Robert J. Desnick

Safety and efficacy of recombinant human alpha-galactosidase a replacement therapy in Fabry's disease

BACKGROUND Fabrys disease, lysosomal alpha-galactosidase A deficiency, results from the progressive accumulation of globotriaosylceramide and related glycosphingolipids. Affected patients have microvascular disease of the kidneys, heart, and brain. METHODS We evaluated the safety and effectiveness of recombinant alpha-galactosidase A in a multicenter, randomized, placebo-controlled, double-blind study of 58 patients who were treated every 2 weeks for 20 weeks. Thereafter, all patients received recombinant alpha-galactosidase A in an open-label extension study. The primary efficacy end point was the percentage of patients in whom renal microvascular endothelial deposits of globotriaosylceramide were cleared (reduced to normal or near-normal levels). We also evaluated the histologic clearance of microvascular endothelial deposits of globotriaosylceramide in the endomyocardium and skin, as well as changes in the level of pain and the quality of life. RESULTS In the double-blind study, 20 of the 29 patients in the recombinant alpha-galactosidase A group (69 percent) had no microvascular endothelial deposits of globotriaosylceramide after 20 weeks, as compared with none of the 29 patients in the placebo group (P<0.001). Patients in the recombinant alpha-galactosidase A group also had decreased microvascular endothelial deposits of globotriaosylceramide in the skin (P<0.001) and heart (P<0.001). Plasma levels of globotriaosylceramide were directly correlated with clearance of the microvascular deposits. After six months of open-label therapy, all patients in the former placebo group and 98 percent of patients in the former recombinant alpha-galactosidase A group who had biopsies had clearance of microvascular endothelial deposits of globotriaosylceramide. The incidence of most treatment-related adverse events was similar in the two groups, with the exception of mild-to-moderate infusion reactions (i.e., rigors and fever), which were more common in the recombinant alpha-galactosidase A group. IgG seroconversion occurred in 88 percent of patients who received recombinant alpha-galactosidase A. CONCLUSIONS Recombinant alpha-galactosidase A replacement therapy cleared microvascular endothelial deposits of globotriaosylceramide from the kidneys, heart, and skin in patients with Fabrys disease, reversing the pathogenesis of the chief clinical manifestations of this disease.

Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency

Pycnodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature, maps to chromosome 1q21. Cathepsin K, a cysteine protease gene that is highly expressed in osteoclasts, localized to the pycnodysostosis region. Nonsense, missense, and stop codon mutations in the gene encoding cathepsin K were identified in patients. Transient expression of complementary DNA containing the stop codon mutation resulted in messenger RNA but no immunologically detectable protein. Thus, pycnodysostosis results from gene defects in a lysosomal protease with highest expression in osteoclasts. These findings suggest that cathepsin K is a major protease in bone resorption, providing a possible rationale for the treatment of disorders such as osteoporosis and certain forms of arthritis.

Fabry Disease, an Under-Recognized Multisystemic Disorder: Expert Recommendations for Diagnosis, Management, and Enzyme Replacement Therapy

