Clinical characteristics.

Alexander disease is a progressive disorder of cerebral white matter that predominantly affects infants and children and has variable life expectancy. The later-onset forms present with a slower clinical course. The infantile form comprises about 42% of affected individuals, the juvenile form about 22%, and the adult form about 33%. A neonatal form is also recognized.

• The neonatal form leads to severe disability or death within two years. Characteristics include seizures, hydrocephalus, severe motor and intellectual disability, and elevated CSF protein concentration. MRI shows severe white matter abnormalities with involvement of the basal ganglia and cerebellum.
• The infantile form presents in the first two years of life, typically with progressive psychomotor retardation with loss of developmental milestones, megalencephaly, frontal bossing, and seizures. Other findings include hyperreflexia and pyramidal signs, ataxia, and occasional hydrocephalus secondary to aqueductal stenosis. Affected children survive weeks to several years.
• The juvenile form usually presents between ages four and ten years, occasionally in the mid-teens. Findings can include bulbar/pseudobulbar signs, ataxia, gradual loss of intellectual function, seizures, normocephaly or megalencephaly, and breathing problems. Survival ranges from the early teens to the 20s-30s.
• The adult form is the most variable.

Diagnosis/testing.

Diagnosis of Alexander disease is based on clinical findings, and confirmed with MRI changes and identification of a heterozygous pathogenic variant in GFAP, which encodes glial fibrillary acidic protein.

Management.

Treatment of manifestations: Treatment is supportive and includes attention to general care and nutritional requirements, antibiotic treatment for intercurrent infection, antiepileptic drugs (AEDs) for seizure control, assessment for learning disabilities and cognitive impairment, and physical and occupational therapy as needed.

Prevention of secondary complications: It is essential to pay attention to nutritional status, swallowing ability, and early signs of scoliosis.

Surveillance: Examinations at regular intervals by a multidisciplinary team with particular attention to growth, gastrointestinal function/nutritional intake, orthopedic and neurologic status, strength and mobility, communication skills, and psychological complications.

Genetic counseling.

Alexander disease is inherited in an autosomal dominant manner. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent is affected or has a pathogenic variant in GFAP, the risk to the sibs of inheriting the GFAP pathogenic variant is 50%. Sibs of a proband are at low risk for Alexander disease if the pathogenic variant is de novo (as is usually the case); however, the possibility of germline mosaicism exists. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.

Suggestive Findings

Diagnosis of Alexander disease should be suspected in individuals with the following clinical and neuroimaging findings:

Clinical findings by age of presentation

• Children under age two years may present with progressive psychomotor retardation, developmental regression, megalencephaly with frontal bossing, seizures, pyramidal signs, ataxia, and occasional hydrocephalus secondary to aqueductal stenosis.
• Children age two to ten years, up to the mid-teens, may present with bulbar/pseudobulbar signs with nasal speech, lower limb spasticity, ataxia, gradual loss of intellectual function, seizures, megalencephaly, and breathing problems.
• Adults may present with bulbar/pseudobulbar signs, pyramidal tract signs, cerebellar signs, dysautonomia, sleep disturbance, gait disturbance, hemiparesis/hemiplegia or quadriparesis/quadriplegia, seizures, and diplopia.

Neuroimaging findings. From a multi-institutional retrospective survey of MRI studies of 217 individuals with leukoencephalopathy [van der Knaap et al 2001], it has been suggested that the presence of four of the five following criteria establishes an MRI-based diagnosis of Alexander disease:

• Extensive cerebral white-matter abnormalities with a frontal preponderance
• A periventricular rim of decreased signal intensity on T₂-weighted images and elevated signal intensity on T₁-weighted images
• Abnormalities of the basal ganglia and thalami that may include any of the following:
  • Elevated signal intensity and swelling
  • Atrophy
  • Elevated or decreased signal intensity on T₂-weighted images
• Brain stem abnormalities, particularly involving the medulla and midbrain
• Contrast enhancement of one or more of the following: ventricular lining, periventricular rim, frontal white matter, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, brain stem

Rodriguez et al [2001] determined that individuals who exhibited these typical findings on MRI were more likely than not to have the diagnosis of Alexander disease confirmed by molecular genetic testing.

