Clinical Diagnosis

Classic galactosemia (G/G) presents in the neonatal period with prolonged neonatal jaundice. By five days of age poor suck, failure to thrive, bleeding diathesis, and increasing jaundice occur. If classic galactosemia is not treated, hyperammonemia, sepsis, and shock are likely by six to ten days of age. Cataracts are present in approximately 10% of infants.

Most affected infants are detected through newborn screening programs; however, clinicians need to be alert to early signs (poor feeding, prolonged neonatal jaundice) and remove lactose from the diet and initiate soy-based, dietary therapy while awaiting results of newborn screening and/or diagnostic tests.

Testing

See Cuthbert et al [2008] for a detailed discussion of test methods and clinical interpretation of test results.

For laboratories offering biochemical testing, see .

Biochemical assays necessary for diagnosis and monitoring of therapy include the following:

• Erythrocyte galactose-1-phosphate concentration. Metabolism of this precursor is blocked in the GALT reaction sequence. Concentration of erythrocyte galactose-1-phosphate exceeds 2 mg/dL and can be used to monitor the effectiveness of therapy. In classic galactosemia, gal-1-P remains elevated between 2 and 5 mg/dL despite therapy.
• Galactitol. A product of an alternate pathway for galactose metabolism, galactitol can be measured in the urine. Urinary galactitol greater than 78 mmol/mol creatinine is abnormal. Correlation with other measures may not be perfect.
• Total body oxidation of ¹³C galactose to ¹³CO₂. Elimination in breath of less than 5% of ¹³C galactose as ¹³CO₂ two hours after administration of ¹³C-D galactose defines a severe metabolite phenotype [Berry et al 2000]. Such testing is used in Phase II research protocols [Guerrero et al 2000, Webb et al 2003] and may become useful as an early screen for galactosemia before discharge from the nursery [Barbouth et al 2007].
• GC/MS isotope dilution method. Experimental measurements of galactitol and galactonate in urine are made by the GC/MS isotope dilution method [Yager et al 2006].

Activity of galactose-1-phosphate uridyltransferase (GALT) enzyme (EC 2.7.712). The GALT enzyme has a bimolecular function. It first converts UDP-glucose to glucose-1-P. The intermediate UMP-GALT is formed and the second reaction binds galactose-1-phosphate (gal-1-P) and releases UDP-galactose (Figure 1). The overall reaction is rate-limiting in producing uryldylated hexoses for post-translational modification of glycoproteins and glycolipids.

Figure

Figure 1. Galactose metabolism, the Leloir pathway

When GALT enzyme activity is deficient, gal-1-P, galactose, and galactitol accumulate.

• Gal-1-P competes with the UTP-dependent glucose-1-P pyrophosphorylase to reduce UDP-glucose production; thus, both UDP-glu and UDP-gal are reduced, resulting in abnormally glycosylated proteins and glycolipids (Figure 2).
• Galactose is converted to galactitol in cells and produces osmotic effects such as swelling of lens fibers that may result in cataracts and swelling of neurons that may produce pseudotumor cerebri.

Figure

Figure 2. Galactose metabolism, GALT deficiency

Classic galactosemia

• Homozygotes for the classic galactosemia (G) allele (i.e., G/G) have GALT enzyme activity less than 5% of control values.
• Heterozygotes for the classic galactosemia allele and a normal (N) allele (i.e., G/N) have GALT enzyme activity of approximately 50% of control values.

Duarte variant galactosemia

• The Los Angeles (LA) (D₁) (p.Asn314Asp) variant produces no change in GALT enzyme activity in the erythrocyte and has normal promoter activity.
• The Duarte (D₂) (p.Asn314Asp) allele produces bioinstability to the GALT enzyme complex and has reduced promoter expression [Langley et al 1997, Lai et al 1998, Elsas et al 2001].
• Newborns who are G/D heterozygotes may have a positive newborn screen and require further clinical, biochemical, and molecular genetic testing.

Note: (1) Both the D₁ and D₂ mutations have the same abnormal amino acid (p.Asn314Asp) in GALT. The Duarte (D₂ ) variant and LA variant (D₁ ) have the same biochemical isoelectric focusing pattern (i.e., they move toward the anode and lower pH) which differs from that of the G/G biochemical phenotype [Elsas et al 1994]. (2) Molecular analysis is needed to differentiate between the Duarte (D₂) and LA (D₁) variants [Elsas et al 2001]. See Molecular Genetic Testing.

