is the first step in the diagnosis of AIP [Kauppinen 2004].
  
  Note: Although urinary concentration of ALA is also increased, it does not assist in the diagnosis of AIP, but may be of value for excluding other reasons for a neuropsychiatric presentation in a previously undiagnosed individual (see Differential Diagnosis), i.e., ALAD-deficiency porphyria or lead intoxication.

  • Initially the Trace PBG Kit (Thermo Trace/DMA, Arlington, Texas) can be used on a single void urine.

  • PBG concentration can then be quantified on the same urine sample or on a 24-hour urine sample using ion-exchange column chromatography followed by spectrophotometry.

• Molecular genetic testing of HMBS detects a mutation in 98% of families with HMBS deficiency

Presymptomatic testing in at-risk family members. If the HMBS mutation in the proband is known, molecular genetic testing is superior to measurement of urinary PBG for clarifying the genetic status of at-risk relatives.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in HMBS.

Natural History

Most of the time HMBS deficiency remains clinically quiescent; however, it can present in some individuals as acute intermittent porphyria (AIP), manifest as intermittent acute biochemical or clinical episodes precipitated by the action of neurotoxic metabolites formed in the liver.

Acute Intermittent Porphyria (AIP)

In AIP, the visceral, peripheral, autonomic, and/or central nervous systems may be affected, leading to a range of findings that are usually intermittent and sometimes life-threatening. The course of acute attacks is highly variable within an individual and among individuals.

HMBS deficiency, only very rarely expressed clinically before puberty, is more common in women than in men [Anderson et al 2001, Schuurmans et al 2001].

Affected individuals may recover from acute AIP attacks within days, but recovery from severe attacks that are not promptly recognized and treated may take weeks or months. Although clinical expression of AIP is caused by exposure to certain endogenous or exogenous factors in most individuals, it is not uncommon for individuals to have acute attacks in which no precipitating factor can be identified.

Acute attack. Abdominal pain, which may be generalized or localized and not accompanied by muscle guarding or back or limb pain, is the most common symptom and is often the initial sign of an acute attack. Other common gastrointestinal features include nausea, vomiting, constipation or diarrhea, abdominal distention, and ileus. Urinary retention, incontinence, and dysuria are common. Tachycardia and hypertension are frequent, while fever, sweating, restlessness, and tremor are seen less frequently.

Peripheral neuropathy is common. Muscle weakness often begins proximally in the legs but may involve the arms or the legs distally. Bilateral axonal motor neuropathy may also involve the distal radial nerves [King et al 2002]. Motor neuropathy may affect the cranial nerves, or lead to bulbar paralysis, respiratory impairment, and death. Grave neurologic problems, such as permanent quadriplegia, appear to develop after severe attacks.

Patchy sensory neuropathy may also occur [Wikberg et al 2000].

Individuals with manifest disease have significantly more signs of distal chronic, symmetric axonal neuropathy than do individuals with latent disease.

Psychiatric findings can be prominent in AIP and may represent the sole feature of the disease. The psychiatric findings include insomnia, agitation, hysteria, anxiety, apathy or depression, phobias, psychosis, organic disorders, delirium, amnesia, and/or altered consciousness ranging from somnolence to coma. Some individuals develop a psychosis similar to schizophrenia. Suicide is common.

Seizures may occur in acute attacks, especially in individuals with hyponatremia caused by vomiting, inappropriate fluid therapy, or the syndrome of inappropriate antidiuretic hormone release (SIADH). In a survey of 268 individuals with AIP in Sweden, 3.7% reported epileptic seizures that were either tonic-clonic seizures or partial seizures becoming secondarily generalized.

MRI findings. Multiple high-signal white-matter brain lesions are found by MRI in about 25% of individuals with HMBS mutations [Bylesjö et al 2004]. Those with previous acute attacks tend to have more lesions than those who have not experienced an acute attack. These lesions seem to improve following appropriate treatment of the attack [Utz et al 2001, Celik et al 2002]. Some MRI findings may result from rapid correction of hyponatremia rather than AIP [Susa et al 1999]. As most of these MRI findings involve case reports, it remains unknown whether they are generally true.

