[New therapeutic option for acute hepatic porphyrias]. / Neue Therapieoption für akute hepatische Porphyrien.

Givosiran is a small synthetic double-stranded siRNA (small interfering RNA) conjugated with N-acetyl-galactosamine (GalNAc) for specific hepatocyte targeting via the asialoglycoprotein receptor. A prospective randomized multicenter study (Envision) demonstrated the clinical efficacy of monthly subcutaneous injection of Givosiran for the prevention of attacks of acute hepatic porphyria (AHP). This leads to highly selective transcriptional inhibition of the key hepatic enzyme, aminolaevulinate synthase 1, that is overexpressed in AHP. The success of the Envision study has led to the approval of Givosiran in the US and Europe for the treatment of severe AHP. This innovative guided siRNA therapy has opened up the possibility to selectively inhibit the expression of any hepatocyte gene whose overexpression that causes pathology, which can be considered a milestone development in hepatology. However, currently this treatment with givosiran is very costly. Moreover, since some patients experience worsening of kidney function and elevated aminotransferases, monthly monitoring of these parameters is necessary in the first half year of treatment.

Porphyria attacks in prepubertal children and adolescents.

CONTEXT: The clinical and laboratory features of dominant acute hepatic porphyrias (AHPs) in prepubertal children and adolescents have not been well established. OBJECTIVE: To evaluate clinical and laboratory features of AHPs in prepubertal children and adolescents compared to adults. DATA SOURCES: OVID (Embase Classic+Embase and MEDLINE), Scopus, and Google Scholar. STUDY SELECTION: Studies describing symptomatic children or adolescents (<18 years old) with increased urinary porphobilinogen were included. DATA EXTRACTION: Two reviewers independently extracted the data, with a third reviewer arbitrating discrepancies. RESULTS: 100 studies were included describing 112 patients (26 prepubertal children and 86 adolescents). Differences were found between prepubertal children and adolescents regarding sex distribution (female-to-male ratio: 1:2 vs. 4:1), clinical manifestations, and concomitant clinical manifestations. LIMITATIONS: There was variation in the methods used to diagnose porphyria attacks across studies, and some elements of the quality of individual studies were unclear. CONCLUSIONS: Prepubertal children with AHPs and porphyria attacks presented with distinct demographic and clinical characteristics from adolescents and adults. Nearly two-thirds of the affected children were males, and about half had a concomitant medical condition that can constitutively upregulate hepatic δ-aminolevulinic acid synthase-1. Adolescents were comparable to adults in almost all respects.

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks.

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.

International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias.

With the advent of precision and genomic medicine, a critical issue is whether a disease gene variant is pathogenic or benign. Such is the case for the three autosomal dominant acute hepatic porphyrias (AHPs), including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, each resulting from the half-normal enzymatic activities of hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase, respectively. To date, there is no public database that documents the likely pathogenicity of variants causing the porphyrias, and more specifically, the AHPs with biochemically and clinically verified information. Therefore, an international collaborative with the European Porphyria Network and the National Institutes of Health/National Center for Advancing Translational Sciences/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NCATS/NIDDK)-sponsored Porphyrias Consortium of porphyria diagnostic experts is establishing an online database that will collate biochemical and clinical evidence verifying the pathogenicity of the published and newly identified variants in the AHP-causing genes. The overall goal of the International Porphyria Molecular Diagnostic Collaborative is to determine the pathogenic and benign variants for all eight porphyrias. Here we describe the overall objectives and the initial efforts to validate pathogenic and benign variants in the respective heme biosynthetic genes causing the AHPs.

Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management.

Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic pathway. EPP results from the partial deficiency of ferrochelatase, and XLP results from gain-of-function mutations in erythroid specific ALAS2. Both disorders result in the accumulation of erythrocyte protoporphyrin, which is released in the plasma and taken up by the liver and vascular endothelium. The accumulated protoporphyrin is activated by sunlight exposure, generating singlet oxygen radical reactions leading to tissue damage and excruciating pain. About 2-5% of patients develop clinically significant liver dysfunction due to protoporphyrin deposition in bile and/or hepatocytes which can advance to cholestatic liver failure requiring transplantation. Clinically these patients present with acute, severe, non-blistering phototoxicity within minutes of sun-exposure. Anemia is seen in about 47% of patients and about 27% of patients will develop abnormal serum aminotransferases. The diagnosis of EPP and XLP is made by detection of markedly increased erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin. Genetic testing by sequencing the FECH or ALAS2 gene confirms the diagnosis. Treatment is limited to sun-protection and there are no currently available FDA-approved therapies for these disorders. Afamelanotide, a synthetic analogue of α-melanocyte stimulating hormone was found to increase pain-free sun exposure and improve quality of life in adults with EPP. It has been approved for use in the European Union since 2014 and is not available in the U.S. In addition to the development of effective therapeutics, future studies are needed to establish the role of iron and the risks related to the development of hepatopathy in these patients.

Murine models of the human porphyrias: Contributions toward understanding disease pathogenesis and the development of new therapies.

Mouse models of the human porphyrias have proven useful for investigations of disease pathogenesis and to facilitate the development of new therapeutic approaches. To date, mouse models have been generated for all major porphyrias, with the exception of X-linked protoporphyria (XLP) and the ultra rare 5-aminolevulinic acid dehydratase deficient porphyria (ADP). Mouse models have been generated for the three autosomal dominant acute hepatic porphyrias, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). The AIP mice, in particular, provide a useful investigative model as they have been shown to have acute biochemical attacks when induced with the prototypic porphyrinogenic drug, phenobarbital. In addition to providing important insights into the disease pathogenesis of the neurological impairment in AIP, these mice have been valuable for preclinical evaluation of liver-targeted gene therapy and RNAi-mediated approaches. Mice with severe HMBS deficiency, which clinically and biochemically mimic the early-onset homozygous dominant AIP (HD-AIP) patients, have been generated and were used to elucidate the striking phenotypic differences between AIP and HD-AIP. Mice modeling the hepatocutaneous porphyria, porphyria cutanea tarda (PCT), made possible the identification of the iron-dependent inhibitory mechanism of uroporphyrinogen decarboxylase (UROD) that leads to symptomatic PCT. Mouse models for the two autosomal recessive erythropoietic porphyrias, congenital erythropoietic porphyria (CEP) and erythropoeitic protoporphyria (EPP), recapitulate many of the clinical and biochemical features of the severe human diseases and have been particularly useful for evaluation of bone marrow transplantation and hematopoietic stem cell (HSC)-based gene therapy approaches. The EPP mice have also provided valuable insights into the underlying pathogenesis of EPP-induced liver damage and anemia.

Experiences and concerns of patients with recurrent attacks of acute hepatic porphyria: A qualitative study.

BACKGROUND: The acute hepatic porphyrias (AHPs) are rare inborn errors of heme biosynthesis, characterized clinically by life-threatening acute neurovisceral attacks. Patients with recurrent attacks have a decreased quality of life (QoL); however, no interactive assessment of these patients' views has been reported. We conducted guided discussions regarding specific topics, to explore patients' disease experience and its impact on their lives. METHODS: Sixteen AHP patients experiencing acute attacks were recruited to moderator-led online focus groups. Five groups (3-4 patients each) were conducted and thematic analyses to identify, examine, and categorize patterns in the data was performed. RESULTS: All patients identified prodromal symptoms that began days prior to acute severe pain; the most common included confusion ("brain fog"), irritability, and fatigue. Patients avoided hospitalization due to prior poor experiences with physician knowledge of AHPs or their treatment. All patients used complementary and alternative medicine treatments to avoid hospitalization or manage chronic pain and 81% reported varying degrees of effectiveness. All patients indicated their disease impacted personal relationships due to feelings of isolation and difficulty adjusting to the disease's limitations. CONCLUSION: Patients with recurrent attacks recognize prodromal warning symptoms, attempt to avoid hospitalization, turn to alternative treatments, and have markedly impaired QoL. Counseling and individualized support is crucial for AHP patients with recurrent attacks.