Fabry disease is an X-linked recessive lysosomal storage disorder that is caused by the deficient activity of -galactosidase A (-Gal A, also termed ceramide trihexosidase) (1, 2) and the resultant accumulation of globotriaosylceramide (also termed ceramide trihexoside) and related glycosphingolipids (3-5). In patients with the classic phenotype, levels of -Gal A activity are very low or undetectable. Patients with detectable -Gal A activity have a milder, variant phenotype (6-8). In classically affected males, the progressive glycosphingolipid accumulation, particularly in the vascular endothelium (Figure 1), leads to renal, cardiac, and cerebrovascular manifestations and early death. The disease is panethnic, and estimates of incidence range from about 1 in 40 000 to 60 000 males (5, 9). Fabry disease predominantly affects males, although carrier (heterozygous) females also can be affected to a mild or severe degree because of random X-chromosomal inactivation (5). Figure 1. Distinctive laboratory findings in Fabry disease. A B In the absence of a family member who has already received a diagnosis of the disorder, many cases are not diagnosed until adulthood (average age, 29 years) (9, 10), when the pathology of the disorder may already be advanced. Although clinical onset occurs in childhood, disease presentation may be subtle, and its signs and symptoms are often discounted as malingering or are mistakenly attributed to other disorders, such as rheumatic fever, erythromelalgia, neurosis, the Raynaud syndrome, multiple sclerosis, chronic intermittent demyelinating polyneuropathy, lupus, acute appendicitis, growing pains, or petechiae (5, 11). Fabry disease was first identified a century ago, but until now, no disease-specific treatment has been available. Patients have been managed with supportive, nonspecific treatment for pain management, cardiac and cerebrovascular complications, and end-stage renal disease. These interventions may prolong life, but their utility is limited because they do not address the underlying cause of the disease, that is, the lack of -Gal A and the progressive accumulation of globotriaosylceramide. Recently, enzyme replacement with human -Gal A has been shown to safely reverse the pathogenesis of the major clinical manifestations, to decrease pain, and to stabilize renal function in patients with Fabry disease (12, 13). The European Agency for the Evaluation of Medicinal Products has approved the treatment, and the U.S. Food and Drug Administration is currently reviewing it. Thus, recommendations for the diagnosis and treatment of Fabry disease are timely. Formation of Expert Panel and Basis of Recommendations In June and July of 2001, two groups of investigators published randomized, placebo-controlled trials that demonstrated that enzyme replacement therapy in Fabry disease can reverse the major pathologic consequences and improve outcomes (12, 13). With a disease-specific therapy finally available, the need for prompt and accurate diagnosis of this devastating, progressive disease became paramount so that patients could be identified and treated before incurring irreversible organ damage. Recognizing the need for initial guidelines for diagnosis, management, and the use of enzyme replacement therapy, Dr. Robert Desnick and Dr. Roscoe Brady (senior authors of the enzyme replacement trials) assembled an international panel of experts with extensive clinical experience and diverse subspecialty expertise in Fabry disease and lysosomal storage disorders. Panelists met face-to-face to identify and discuss salient issues. An independent coordinator conducted numerous global and specific searches of the MEDLINE database (19912001), including a global search of the recent literature on Fabry disease. The coordinator then interviewed each panelist in detail and, with the first author, prepared a draft statement. In a second face-to-face session, the draft was reviewed, revised, and finalized by the panel. A teleconference was convened to revise the manuscript after journal review. Support for the expert panel process was obtained from the Genzyme Corporation (Cambridge, Massachusetts), which had no formative role in the literature review, the formulation of recommendations, or the drafting and revising of the manuscript. As would be expected for a rare, under-recognized disease, the literature on Fabry disease mostly consists of single or small case studies and reviews in addition to book chapters written by Fabry experts. The few larger studies focus on disease manifestations and mechanisms of disease rather than the effectiveness of interventions or disease management. The literature on enzyme replacement therapy is limited to the clinical trials published in the last 2 years. Thus, clinical experience and expertise played an important role in the formulation of these recommendations. Disease Pathophysiology and Clinical Manifestations The major debilitating manifestations of Fabry disease result from the progressive accumulation of globotriaosylceramide in the vascular endothelium (Figure 1), leading to ischemia and infarction, especially in the kidney, heart, and brain. The ischemia and infarction of small vessels are primarily due to vascular occlusion (5); however, evidence for a prothrombotic state has recently been published (14). In addition, early and substantial deposition of globotriaosylceramide occurs in podocytes, leading to proteinuria and, with age, in cardiomyocytes, causing cardiac hypertrophy and conduction abnormalities (Figure 1). Patients are generally divided into two major groups on the basis of the absence or presence of residual -Gal A activity: classic disease and milder, later-onset, atypical variants (5). Presentation and clinical course can vary within these phenotypes, and an intermediate phenotype has also been described (15-17). The Classic Phenotype Males with classic disease have no or very low -Gal A activity, resulting in severe renal, cardiac, and cerebrovascular disease manifestations. Before treatment of uremia became available, the average lifespan of affected males was about 40 years (18). With the advent of renal dialysis or transplantation, the median survival was about 50 years (19). Clinical manifestations (Figures 1 and 2), which usually begin in childhood or adolescence, include intermittent pain in the extremities (acroparesthesias); episodic Fabry crises of acute pain lasting hours to days; characteristic skin lesions (angiokeratomas); a corneal opacity that does not affect vision; hypohidrosis; heat, cold, and exercise intolerance; mild proteinuria; and gastrointestinal problems. By adulthood, the renal involvement inevitably results in end-stage renal disease, which requires dialysis or transplantation (20, 21). Cardiac manifestations include left ventricular hypertrophy, valvular disease (especially mitral insufficiency), ascending aortic dilatation, coronary artery disease, and conduction abnormalities (Figure 1), leading to congestive heart failure, arrhythmias, and myocardial infarction (5, 22-24). Cerebrovascular manifestations include early stroke, transient ischemic attacks, white matter lesions, hemiparesis, vertigo or dizziness, and complications of vascular disease (such as diplopia, dysarthria, nystagmus, tinnitus, hemiataxia, memory loss, and hearing loss) (5, 25). Figure 2. Distinctive clinical features of Fabry disease. A B C Clinical manifestations in carrier females range from asymptomatic to full-blown disease as severe as that in affected males (5, 26-28). Although many carriers will be relatively asymptomatic and have a normal lifespan, carriers may experience symptoms in childhood and adolescence (such as pain and proteinuria) and adulthood (such as cardiac or, more rarely, renal manifestations). In late adulthood, some carriers develop left ventricular hypertrophy and substantial cardiomyopathy. Data on carriers are limited. A recent study of obligate carrier females found significant disease manifestations in 20 of 60 women, including 17 of whom who had experienced transient ischemic attacks or cerebrovascular accidents (28). Atypical Variants Atypical male variants have a milder, later-onset phenotype (5-7, 17, 29). Because of low residual -Gal A levels, these patients do not have the early major clinical manifestations of classic Fabry disease. For example, cardiac variants present with cardiomegaly and mild proteinuria usually after 40 years of age, when patients with classic Fabry disease would be severely affected or would have died (6, 7, 29). Two recent studies have suggested that the cardiac variant of Fabry disease may be an important cause of idiopathic left ventricular hypertrophy (7) or late-onset hypertrophic cardiomyopathy (30). Tissue biopsies or autopsy studies of cardiac variants reveal globotriaosylceramide accumulation in the myocardium and not in the vascular endothelium throughout the body (5, 6, 29). These findings suggest that even low levels of -Gal A can prevent globotriaosylceramide accumulation in the microvasculature and that this lack of accumulation is associated with the absence or attenuation of disease manifestations. Thus, reversal of the underlying vascular endothelial pathology by enzyme replacement therapy will probably be clinically therapeutic in patients with classic Fabry disease. Enzymatic and Molecular Diagnosis In affected males with the classic or variant phenotype, the disease is readily diagnosed by determining the -Gal A activity in plasma or peripheral leukocytes. In contrast, female carriers can have normal to very low -Gal A activity; therefore, their specific family mutation in the -Gal A gene must be demonstrated. Most kindreds have family-specific or private mutations; to date, more than 300 mutations have been identified, of which most are missense (amino acid substitutions) or nonsense (causing premature truncation of the amino acid sequence) mutations. Spli