Hepatocellular carcinoma. Individuals with an HMBS mutation have an increased risk of developing hepatocellular carcinoma (HCC) [Linet et al 1999, Schaffer et al 2001]. A retrospective population-based study in two municipalities in northern Sweden with a high prevalence of AIP found HCC in 27% of deceased individuals with AIP versus 0.2% of those without AIP (p<0.0001). This association may be related to the fact that 4,5-dioxovaleric acid, an oxidation product of ALA, is capable of alkylating guanine moieties within both nucleosides and isolated DNA [Douki et al 1998], possibly leading to carcinogenic mutations in liver cells.

Renal involvement. Some individuals, especially those with long-standing repeated attacks, have renal insufficiency without another apparent cause. Although many have hypertension, others are normotensive despite renal insufficiency [Andersson et al 2000b].

Renal histopathology typically shows diffuse glomerulosclerosis, interstitial changes, and ischemic lesions. Protracted vasospasm in attacks of AIP is a possible cause [Andersson et al 2000b].

Increased urinary excretion of lipid peroxides in an individual with AIP with tubulointerstitial nephritis suggests that lipid peroxides cause oxidative injury to the mitochondria in the renal tubular cells [Onozato et al 2001].

Cutaneous manifestations are not observed in individuals with AIP [Sassa & Shibahara 2002].

Precipitating factors. In HMBS deficiency, attacks of acute porphyria may be precipitated by several different endogenous or exogenous factors [Sassa & Shibahara 2002]. Precipitating factors include the following [Anderson et al 2001]:

• Induction of hepatic ALA synthase (non-erythroid ALAS or ALAS-N). Most precipitating factors increase the level of ALAS-N activity in the liver, which is normally the rate-limiting enzyme in hepatic heme biosynthesis. With increased ALAS-N enzyme activity, the partially deficient HMBS enzyme activity becomes the rate-limiting step in heme biosynthesis, causing the accumulation of the porphyrin precursors ALA and PBG, which accompany the acute attack.
  
  Note: ALAS-N inducers do not influence gene expression of the erythroid-specific ALAS (ALAS-E), which probably accounts for the absence of hematologic abnormalities in individuals with AIP.

• Many lipid-soluble foreign chemicals are detoxified in the liver by cytochrome P450. Lipid-soluble foreign chemicals that induce some of the heme-based enzymes, thus accelerating the biosynthesis of heme by the coordinated porphyrogenic induction of ALAS-N, include the following:

  • Components in alcoholic beverages [Thunell et al 1992]

  • Prescription drugs including barbiturates, sulfa-containing antibiotics, most antiepileptic drugs (AEDs), progestagens, synthetic estrogens, and several others [Thunell et al 2007]

  • Organic solvents used, for example, in painting and cleaning

  • Biocides

  • Smoking (i.e., chemicals in tobacco smoke such as polycyclic aromatic hydrocarbons)

  • Cannabis

• Fasting. A common precipitating factor is inadequate caloric intake [Anderson et al 2005] often prior to abdominal x-ray or in connection with, for example, dieting or long-distance athletics. Via the action of different intranuclear transcription factors under hormonal control, hypoglycemia activates the nuclear receptors PXR and CAR that are directly responsible for initiating transcription of the enzyme hepatic ALAS-N [Thunell 2006]. Fasting also induces hepatic microsomal heme oxygenase-1, resulting in decreased hepatic heme concentrations and, thus, loss of heme repression of the ALAS-N formed via induction of transcription.

• Stress. Psychosocial and other stresses, including intercurrent illnesses, infections, alcoholic excess, and surgery, induce hepatic ALAS-N through activation of the two nuclear receptors PXR and CAR that initiate its transcription. Also the gene encoding heme oxygenase-1 is upregulated through reduction of the hepatocyte intracellular heme content.

