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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Pyridoxine-dependent seizures are characterized by intractable seizures that are not controlled with anticonvulsants but that respond both clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). Multiple types of clinical seizures have been reported in individuals with pyridoxine-dependent seizures. Although dramatic presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical, recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events, and infantile spasms also occur. Affected individuals may have electrographic seizures without clinical correlates. Individuals with the classic neonatal presentation begin to experience seizures soon after birth. Atypical features include late-onset seizures (up to age 2 years); seizures that initially respond to anticonvulsants and then become intractable; seizures during early life that do not respond to pyridoxine but that are then controlled with pyridoxine several months later; and prolonged seizure-free intervals (up to 5 1/2 months) that occur after pyridoxine discontinuation. Intellectual disability is common.
Diagnosis/testing. The diagnosis of pyridoxine-dependent seizures is made entirely on clinical grounds. Diagnosis may be made in individuals experiencing clinical seizures by administering 100 mg of pyridoxine intravenously while monitoring the EEG, oxygen saturation, and vital signs. In individuals with pyridoxine-dependent seizures, clinical seizures generally cease over several minutes. If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. A corresponding change should be observed in the EEG, though it may be delayed by several hours. ALDH7A1 is the only gene known to be associated with pyridoxine-dependent seizures; molecular genetic testing is available clinically.
Management. Pyridoxine-dependent seizures are initially controlled with the addition of daily supplements of pyridoxine; subsequently, all anticonvulsants can be withdrawn and seizure control continued with daily pyridoxine monotherapy in pharmacologic doses. To prevent exacerbation of clinical seizures and/or encephalopathy during an acute illness, the daily dose of pyridoxine may be doubled for several days. Surveillance includes monitoring for development of clinical signs of a sensory neuropathy and regular assessments of intellectual function. Special education programs are offered to affected individuals. If a younger sib of a proband presents with encephalopathy or a seizure, pyridoxine is administered acutely (under EEG monitoring) for both diagnostic and therapeutic purposes.
Genetic counseling. Pyridoxine-dependent seizures are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
As recommended by Goutières & Aicardi (1985), pyridoxine dependency should be considered as the cause of intractable seizures in the following situations:
Cryptogenic seizures in a previously normal infant without an abnormal gestational or perinatal history
The occurrence of long-lasting focal or unilateral seizures, often with partial preservation of consciousness
Irritability, restlessness, crying, and vomiting preceding the actual seizures
A history of a severe convulsive disorder in a sib, often leading to death during status epilepticus
Parental consanguinity
Diagnosis may be made:
On an acute basis in individuals experiencing clinical seizures by administering 100 mg of pyridoxine intravenously while monitoring the EEG, oxygen saturation, and vital signs. In individuals with pyridoxine-dependent seizures, clinical seizures generally cease over several minutes. If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. A corresponding change should be observed in the EEG; in some circumstances, the change may be delayed by several hours [Gospe & Hecht 1998, Baxter 2001, Gospe 2002]. In some individuals with pyridoxine-dependent seizures, significant neurologic and cardiorespiratory depression follow this trial, making close systemic monitoring essential [Kroll 1985, Bass et al 1996].
By administering 15 mg/kg/day of pyridoxine orally. In individuals with pyridoxine-dependent seizures, clinical seizures should cease within a week [Baxter 2001, Gospe 2002, Gospe 2006].
In either of the above situations, the diagnosis of pyridoxine-dependent seizures must be confirmed by withdrawing anticonvulsants, followed by withdrawal of daily pyridoxine supplementation. The diagnosis of pyridoxine-dependent seizures is established if seizures recur and are again controlled by pyridoxine monotherapy.
Elevated levels of pipecolic acid in plasma and cerebral spinal fluid have been demonstrated in several individuals with pyridoxine-dependent seizures both before and after long-term treatment with pyridoxine [Plecko et al 2000, Plecko et al 2005]. It has been suggested that pipecolic acid may serve as a nonspecific diagnostic marker for this disorder [Plecko et al 2005].