A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing

BACKGROUND The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).

A Phase 1/2 Clinical Trial of Enzyme Replacement in Fabry Disease: Pharmacokinetic, Substrate Clearance, and Safety Studies

Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.

Long-Term Safety and Efficacy of Enzyme Replacement Therapyfor Fabry Disease

Elsewhere, we reported the safety and efficacy results of a multicenter phase 3 trial of recombinant human alpha -galactosidase A (rh-alpha GalA) replacement in patients with Fabry disease. All 58 patients who were enrolled in the 20-wk phase 3 double-blind, randomized, and placebo-controlled study received subsequently 1 mg/kg of rh-alpha GalA (agalsidase beta, Fabrazyme, Genzyme Corporation) biweekly in an ongoing open-label extension study. Evidence of long-term efficacy, even in patients who developed IgG antibodies against rh- alpha GalA, included the continuously normal mean plasma globotriaosylceramide (GL-3) levels during 30 mo of the extension study and the sustained capillary endothelial GL-3 clearance in 98% (39/40) of patients who had a skin biopsy taken after treatment for 30 mo (original placebo group) or 36 mo (original enzyme-treated group). The mean serum creatinine level and estimated glomerular filtration rate also remained stable after 30-36 mo of treatment. Infusion-associated reactions decreased over time, as did anti-rh- alpha GalA IgG antibody titers. Among seroconverted patients, after 30-36 mo of treatment, seven patients tolerized (no detectable IgG antibody), and 59% had > or =4-fold reductions in antibody titers. As of 30 mo into the extension trial, three patients were withdrawn from the study because of positive serum IgE or skin tests; however, all have been rechallenged successfully at the time of this report. Thus, enzyme replacement therapy for 30-36 mo with agalsidase beta resulted in continuously decreased plasma GL-3 levels, sustained endothelial GL-3 clearance, stable kidney function, and a favorable safety profile.