• International air travel. Dehydration, missed meals, alcohol use, infection, hypoxia, and stress that may occur during international air travel are risk factors for an acute attack [Peters & Deacon 2003].

• Endocrine factors Porphyrogenic transcription of ALAS-N is initiated on activation of the nuclear receptors PXR and CAR controlled by the hormones glucagon, ghrelin, growth hormone, adrenal androgens, and cortisol [Thunell 2006]. Reproductive hormones play an important role in the clinical expression of AIP which is more common in women than men, especially premenstrually [Schuurmans et al 2001]. A subset of women experience debilitating cyclical premenstrual exacerbations of AIP. Synthetic estrogens, progesterones, and ovulation stimulants are risk factors for an acute attack. Hormone replacement therapy (HRT) in menopausal women with a history of AIP rarely precipitates acute attacks, whereas 25% of women with manifest AIP on HRT report acute attacks [Andersson et al 2003]. On the other hand, women with AIP often fare well during pregnancy, despite massive increases in the serum concentration of various steroid hormones [Anderson et al 2001, Aggarwal et al 2002].

Protective factors. Development of type 2 diabetes mellitus (DM) may reduce disease severity. Thus, after the onset of DM, individuals with AIP have been observed to no longer experience acute attacks or other AIP-related symptoms [Lithner 2002]. Urinary ALA and PBG excretion also decrease [Andersson et al 1999].

Note: The beneficial effect of carbohydrate loading, a standard treatment for acute attacks, may be mediated by repression of activated ALAS-N gene transcription, as well as by post-transcriptional repression of ALAS-N formed [Thunell 2006].

Mortality. In the US, mortality caused by symptomatic AIP was previously threefold higher than in the general population. Most deaths from AIP occurred during acute attacks, which were often confounded by delayed diagnosis and treatment. Although survival improved after 1971, the year in which hemin therapy became available, the improvement has not been statistically significant.

In Sweden, on the other hand, since the availability of heme therapy in combination with information directed to health care providers and patients regarding the pathophysiology of the disease and factors to avoid, mortality during an acute attack is rare among the approximately 1000 HMBS heterozygotes [Thunell et al 2006]. The Porphyria Patients’ Associations have played a key role in disseminating the advice of specialists.

Pathogenesis. Studies of HMBS homozygotes report peripheral neuropathy and a progressive loss of cerebral volume, delayed myelination, a strikingly abnormal pattern of myelin signal intensities, and multifocal vacuolation/cavitation of perivascular white matter [Solis et al 2004]. The MRI changes suggest a primary process affecting cerebral myelination with neuronal/axonal sparring. The mechanisms underlying the neurologic findings are not well understood.

Presently two major hypotheses for the acute neurologic attack are proposed:

• Direct neurotoxicity caused by accumulated ALA, which seems to be the most likely mechanism [Solis et al 2004]. Immature oligodendrocytes are highly susceptible to glutamate-dependent and other excitatory processes. Homology of accumulated ALA with glutamate could thus selectively damage white matter regions. Further, oligodendrocytes express GABA receptors, and GABA is known to increase calcium concentration in oligodendrocyte precursors. Homology of accumulated ALA with GABA may also give rise to blocking of hypothalamic GABA-receptors that, if activated, attenuate CRH release caused by porphyrogenic stressors [Thunell 2006].

• Heme deficiency in the central nervous system caused by impaired heme biosynthesis secondary to reduced HMBS enzyme activity. Heme deficiency should conceivably first affect gray matter through interference with the mitochondrial electron transport system. However, the anatomical changes expected to result from such interference were not observed in a homozygous HMBS-deficient proband, nor were signs of impaired mitochondrial respiratory chain [Solis et al 2004].

• Although heme deficiency is observed in the central nervous system in AIP [Solis et al 2004], the findings of Solis et al argue that ALA neurotoxicity, and not neural heme deficiency, is the cause for the neurologic engagement in AIP.

Other hypotheses include:

• Decreased plasma melatonin concentration, which enhances ALA-mediated lipid peroxidation [Carneiro & Reiter 1998, Princ et al 1998b]. ALA-induced lipid peroxidation in the cerebellum and hippocampus was reduced by melatonin in a rat model [Carneiro & Reiter 1998].

