ALA dehydratase porphyria

INTRODUCTION — The porphyrias are metabolic disorders caused by altered activity of enzymes within the heme biosynthetic pathway. Delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria (ADP; OMIM 612740, also called Doss porphyria and plumboporphyria) is the rarest of the inherited porphyrias, with only eight documented cases reported worldwide (all in males). (See 'Epidemiology' below.)

ADP is an autosomal recessive disorder resulting from severe deficiency of ALAD, the second enzyme in the pathway of heme synthesis. The incidence, pathophysiology, diagnosis, and treatment of ADP will be reviewed here. An overview of porphyrias is presented separately. (See "Porphyrias: An overview".)

DEFINITION AND HISTORY — Delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria (ADP) is an acute porphyria resulting from severe ALAD deficiency that is caused by a genetic defect. The first two cases [1] and the fifth [2] were identified in Germany by Doss, and therefore the disease is referred to as Doss porphyria. It has also been termed plumboporphyria because ALAD is inhibited by lead, and lead poisoning can mimic the clinical and biochemical findings of ADP. ADP is classified as one of the four acute hepatic porphyrias, but it may also have a significant erythropoietic component.

PATHOPHYSIOLOGY

Classification — ADP is classified as an acute hepatic porphyria because ALA elevation, neuropathic symptoms, and response to treatment with hemin are prominent features. (See "Porphyrias: An overview", section on 'Classification and clinical categories'.)

However, other features suggest ADP may have a significant erythropoietic component as well:

●In one case, exosomal ALAS1 mRNA, a marker for activity of this rate-limiting enzyme for hepatic heme biosynthesis, was shown to be elevated in plasma and urine to a degree comparable to other acute hepatic porphyrias [3]. Substantial elevation of erythrocyte porphyrins, as in other porphyrias with bi-allelic mutations, suggests disruption of erythroid heme biosynthesis as well.

●Late-onset ADP was associated with a myeloproliferative disorder in one case, and such an association has hitherto been described only in erythropoietic porphyrias [4].

●A 2019 report described a case in which suppression of erythropoiesis with blood transfusions and hydroxyurea (hydroxycarbamide) resulted in improvement [5].

●A case report described failure of the disease to respond to liver transplantation in an infant, albeit with very severe disease [6-9]. In contrast, liver transplantation has been beneficial in acute intermittent porphyria (AIP), the prototype and most common of the acute hepatic porphyrias. (See 'Treatment' below.)

Enzymology — Heme synthesis defects can cause accumulation of pathogenic intermediates in red blood cell precursor and hepatocytes. These can leak into the plasma and cause toxicity to a variety of tissues. ALA dehydratase porphyria (ADP) is caused by severe reduction in the activity of the second enzyme in the heme biosynthetic pathway, delta-aminolevulinic acid (ALA) dehydratase (ALAD, also called porphobilinogen synthase [PBGS]; EC 4.2.1.24) (figure 1). ALAD catalyzes the formation of the monopyrrole porphobilinogen (PBG) from two molecules of ALA (figure 2), the obligate heme precursor.

Relative to activities of other enzymes in the heme biosynthetic pathway, ALAD is present in vast abundance in mammalian cells. In the liver, for example, the activity of ALAD is 80- to 100-fold that of ALA synthase, the first enzyme in the heme biosynthetic pathway and the rate-limiting enzyme in the liver (table 1) [10]. This physiologic abundance of ALAD helps to explain why heterozygotes with half-normal ALAD activity are asymptomatic.

Human ALAD is a homo-octamer with a subunit size of 36,274 daltons [11]. The enzyme binds eight zinc atoms (Zn²⁺⁾ per subunit, four of which are bound to sulfhydryl groups and are required for enzyme activity [12]. The quaternary structure of the enzyme is important for enzymatic activity. The enzyme contains an iron-sulfur cluster that is important for its activity [13]. Pathogenic variants in ALAD can promote the formation of hexamers rather than octamers; these hexamers have reduced enzymatic activity relative to octamers [14,15]. (See 'ALAD variants' below.)