Recently, it has been demonstrated that elevated urinary concentration of α-aminoadipic semialdehyde (α-AASA) is a specific biomarker for pyridoxine-dependent seizures [Mills et al 2006]. Measurement of urinary α-AASA concentration is available clinically on a limited basis.
Gene. ALDH7A1 is the only gene known to be associated with pyridoxine-dependent seizures [Mills et al 2006].
Loci. A genome-wide linkage scan utilizing five families of North American descent (four of whom were consanguineous) mapped a locus for pyridoxine-dependent seizures at chromosome 5q31 [Cormier-Daire et al 2000]. The recently identified gene ALDH7A1 maps to this region.
However, a study of six North American families excluded assignment to the 5q31 locus in one family, indicating genetic heterogeneity for pyridoxine-dependent seizures [Bennett et al 2005].
Clinical testing. Sequence analysis is available clinically. Mills et al (2006) and Plecko et al (2007) studied 29 individuals from 24 families with "classic neonatal pyridoxine-dependent seizures," all of whom were determined to be homozygous or compound heterozygous for mutations in ALDH7A. No individuals with atypical presentation were included in the two studies.
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Mutation Detection Frequency 1, 2 | Test Availability |
|---|---|---|---|
| Sequence analysis | ALDH7A1 sequence variants | ~95% of individuals with elevated urinary α-AASA 3 | Clinical
 |
1. Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, genetic mechanism, and/or test method
2. All individuals evaluated had "classic neonatal pyridoxine-dependent seizures."
3. Mills et al 2006, Plecko et al 2007
No other phenotypes are known to be associated with mutations in ALDH7A1.
The one clinical feature characteristic of all individuals with pyridoxine-dependent seizures is intractable seizures that are not controlled with anticonvulsants but that respond both clinically and electrographically to large daily supplements of pyridoxine.
Classic pyridoxine-dependent seizures. Multiple types of clinical seizures have been reported in individuals with pyridoxine-dependent seizures. Although dramatic presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical, recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events, and infantile spasms also occur. Affected individuals may have electrographic seizures without clinical correlates.
Individuals with the classic neonatal presentation begin to experience seizures soon after birth. In retrospect, many mothers recount unusual intrauterine movements that may have started in the late second trimester and that likely represent fetal seizures [Bejsovec et al 1967, Baxter 2001]. Affected neonates frequently have periods of encephalopathy (irritability, fluctuating tone, poor feeding) that precede the onset of clinical seizures. Low Apgar scores and abnormal cord blood gases may also be observed. For this reason, it is not uncommon for these newborns to be diagnosed with hypoxic-ischemic encephalopathy [Haenggeli et al 1991, Baxter 1999]. Similar periods of encephalopathy may be seen in older infants with pyridoxine-dependent seizures, particularly prior to recurrence of clinical seizures, which occur in individuals treated with pyridoxine whose vitamin requirement may have increased because of growth or intercurrent infection, particularly gastroenteritis.
Intellectual disability is common in individuals with pyridoxine-dependent seizures. Some affected individuals with normal intellectual function have been reported [Haenggeli et al 1991, Ohtsuka et al 1999]. It has been suggested that an earlier onset of clinical seizures has a worse prognosis for cognitive function, and the length of the delay in diagnosis and initiation of effective pyridoxine treatment correlates with increased handicaps [Baxter 2001]. Few formal psychometric assessments in individuals with pyridoxine-dependent seizures have been performed. These limited studies indicate that verbal skills are more impaired than nonverbal skills [Baxter et al 1996, Baynes et al 2003].