• Generation of reactive oxygen species (ROS) by ALA, which may result in oxidative damage to membranes within the central nervous system [Princ et al 1998a]

• Decreased activity of hepatic tryptophan pyrrolase, a heme-dependent enzyme, leading to increased levels of brain tryptophan and increased turnover of 5-hydroxytryptamine, a neurotransmitter

Homozygous HMBS Deficiency

To date, five individuals homozygous or compound heterozygous for two HMBS disease-causing mutations have been described.

• Homozygous mutations were p.Arg167Gln, p.Arg167Trp, p.Leu81Pro; compound heterozygous mutation was p.[Arg167Trp]+[Arg173Gln] [Edixhoven-Bosdijk et al 2002, Hessels et al 2004, Solis et al 2004].

• All individuals had less than 2% of the HMBS enzyme activity found in controls.

• Clinical symptoms occurred early in childhood and were debilitating; symptoms included severe ataxia, dysarthria, severe psychomotor delay, and central and peripheral neurologic manifestations.

• MRI studies in one such individual showed white matter abnormalities that suggested selective postnatal involvement of cerebral oligodendrocytes [Solis et al 2004].

Genotype-Phenotype Correlations

Genotype-phenotype correlations are not evident in HMBS deficiency [Elder 1998], in part because of (1) HMBS enzyme activity in heterozygotes that is adequate for normal heme synthesis and (2) the effect of environmental factors on clinical expression of the disease. Unidentified modifying genes may also be important.

In a Swedish study of 468 individuals with DNA-verified HMBS deficiency, a higher prevalence of AIP was found in individuals with p.Trp198X or p.Arg173Trp mutations than in those with p.Arg167Trp mutations [Andersson et al 2000a].

These findings suggest that the lower HMBS enzymatic activity observed in individuals with the p.Trp198X or p.Arg173Trp mutations versus that observed in individuals with the p.Arg167Trp mutation may contribute to genotype-phenotype correlations, but other factors may also play a role.

Penetrance

Penetrance defined as the presence of symptoms of AIP and increased urinary excretion of ALA and PBG in individuals heterozygous for an HMBS mutation has ranged from less than 10% to 20% [Anderson et al 2005] to 52% [Schuurmans et al 2001]. Reduced penetrance is thought to be the result in large part of the requirement of an additional factor (e.g., drugs, hormones, decreased caloric intake, stress) for clinical expression of the disease.

Nomenclature

AIP and the other acute hepatic porphyrias have been classified as pharmacogenetic or ecogenetic to emphasize the importance of additional factors, including certain drugs, on clinical expression of the underlying genetic defect [Sassa & Shibahara 2002].

The term acute intermittent porphyria (AIP) is of historic origin and today should be reserved for the clinical manifestations of those with an HMBS mutation. The following new, more precise nomenclature is being applied in most scientific publications, but is not yet in general use.

• The disorder is called hydroxymethylbilane synthase (HMBS) deficiency.

• An individual with a mutation in HMBS that predisposes to the clinical manifestations (i.e., AIP) is called an HMBS heterozygote, who can then be further described by the specific mutation, e.g., a p.Arg167Trp HMBS heterozygote.

Obsolete terms for AIP are:

• Intermittent acute hepatic porphyria (IAP) or Swedish porphyria

• Acute pyrroluria (because individuals with AIP produce and excrete excess the porphyrin precursors ALA and PBG)

Prevalence

In most countries AIP is the most common of the acute hepatic porphyrias [Sassa & Shibahara 2002].

Although it has been reported in many populations, the highest prevalence of HMBS deficiency occurs in northern Sweden, where it is 1:10,000 [Floderus et al 2002]. The prevalence of HMBS deficiency is estimated to be 1-2 per 100,000 in the rest of Europe [www.porphyria-europe.com].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with hydroxymethylbilane synthase (HMBS) deficiency, neurologic evaluation including MRI is recommended.