Studies of individuals with molecularly confirmed Alexander disease have expanded the MRI findings to include the following atypical MRI findings [van der Knaap et al 2005, van der Knaap et al 2006]:

• Predominant or isolated involvement of posterior fossa structures
• Multifocal tumor-like brain stem lesions and brain stem atrophy
• Slight, diffuse signal changes involving the basal ganglia and/or thalamus
• Garland-like feature along the ventricular wall
• Characteristic pattern of contrast enhancement
• Any other findings that suggest, but do not meet, the strict criteria

Note: (1) It has been suggested that signal abnormalities or atrophy of the medulla or spinal cord are sufficient findings to warrant molecular genetic testing of GFAP [Salvi et al 2005, van der Knaap et al 2006]. (2) Atypical MRI findings were more commonly observed in juvenile- and adult-onset Alexander disease, indicating that these forms have more variable disease manifestations.

Establishing the Diagnosis

The diagnosis of Alexander disease is established in a proband by detection of a heterozygous pathogenic variant of GFAP (see Table 1).

Approaches to molecular genetic testing can include the following:

• Sequence analysis of GFAP. If no pathogenic variant is found, deletion/duplication analysis could be considered.
• Use of a multi-gene panel that includes GFAP and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.
• More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if single-gene testing (and/or use of a multi-gene panel that includes GFAP) fails to confirm a diagnosis in an individual with features of Alexander disease. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Alexander disease is a progressive disorder of cerebral white matter that predominantly affects infants and children. Life expectancy is variable. Most individuals with Alexander disease present with nonspecific neurologic signs and symptoms.

Three forms are typically recognized: infantile, juvenile, and adult. It has been suggested that the subset of infants with neonatal onset (i.e., within 30 days of birth) constitutes a separate neonatal form [Springer et al 2000].

The infantile form of Alexander disease accounts for 42% (124/293) of reported individuals with an identifiable GFAP pathogenic variant (see Table 2). The juvenile form accounts for 22% (63/293) and the adult form 33% (96/293) (see Table 2).

Ten (3%) of the 293 individuals with an identifiable GFAP pathogenic variant were reported to be asymptomatic [Stumpf et al 2003, Shiihara et al 2004, Yoshida et al 2011, Messing et al 2012, Wada et al 2013]. The current clinical status of these individuals is unknown.

Neonatal form. Springer et al [2000] suggested that the neonatal form is characterized by the following:

• Onset within the first month of life
• Rapid progression leading to severe disability or death with the first two years of life. Regression may be difficult to identify at such an early age and may be manifest as loss of sucking.
• Seizures as an early and obligatory symptom. Seizures are generalized, frequent, and often intractable.
• Hydrocephalus with raised intracranial pressure, primarily caused by aqueductal stenosis
• Severe motor and intellectual disability, without prominent spasticity or ataxia
• Severe white-matter abnormalities with frontal predominance and extensive pathologic periventricular enhancement demonstrated on neuroradiologic contrast imaging
• Involvement of the basal ganglia and cerebellum
• Elevated CSF protein concentration

Infantile form. Onset of the infantile form occurs during the first two years of life. Affected children survive a few weeks to several years, but usually not beyond the early teens. Variable presentations, in decreasing order of frequency, include the following:

• Progressive psychomotor retardation with loss of developmental milestones
• Frontal bossing and megalencephaly including enlargement of cerebellum and brain stem
• Seizures
• Hyperreflexia and pyramidal signs
• Ataxia
• Hydrocephalus secondary to aqueductal stenosis

Juvenile form. The juvenile form of Alexander disease usually presents between age four and ten years, occasionally in the mid-teens. Sometimes the initial presentation suggests a focal brain stem lesion, such as tumor. Survival is variable, ranging from the early teens to the 20s-30s. Affected children can present with one or more of the following signs and symptoms, ordered by decreasing frequency:

• Bulbar/pseudobulbar signs including speech abnormalities, swallowing difficulties, frequent vomiting
• Lower limb spasticity
• Poor coordination (ataxia)
• Gradual loss of intellectual function
• Seizures
• Megalencephaly
• Breathing problems

Adult form. The adult form of Alexander disease is the most variable. It can be similar to the juvenile form with later onset and slower progression [Martidis et al 1999, Namekawa et al 2002, Okamoto et al 2002, Brockmann et al 2003, Kinoshita et al 2003, Stumpf et al 2003]. Survival ranges from a few years to a number of decades following the onset of symptoms. Some individuals have been diagnosed incidentally during autopsy for other conditions. Reports of molecularly confirmed familial cases support the existence of asymptomatic adults with Alexander disease [Stumpf et al 2003, Shiihara et al 2004, Messing et al 2012, Wada et al 2013]. Based on a retrospective study of 13 individuals with late-onset Alexander disease, brain stem and/or spinal cord involvement may be common, resulting in symptoms such as nystagmus, dysphagia, dysarthria, spasticity/hyperreflexia, positive Babinski sign, gait abnormality, and weakness, though individual-to-individual and intrafamilial variability is seen [Graff-Radford et al 2014]. The full set of signs and symptoms variably seen in affected individuals comprises the following:

• Bulbar/pseudobulbar signs: palatal myoclonus, dysphagia, dysphonia, dysarthria, slurred speech
• Pyramidal tract signs: spasticity, hyperreflexia, positive Babinski sign
• Cerebellar signs: ataxia, nystagmus, dysmetria
• Dysautonomia: incontinence, constipation, pollakiuria (urinary frequency), urinary retention, impotence, sweating abnormality, hypothermia, orthostatic hypotension
• Sleep disturbance: sleep apnea
• Gait disturbance
• Hemiparesis/hemiplegia or quadriparesis/quadriplegia
• Seizures
• Diplopia
• Fluctuating course

EEG. Electroencephalographic studies are nonspecific, usually showing slow waves over the frontal areas of the brain. Focal epileptiform discharges may also be seen [Gordon 2003].

CSF studies. Increased levels of αβ-crystallin and heat shock protein 27 have been observed in cerebrospinal fluid (CSF) of individuals with Alexander disease. Increased levels of glial fibrillary acidic protein were documented in the CSF of individuals with a molecularly confirmed diagnosis [Kyllerman et al 2005].

Other. The causal relationship of the following other findings observed in individuals with a GFAP pathogenic variant is unknown.

• Post-term delivery, hypotonia, frequent syncopal episodes, unusual nevi, hypothyroidism [Gorospe et al 2002]
• Hypertension and diabetes mellitus [Brockmann et al 2003]
• Arched palate and short neck [Stumpf et al 2003]
• Linear growth failure [Gorospe et al 2002, van der Knaap et al 2006]
• Precocious puberty [van der Knaap et al 2006]
• Mood disturbances, osteopenia, microcoria, primary ovarian failure, hypothyroidism [Sreedharan et al 2007]
• Vertebral anomalies:
  • Scoliosis [Nonomura et al 2002, Okamoto et al 2002, Hinttala et al 2007]
  • Kyphosis [Stumpf et al 2003, van der Knaap et al 2006, Delnooz et al 2008]
  • Lordosis [van der Knaap et al 2006]

Some asymptomatic individuals have been identified as having a GFAP pathogenic variant with suggestive MRI findings discovered incidentally during evaluation for other unrelated conditions (e.g., accidental eye injury, short stature) [Gorospe et al 2002, Guthrie et al 2003]. Due to lack of follow-up studies, it is not clear whether these individuals remain asymptomatic, or whether symptoms will emerge gradually with time.

Histologic studies. Prior to the definition of the molecular genetic basis of Alexander disease, the demonstration of enormous numbers of Rosenthal fibers on brain biopsy or at autopsy was the only method for definitive diagnosis of the disease. Rosenthal fibers are intracellular inclusion bodies composed of aggregates of glial fibrillary acidic protein, vimentin, αβ-crystallin, and heat shock protein 27 found exclusively in astrocytes. Rosenthal fibers increase in size and number during the course of the disease.

Genotype-Phenotype Correlations

The number of individuals with confirmed pathogenic variants in GFAP is too small to make any conclusive genotype-phenotype correlations. Currently, the following observations hold true, but given the variable expressivity of the disorder, exceptions may occur:

• Disparate clinical presentations among affected members within the same family suggest that modifier genes and other factors may play a role in expression of the clinical phenotype.
• Ten recurrent pathogenic variants (p.Met73Thr, p.Leu76Phe, p.Asn77Ser, p.Lys86_Val87delinsGluPhe, p.Leu97Pro, p.Arg239His, p.Arg239Leu, p.Leu352Pro, p.Glu373Lys, and p.Asp417MetfsTer15table3) have been seen only in the infantile form (see Table 2 for references related to these pathogenic variants).
• One recurrent pathogenic variant (p.Leu235Pro) has been found exclusively in the juvenile form (see Table 2 for references related to this pathogenic variant).
• Seven recurrent pathogenic variants (p.Arg66Gln, p.Arg70Trp, p.Arg70Gln, p.Met74Thr, p.Glu205Lys, p.Leu359Pro, and p.Ala364Thr) have been found exclusively in the adult form (see Table 2 for references related to these pathogenic variants).
• Five recurrent pathogenic variants (p.Arg79Cys, p.Arg79Leu, p.Arg88Cys, p.Arg239Cys, and p.Arg239Pro) have been seen in both the infantile and juvenile but not adult forms, while five recurrent pathogenic variants (p.Val87Ile, p.Glu210Lys, p.Arg258Cys, p.Arg276Leu, and p.Ser393Ile) were seen in both the juvenile and adult but not infantile forms. (See Table 2 for references related to these pathogenic variants).
• Only one pathogenic variant (p.Arg416Trp) has been seen in all forms of Alexander disease (see Table 2 for references related to this pathogenic variant).