Atypical pyridoxine-dependent seizures. Recent case reports have focused on late-onset and other atypical features of this phenotypically heterogenous disorder [Clarke et al 1979, Bankier et al 1983, Goutières & Aicardi 1985, Coker 1992, Chou et al 1995, Bass et al 1996, Grillo et al 2001]. These include late-onset seizures (up to age 2 years); seizures that initially respond to anticonvulsants and then become intractable; seizures during early life that do not respond to pyridoxine but that are then controlled with pyridoxine several months later; and prolonged seizure-free intervals (up to 5 1/2 months) that occur after pyridoxine discontinuation.
EEG/Neuroimaging. While a variety of EEG [Mikati et al 1991, Nabbout et al 1999] and imaging abnormalities [Tanaka et al 1992, Jardin et al 1994, Baxter et al 1996, Shih et al 1996, Gospe & Hecht 1998] have been described in individuals with pyridoxine-dependent seizures, none is pathognomonic for this disorder.
No genotype-phenotype correlations are known as only individuals with classic neonatal-onset pyridoxine-dependent seizures were studied by Mills et al (2006). Future studies of "atypical cases" are needed before genotype-phenotype correlations will be possible.
First described by Hunt et al (1954), pyridoxine-dependent seizures are generally considered to be a rare cause of intractable neonatal seizures. Approximately 100 individuals experiencing pyridoxine-dependent seizures have now been reported [Baxter 1999]. Only a few epidemiologic studies of this condition have been conducted. In the Northern region of the United Kingdom, the prevalence of pyridoxine-dependent seizures in children under 16 years of age was estimated to be 1:100,000 [Baxter et al 1996]. National studies in the United Kingdom and the Republic of Ireland noted a prevalence of approximately 1:700,000 [Baxter 1999].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Pyridoxine-dependent seizures should be considered as a cause of intractable seizures presenting in neonates, infants, and children up to the third year of life for which an underlying lesion (i.e., symptomatic epilepsy) has not been identified.
In particular, this diagnosis needs to be investigated in any neonate who presents with encephalopathy and seizures and in whom there is no convincing evidence of hypoxic-ischemic encephalopathy or other identifiable underlying metabolic disturbance [Baxter 1999, Gospe 2002].
Some young individuals with intractable seizures may have only partial improvement in seizure control with the addition of pyridoxine. In this situation, or in instances in which seizures recur after anticonvulsants are withdrawn and pyridoxine is continued, individuals should not be diagnosed with pyridoxine-dependent seizures, but rather with "pyridoxine-responsive seizures" [Hansson & Hagberg 1968, Baxter 1999].
While other inborn pyridoxine-dependency states have been described (e.g., pyridoxine-dependent anemia and pyridoxine-dependent forms of homocystinuria, xanthurenic aciduria, and cystathioninuria), these conditions are not genetically related to pyridoxine-dependent seizures.
A rare form of neonatal epileptic encephalopathy that responds to pyridoxal phosphate (PLP), but not pyridoxine, has been reported. Affected individuals have mutations in the PNPO gene that encodes pyridox(am)ine 5'-phosphate oxidase, an enzyme that interconverts the phosphorylated forms of pyridoxine and pyridoxamine to PLP [Mills et al 2005]. The seizures in infants with this condition do not respond to pyridoxine; therefore, this disorder is clinically distinct from pyridoxine-dependent seizures. There have been reports of other children with intractable epilepsy who show a clinical response to PLP rather than to pyridoxine. The biochemical basis of the epileptic condition in these children has not been established [Gospe 2006].
Other causes of neonatal intractable seizures include the following:
"Folinic acid-responsive seizures," a rare and poorly characterized condition. Affected neonates respond to daily folinic acid (citrovorum factor) supplementation [see Hyland et al 1995, Torres et al 1999].
Lissencephaly or other brain malformations that are distinguishable by the presence of structural brain malformations
Other rare inborn errors of metabolism that are identified by elevated ammonia, lactate, or anion gap on laboratory testing
Severe acquired neurologic disorders such as intracerebral hemorrhage or infectious diseases (meningitis, encephalitis)
Following diagnosis of pyridoxine-dependent seizures, developmental assessment is appropriate.