Treatment of Manifestations

Treatment of acute AIP attacks entails the following [Sassa & Shibahara 2002]:

• Stopping immediately all medications that can exacerbate the hepatic porphyrias, including alcohol [Doss et al 2000] and tobacco. See Agents/Circumstances to Avoid.

• Restoring energy balance if needed, including total parenteral nutrition (TPN) for individuals unable to tolerate oral feeding

• For mild attacks, intravenous administration of dextrose to provide a minimum of 400 g of carbohydrate/day [Anderson et al 2005]. If improvement is unsatisfactory after two days of administration of carbohydrate, intravenous administration of hemin preparations is recommended.

• Prompt treatment of intercurrent infections and other diseases

• Prompt treatment of hypertension, pain, and electrolyte disturbances, especially hyponatremia caused by the syndrome of inappropriate anti-diuretic hormone (SIADH)

• Use of bedside spirometry to measure vital capacity to determine if mechanical support of respiration is required because of bulbar paralysis. Note that weakening of the voice may indicate respiratory involvement.

• Intravenous hemin preparations (hematin, heme albumin or heme arginate), which, except for mild attacks, should be started without an initial trial of carbohydrate [Anderson et al 2005]. Hemin preparations repress ALAS-N enzyme activity, and thus reduce ALA and PBG accumulation. They are most effective in curtailing acute neurovisceral attacks. Intravenous administration of hemin preparations may be life-saving when employed early. Their early use, when neuronal damage is still reversible, may also help to avoid paresis or prevent its progression.
  
  The recommended initial dose for hemin is 3-4 mg of heme/kg IV, given over a period of ten to 15 minutes, once daily for four days. Treatment may be extended, depending upon the clinical course. No more than 6 mg/kg should be given in any 24-hour period, since reversible renal shutdown has been reported at higher doses.
  
  The only available hemin preparation in the US is Panhematin™, which has been approved by the FDA for treatment of acute porphyric attacks (Ovation Pharmaceuticals, Deerfield, IL). This product contains hematin (heme hydroxide) prepared using hemin chloride, sodium carbonate, HCl, and sorbitol. It is supplied as a dried powder, which must be reconstituted with sterile water immediately before intravenous injection.
  
  Note: (1) Panhematin™ may cause phlebitis after its intravenous injection. This problem can be minimized by reconstituting Panhematin™ with an equimolar amount of human serum albumin and/or by using a large vein or a central catheter for infusion. (2) Terminal filtration through a sterile 0.45-micron or smaller filter before injection is recommended to remove any undissolved particulate matter. (3) Because the administration of Panhematin™ reconstituted with sterile water is associated with transient, mild coagulopathy, concurrent anticoagulant therapy should be avoided. (4) Heme arginate, another hemin preparation, is more stable in solution, but is not available in the US.
  
  Heme arginate is today firmly established for effective use in symptomatic acute porphyria. It has the same advantage as hemin in treating an acute attack, but has fewer side-effects [Balla et al 2000, Elder & Hift 2001, Schoenfeld & Mamet 2006]. It is a stable reaction product between hemin and L-arginine and is available as solution.
  
  Coagulopathy and phlebitis, which are caused by degradation products of heme, are less common with heme arginate or Panhematin™ reconstituted with albumin than with Panhematin™ reconstituted with sterile water.

• Liver transplantation. A 19-year-old woman with severe AIP had an excellent biochemical and clinical remission lasting for more than 1.5 years following orthotopic cadaveric liver transplantation [Soonawalla et al 2004]. Consideration of liver transplantation, however, should be reserved for those individuals with the most severe repeated symptoms who fail to respond to other treatments. Recommendations have been put forth [Seth et al 2007].

• Kidney transplantation has been performed for those with AIP without complications [Nunez et al 1987, Warholm & Wilczek 2003].

• Combined liver and kidney transplantation, which has been successful, can be considered in those with AIP with repeated severe attacks and renal failure.

