Infantile Alexander Disease: Spectrum of GFAP Mutations and Genotype-Phenotype Correlation
2001; Elsevier BV; Volume: 69; Issue: 5 Linguagem: Inglês
10.1086/323799
ISSN1537-6605
AutoresDiana Rodriguez, Fernande Gauthier, Enrico Bertini, Marianna Bugiani, Michael Brenner, Sylvie Nguyen, Cyril Goizet, A. Gélot, Robert Surtees, Jean‐Michel Pédespan, X. Hernandoréna, Mónica Troncoso, G. Uziel, Albee Messing, G Ponsot, Danielle Pham-Dinh, André Dautigny, Odile Boespflug‐Tanguy,
Tópico(s)RNA and protein synthesis mechanisms
ResumoHeterozygous, de novo mutations in the glial fibrillary acidic protein (GFAP) gene have recently been reported in 12 patients affected by neuropathologically proved Alexander disease. We searched for GFAP mutations in a series of patients who had heterogeneous clinical symptoms but were candidates for Alexander disease on the basis of suggestive neuroimaging abnormalities. Missense, heterozygous, de novo GFAP mutations were found in exons 1 or 4 for 14 of the 15 patients analyzed, including patients without macrocephaly. Nine patients carried arginine mutations (four had R79H; four had R239C; and one had R239H) that have been described elsewhere, whereas the other five had one of four novel mutations, of which two affect arginine (2R88C and 1R88S) and two affect nonarginine residues (1L76F and 1N77Y). All mutations were located in the rod domain of GFAP, and there is a correlation between clinical severity and the affected amino acid. These results confirm that GFAP mutations are a reliable molecular marker for the diagnosis of infantile Alexander disease, and they also form a basis for the recommendation of GFAP analysis for prenatal diagnosis to detect potential cases of germinal mosaicism. Heterozygous, de novo mutations in the glial fibrillary acidic protein (GFAP) gene have recently been reported in 12 patients affected by neuropathologically proved Alexander disease. We searched for GFAP mutations in a series of patients who had heterogeneous clinical symptoms but were candidates for Alexander disease on the basis of suggestive neuroimaging abnormalities. Missense, heterozygous, de novo GFAP mutations were found in exons 1 or 4 for 14 of the 15 patients analyzed, including patients without macrocephaly. Nine patients carried arginine mutations (four had R79H; four had R239C; and one had R239H) that have been described elsewhere, whereas the other five had one of four novel mutations, of which two affect arginine (2R88C and 1R88S) and two affect nonarginine residues (1L76F and 1N77Y). All mutations were located in the rod domain of GFAP, and there is a correlation between clinical severity and the affected amino acid. These results confirm that GFAP mutations are a reliable molecular marker for the diagnosis of infantile Alexander disease, and they also form a basis for the recommendation of GFAP analysis for prenatal diagnosis to detect potential cases of germinal mosaicism. In 1949, W. Stewart Alexander described a "progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant" (Alexander Alexander, 1949Alexander WS Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant.Brain. 1949; 72: 373-381Crossref PubMed Scopus (239) Google Scholar) and suggested that the primary pathogenesis was a specific dysfunction of astrocytes. Since this first description, the dysfunction of astrocytes has been observed in various age groups, with diverse symptoms (Russo et al. Russo et al., 1976Russo LS Aron A Anderson PJ Alexander's disease: a report and reappraisal.Neurology. 1976; 26: 607-614Crossref PubMed Google Scholar; Borrett and Becker Borrett and Becker, 1985Borrett D Becker LE Alexander's disease, a disease of astrocytes.Brain. 1985; 108: 367-385Crossref PubMed Scopus (108) Google Scholar; Pridmore et al. Pridmore et al., 1993Pridmore CL Baraitser M Harding B Boyd SG Kendall B Brett EM Alexander's disease: clues to diagnosis.J Child Neurol. 