Penetrance

Penetrance appears to be nearly 100% in individuals with the infantile and juvenile forms [Li et al 2002, Messing & Brenner 2003a].

Asymptomatic, neurologically intact individuals with the juvenile form of Alexander disease are occasionally diagnosed after evaluation for other conditions, as illustrated in the following three cases. Note, however, that long-term follow up has not been reported.

• In a prospective study in which 12 of 13 patients suspected of having Alexander disease were found to have a GFAP pathogenic variant, two were minimally affected [Gorospe et al 2002]. One underwent brain MRI after eye injury. Before the accident, he performed well in school except in mathematics, and he had no neurologic symptoms except for clumsiness and incoordination reported by the parents. The second individual had high normal head circumference and short stature, for which an endocrinologist had ordered a brain MRI to assess the pituitary gland.
• Similar to the latter case of Gorospe et al [2002], Guthrie et al [2003] reported a third case: a child with normal development except for macrocephaly and growth retardation whose brain MRI findings and GFAP testing were consistent with Alexander disease.

In some instances, variable expressivity may masquerade as incomplete penetrance.

• Variable expressivity is most frequently observed in familial adult cases, in which mildly affected parents and sibs of affected individuals have a GFAP pathogenic variant [Namekawa et al 2002, Okamoto et al 2002, Brockmann et al 2003, Messing & Brenner 2003a, Stumpf et al 2003, Thyagarajan et al 2004, van der Knaap et al 2006].
• In contrast, in one family all three individuals with a GFAP pathogenic variant had mild phenotypes: a boy age 16 months had macrocephaly; his mother (age 34 years) and sister (age 7 years) had normal physical and neurologic examinations, including head circumference, but their brain MRIs showed abnormal signal intensities in the deep frontal white matter and caudate [Shiihara et al 2004]. Clinical follow up has not been reported.

Prevalence

Alexander disease is thought to be rare; actual prevalence figures have not been reported. Since the description of the first affected individual, more than 550 cases have been reported. GFAP pathogenic variants have been confirmed in 293 reported individuals (see Table 2).

The disorder is known to occur in diverse ethnic and racial groups [Gorospe & Maletkovic 2006].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Alexander disease, the following evaluations are recommended:

• Complete neurologic assessment
• Formal, age-appropriate developmental assessment
• Assessment of feeding/eating, digestive problems (including constipation and gastroesophageal reflux), and nutrition using history, growth measurements, and, if needed, gastrointestinal investigations
• Video/EEG monitoring to obtain definitive information about the occurrence of seizures and the need for antiepileptic drugs
• Psychological assessment for older patients to determine their awareness and understanding of the disease and its consequences
• Examination for possible scoliosis
• Assessment of family and social structure to determine availability of adequate support system
• Clinical genetics consultation

Treatment of Manifestations

No specific therapy is currently available for Alexander disease.

Management is supportive and includes attention to general care, nutritional requirements, antibiotic treatment for intercurrent infection, and antiepileptic drugs (AED) for seizure control.

Learning disabilities and other cognitive impairments are addressed as in individuals who do not have Alexander disease.

Physical and occupational therapy are indicated when assessment reveals the need for adaptive measures to maximize strength and motor capabilities.

Prevention of Secondary Complications

The following are appropriate:

• Swallow studies and nutritional intervention (i.e., gastrostomy tube placement) for those with severe feeding difficulties
• Speech assessments to identify problems amenable to interventions such as assistive communication devices
• Early recognition of abnormal tone and spinal problems (i.e., scoliosis) in order to prevent long-term complications

Surveillance

Depending on age, affected individuals should be examined at regular intervals by a multidisciplinary team with particular attention to growth, nutritional intake, orthopedic and neurologic status, gastrointestinal function, strength and mobility, communication skills, and psychological complications.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

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.