Once seizures come under control with the addition of daily supplements of pyridoxine, all anticonvulsants can be withdrawn, and seizure control will continue with daily pyridoxine monotherapy in pharmacologic doses.
Special education programs should be offered.
While the effective treatment of individuals with pyridoxine-dependent seizures requires lifelong pharmacologic supplements of pyridoxine, the rarity of this disorder has precluded controlled studies to evaluate the optimal dose.
The recommended daily allowance (RDA) for pyridoxine is 0.5 mg for infants and 2.0 mg for adults. In general, individuals with pyridoxine-dependent seizures have excellent seizure control when treated with 50-100 mg of pyridoxine per day. Seizures in some individuals are controlled on much smaller doses [Haenggeli et al 1991, Grillo et al 2001] and others require somewhat higher doses [Haenggeli et al 1991].
Affected individuals may have exacerbations of clinical seizures and/or encephalopathy during an acute illness, such as gastroenteritis or a febrile respiratory infection. To prevent such an exacerbation in these circumstances, the daily dose of pyridoxine may be doubled for several days until the acute illness resolves.
Recent studies indicate that higher doses may enhance intellectual development; it has been suggested that a dose of 15-18 mg/kg/day may be optimal [Baxter 2001] and that the dosage should not exceed 500 mg per day. Such therapy is required for life; affected individuals are metabolically dependent on the vitamin, rather than pyridoxine deficient.
The over-zealous use of pyridoxine must be avoided, as a reversible sensory neuropathy (ganglionopathy) caused by pyridoxine neurotoxicity can develop. While primarily reported in adults who have received "megavitamin therapy" with pyridoxine, a non-disabling sensory neuropathy has been reported in one adolescent with possible pyridoxine-dependent seizures who received two grams of pyridoxine per day [McLachlan & Brown 1995].
Affected individuals should be followed for the development of clinical signs of a sensory neuropathy, including regular assessments of joint-position sense, ankle jerks, gait, and station [Baxter 2001].
Regular assessments of intellectual function should be offered.
If a younger sib of a proband presents with encephalopathy or a seizure, pyridoxine should be administered acutely (ideally under EEG monitoring) for both diagnostic and therapeutic purposes.
In addition, if elevated plasma pipecolic acid concentrations have been demonstrated in the proband, a similar pipecolic acid elevation in a younger sib would support a diagnosis of pyridoxine-dependent seizures.
Note: It would be unlikely for the proband's older sibs who have not experienced seizures to be pyridoxine dependent.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Pyridoxine-dependent seizures are inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected individual are obligate heterozygotes, and therefore carry one mutant allele.
Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Pyridoxine dependency must be considered as the etiology of seizures presenting in a younger sib of a proband. In this situation, pyridoxine administration should be the first treatment for seizures offered to the individual.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband
Adults diagnosed with the disorder are being followed, but the fertility status of these individuals is not known, and there are no published reports concerning the offspring of individuals with pyridoxine-dependent seizures.
If affected individuals reproduce, their offspring will be obligate heterozygotes (carriers).
Heterozygotes (carriers) are asymptomatic.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for at-risk family members is available on a clinical basis once the mutations have been identified in the family.
Pregnancy management. As there is a 25% recurrence risk for couples who have a child with this disorder, it has been recommended that mothers take 50-100 mg of pyridoxine per day during the last half of subsequent pregnancies in order to reduce the severity of intellectual impairment in a possibly affected fetus [Baxter & Aicardi 1999, Gospe 2002].
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| ALDH7A1 | 5q31 | Alpha-aminoadipic semialdehyde dehydrogenase |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 107323 | ALDEHYDE DEHYDROGENASE 7 FAMILY, MEMBER A1; ALDH7A1 |
| 266100 | EPILEPSY, PYRIDOXINE-DEPENDENT; EPD |
| Gene Symbol | Entrez Gene |
|---|---|
| ALDH7A1 | 501 (MIM No. 107323) |
For a description of the genomic databases listed, click here.