Markedly reduced ALAD activity from any cause produces three principal biochemical findings, namely marked elevations of urinary ALA, urinary coproporphyrin III, and erythrocyte zinc protoporphyrin. (See 'Clinical features' below.)

This combination of biochemical findings is not specific for ADP, because the activity of normal ALAD can be inhibited in the following clinical scenarios:

●Lead – Lead is a potent inhibitor of ALAD, and lead poisoning (plumbism) can produce the same symptoms and biochemical abnormalities as ADP, including increased urinary ALA and coproporphyrin III and erythrocyte zinc protoporphyrin [16,17]. Reduced ALAD activity may be sufficient to explain these abnormalities, although lead inhibition of coproporphyrinogen oxidase and ferrochelatase may also contribute to accumulation of coproporphyrin III and zinc protoporphyrin, respectively.

Lead inhibits ALAD activity by displacing zinc from the ALAD enzyme [12]. Over 80 percent of blood lead is bound to erythrocyte ALAD [18]. Individuals with heterozygous ALAD deficiency may have increases susceptibility to lead poisoning [19].

Lead levels are normal in ADP. In contrast to lead poisoning, erythrocyte ALAD activity in individuals with ADP is not restored by the addition of zinc or dithiothreitol in vitro [20]. It is not established whether the common ALAD variant K59N, which by itself does not reduce enzyme activity, predisposes to lead poisoning [21]. (See 'ALAD variants' below.)

●Hereditary tyrosinemia – The most potent inhibitor of ALAD is succinylacetone [22]; this is a structural analogue of ALA that is found in excess concentrations in the urine and blood of patients with hereditary tyrosinemia type 1 (HT1). As a result, approximately 40 percent of children with HT1 develop the same signs and symptoms as in ADP [23]. (See "Disorders of tyrosine metabolism".)

●Unclear causes – Reduced ALAD activity has been reported in a number of other experimental and clinical conditions of uncertain significance. As examples, exposure to iron, trichloroethylene, and styrene reduces ALAD activity in rats. Erythrocyte ALAD activity is moderately decreased in humans and rats with diabetes mellitus, in patients undergoing dialysis for chronic kidney failure (perhaps related to zinc deficiency), and in smokers and individuals with an alcohol use disorder [20].

The fact that neuropathic symptoms of ADP are the same as in other acute porphyrias suggests that ALA or its metabolites, rather than PBG, which is also elevated in other acute porphyrias, may be neurotoxic. This notion is further supported by the finding that patients with hereditary tyrosinemia frequently develop clinical findings indistinguishable from ADP, including neurologic abnormalities, most likely via the marked inhibition of ALAD by succinylacetone [22,24,25]. (See "Disorders of tyrosine metabolism".)

ADP has only been reported in males (see 'Epidemiology' below). The reason for this is not explained. In other acute hepatic porphyrias, symptoms are more common in females.

Molecular genetics — ADP is an autosomal recessive disorder. The human ALAD gene is localized to chromosome 9q34 [26]. The ALAD gene contains two alternative noncoding exons, 1A and 1B, and 11 coding exons, 2 through 12, and two promoter regions generate housekeeping and erythroid-specific transcripts by alternate splicing [27,28].

The promoter region upstream of the housekeeping exon 1A is GC-rich and contains three potential Sp1 elements and a CCAAT box. Further upstream are three potential GATA-1 binding sites and an AP1 site. The promoter region upstream of the erythroid-specific exon 1B has several CACCC boxes and two potential GATA-1 binding sites. The housekeeping transcript includes exon 1A but not 1B, while the erythroid-specific transcript contains exon 1B but not 1A. Expression of an erythroid specific ALAD transcript in the bone marrow, as well as erythroid specific expression of delta-aminolevulinate synthase (ALAS), porphobilinogen deaminase (PBGD), and uroporphyrinogen III synthase (UROS), ensure sufficient heme biosynthesis for normal production of large amounts of hemoglobin [28].