THINK PORPHYRIA: CASE REPORT AND REVIEW OF LITERATURE.

Porphyrias are a group of rare disorders caused by enzyme defects in haem biosynthesis pathway. Acute intermittent porphyria is the most common hepatic porphyria. The disorder presents with severe neuropathic abdominal pain that can be accompanied by a wide range of gastrointestinal, psychiatric and neurological symptoms, making the diagnosis clarification very challenging. We report a case of a 27-year-old female patient who presented with acute abdominal pain, vomiting and marked hyponatremia, developed seizures and disorientation, and eventually required intensive care unit treatment to maintain breathing. Her symptoms were initially misinterpreted as a functional gastrointestinal disorder, thus delaying the needed specific treatment. She was diagnosed a week after the initial hospital admission, and her condition improved after receiving treatment with intravenous glucose and haemin. For patients with acute neurovisceral attacks, early clinical recognition is essential. Severe hyponatremia, urine that develops orange colour on exposure to light and gastrointestinal symptom combination with neurologic symptoms are three valuable clues that may lead to the right diagnosis faster. Pathophysiology of hyponatremia in case of acute intermittent porphyria in only partly understood and can be associated with syndrome of inappropriate antidiuretic hormone secretion, gastrointestinal or renal sodium loss.

Drugs and acute porphyrias: reasons for a hazardous relationship.

The porphyrias are a group of metabolic diseases caused by inherited or acquired enzymatic deficiency in the metabolic pathway of heme biosynthesis. Simplistically, they can be considered as storage diseases, because the partial enzymatic defect gives rise to a metabolic "bottleneck" in the biosynthetic pathway and hence to an accumulation of different metabolic intermediates, potentially toxic and responsible for the various (cutaneous or neurovisceral) clinical manifestations observed in these diseases. In the acute porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and the very rare delta-aminolevulinic acid dehydratase ALAD-d porphyria), the characteristic severe neurovisceral involvement is mainly ascribed to a tissue accumulation of delta-aminolevulinic acid, a neurotoxic nonporphyrin precursor. Many different factors, both endogenous and exogenous, may favor the accumulation of this precursor in patients who are carriers of an enzymatic defect consistent with an acute porphyria, thus contributing to trigger the serious (and potentially fatal) clinical manifestations of the disease (acute porphyric attacks). To date, many different drugs are known to be able to precipitate an acute porphyric attack, so that the acute porphyrias are also considered as pharmacogenetic or toxygenetic diseases. This article reviews the different biochemical mechanisms underlying the capacity of many drugs to precipitate a porphyric acute attack (drug porphyrogenicity) in carriers of genetic mutations responsible for acute porphyrias, and addresses the issue of prescribing drugs for patients affected by these rare, but extremely complex, diseases.

Sustained enzymatic correction by rAAV-mediated liver gene therapy protects against induced motor neuropathy in acute porphyria mice.