For many years, it was hypothesized that pyridoxine-dependent seizures were caused by an abnormality of the enzyme glutamic acid decarboxylase (GAD), which uses PLP as a cofactor [Scriver 1960]. GAD converts glutamic acid, an excitatory neurotransmitter, into gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter. Both of these neurotransmitters play important roles in the control of epileptic processes. A number of clinical neurochemical studies indirectly supported this hypothesis [Lott et al 1978, Kurlemann et al 1991, Gospe et al 1994]. However, four different laboratories failed to document linkage to either isoform of GAD [Kaufman et al 1987, Kure et al 1998, Battaglioli et al 2000, Cormier-Daire et al 2000].
Mutations in ALDH7A1 have been demonstrated to cause pyridoxine-dependent seizures. ALDH7A1 encodes the protein aldehyde dehydrogenase family 7 member A1 (antiquitin-1), an aldehyde dehydrogenase with a previously uncertain physiologic substrate [Lee et al 1994]. It has now been demonstrated that antiquitin-1 functions as a Δ1-piperideine-6-carboxylate (P6C)-α-AASA dehydrogenase. Abnormal activity of this enzyme results in increased levels of P6C, which is the cyclic Schiff base of α-AASA; these two substances are in equilibrium with one another. P6C, in turn, inactivates PLP by condensing with the cofactor and this likely results in abnormal metabolism of neurotransmitters [Mills et al 2006].
Normal allelic variants: ALDH7A1 has 1809 bases and consists of 18 exons that range from 42 bp to 352 bp in size. The coding region is 1533 bp in length. The gene encodes a protein with 510 amino acid residues [Mills et al 2006]. The deduced molecular weight of the encoded Δ1-piperideine-6-carboxylate (P6C)-α-AASA dehydrogenase protein is 55285 [Lee et al 1994].
Pathologic allelic variants: Mutations have been documented in 13 affected individuals from eight kindreds (four of which are consanguineous) These include two splice site mutations (predicted to cause exon skipping), two missense mutations, two nonsense mutations (probably leading to nonsense-mediated mRNA decay), and one single base deletion that results in a frameshift that alters the final seven amino acids and extends the C terminus by an additional ten residues. One individual was a compound heterozygote for a missense mutation and nonsense mutation while the other cases were homozygous [Mills et al 2006].
Normal gene product: Antiquitin-1 is an aldehyde dehydrogenase with Δ1-piperideine-6-carboxylate-α-aminoadipic semialdehyde dehydrogenase activity.
Abnormal gene product: The two missense mutations, one nonsense mutation, and the one documented single base deletion all result in absent α-AASA dehydrogenase enzyme activity while the second nonsense mutation resulted in α-AASA dehydrogenase enzyme activity that was 1.8% of normal.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
American Epilepsy Society
342 North Main Street
West Hartford CT 06117-2507
Phone: 860-586-7505
Fax: 860-586-7550
Email: info@aesnet.org
www.aesnet.org
Epilepsy Foundation
8301 Professional Place
East Landover, MD 20785-2238
Phone: 800-EFA-1000 (800-332-1000); 301-459-3700
Fax: 301-577-4941
Email: webmaster@efa.org
www.efa.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Pyridoxine-Dependent Seizures Patient Registry
For diagnosed patients in the United States and Canada, operated through Children's Hospital and Regional Medical Center in Seattle, WA. The registry may be contacted through the author, or at pyridoxine@seattlechildrens.org.
24 July 2007 (cd) Revision: clinical testing available: analyte and sequence analysis; prenatal diagnosis
9 June 2006 (sg) Revision: mutations in ALDH7A1 found to be causative
8 March 2006 (me) Comprehensive update posted to live Web site
18 December 2003 (me) Comprehensive update posted to live Web site
7 December 2001 (me) Review posted to the live Web site
17 September 2001 (sg) Original submission