ALAD variants — Fourteen ALAD variants have been identified in eight patients with ADP, and thus this disease is highly heterogeneous at the molecular level (table 2) [3,29,30]. Seven patients inherited a separate ALAD variant from each parent, while the sixth was heterozygous for an ALAD variant and developed a myeloproliferative disorder (polycythemia vera) accompanied by expansion of a clone of erythroid cells that expressed only the dysfunctional protein, such that these erythroid cells were markedly ALAD deficient [4,31].

The first molecular analysis of the ALAD gene variant in ADP was made in a German patient [32,33]. Expression studies of cDNAs derived from this patient demonstrated that one mutation produced an enzyme with little enzymatic activity but a normal half-life, while the other produced an enzyme with partial activity and a markedly decreased half-life. Thus, most of the ALAD protein in this individual's cells would be expected to be inactive. Three other patients with ADP were also found to express a form of the ALAD protein, indicating that other ALAD variants may produce stable proteins with decreased enzymatic activity [20,33,34].

Other types of ALAD disease variants have included a two-base deletion, and two intronic mutations, both in intron 3 [35]. Studies of these variants in cell-free systems have indicated that conformational effects that affect protein oligomerization are important in determining enzyme activity (by causing formation of a hexameric rather than an octameric enzyme) [14,15]. One variant was at the binding site of the iron-sulfur cluster [13]. (See 'Enzymology' above.)

The Belgian male with onset of symptoms at age 63 in association with a myeloproliferative disorder was shown to have two separate genetic variations in one ALAD allele [31]; the other allele was entirely normal. Therefore, this man was heterozygous for ALAD deficiency. His family members who had decreased ALAD activity (approximately 50 percent of normal) were also heterozygous for the same genetic changes. Heterozygous ALAD deficiency in this man was clinically "silent" until he developed polycythemia vera, leading to expansion of a polycythemic clone that carried only the pathogenic variant in ALAD [31]. A causal relationship between the myeloproliferative disorder and ADP was strongly suggested by temporal relationships between the onset of his porphyric symptoms and the onset and relapses of his myeloproliferative disorder [4,31].

Interestingly, expression of ALAD cDNAs from this individual in CHO cells revealed that only one of the changes was pathogenic: cDNAs expressing the G133R mutation alone and in combination with the K59N variant produced proteins with 8 and 16 percent ALAD activity, respectively, whereas a cDNA for the K59N variant alone produced a protein with normal ALAD activity. Subsequently, the K59N variant was found to be present in approximately 10 percent of the general population, and modeling of the K59N protein suggested that it may have normal folding, assembly, and functioning [21,36].

Another significant ALAD disease variant, producing an F12L amino acid substitution, was found in an asymptomatic Swedish girl, after she was found to have markedly decreased ALAD activity (12 percent of normal) during neonatal screening for hereditary tyrosinemia [37]. A cDNA expressing this variant produced a protein that underwent premature processing, resulting in practically no enzymatic activity [37]. This heterozygous variant resulted in very low enzyme activity because it favored formation of an ALAD hexamer rather than the normally-occurring octamer [38].

EPIDEMIOLOGY — Only eight reported cases of ADP have been confirmed at the molecular level. Strikingly, all of the affected individuals were male, which is unexplained [3]. In at least one case, investigators did not find a gain of function mutation of erythroid specific ALAS2, an X-linked modifying gene in some other porphyrias that might explain male predominance [3].

The ages of onset were as follows:

●Two cases at birth [5,6]

●One at the age of 7 years [39]

●Four at the age of 12 to 15 years (three in Germany [1,2,39-44], one in the US [29])

●One at the age of 63 years (in a Belgian man) [4,31]

Some other cases reported as ADP based on incomplete biochemical findings have not been confirmed by DNA studies, and later negative findings were not reported.

No ethnic predominance is evident.