Acute intermittent porphyria (AIP) is characterized by a hereditary deficiency of hepatic porphobilinogen deaminase (PBGD) activity. Clinical features are acute neurovisceral attacks accompanied by overproduction of porphyrin precursors in the liver. Recurrent life-threatening attacks can be cured only by liver transplantation. We developed recombinant adeno-associated virus (rAAV) vectors expressing human PBGD protein driven by a liver-specific promoter to provide sustained protection against induced attacks in a predictive model for AIP. Phenobarbital injections in AIP mice induced porphyrin precursor accumulation, functional block of nerve conduction, and progressive loss of large-caliber axons in the sciatic nerve. Hepatocyte transduction showed no gender variation after rAAV2/8 injection, while rAAV2/5 showed lower transduction efficiency in females than males. Full protection against induced phenobarbital-attacks was achieved in animals showing over 10% of hepatocytes expressing high amounts of PBGD. More importantly, sustained hepatic expression of hPBGD protected against loss of large-caliber axons in the sciatic nerve and disturbances in nerve conduction velocity as induced by recurrent phenobarbital administrations. These data show for the first time that porphyrin precursors generated in the liver interfere with motor function. rAAV2/5-hPBGD vector can be produced in sufficient quantity for an intended gene therapy trial in patients with recurrent life-threatening porphyria attacks.

Hepatic porphyrias: diagnosis and management.

Porphyrias are a group of metabolic disorders in which there are defects in the normal pathway for the biosynthesis of heme, the critical prosthetic group for numerous hemoproteins. The clinical manifestations of the porphyrias can be highly varied, and patients may present to general physicians and be referred to a wide variety of subspecialists because of these manifestations. However, two major clinical forms are represented by the so-called "acute" porphyrias, in which patients suffer recurrent bouts of pain, especially pain in the abdomen, and the "cutaneous" porphyrias, in which patients have painful skin lesions. Knowledge of the factors chiefly responsible for regulating the rate of synthesis of heme has helped to explain how drugs and other factors may cause porphyria. Knowledge of the physical and chemical properties of porphyrins also forms an important part of the foundation for understanding the clinical manifestations of these diseases. Thus, the porphyrias can best be understood after reviewing the chemical properties of porphyrins and heme and the control of their biosynthesis.

Diagnosis and treatment of the hepatic porphyrias.

Porphyrias are a peculiar group of diseases resulting from hereditary or acquired partial deficiencies in seven of the eight enzymes in the biosynthetic pathway of heme. Biosynthesis of heme takes place in the erythropoietic system or in the hepatic tissue. Depending on the main location of the enzyme defect, porphyrias can be classified as erythropoietic or hepatic. There are seven basic clinical forms of porphyria related to a deficiency of each of the involved enzymes. Clinical manifestations in porphyria may be neurovisceral or cutaneous. Patients may present with acute attacks (acute porphyrias), cutaneous lesions (cutaneous porphyrias), or both (mixed porphyrias). Study of patients supected of having porphyria should include several steps: 1) clinical evaluation, 2) biochemical study, which enables us to classify the patient to a specific form of porphyria, followed if possible by 3) enzymatic assay(s), and 4) genetic studies to confirm an enzyme deficiency and its level and the causal genetic mutation. Unfortunately no curative treatment is available for any of the porphyrias. However, symptomatic treatments are available and are discussed in this article.

Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria.

Hereditary coproporphyria (HCP) is the least common of the autosomal dominant acute hepatic porphyrias. It results from mutations in the CPO gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase. A few patients have also been reported who are homoallellic or heteroallelic for CPO mutations and are clinically distinct from those with HCP. In such patients the presence of a specific mutation (K404E) on one or both alleles produces a neonatal hemolytic anemia that is known as "harderoporphyria"; mutations on both alleles elsewhere in the gene give rise to the "homozygous" variant of HCP. The molecular relationship between these disorders and HCP has not been defined. We describe the molecular investigation and clinical features of 17 unrelated British patients with HCP. Ten novel and four previously reported CPO mutations, together with three previously unrecognized single-nucleotide polymorphisms, were identified in 15 of the 17 patients. HCP is more heterogeneous than other acute porphyrias, with all but one mutation being restricted to a single family, with a predominance of missense mutations (10 missense, 2 nonsense, 1 frameshift, and 1 splice site). Of the four known mutations, one (R331W) has previously been reported to cause disease only in homozygotes. Heterologous expression of another mutation (R401W) demonstrated functional properties similar to those of the K404E harderoporphyria mutation. In all patients, clinical presentation was uniform, in spite of the wide range (1%-64%) of residual coproporphyrinogen oxidase activity, as determined by heterologous expression. Our findings add substantially to knowledge of the molecular epidemiology of HCP, show that single copies of CPO mutations that are known or predicted to cause "homozygous" HCP or harderoporphyria can produce typical HCP in adults, and demonstrate that the severity of the phenotype does not correlate with the degree of inactivation by mutation of coproporphyrinogen oxidase.