Newborn screening. Galactosemia can be detected in virtually 100% of affected infants in states that include testing for galactosemia in their newborn screening programs [National Newborn Screening Status Report (pdf)].

• Newborn screening utilizes a small amount of blood obtained from a heel prick to assay galactose-1-phosphate uridyltransferase (GALT) enzyme activity and quantify total red blood cell (RBC) gal-1-P concentration and galactose.
• A second tier of molecular testing for specific GALT mutations should also be available, since this is the most sensitive and specific laboratory test.
  
  Note: The newborn with questionable results on newborn screening should continue to be treated with soy-based formula pending definitive results of confirmatory testing.

Newborn Screening under investigation: Total body oxidation of ¹³C-D galactose to ¹³CO₂ in expired air (“the breath test”) remains a research endeavor; however, it may be used in the future before discharge of the neonate from the nursery [Berry et al 2000, Barbouth et al 2007].

Molecular Genetic Testing

Gene. GALT is the only gene in which mutation is known to be associated with the classic signs of galactosemia.

Clinical testing

• Classic (G/G) galactosemia
  • Targeted mutation analysis. Mutation analysis for the eight common GALT galactosemia (G) mutations (p.Gln188Arg, p.Ser135Leu, p.Lys285Asn, p.Leu195Pro, p.Tyr209Cys, p.Phe171Ser, 5kbdel, c.253-2A>G) is available on a clinical basis (laboratories may offer all, a subset, or an expanded panel of these mutations) [Elsas & Lai 1998].
    
    Note: The 5kbdel allele is a complex deletion that involves a 3163-nt deletion of the GALT promoter and a 5' gene region along with a 2295-bp deletion of the 3' gene; only segments of exon 8 and intron 8 are retained [Coffee et al 2006]. The 5kbdel complex deletion is detectable by any of a variety of methods that detect deletions (e.g., Southern blot analysis, deletion-specific PCR, quantitative PCR, MLPA). Misdiagnoses are made when typical GALT primers are used [Barbouth et al 2006, Coffee et al 2006].
  • Sequence analysis. Sequence analysis indentifies the common mutations identified by targeted mutation analysis as well sequence variants such as small intragenic deletions/insertions, missense, nonsense, and splice site mutations.
  • Deletion/duplication analysis. Deletion of GALT exons and multi-exons has been detected in affected individuals.
• Duarte variant (D/G) galactosemia
  • Targeted mutation analysis. For individuals with Duarte variant (D/G) galactosemia identified by biochemical testing of the individual and both parents, the Duarte allele (p.Asn314Asp) can be identified by targeted mutation analysis.
    
    The Duarte and LA alleles have the same p.Asn314Asp missense mutation:
    • The Duarte variant p.Asn314Asp missense mutation has a GTCA deletion in cis configuration in the promoter region (c.-116_-119delGTCA) that impairs a positive regulatory domain. Identification of the Duarte variant requires detecting both cis sequence abnormalities.
    • The LA variant allele contains the identical p.Asn314Asp missense mutation but does not have the GTCA promoter deletion [Langley et al 1997, Elsas et al 2002].
  • Sequence analysis and deletion/duplication analysis described above apply for detection of the non-Duarte allele in D/G galactosemia.

Table 1. Summary of Molecular Genetic Testing Used in Classic (G/G) Galactosemia

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency 1, 2		Test Availability
			Two mutations	One common/ one private mutation
GALT	Targeted mutation analysis	Eight common GALT G mutations 3, 4, 5	80% 3, 5	10%	Clinical
	Sequence analysis	Private 6 and common GALT G mutations	99% 7
	Deletion/ duplication analysis 8	Partial- or whole-gene deletions	See footnote 9

Test Availability refers to availability in the GeneTests™ Laboratory Directory. 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.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. In individuals with biochemically confirmed G/G galactosemia

3. Common alleles identified by targeted mutation analysis (p.Gly188Arg, p.Ser135Leu, p.Lys285Asn, p.Leu195Pro, p.Tyr209Cys, p.Phe171Ser, c.253-2A>G, 5kbdel)