1993; 8: 134-144Crossref PubMed Scopus (74) Google Scholar; Springer et al. Springer et al., 2000Springer S Erlewein R Naegele T Becker I Auer D Grodd W Krageloh-Mann I Alexander disease: classification revisited and isolation of a neonatal form.Neuropediatrics. 2000; 31: 86-92Crossref PubMed Scopus (43) Google Scholar; Messing et al. Messing et al., 2001Messing A Goldman JE Johnson AB Brenner M Alexander disease: new insights from genetics.J Neuropathol Exp Neurol. 2001; 60: 563-573Crossref PubMed Scopus (62) Google Scholar). Histologically, Alexander disease (MIM 203450) is characterized by the presence in astrocytes of cytoplasmic inclusions, termed "Rosenthal fibers." These inclusions, which contain the intermediate filament protein GFAP (MIM 137780) in association with small heat-shock proteins, are found predominately in astrocytes located in subependymal, subpial, and periventricular areas. The disease is also usually associated with myelin loss in a rostrocaudal gradient. The most notable features of the infantile form of Alexander disease, which begins during the first two years of life, are macrocephaly (and sometimes hydrocephaly), psychomotor regression, seizures, and spasticity. The patient dies within the first decade. MRI is useful for diagnosis and shows signaling changes in white matter, with frontal predominance, and in some patients abnormalities of the basal ganglia and the thalamus, contrast enhancement, and variable enlargement of the ventricles (Pridmore et al. Pridmore et al., 1993Pridmore CL Baraitser M Harding B Boyd SG Kendall B Brett EM Alexander's disease: clues to diagnosis.J Child Neurol. 1993; 8: 134-144Crossref PubMed Scopus (74) Google Scholar; Johnson et al. Johnson, 1996Johnson AB Alexander disease.in: Moser HG Handbook of clinical neurology. Vol 22. Neurodystrophies and neurolipidoses. Elsevier, Amsterdam1996: 701-710Google Scholar; Springer et al. Springer et al., 2000Springer S Erlewein R Naegele T Becker I Auer D Grodd W Krageloh-Mann I Alexander disease: classification revisited and isolation of a neonatal form.Neuropediatrics. 2000; 31: 86-92Crossref PubMed Scopus (43) Google Scholar; van der Knaap et al. van der Knaap et al., 2001van der Knaap MS Naidu S Breiter SN Blaser S Stroink H Springer S Begeer JC van Coster R Barth PG Thomas NH Valk J Powers JM Alexander disease: diagnosis with MR imaging.Am J Neuroradiol. 2001; 22: 541-552PubMed Google Scholar). On the basis of the presence of Rosenthal fibers, juvenile and adult forms have been identified. Juvenile patients have a slower clinical course (with bulbar signs, ataxia, and spasticity), and their intellectual abilities are usually preserved (Russo et al. Russo et al., 1976Russo LS Aron A Anderson PJ Alexander's disease: a report and reappraisal.Neurology. 1976; 26: 607-614Crossref PubMed Google Scholar; Borrett and Becker Borrett and Becker, 1985Borrett D Becker LE Alexander's disease, a disease of astrocytes.Brain. 1985; 108: 367-385Crossref PubMed Scopus (108) Google Scholar; Reichard et al. Reichard et al., 1996Reichard EA Ball Jr, WS Bove KE Alexander disease: a case report and review of the literature.Pediatr Pathol Lab Med. 1996; 16: 327-343Crossref PubMed Scopus (18) Google Scholar). Adult patients have heterogeneous symptoms; some patients have relapsing-remitting neurological symptoms that mimic multiple sclerosis and are only diagnosed as Alexander disease during neuropathological examination (Seil et al. Seil et al., 1968Seil FJ Schochet Jr, SS Earle KM Alexander's disease in an adult: report of a case.Arch Neurol. 1968; 19: 494-502Crossref PubMed Scopus (48) Google Scholar; Herndon et al. Herndon et al., 1970Herndon RM Rubinstein LJ Freeman JM Mathieson G Light and electron microscopic observations on Rosenthal fibers in Alexander's disease and in multiple sclerosis.J Neuropathol Exp Neurol. 1970; 29: 524-551Crossref PubMed Scopus (138) Google Scholar; Howard et al. Howard et al., 1993Howard RS Greenwood R Gawler J Scaravilli F Marsden CD Harding AE A familial disorder associated with palatal myoclonus, other brainstem signs, tetraparesis, ataxia and Rosenthal fibre formation.J Neurol Neurosurg Psychiatry. 