Prevention of Primary Manifestations

Preventive measures

• Adequate nutrition. Caloric supplementation may suppress clinical manifestations of HMBS deficiency. Adequate nutrition is especially helpful in individuals with previous poor intake or with excessive rapid weight loss.

• Avoidance of drugs and chemicals known to exacerbate porphyria. See Agents/Circumstances to Avoid.
  
  Note: The Nordic Drug Database (www.drugs-porphyria.org/) with versions in English, French, Norwegian, and Swedish includes advice regarding prescription drugs (i.e., which are safe to use and which need to be avoided). Further language versions are planned.

• Prompt treatment of intercurrent diseases or infections

• Use of low-dose oral contraceptives to prevent cyclic attacks; however, these may exacerbate porphyria.

• Administration of nasal or subcutaneous long-acting agonistic GnRH analogs to inhibit ovulation and prevent premenstrual attacks in women with cyclic exacerbations of AIP. Note, however, that such therapy can actually worsen manifestations, and thus should only be pursued by experts in management of porphyria.

• Although a regimen of intravenous hemin therapy for prevention of attacks has not been established, 3-4 mg/kg given intravenously once or twice a week has been effective in some individuals [Anderson KE, personal communication].

Porphyria advocacy groups have actively worked to protect at-risk individuals through education regarding:

• Triggering factors to be avoided, including porphyrogenic prescription drugs

• Self-treatment early in an attack

• Availability of appropriate medical intervention and experienced health care providers [Thunell et al 2006]

Booklets from the Porphyria Patients’ Associations, revised by specialists, are presently available in Canada and Sweden and are planned for other countries. Contact information for these organizations is available; see Resources.

Prevention of Secondary Complications

As suicide is more common than in the general population among individuals with AIP, psychological support, early psychiatric care, and effective pain management are important.

End-stage renal disease (ESRD), which is thought to result from chronic systemic arterial hypertension, may be delayed through effective blood pressure control [Andersson et al 2000b].

Surveillance

Because 100 mg of hemin contains 8 mg of iron, frequent administration of hemin may increase the risk for iron overload. Periodic monitoring of serum ferritin concentration and/or transferrin saturation is therefore appropriate in individuals treated repeatedly with hemin.

Periodic hepatic imaging is appropriate after age 50 years because of the increased incidence of hepatocellular carcinoma in individuals with HMBS deficiency [Linet et al 1999, Schaffer et al 2001].

Note: Monitoring serum α-fetoprotein concentration is much less useful in monitoring for hepatocellular carcinoma (HCC) associated with HMBS deficiency than HCC of other etiologies, because it is seldom increased in persons with AIP who have HCC.

Agents/Circumstances to Avoid

Alcohol and smoking should be avoided.

Drugs that can induce acute attacks

• Knowledge about the safety of many drugs and other over-the-counter preparations in acute porphyrias is incomplete. However, evidence-based guidelines for assessment of drug porphyrogenicity have recently been published [Thunell et al 2007]. Prescription-drug porphyrogenicity classifications based on the principles suggested are found on www.drugs-porphyria.org/.

• Lists of unsafe and potentially unsafe agents are also available at the following Web sites:

  • Drugs-porphyria.org

  • The American Porphyria Foundation

  • European Porphyria Initiative

• Barbiturates and sulphonamide antibiotics are notorious triggers of acute porphyria.

• Gestagens and synthetic estrogens have precipitated many attacks.

• Almost all antiepileptic drugs (AEDs) can exacerbate acute porphyria, including AIP. Gabapentin and vigabatrin may be safer than other AEDs [Hahn et al 1997].

• Several other prescription drugs are porphyrogenic and should if possible be avoided.

Testing of Relatives at Risk

It is appropriate to:

• Clarify the genetic status of at-risk relatives by HMBS molecular genetic testing if the mutation has been identified in an affected family member.
  
  Note: Molecular genetic testing is accurate for detecting HMBS mutations, but cannot predict a clinical attack of AIP; however, elevated urinary PBG concentration may indicate increased risk of an acute attack in individuals known to be heterozygous for an HMBS mutation.