4. The c.253-2A>G allele is common in Hispanics; the 5kbdel allele is common in Ashkenazim.

5. Mutations included in targeted mutation panels may vary by laboratory; detection rates will vary accordingly.

6. Examples of “private” mutations detected by sequence analysis include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

7. Includes detection of the common mutations identified by targeted mutation analysis

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

9. Detection rates may vary among testing laboratories.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

• Quantitative measurement of erythrocyte concentration of gal-1-P and erythrocyte GALT enzyme activity establishes the diagnosis of galactosemia. Note: Infants who have a positive newborn screening test or symptoms, or older children with a positive Clinitest^® reaction (copper-oxidizing aldehyde) and a negative Glucostix^® reaction (glucose oxidase-impregnated strip) warrant measurement of GALT enzyme activity.
• Molecular genetic testing is used to confirm the diagnosis of galactosemia and to distinguish the Duarte variant allele from the LA variant allele. The Duarte allele and the LA allele have the same p.Asn314Asp missense mutation. They are differentiated by molecular analysis of the GALT promoter region: the true Duarte allele (D₂) has a c.-116_-119GTCAdel in a positive regulatory region on the same allele as p.Asn314Asp. (The LA variant [D₁] does not have this mutation.)
  
  If biochemical testing has confirmed the diagnosis of galactosemia and if neither or only one disease-causing mutation is detected by targeted mutation analysis, sequence analysis followed by deletion/duplication analysis, if necessary, can be used to detect mutations not included in the targeted mutation analysis panel.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes and are not at risk of developing the disorder.

Prognosis. Molecular genetic testing defines the genotype and enables prognosis [Guerrero et al 2000, Webb et al 2003].

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are associated with GALT mutations.

Natural History

Genotype-Phenotype Correlations

Significant genotype-phenotype correlations have been noted [Shield et al 2000, Tyfield 2000].

Approximately 70% of the G alleles in the white population of northern European ethnicity have a substitution of an arginine for a glutamine at amino acid position 188 (p.Gln188Arg). In the homozygous state, the mutation destabilizes the GALT UMP complex and ablates the second dissociation reaction [Lai et al 1999]. It is associated with increased risks for premature ovarian insufficiency (POI) and dyspraxic speech [Robertson & Singh 2000]. In one cross-sectional retrospective study correlating genotype with outcome in individuals with classic galactosemia, a greater proportion of individuals with a poor outcome were homozygous for the p.Gln188Arg mutation, and a greater proportion with a good outcome were not homozygous for the p.Gln188Arg mutation. An adult male homozygous for the p.Gln188Arg mutation began normal lactose intake at age three years and had no known clinical deficits [Panis et al 2006a].

The Duarte variant is the allele in which an aspartate substituted for asparagine at residue 314 (p.Asn314Asp) imparts bioinstability to the GALT enzyme. In the homozygous state (D/D or p.[Asn314Asp]+[p.Asn314Asp]), erythrocyte GALT enzyme activity is reduced by only 50%. Compound heterozygotes with the mutation (i.e., D/G) have good prognoses [Langley et al 1997, Lai et al 1998]. However, two D alleles, D₂ (Duarte) and D₁ (LA variant), are now known. The D₂ allele is defined by a deletion in a positive response element and may have more effect on the outcome than the D₁ allele.

The p.Ser135Leu allele, in which a leucine is substituted for serine at amino acid 135, is prevalent in Africa. If therapy is initiated in the neonatal period, African Americans with galactosemia who have this allele in either the homozygous state or compound heterozygous state have a good prognosis. Generally, these individuals do not have neonatal hepatotoxicity or chronic problems (i.e., dyspraxia, POI, and intellectual disability) when treated from infancy [Lai et al 1996].

Substitution of an asparagine for a lysine at position 285 (p.Lys285Asn) is prevalent in southern Germany, Austria, and Croatia and has a poor prognosis for neurologic and cognitive dysfunction in either the homozygous state or compound heterozygous state with p.Gln188Arg.

Other compound heterozygotes (e.g., with the p.[Gln188Arg]+[p.Arg333Gly] mutation) have a good long-term outcome [Ng et al 2003].

Penetrance

Although the range of clinical expression for GALT mutations is wide, most G alleles are fully penetrant in the homozygous state.