Erythropoietic and hepatic porphyrias.

Porphyrias are divided into erythropoietic and hepatic manifestations. Erythropoietic porphyrias are characterized by cutaneous symptoms and appear in early childhood. Erythropoietic protoporphyria is complicated by cholestatic liver cirrhosis and progressive hepatic failure in 10%, of patients. Acute hepatic porphyrias (delta-aminolaevulinic acid dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) are characterized by variable extrahepatic gastrointestinal, neurological-psychiatric and cardiovascular manifestations requiring early diagnosis to avoid life-threatening complications. Acute hepatic porphyrias are pharmacogenetic and molecular regulatory diseases (without porphyrin accumulation) mainly induced by drugs, sex hormones, fasting or alcohol. The disease process depends on the derepression of hepatic delta-aminolaevulinic acid synthase following haem depletion. In contrast to the acute porphyrias, nonacute, chronic hepatic porphyrias such as porphyria cutanea tarda are porphyrin accumulation disorders leading to cutaneous symptoms associated with liver disease, especially caused by alcohol or viral hepatitis. Alcohol, oestrogens, haemodialysis, hepatitis C and AIDS are triggering factors. Porphyria cutanea tarda is the most common porphyria, followed by acute intermittent porphyria and erythropoietic protoporphyria. The molecular genetics of the porphyrias is very heterogenous. Nearly every family has its own mutation. The mutations identified account for the corresponding enzymatic deficiencies, which may remain clinically silent throughout life. Thus, the recognition of the overt disorder with extrahepatic manifestations depends on the demonstration of biochemical abnormalities due to these primary defects and compensatory hepatic overexpression of hepatic delta-aminolaevulinic acid synthase in the acute porphyrias. Consequently, haem precursors are synthesized in excess. The increased metabolites upstream of the enzymatic defect are excreted into urine and faeces. The diagnosis is based on their evaluation. Primary enzymatic or molecular analyses are noncontributary and may be misleading. Acute polysymptomatic exacerbations accompany a high excretory constellation of porphyrin precursors delta-aminolaevulinic acid and porphobilinogen. Homozygous or compound heterozygous variants of acute hepatic porphyrias may already manifest in childhood.

Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation.

Variegate porphyria (VP) is a low-penetrance, autosomal dominant disorder characterized clinically by skin lesions and acute neurovisceral attacks that occur separately or together. It results from partial deficiency of protoporphyrinogen oxidase encoded by the PPOX gene. VP is relatively common in South Africa, where most patients have inherited the same mutation in the PPOX gene from a common ancestor, but few families from elsewhere have been studied. Here we describe the molecular basis and clinical features of 108 unrelated patients from France and the United Kingdom. Mutations in the PPOX gene were identified by a combination of screening (denaturing gradient gel electrophoresis, heteroduplex analysis, or denaturing high-performance liquid chromatography) and direct automated sequencing of amplified genomic DNA. A total of 60 novel and 6 previously reported mutations (25 missense, 24 frameshift, 10 splice site, and 7 nonsense) were identified in 104 (96%) of these unrelated patients, together with 3 previously unrecognized single-nucleotide polymorphisms. VP is less heterogeneous than other acute porphyrias; 5 mutations were present in 28 (26%) of the families, whereas 47 mutations were restricted to 1 family; only 2 mutations were found in both countries. The pattern of clinical presentation was identical to that reported from South Africa and was not influenced by type of mutation. Our results define the molecular genetics of VP in western Europe, demonstrate its allelic heterogeneity outside South Africa, and show that genotype is not a significant determinant of mode of presentation.