Mode of Inheritance

Alexander disease is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• The infantile and juvenile forms of Alexander disease are usually caused by a de novo pathogenic variant in GFAP. Typically, the parents of individuals with molecularly confirmed infantile and juvenile forms do not have clinical features of Alexander disease or an identified GFAP pathogenic variant [Brenner et al 2001, Rodriguez et al 2001, Gorospe et al 2002].
• A study on unrelated individuals with Alexander disease revealed that the GFAP pathogenic variant was on the paternal chromosome in a majority of individuals (24 of 28), suggesting that most instances of de novo mutation occur during spermatogenesis rather than in the embryo [Li et al 2006].
• Individuals with the slowly progressive adult form who have an affected parent have been reported [Namekawa et al 2002, Okamoto et al 2002, Stumpf et al 2003, Thyagarajan et al 2004, van der Knaap et al 2006, Messing et al 2012].

Note: Although individuals diagnosed with the adult form of Alexander disease may have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, germline mosaicism in the parent, or incomplete penetrance.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent (asymptomatic or affected) has a pathogenic variant in GFAP, the risk to the sibs of inheriting the GFAP pathogenic variant is 50%.
• If the proband’s pathogenic variant cannot be detected in the leukocyte DNA of either parent, two possible explanations are a de novo pathogenic variant in the proband or germline mosaicism in a parent.
  • Because most individuals with Alexander disease have the altered gene as a result of a de novo pathogenic variant, the expected risk of being affected to sibs of a proband with an infantile, juvenile, or adult form is lower than 1/200 (i.e., <0.5%). This risk takes into account the possibility of germline mosaicism.
  • Reports of neuropathologically and molecularly proven Alexander disease that runs in families in which the parents are neurologically intact suggest the possibility of germline mosaicism [Messing et al 2001, Namekawa et al 2002, Messing & Brenner 2003a, Messing et al 2012].

Offspring of a proband

• Individuals with the infantile or juvenile form of Alexander disease typically do not reproduce.
• Each child of an individual with the slowly progressing adult form of Alexander disease has a 50% chance of inheriting the pathogenic variant.

Other family members

• The risk to other family members depends on the genetic status of the proband's parents.
• If a parent is affected or has a GFAP pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adult relatives of individuals with Alexander disease is possible after molecular genetic testing has identified the specific pathogenic variants in the family. Such testing should be performed in the context of formal genetic counseling. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant (i.e., the pathogenic variant is not detected in leukocyte DNA) or clinical evidence of the disorder, the pathogenic variant likely occurred de novo. However, possible non-medical considerations include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption.

Family planning

• The optimal time for determination of genetic risk 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the GFAP pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for Alexander disease are possible.

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• Schuelke M, Smeitink J, Mariman E, Loeffen J, Plecko B, Trijbels F, Stockler-Ipsiroglu S, van den Heuvel L. Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nat Genet. 1999;21:260–1. [PubMed: 10080174]
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• van der Knaap MS, Ramesh V, Schiffmann R, Blaser S, Kyllerman M, Gholkar A, Ellison DW, van der Voorn JP, van Dooren SJ, Jakobs C, Barkhof F, Salomons GS. Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord. Neurology. 2006;66:494–8. [PubMed: 16505300]
• van der Knaap MS, Salomons GS, Li R, Franzoni E, Gutierrez-Solana LG, Smit LM, Robinson R, Ferrie CD, Cree B, Reddy A, Thomas N, Banwell B, Barkhof F, Jakobs C, Johnson A, Messing A, Brenner M. Unusual variants of Alexander's disease. Ann Neurol. 2005;57:327–38. [PubMed: 15732098]
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Suggested Reading

• Barkovich AJ, Messing A. Alexander disease: not just a leukodystrophy anymore. Neurology. 2006;66:468–9. [PubMed: 16505295]
• Quinlan RA, Brenner M, Goldman JE, Messing A. GFAP and its role in Alexander disease. Exp Cell Res. 2007;313:2077–87. [PMC free article: PMC2702672] [PubMed: 17498694]
• Sawaishi Y. Review of Alexander disease: beyond the classical concept of leukodystrophy. Brain Dev. 2009;31:493–8. [PubMed: 19386454]

Author History

J Rafael Gorospe, MD, PhD; NIH – National Center for Research Resource (2002-2015)
Sakkubai Naidu, MD (2015-present)
Siddharth Srivastava, MD (2015-present)

Revision History

• 8 January 2015 (me) Comprehensive update posted live
• 22 April 2010 (me) Comprehensive update posted live
• 9 March 2007 (cd,jrg) Revision: sequence analysis of select exons and targeted mutation analysis no longer clinically available
• 2 October 2006 (me) Comprehensive update posted to live Web site
• 28 September 2004 (me) Comprehensive update posted to live Web site
• 5 May 2003 (cd,jrg) Revision: molecular genetic testing clinically available
• 15 November 2002 (me) Review posted to live Web site
• 24 April 2002 (jrg) Original submission