Nomenclature

Classic galactosemia is a clinical term that was defined by the chronic effects of severe GALT deficiency (i.e., premature ovarian insufficiency, liver disease, growth restriction, ataxia, tremor, dyspraxic speech, impaired executive functions). Since the implementation of newborn screening for GALT deficiency in all states in the US and the routine use of GALT molecular genetic testing, this term is now used for the biochemical phenotype of GALT enzyme activity less than 5%, gal-1-P accumulation above 20 mg/dL, and the presence of two severe GALT mutant alleles such as p.Gln188Arg and 5kbdel. Less severe mutations such as p.Ser135Leu and c.253-2A>G may produce a positive newborn screen, but may not result in chronic signs if treated in the newborn period. Individuals with these mutations are still considered to have “classic galactosemia.”

Variant galactosemia is a clinical term used for the D/G GALT biochemical phenotypes in which at least one mutation is the p.Asn314Asp allele. This term may also be used when newborn screening identifies GALT enzyme deficiency that is between 5% and 50% of control values, for which nutritional intervention is not considered necessary and with which there is no evidence for hepatocellular damage, cataracts, or developmental delays during infancy.

Other mechanisms of impairment in the Leloir metabolic pathway including galactokinase (GALK) deficiency and UDP-galactose epimerase (GALE) deficiency, in which total galactose concentration in blood may be elevated during infancy, should be defined by their specific enzyme (GALE or GALK) deficiency.

Prevalence

Based on the results of newborn screening programs, the prevalence of classic galactosemia (G/G) is approximately 1:30,000. However, when GALT enzyme activity lower than 5% and erythrocyte galactose-1-phosphate concentration higher than 2 mg/dL are used as diagnostic criteria, some newborn screening programs record a prevalence of 1:10,000 [Bosch et al 2005].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with galactosemia, measurement of RBC gal-1-P concentration and urinary galactitol is recommended as a baseline in monitoring the effect of treatment (see Surveillance).

Treatment of Manifestations

Lactose restriction reverses liver disease in newborns who already have hepatocellular disease.

Infertility. Because FSH as a glycoprotein may be abnormal, stimulation with FSH may be useful in producing ovulation in some women. One female with premature ovarian insufficiency (POI) conceived following FSH therapy, and subsequently delivered a normal child [Menezo et al 2004]. Others have found that POI in classic galactosemia may be caused by reduced number or maturation of ovarian follicles and is potentially treatable by exogenous pharmacologic stimulation by gonadotropic hormones [Rubio-Gozalbo et al 2010].

Prevention of Primary Manifestations

Prevention of Secondary Complications

Calcium supplements are indicated in the neonatal period (750 mg/day) and in childhood (>1200 mg/day) [Elsas & Acosta 1998, Elsas & Acosta 2012]. Because bone mineral content may be diminished in children with galactosemia, supplements of vitamin D to more than 1000 IU/day and vitamin K have also been advocated [Panis et al 2006b].

Surveillance

Affected individuals should be monitored routinely for the accumulation of toxic analytes such as RBC gal-1-P (levels <5 mg/dL are considered within the therapeutic range) and urinary galactitol. If sudden increases are detected, dietary sources of excess galactose should be sought or evaluation undertaken for other causes, including infection.

Ophthalmologic examination, developmental evaluation, and focus on speech development with appropriate interventions are recommended.

Agents/Circumstances to Avoid

Lactose-containing drug preparations should be avoided.

Casein hydrolysates (Alimentum^®, Nutramigen^®, Pregestimil^®) are not recommended for dietary treatment because they contain small amounts of bioavailable lactose.

Medications with lactulose should not be used to treat hyperammonemia associated with liver disease, as lactulose contains free lactose [Elsas & Acosta 2006].

Evaluation of Relatives at Risk

Prenatal testing is advised for at-risk sibs so that the parents can be prepared for treatment of the newborn [Elsas 2001].