Sustained, Long-Term Renal Stabilization After 54 Months of Agalsidase β Therapy in Patients with Fabry Disease

Fabry disease, an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human alpha-galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase beta and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase beta for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n = 8) maintained complete GL-3 clearance in renal capillary endothelial cells and multiple cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n = 41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time. Long-term agalsidase beta therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.

Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium.

The autosomal dominant, giant-platelet disorders, May-Hegglin anomaly (MHA; MIM 155100), Fechtner syndrome (FTNS; MIM 153640) and Sebastian syndrome (SBS), share the triad of thrombocytopenia, large platelets and characteristic leukocyte inclusions (?Döhle-like? bodies). MHA and SBS can be differentiated by subtle ultrastructural leukocyte inclusion features, whereas FTNS is distinguished by the additional Alport-like clinical features of sensorineural deafness, cataracts and nephritis. The similarities between these platelet disorders and our recent refinement of the MHA (ref. 6) and FTNS (ref. 7) disease loci to an overlapping region of 480 kb on chromosome 22 suggested that all three disorders are allelic. Among the identified candidate genes is the gene encoding nonmuscle myosin heavy chain 9 (MYH9; refs 8?10), which is expressed in platelets and upregulated during granulocyte differentiation. We identified six MYH9 mutations (one nonsense and five missense) in seven unrelated probands from MHA, SBS and FTNS families. On the basis of molecular modelling, the two mutations affecting the myosin head were predicted to impose electrostatic and conformational changes, whereas the truncating mutation deleted the unique carboxy-terminal tailpiece. The remaining missense mutations, all affecting highly conserved coiled-coil domain positions, imparted destabilizing electrostatic and polar changes. Thus, our results suggest that mutations in MYH9 result in three megakaryocyte/platelet/leukocyte syndromes and are important in the pathogenesis of sensorineural deafness, cataracts and nephritis.The autosomal dominant, giant-platelet disorders1, May-Hegglin anomaly2,3 (MHA; MIM 155100), Fechtner syndrome4 (FTNS; MIM 153640) and Sebastian syndrome5 (SBS), share the triad of thrombocytopenia, large platelets and characteristic leukocyte inclusions (?Döhle-like? bodies). MHA and SBS can be differentiated by subtle ultrastructural leukocyte inclusion features, whereas FTNS is distinguished by the additional Alport-like clinical features of sensorineural deafness, cataracts and nephritis4. The similarities between these platelet disorders and our recent refinement of the MHA (ref. 6) and FTNS (ref. 7) disease loci to an overlapping region of 480 kb on chromosome 22 suggested that all three disorders are allelic. Among the identified candidate genes is the gene encoding nonmuscle myosin heavy chain 9 (MYH9; refs 810), which is expressed in platelets9 and upregulated during granulocyte differentiation10. We identified six MYH9 mutations (one nonsense and five missense) in seven unrelated probands from MHA, SBS and FTNS families. On the basis of molecular modelling, the two mutations affecting the myosin head were predicted to impose electrostatic and conformational changes, whereas the truncating mutation deleted the unique carboxy-terminal tailpiece. The remaining missense mutations, all affecting highly conserved coiled-coil domain positions, imparted destabilizing electrostatic and polar changes. Thus, our results suggest that mutations in MYH9 result in three megakaryocyte/platelet/leukocyte syndromes and are important in the pathogenesis of sensorineural deafness, cataracts and nephritis.

Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel

Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel

Recommendations for the Diagnosis and Treatment of the Acute Porphyrias

Key Summary Points Early Diagnosis of Acute Porphyria Consider in all adults with unexplained symptoms seen in acute porphyrias (Table 2); certain clinical features are suggestive: women of reproductive age; abdominal pain; muscle weakness; hyponatremia; and dark or reddish urine. Establish diagnosis promptly by testing for increased porphobilinogen in a single-void urine (we recommend the Trace PBG Kit [Thermo Trace/DMA, Arlington, Texas]). If porphobilinogen is increased, begin treatment immediately. To establish the type of acute porphyria, save the same urine sample for measurement of ALA, porphobilinogen, and porphyrin levels, and measure plasma porphyrin levels, fecal porphyrin levels, and erythrocyte porphobilinogen deaminase levels (Table 5 and Figure). Treatment of the Acute Attack Hospitalize patient for control of acute symptoms and withdraw all unsafe medications (see Table 3) and other possible precipitating factors. Provide nutritional support and symptomatic and supportive treatment; consider seizure precautions, especially if patient is hyponatremic; use medications that are known to be safe in the acute porphyrias; and use intravenous fluids to correct dehydration and electrolyte imbalances, narcotic analgesics for pain, phenothiazine for nausea or vomiting, and -adrenergic blockers for hypertension and symptomatic tachycardia. Begin hemin (3 to 4 mg/kg daily for at least 4 days) as soon as possible. Intravenous glucose alone (10%, at least 300 g daily) may resolve mild attacks (mild pain, no paresis, or hyponatremia) or can be given while awaiting delivery of hemin. Monitor patient closely: Check vital capacity (if impaired, place patient in intensive care) and neurologic status, including muscle strength (especially proximal); check serum electrolytes, creatinine, and magnesium levels at least daily; and watch for bladder distention. Follow-up Educate patient and family about the disease, its inheritance, precipitating factors, and important preventive measures. Encourage patients to wear medical alert bracelets and keep records of diagnostic studies and recommended therapy. Treat chronic manifestations (such as pain and depression) and disability. Provide access to genetic testing for patient and family members. The acute porphyrias are well-defined genetic disorders of heme biosynthesis characterized by acute life-threatening attacks of nonspecific neurologic symptoms (1). Although the specific enzyme and gene defects have been identified, diagnosis and treatment of these 4 disorders still present formidable challenges because their symptoms and signs mimic other, more common conditions. Delaying diagnosis and treatment of acute porphyric attacks can be fatal or can cause long-term or permanent neurologic damage. Updated, consistent recommendations for timely diagnosis and treatment of these disorders have been lacking, despite the existence of rapid, sensitive, and specific biochemical tests (2) and the availability of an effective therapy, which was first described more than 30 years ago (3) and was approved by the U.S. Food and Drug Administration (FDA) more than 20 years ago. Formation of an Expert Panel and Basis of Recommendations Concerns about misdiagnosis, delayed diagnosis, and inappropriate therapy prompted the American Porphyria Foundation to assemble a panel of experts on the acute porphyrias who were selected on the basis of their clinical and research experience and their contributions to the medical literature. The panel, which represents specialties including internal medicine, pediatrics, genetics, gastroenterology, hepatology, and hematology, was charged with formulating updated recommendations for diagnosing and treating the acute porphyrias. With support from the American Porphyria Foundation, the panel members convened for a day-long meeting to formulate clinical recommendations. Two members, assisted by a medical writer funded by the Foundation, prepared a draft manuscript based on the panels discussion and recommendations. All panel members participated in the review and revision of the manuscript and agreed to the final version. Recommendations are based on the clinical experience of the authors and their review of the literature. Because the acute porphyrias are rare, most of the literature consists of reviews, small series, and case studies. A detailed MEDLINE search on treatment of acute attacks, for example, revealed 71 papers (55 in English and 16 with English abstracts) published between 1966 and October 2004. Of these, 41 were single-case reports, 13 were case series of 10 or fewer patients, and 17 (11 in English) were studies with more than 10 patients (4-20). Altogether, 53 papers discuss more than 1000 patients who received hemin therapy with or without initial treatment with glucose. The American Porphyria Foundation partially funded this review. This