None of the patients with pathogenic variants in ALAD were related, and most of the variants were distinct. (See 'ALAD variants' above.)

Greater awareness of porphyrias appears to account for occurrence of seven of the eight documented cases in Europe.

The frequency of genetic carriers for ALAD deficiency (heterozygotes) in the general population in Sweden is estimated to be approximately 2 percent [6]. Individuals heterozygous for ALAD deficiency (eg, parents of affected individuals) have partial deficiency of ALAD (approximately 50 percent of normal activity) and are asymptomatic [45]. They might be at increased risk for illness when exposed to environmental toxins such as lead that inhibit ALAD activity. One male patient with acute porphyria was heterozygous for a pathogenic variant in the CPOX gene (encodes coproporphyrinogen oxidase), as seen in hereditary coproporphyria, but there was also a contributing heterozygous ALAD variant that was evident from an unusual pattern of porphyrins and porphyrin precursors [46].

CLINICAL FEATURES — The full spectrum of clinical features for ADP is unknown, since so few cases have been reported. Moreover, follow-up is complete only in the two patients reported to have died.

Descriptions of the disease course in the other six patients are incomplete.

●Four of the reported patients had a similar initial clinical presentation, with symptoms and signs that were indistinguishable from other acute porphyrias (acute intermittent porphyria [AIP], hereditary coproporphyria [HCP], variegate porphyria [VP]), beginning near puberty (onset at 12 to 15 years of age). These symptoms, which include abdominal pain, predominantly motor neuropathy causing significant muscle weakness, and neuropsychiatric manifestations, are described in detail separately. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.)

Effects on the skin and other organ systems were absent.

Three of these patients were German males [1,2]; the fourth was recognized in the US, with unrelated parents from Colombia [29].

●The other four patients with ADP had clinical features that were quite different:

•One was a Swedish infant with severe symptoms beginning at birth and progressing to pain, vomiting, hyponatremia, polyneuropathy, and respiratory muscle motor dysfunction [6-9].

•Symptoms began at birth in the most recent case reported from the Netherlands [5] and at age 7 in the most recent German case [39].

•The patient in Belgium developed symptoms of acute porphyria at 63 years of age in association with a myeloproliferative disorder (polycythemia vera). Porphyric neuropathy gradually worsened and caused loss of strength in both arms [4,31,47,48].

ADP would be expected to be exacerbated by drugs, hormones, and chemicals that precipitate attacks of the other acute porphyrias (table 3). Given the paucity of reported cases, however, these associations are not established for ADP.

Biochemical findings have been distinctive relative to other acute porphyrias, with the following findings:

●Marked elevations of urinary ALA and coproporphyrin III

●Marked elevations of erythrocyte zinc protoporphyrin

●Little or no elevation in urinary porphobilinogen (PBG), which is found in other acute porphyrias

●Little or no elevation of plasma and fecal porphyrins

All cases had severe deficiencies of ALAD activity, as measured in erythrocytes.

EVALUATION AND DIAGNOSTIC TESTING

Evaluation — The acute porphyrias should be included in the differential diagnosis of patients presenting with neurovisceral symptoms such as abdominal pain, neuropathy, and neuropsychiatric symptoms, especially when initial clinical evaluation does not suggest another cause. (See "Porphyrias: An overview", section on 'Acute hepatic porphyrias (AHP; exemplified by AIP)'.)

An accurate diagnosis of acute porphyria is important to institute appropriate therapy and to avoid progressive neurological impairment. Because the presenting symptoms and signs are nonspecific and readily mimicked by more common diseases, screening for acute porphyrias is important even when the index of suspicion is not high. (See "Porphyrias: An overview", section on 'Initial testing (suspected AHP)'.)

As with other porphyrias, the preferred approach to diagnostic testing is first-line testing for screening, and more extensive second-line testing if the screening results are positive (table 4) [49]. The initial screening test for acute porphyrias is measurement of both urinary porphobilinogen (PBG) and total porphyrins on a spot urine sample obtained during an acute attack.