If prenatal testing is not performed, each at-risk newborn should be screened for galactosemia using the GALT enzyme activity of erythrocytes as well as molecular genetic testing of buffy coat DNA immediately after delivery. Note: Treatment with soy formula should be implemented while diagnostic tests are underway.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Research suggests that despite exogenous galactose restriction, endogenous galactose production may approach 2.0 g/day [Berry et al 2004, Schadewaldt et al 2004]. If this is true, "self-intoxication" with galactose may be more of a problem than restriction of galactose from exogenous sources in the management of older children and adults who no longer depend on milk as their primary source of energy. Approaches to lowering endogenous production of gal-1-P are under investigation using small inhibitors of the GALK enzyme [Tang et al 2010]. Although in vitro studies of GALT enzyme-deficient human fibroblasts demonstrated proof of concept, a GALT enzyme-deficient mouse model is needed that expresses an ARHI signal. Note that GALT knockout mice do not express the human phenotype of galactosemia and have lost ARHI (DIRAS3) during evolution [Lai et al 2008, Rubio-Gozalbo et al 2010, Tang et al 2010].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Some have considered ovarian biopsy with egg preservation for future use if serum concentrations of FSH and LH rise, indicating premature ovarian insufficiency.

The efficacy of restricting lactose in the diets of pregnant women who are at risk of having a child with galactosemia is unknown but probably not significant.

Uridine supplements have not been of value.

Genetics clinics, staffed by genetics professionals, provide 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.

Mode of Inheritance

Galactosemia is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.
• Heterozygotes (carriers) are asymptomatic and do not develop galactosemia.

Sibs of a proband

• At conception, each sib of a proband with G/G galactosemia has a 25% chance of being affected, a 50% chance of being a carrier (heterozygote) of a disease-causing allele, and a 25% chance of having two normal alleles.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. Older asymptomatic sibs of a proband should be offered carrier testing using molecular genetic testing when they are of reproductive age.
• At conception, each sib of a proband with D/G galactosemia is at a 25% risk for D/G galactosemia if the parents are D/N and G/N and a 25% risk for G/G galactosemia if the parents are D/G and G/N. Thus, molecular genetic testing of the parents is recommended.

Offspring of a proband

• Affected females are at increased risk for premature ovarian insufficiency, but may have children.
• Offspring of one parent with (G/G) galactosemia and one parent with two normal alleles (N/N) are obligate heterozygotes (G/N).
• If one parent is affected (G/G) and the other parent is a carrier for a G allele (G/N or D/G), each child has a 50% chance of being a heterozygote and a 50% chance of having G/G galactosemia.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Biochemical testing. Carrier testing is done by measuring GALT enzyme activity, which is approximately 50% of control values in carriers.

Molecular genetic testing. Carrier testing for at-risk family members is possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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.

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, are carriers, or are at risk of being carriers.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing is possible for fetuses at 25% risk for classic (G/G) galactosemia using either GALT enzyme activity or molecular genetic testing if the two disease-causing GALT mutations in the family are known [Elsas 2001]. Analysis of GALT enzyme activity and molecular diagnosis rely on cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15 to 18 weeks' gestation.

Note: When a fetus has GALT deficiency, amniotic fluid concentration of galactitol is elevated in the late third trimester.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Other issues to consider. Prenatal diagnosis of a treatable condition may be controversial if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing. Although most centers would consider this to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Suggested Reading

1. Bosch AM. Classical galactosaemia revisited. J Inherit Metab Dis. 2006;29:516–25. [PubMed: 16838075]
2. Fridovich-Keil JL, Tyfield LA. Galactosemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 72. Available at www​.ommbid.com. Accessed 1-9-13.
3. Lai K, Elsas LJ, Wierenga KJ. Galactose toxicity in animals. IUBMB Life. 2009;61:1063–74. [PMC free article: PMC2788023] [PubMed: 19859980]

Author Notes

Dr Louis J Elsas II was a physician, teacher, and pioneering researcher in the field of medical genetics. In a career spanning nearly 50 years, he held positions first at Yale University (as a fellow in medical genetics and later a member of the faculty), and then at Emory University School of Medicine, where he developed new treatments for infants with metabolic disorders including galactosemia and PKU; while there he also created a course in human and molecular genetics that became a national model, helping to define medical genetics as a recognized specialty. After retiring from Emory, Dr Elsas moved to the University of Miami and became the first director of the Dr John T Macdonald Foundation Center for Medical Genetics at the Miller School of Medicine. Dr Elsas died September 16, 2012 following an extended illness.

Revision History

• 26 October 2010 (me) Comprehensive update posted live
• 27 September 2007 (me) Comprehensive update posted to live Web site
• 2 May 2005 (me) Comprehensive update posted to live Web site
• 27 March 2003 (me) Comprehensive update posted to live Web site
• 4 February 2000 (me) Review posted to live Web site
• 31 August 1999 (le) Original submission