nonprofit organization provides information and support to patients with porphyria and their physicians. It receives funding from private sources in addition to a nonrestricted grant from Ovation Pharmaceuticals, the manufacturer of hemin for injection (Panhematin), the only FDA-approved hemin therapy for the acute porphyrias. The Foundation and Ovation Pharmaceuticals had no role in the literature review, the formulation of recommendations, or the drafting and revising of the manuscript. Overview of the Acute Porphyrias Acute Porphyrias Are Inborn Errors of Heme Biosynthesis Each of the acute porphyrias results from the deficient activity of a distinct enzyme in the heme biosynthetic pathway (1). Porphyrias are classified as hepatic or erythroid, depending on whether most of the heme biosynthetic intermediates arise from, and accumulate in, the liver or in developing erythrocytes. They are also classified clinically as acute or cutaneous on the basis of their major clinical manifestations. Of the 5 hepatic porphyrias, 4 characteristically present with acute attacks of neurologic manifestationshence the designation acute porphyrias, a term that does not fully describe the clinical features, which can be prolonged and chronic. Table 1 shows the genetic and enzymatic features of the 4 acute hepatic porphyrias (21): acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and the very rare 5-aminolevulinic acid (ALA)dehydratase porphyria. The combined prevalence of these diseases is approximately 5 cases per 100000 persons (1). Numerous mutations have been identified for each disorder. The major manifestations of the acute porphyrias are neurologic, including neuropathic abdominal pain, peripheral neuropathy, and mental disturbances (Table 2) (1, 4, 22-25). These develop during adult life, are more common in women than in men, and are treated by methods to restore heme homeostasis. Variegate porphyria and, much less commonly, hereditary coproporphyria can also cause chronic, blistering lesions on sun-exposed skin that are identical to those in porphyria cutanea tarda, a much more common condition. Photocutaneous lesions may occur without neuropathic manifestations. Table 1. Characteristics of the 4 Acute Porphyrias Table 2. Common Presenting Symptoms and Signs of Acute Porphyria In addition to their highly variable neurologic signs and symptoms, the acute porphyrias are distinct from other porphyrias because of their common overproduction of the porphyrin precursors ALA (an amino acid), and porphobilinogen (a pyrrole). This striking biochemical feature is important for laboratory diagnosis and has implications for pathogenesis of the neurologic manifestations. While porphyrins (tetrapyrroles) are also increased, their measurement is of little value for initial diagnosis because they are also increased (in urine, feces, erythrocytes, or plasma) in other porphyrias and many other medical conditions. Pathogenesis of Acute Attacks The enzyme deficiency in each disorder is partial (approximately 50% of normal in the 3 most common acute porphyrias), and the remaining enzyme activity is usually sufficient for heme homeostasis. Because ALA dehydratase activity normally greatly exceeds that of the other enzymes in the pathway, a more severe deficiency of this enzyme (5% of normal) is required to cause manifestations of ALA-dehydratase porphyria. These enzymatic defects predispose the affected persons to the effects of precipitating factors, including many drugs (for example, barbiturates, anticonvulsants, rifampin, and progestins), endogenous steroid hormones (especially progesterone), fasting, dieting, smoking, and stress from illness, all of which can increase the demand for hepatic heme and induce synthesis of ALA synthase, the first enzyme in the heme biosynthetic pathway. Because hepatic ALA synthase is rate-controlling, production of heme pathway intermediates increases to the point at which the inherited partial enzyme deficiency becomes limiting, and intermediates accumulate in the liver. Porphobilinogen and ALA levels are increased in all patients with acute symptoms of these disorders and in some who are asymptomatic. The cause of hepatic overproduction of porphyrin precursors in the acute porphyrias is better understood than are the mechanisms for neurologic damage. Presumably, symptoms result primarily from the porphyrin precursors themselves rather than a deficiency of heme in nerve tissue (26, 27). Chronic symptoms and signs may reflect previous, unresolved neurologic damage. In the very rare cases of homozygous acute intermittent porphyria (26), variegate porphyria (28), and hereditary coproporphyria (29), severe neurologic manifestations begin in childhood. An allogeneic liver transplantation in a woman with heterozygous acute intermittent porphyria normalized her urinary ALA and porphobilinogen levels in 24 hours and completely eliminated her recurrent neurologic attacks, which supports the hepatic overproduction of porphyrin precursors in causing the neurologic symptoms (27). Si