Measuring creatinine in the spot urine sample, so results can be expressed per gram of creatinine, is essential.

Urinary PBG will not be significantly increased in individuals with ALA dehydratase porphyria (ADP). However, a case of ADP will not be missed if urinary total porphyrins are measured on the same urine sample (algorithm 1).

Initial measurement of ALA is not essential, because urine ALA elevation (from any cause) is always accompanied by elevation in porphyrins. Of note, first-line measurement of urinary total porphyrins is also important in screening for hereditary coproporphyria (HCP) and variegate porphyria (VP), because PBG can decrease rapidly after an acute attack in these conditions. (See 'Differential diagnosis' below.)

Initial testing should be done on a spot (single void) urine specimen, with normalization to creatinine, rather than on a 24-hour collection because levels can decline as the acute attack resolves, and a 24-hour collection can unnecessarily delay diagnosis and treatment.

If first-line/screening testing for acute porphyrias is negative but suspicion remains, perhaps because symptoms are improved or resolved, extensive second-line testing is seldom indicated. Rather, the same first-line urine testing should be repeated if symptoms recur.

Second-line testing in a patient found to have elevation in total urine porphyrins but without PBG elevation should include:

●Measurement of ALA in the same urine sample (markedly elevated in ADP)

●Fractionation of porphyrins also in the same urine sample (predominantly coproporphyrin III in ADP)

●Measurement of erythrocyte protoporphyrin (markedly elevated in ADP; predominantly zinc protoporphyrin rather than metal-free protoporphyrin)

All new cases of ADP should be confirmed by measuring ALAD activity in erythrocytes and by ALAD mutation analysis.

Based on limited reported experience, plasma and fecal porphyrins are likely to be normal or minimally elevated in ADP.

Because other conditions can inhibit erythrocyte ALAD activity, leading to increases in urinary ALA and coproporphyrinogen III and erythrocyte zinc protoporphyrin, other causes of impaired ALAD activity must also be eliminated. (See 'Enzymology' above and 'Differential diagnosis' below.)

The following testing is appropriate to exclude other causes of ALAD deficiency:

●Blood lead level, to evaluate for lead poisoning. Lead poisoning is characterized by elevated lead levels and restoration of erythrocyte ALAD activity by the addition of zinc or dithiothreitol [20]. (See "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Lead exposure, toxicity, and poisoning in adults".)

●Urine organic acids, to evaluate for hereditary tyrosinemia type 1 (HT1). HT1 presents in infancy with progressive liver disease and renal tubular dysfunction; urinary organic acid testing in HT1 will reveal the presence of succinylacetone and other tyrosyl compounds. Not all newborn screening programs include screening for hereditary tyrosinemia. (See "Disorders of tyrosine metabolism", section on 'Hereditary tyrosinemia type 1'.)

ADP is an extremely rare disease, and the few reported cases have been heterogeneous clinically and at the molecular level. It is thus essential to evaluate and confirm new cases of ADP at the molecular level. ALAD gene sequencing can be done once markedly deficient ALAD activity has been identified, while other potential causes of ALAD inhibition are being eliminated. (See 'Diagnosis' below.)

Diagnosis — The diagnosis of ADP is made by documenting the elevation of urinary ALA and coproporphyrin III and erythrocyte zinc protoporphyrin, marked reduction of ALAD activity in red blood cells and eliminating other potential causes of ALAD deficiency, as described above (see 'Evaluation' above); it is confirmed by the identification of compound heterozygous (or homozygous) pathogenic variants in ALAD. Laboratories that can perform DNA testing can be found on the Genetic Testing Registry website.

The assessment of an acute attack in a patient with known ADP is made largely on clinical grounds. (See 'Clinical features' above.)

Differential diagnosis — The symptoms and signs of acute porphyrias are relatively nonspecific, including abdominal pain and neurologic manifestations [50]. The major conditions in the differential diagnosis include other causes of the neurovisceral symptoms including other acute porphyrias and other conditions in which ALAD activity is inhibited.

