Page 925 - Williams Hematology ( PDFDrive )

900 Part VI: The Erythrocyte Chapter 58: The Porphyrias 901

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Marrow transplantation can achieve remission in human EPP, subjects was shown to cause substantial coproporphyrinuria. The
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as well in murine models of protoporphyria. Sequential liver and pathogenesis of the neurologic symptoms is poorly understood, as in
marrow transplantation can correct the overproduction of protopor- other acute porphyrias.
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phyrin by the marrow and prevent recurrence of liver disease. Prom-
ising studies in murine models suggest a future role for gene therapy in Clinical Features
human EPP. 163,165 The four adolescent males had intermittent symptoms resembling
other acute porphyrias, including abdominal pain, vomiting, extrem-
ity pain, and motor neuropathy, although exacerbating factors were
ACUTE PORPHYRIAS less evident. 168,174 Two German cases had initial acute attacks and then
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remained well during 20 years of followup. The third German case
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The acute porphyrias are comprised of four disorders caused by differ- and the U.S. case had further attacks and were maintained on prophy-
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ent enzyme deficiencies, and are distinctive for neurologic symptoms lactic hemin infusions. The Swedish infant had more severe neurologic
that usually occur as acute exacerbations during adult life. Similar disease, including failure to thrive, and died after liver transplanta-
symptoms occur in lead poisoning, hereditary tyrosinemia type I, and tion. The 63-year-old man in Belgium, developed an acute motor
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in some reported cases of porphyria with dual enzyme deficiencies. polyneuropathy concurrently with a myeloproliferative disorder. 88,164,178
δ-AMINOLEVULINIC ACID DEHYDRATASE Diagnosis
A biochemical diagnosis of ADP includes demonstration of markedly
PORPHYRIA deficient erythrocyte ALAD activity, marked elevation in urinary ALA
Definition and History and coproporphyrin III and erythrocyte zinc protoporphyrin, with little
ADP is an autosomal recessive disorder resulting from severe deficiency or no increase in urinary PBG. Erythrocyte ALAD activity is approx-
of ALAD activity (see Table 58–1 and Fig. 58–1). This is the rarest of the imately half-normal in both parents. Lead poisoning is differentiated
porphyrias, with only six cases documented at the molecular level. 50,168 by increased blood lead and restoration of ALAD activity in vitro by
reduced glutathione or dithiothreitol. 167,179 Although biochemical mea-
Pathophysiology surements can strongly suggest ADP, the diagnosis must be confirmed
All reported cases were males. 164,166–169 Compound heterozygosity for by DNA studies.
two distinct ALAD mutations was documented in five cases (see Fig. Patients with hereditary tyrosinemia type I may also have ALAD
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58–4, step 2). 167,168 Four (three in Germany and one in the United States) inhibition and increased excretion of ALA. Dioxoheptanoic acid
experienced onset of symptoms in their teens, whereas one Swedish (succinylacetone), a structural analogue of ALA and a potent ALAD
case developed severe symptoms in infancy. The sixth patient was a inhibitor, accumulates as a result of an inherited deficiency of fumary-
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Belgian male who developed ADP at age 63 years and was found to have lacetoacetate hydrolase in these patients. The presence of this inhibitor
two inherited base transitions in one allele, and was therefore heterozy- can be demonstrated in urine by measuring ALAD activity in normal
gous for ALAD deficiency. 164,169 He also developed polycythemia vera blood after addition of a patient’s urine. ALAD protein is not reduced
and his erythrocyte ALAD activity was less than 1 percent of normal, in this disease. 180
while lymphocyte ALAD activity was greater than 20 percent of normal.
Heterozygous ALAD deficiency was apparently clinically silent in this Therapy
patient until there was expansion of a clone of erythroid cells that car- Because few cases have been documented, treatment recommendations
ried the mutant ALAD allele. 169 are based on limited experience. Hemin was beneficial in the four male
Thus ADP is highly heterogeneous at the molecular level, with a patients, but there was little or no response to glucose. A long-term pre-
total of 11 mutant alleles identified in these 6 patients. An additional ventive hemin regimen was effective in two of these patients. The Swed-
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mutation was found in a healthy Swedish girl with markedly decreased ish infant did not respond to glucose or hemin, and did not improve
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ALAD activity (12% of normal), which was detected by ALAD mea- greatly after liver transplantation. Whether transplantation would
surement during neonatal screening for hereditary tyrosinemia. The benefit less severe cases is unknown. Hemin produced a biochemical
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same mutation was found in a U.S. male patient with acute porphyria response but no clinical improvement in the late-onset case in Belgium,
who also had a CPO mutation and an unusual pattern of porphyrin who had a peripheral neuropathy but no acute attacks. 178
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precursors and porphyrins reflecting dual enzyme deficiencies. Thus,
heterozygous ALAD deficiency may rarely be combined with another ACUTE INTERMITTENT PORPHYRIA
enzyme deficiency, or may itself cause porphyria if a marrow disorder
leads to clonal expansion of the mutant ALAD allele. Definition and History
Human ALAD consists of eight identical oligomers, each with two AIP is an autosomal dominant disorder caused by a partial deficiency
zinc-binding sites. Lead can bind at least one of these sites and impair of PBG deaminase (see Table 58–1 and Fig. 58–1). Symptoms usually
enzyme activity. Some mutations found in ADP may affect zinc binding, occur as acute attacks and are neurologic in origin. In most countries
or favor assembly of a hexameric enzyme with decreased activity. Thus this is the most common acute porphyria and the second most common
ADP has been described as a conformational disease. 50 porphyria. Most individuals who inherit the enzyme deficiency (proba-
ADP is classified as one of the hepatic porphyrias because it closely bly more than 90 percent) never develop symptoms, but are at some risk
resembles the other acute porphyrias. However, the site of overproduc- to develop symptoms after puberty. The first case of acute porphyria was
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tion of ALA is not established, and the Swedish infant with severe, early described in 1889 by Stokvis who noted a relationship of the symptoms
onset disease did not benefit from liver transplantation. Substantial to the drug sulfonal, which is related to the barbiturates.
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increase in erythrocyte zinc protoporphyrin also suggests an erythroid Prevalence of AIP was estimated to be 1 to 2 per 100,000 popu-
component. The excess urinary coproporphyrin III in ADP may orig- lation in Europe, and 2.4 per 100,000 population in Finland. Up
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inate from metabolism of ALA to porphyrinogens in a tissue other to 300 PBGD mutations have been described in AIP, with many found
than the site of ALA overproduction. Indeed, ALA loading in normal in only one or a few families. 183,184 The disease occurs in all races, but

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