• Advise relatives with HMBS deficiency without clinical or biochemical manifestations to practice preventive measures and avoid known risk factors.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Synthetic heme analogs, e.g., tin-protoporphyrin or tin-mesoporphyrin, which inhibit heme oxygenase activity, result in decreased heme catabolism and increased hepatic heme concentration. These agents diminish the output of ALA, PBG, and/or porphyrins in individuals with AIP and VP. Their use to prolong the effects of hemin remains investigational.

Enzyme substitution by way of infusion into blood of recombinant HMBS enzyme has been tried and proven to be safe and effective with regard to removal of PBG and ALA from plasma and urine [Sardh et al 2007]; however, no clinical effect could be demonstrated.

Gene therapy using adenovirus and adenovirus-associated vectors have been effective over the long term in correcting hepatic HMBS deficiency in animal models of AIP [Johansson et al 2004].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

The NIH-funded Porphyrias Consortium provides expert diagnosis and treatment of porphyrias as well as clinical and therapeutic studies.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

The RDCRN Patient Contact Registry
The Porphyrias Consortium
rarediseasesnetwork.epi.usf.edu/porphyrias

Other

Medical alert bracelets and wallet cards should be provided to HMBS heterozygotes to help them avoid unnecessary exposure to unsafe drugs or substances.

Cimetidine has been suggested as an alternative treatment [Rogers 1997], although evidence for clinical efficacy remains elusive. Cimetidine, an inhibitor of hepatic cytochrome P450 enzymes, ameliorates experimental porphyrias caused by chemicals that are activated by these enzymes, but this mechanism does not necessarily relate to human genetic porphyrias.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

HMBS deficiency is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• The majority of individuals diagnosed with HMBS deficiency have inherited the mutation from one of their parents, who may or may not be symptomatic.

• A proband with HMBS deficiency may also have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is unknown but is with all probability small.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include urinary ALA and PBG determinations and, if the proband's HMBS mutation has been identified, molecular genetic testing of HMBS.

Note: In persons with HMBS deficiency the family history is sometimes negative because of failure to recognize the disorder in family members who have HMBS deficiency without clinical or biochemical manifestations.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents, i.e., whether one or both parents have an HMBS mutation.

• If only one of the parents of the proband has an HMBS mutation, which is the rule, the risk to each sib of inheriting the mutation is 50%. Because clinical penetrance is low (10%-50%), it is not possible to predict whether individuals who inherit an HMBS mutation will be symptomatic, or if they are, the age of onset, severity, or type of symptoms.

Offspring of a proband. Each child of an individual with HMBS deficiency has a 50% chance of inheriting the HMBS mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for HMBS deficiency is available using either assay of erythrocyte HMBS enzyme activity or, if the mutation is known in an affected family member, molecular genetic testing of HMBS. Such testing is not useful in predicting if or when individuals who inherit the HMBS mutation will become symptomatic. Identification of individuals at risk for AIP, however, alters management because avoidance of known risk factors and other measures may be helpful in preventing acute attacks and other symptoms. Before testing at-risk individuals for AIP, it is necessary to first test an affected family member to identify the specific mutation in the family.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder or the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing can determine if the HMBS mutation present in one parent is present in the fetus by analysis of the DNA present in amniotic fluid cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Because most individuals with HMBS deficiency remain asymptomatic throughout life, because neither molecular genetic testing nor biochemical testing can predict a clinical attack of AIP, and because treatment and prognosis of adults with AIP has improved considerably, requests for prenatal testing are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Author History

Shigeru Sassa, MD, PhD; The Rockefeller University (2005-2010)
Stig Thunell, MD, PhD (2010-present)

Revision History

• 1 September 2011 (cd) Revision: addition of links to Rare Diseases Clinical Research Network Porphyrias Consortium and Registry (Management)

• 23 March 2010 (me) Comprehensive update posted live

• 27 September 2005 (me) Review posted to live Web site

• 3 January 2005 (ss) Original submission