●Acute intermittent porphyria (AIP) — AIP is an acute porphyria resulting from partial deficiency of the heme biosynthetic enzyme porphobilinogen (PBG) deaminase [50]. AIP presents with neurovisceral symptoms. Unlike ADP, AIP is characterized by elevated urinary PBG (algorithm 1). (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis".)

●Hereditary coproporphyria (HCP) — HCP is an acute and cutaneous porphyria resulting from partial deficiency of the heme biosynthetic enzyme coproporphyrinogen oxidase. HCP presents with acute neurovisceral symptoms and, less commonly, blistering skin lesions. Unlike ADP, HCP is characterized by elevated urinary PBG and fecal porphyrins (algorithm 1). (See "Hereditary coproporphyria".)

●Variegate porphyria (VP) — VP is an acute and cutaneous porphyria resulting from partial deficiency of the heme biosynthetic enzyme protoporphyrinogen oxidase. VP presents with acute neurovisceral symptoms and, quite commonly, blistering skin lesions. Unlike ADP, VP is characterized by elevated urinary PBG, plasma porphyrins, and fecal porphyrins (algorithm 1). (See "Variegate porphyria".)

●Lead poisoning — Lead inhibits ALAD, producing gastrointestinal and neurocognitive symptoms and deficient ALAD activity that could mimic ADP. Unlike ADP, lead poisoning is associated with elevated blood lead level. Heterozygosity for an ALAD mutation could increase susceptibility to develop lead poisoning. (See "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Lead exposure, toxicity, and poisoning in adults".)

●Hereditary tyrosinemia type 1 (HT1) — HT1 is an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH), an enzyme involved in tyrosine metabolism. Accumulation of metabolites causes a variety of clinical effects, one of which is inhibition of ALAD by succinylacetone. Thus, individuals with HT1 could have neurovisceral symptoms identical to ADP. Unlike those with ADP, children with HT1 also have symptoms related to other metabolic effects, including progressive liver disease and renal tubular dysfunction. Those with HT1 have elevated urinary organic acids and FAH gene mutations. (See "Disorders of tyrosine metabolism", section on 'Hereditary tyrosinemia type 1'.)

●Other neuropathies — Neuropathies can have a variety of clinical presentations and etiologies. Unlike ADP and other acute porphyrias, acquired neuropathies (except when due to lead poisoning or HT1) are not associated with biochemical (or genetic) evidence of deficient activity of ALAD or another heme biosynthetic pathway enzyme. (See "Overview of acquired peripheral neuropathies in children" and "Overview of polyneuropathy" and "Overview of hereditary neuropathies".)

●Other causes of abdominal pain — Abdominal pain can occur in numerous clinical settings. Unlike ADP and other acute porphyrias, other causes of abdominal pain (with the exception of lead poisoning and HT1) do not produce biochemical (or genetic) evidence of deficient activity of ALAD or other heme biosynthetic pathway enzyme.

Acute porphyria should be considered in the differential diagnosis of abdominal pain when an initial workup for more common causes is negative. (See "Evaluation of the adult with abdominal pain" and "Causes of acute abdominal pain in children and adolescents" and "Chronic abdominal pain in children and adolescents: Approach to the evaluation", section on 'Etiology'.)

TREATMENT — Treatment experience is limited in ADP. The following are likely to be helpful:

●Withdrawal of any drugs or other factors known to exacerbate acute porphyrias (table 3). It is strongly recommended that clinicians consult the website of the International Porphyria Network (IPNET: https://porphyrianet.org/en/content/worldwide-network), which is frequently updated; lists many other drugs, including those that are not classified with certainty; and provides evidence for these classifications.

●Management of acute attacks with control of pain, nausea, anxiety, autonomic symptoms, and electrolyte abnormalities. (See "Acute intermittent porphyria: Management", section on 'Overview of approach'.)