Porfirias en la infancia: revisión casuística de 17 casos de niños con porfiria en un servicio de dermatología pediátrica manifestaciones cutáneas evaluación de características hereditarias propuesta terapéutica revisión bibliográfica / Porphyria of infancy: review of 17 cases from a pediatric dermatology service the cutaneous manifestations and hereditary characteristics

Entre agosto de 1987 y diciembre de 1996 se observaron en nuetros servicio de dermatolgía pediátrica, sobrre un total de 37.467 pacientes con consulta de primera vez, 17 niños con diagnóstico confirmado, con una prevalencia del 0,057 por ciento (1 caso de porfiria cada 2.000 consultas de primera vez). Los 17 casos se distribuyeron de la siguiente manera. Porfiria Cutánea Tarda (PCT): 9 casos (52,9 por ciento); Protoporfiria eritropoyética (PPE): 6 casos (35,3 por ciento); Porfiria Variegata (PV): 1 caso (5,9 por ciento) y Porfiria Eritropoyéctica Congénita de Günther (PCE): 1 caso (5, 9 por ciento). Relación: PCT/PPE: 1,5:1. La distribución de frecuencia acorde a sexo y edad fue la siguiente: PCT: relación F/M: 2:1 (F= 6 casos; M= 3 casos); Edad: Rango= 3 a 12 años X= 7 años. PPE: relación F/M: 1:2 (F= 2 casos; M= 4 casos); Edad: Rango= 2 a 11 años X= 7 años. PV: 1 caso de una niña de 8 años. PEC: 1 caso de una niña de 2 meses. El diagnóstico de porfirinas en orina, plasma, eritrocitos y materia fecal y el índice de fluorescencia plasmática, acorde a su correlación clínica. Se evaluaron los antecedentes hereditarios en la mayoria de los pacientes, observándose diferentes cuadros de porfiria comprobados en los familiares, fundamentalmente en los niños portadors de PCT. Los síntomas iniciales estuvieron asociados con fenómenos de fotosensibilidad y aparición de lesiones vesico-ampollares en regiones expuetas, principalmente cara y dorso de manos. La hipertricosis fue constante en los casos de PCT. Hubo compromiso abdominal en los casos de PEC y PV y severa onicodistrofia con hipertricosis, anemia hemolítica y mal estado general en el caso de Günther. Un caso de PCT asociado con leucemia mieloide y otro en un paciente post-transplantado renal (no diálisis). En todos los pacientes con PPE se realizaron biopsias hepáticas con resultados normales...

Molecular basis of variegate porphyria: a missense mutation in the protoporphyrinogen oxidase gene.

Variegate porphyria (VP) is an autosomal dominant disorder characterised by a partial defect in the activity of protoporphyrinogen oxidase (PPO), and has recently been genetically linked to the PPO gene on chromosome 1q22-23 (Z=6.62). In this study, we identified a mutation in the PPO gene in a patient with VP and two unaffected family members. The mutation consisted of a previously unreported T to C transition in exon 13 of the PPO gene, resulting in the substitution of a polar serine by a non-polar proline (S450P). This serine residue is evolutionarily highly conserved in man, mouse, and Bacillus subtilis, attesting to the importance of this residue. Interestingly, the gene for Gardner's syndrome (FAP) also segregates in this family, independently of the VP mutation. Gardner's syndrome or familial adenomatous polyposis (FAP) is also an autosomal dominantly inherited genodermatosis, and typically presents with colorectal cancer in early adult life secondary to extensive adenomatous polyps of the colon. The specific gene on chromosome 5 that is the site of the mutation in this disorder is known as APC (adenomatous polyposis coli), and the gene has been genetically linked to the region of 5q22.