●Glucose loading may be tried for treatment of mild symptoms, but there is little evidence that it is effective in ADP [9]. Therefore, hemin is preferred for treating acute attacks of ADP, as done for other acute porphyrias such as acute intermittent porphyria (AIP) [3]. (See "Acute intermittent porphyria: Management", section on 'Hemin'.)

●Treatment with hemin was effective in treating attacks in the four individuals with onset of symptoms at ages 12 to 15 years, and in at least two of those individuals, recurrent attacks were prevented by prophylactic hemin infusions [2,3,29]. In contrast, severe early onset ADP in a Swedish child did not respond to hemin (or to glucose infusions or liver transplantation) [8,9]. Use of hemin is discussed in detail separately. (See "Acute intermittent porphyria: Management", section on 'Acute attack: Primary treatment (hemin)' and "Acute intermittent porphyria: Management", section on 'Prevention of attacks'.)

●Liver transplantation failed to benefit a child with severe ADP [9]. Whether this should be considered in individuals with less-severe refractory disease is unclear. Demonstration of elevation in exosomal ALAS1 mRNA in one individual suggests that givosiran, an RNA interference (RNAi) therapeutic, might be effective at least in some individuals with ADP [3,50]. Details of givosiran administration and evidence for efficacy in other acute porphyrias are presented separately. (See "Acute intermittent porphyria: Management", section on 'Givosiran'.)

●Suppression of erythropoiesis with blood transfusions and hydroxyurea (hydroxycarbamide) was reported to be beneficial in one case [5]. This approach deserves further study.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Porphyria".)

SUMMARY AND RECOMMENDATIONS

●Pathophysiology – Delta-aminolevulinic acid dehydratase porphyria (ALA dehydratase porphyria, ADP) is the rarest porphyria. It is an autosomal recessive disorder resulting from deficiency of ALA dehydratase (ALAD), the second enzyme in heme synthesis (figure 1). In seven of eight reports, the cause was compound heterozygous pathogenic variants in the ALAD gene. (See 'Definition and history' above and 'Pathophysiology' above.)

●Presentation – ADP may present similarly to other acute neurovisceral porphyrias. Four individuals had onset of neurovisceral symptoms around puberty; two severely affected children had symptoms from birth; and a 63-year-old man who was heterozygous for an ALAD mutation developed ADP in association with a myeloproliferative disorder. Urinary ALA and coproporphyrin III are elevated, as is erythrocyte zinc protoporphyrin, with normal or only slightly elevated urinary porphobilinogen (PBG). ALAD activity in erythrocytes is markedly reduced. (See 'Clinical features' above.)

●Evaluation – Testing for acute neurovisceral porphyria involves a spot urine sample for elevated PBG and total porphyrins, with normalization to spot urine creatinine. Second-line testing should follow if PBG or porphyrins are substantially elevated (table 4). ADP is characterized by elevated urinary ALA and coproporphyrin III and erythrocyte zinc protoporphyrin. Confirmation is by documenting ALAD deficiency in red blood cells, eliminating other potential causes of ALAD deficiency, and identification of compound heterozygous (or homozygous) ALAD gene variants. The differential diagnosis includes other causes of neurovisceral symptoms (including other acute porphyrias), lead poisoning, and hereditary tyrosinemia type 1. (See 'Evaluation and diagnostic testing' above.)

●Management – Treatment experience with ADP is limited. Management should include withdrawal of any drugs or other factors known to exacerbate acute porphyrias (table 3). Hemin has been effective for treatment of acute attacks and prevention of recurrence; administration is similar to acute intermittent porphyria (AIP). Givosiran may be reasonable for adults with ≥4 attacks per year, based on experience in AIP. There is little evidence to support glucose loading. (See 'Treatment' above and "Acute intermittent porphyria: Management", section on 'Acute attack: Primary treatment (hemin)' and "Acute intermittent porphyria: Management", section on 'Prevention of attacks'.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.