1993; 56: 977-981Crossref PubMed Scopus (36) Google Scholar; Schwankhaus et al. Schwankhaus et al., 1995Schwankhaus JD Parisi JE Gulledge WR Chin L Currier RD Hereditary adult-onset Alexander's disease with palatal myoclonus, spastic paraparesis, and cerebellar ataxia.Neurology. 1995; 45: 2266-2271Crossref PubMed Scopus (61) Google Scholar). Most of the neuropathologically proved cases of Alexander disease are sporadic, but rare familial cases have been reported (reviewed by Messing et al. Messing et al., 2001Messing A Goldman JE Johnson AB Brenner M Alexander disease: new insights from genetics.J Neuropathol Exp Neurol. 2001; 60: 563-573Crossref PubMed Scopus (62) Google Scholar). In adults, an autosomal dominant mode of inheritance has been suggested (Howard et al. Howard et al., 1993Howard RS Greenwood R Gawler J Scaravilli F Marsden CD Harding AE A familial disorder associated with palatal myoclonus, other brainstem signs, tetraparesis, ataxia and Rosenthal fibre formation.J Neurol Neurosurg Psychiatry. 1993; 56: 977-981Crossref PubMed Scopus (36) Google Scholar; Schwankhaus et al. Schwankhaus et al., 1995Schwankhaus JD Parisi JE Gulledge WR Chin L Currier RD Hereditary adult-onset Alexander's disease with palatal myoclonus, spastic paraparesis, and cerebellar ataxia.Neurology. 1995; 45: 2266-2271Crossref PubMed Scopus (61) Google Scholar), whereas recessive transmission has been postulated for the few described infants who have affected siblings (Wohlwill et al. Wohlwill et al., 1959Wohlwill FJ Bernstein J Yakovlev PI Dysmyelinogenic leukodystrophy: report of a case of a new, presumably familial, type of leukodystrophy with megalencephaly.J Neuropathol Exp Neurol. 1959; 18: 359-383Crossref PubMed Scopus (49) Google Scholar; Springer Springer et al., 2000Springer S Erlewein R Naegele T Becker I Auer D Grodd W Krageloh-Mann I Alexander disease: classification revisited and isolation of a neonatal form.Neuropediatrics. 2000; 31: 86-92Crossref PubMed Scopus (43) Google Scholar). The genetic origin of this disease was still controversial when Rosenthal fibers, indistinguishable from those described in Alexander disease, were found in the brain tissue of transgenic mice overexpressing human GFAP (Messing et al. Messing et al., 1998Messing A Head MW Galles K Galbreath EJ Goldman JE Brenner M Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice.Am J Pathol. 1998; 152: 391-398PubMed Google Scholar; Eng et al. Eng et al., 1998Eng LF Lee YL Kwan H Brenner M Messing A Astrocytes cultured from transgenic mice carrying the added human glial fibrillary acidic protein gene contain Rosenthal fibers.J Neurosci Res. 1998; 53: 353-360Crossref PubMed Scopus (44) Google Scholar). Thus, the GFAP gene became a good candidate for Alexander disease, and missense mutations were found in 10 of 11 sporadic, mostly infantile, neuropathologically proved cases in which the GFAP coding region was sequenced (Brenner et al. Brenner et al., 2001Brenner M Johnson AB Boespflug-Tanguy O Rodriguez D Goldman JE Messing A Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.Nature Genet. 2001; 27: 117-120Crossref PubMed Google Scholar). All these mutations were heterozygous, appeared de novo, and affected only arginine residues. We evaluated the GFAP gene for mutations in 15 patients with sporadic infantile disease. Although they had heterogeneous clinical presentations, all 15 patients had MRI abnormalities suggestive of Alexander disease, and 4 had neuropathologically proved Alexander disease (table 1).Table 1Clinical Features and GFAP Mutations of Patients with Progressive Fibrinoid DegenerationPsychomotor DevelopmentPatientAge at Onset (mo)Delay (mo)DegradationHead CircumferenceaExpressed as standard deviations above the mean.Seizuresb+ = Occasional seizures; ++ = recurrent seizures; and +++ = severe seizures.Status and Age at Follow-Up or Death(years)Neuro- pathlogyExonDomainNucleotide ChangecNucleotide numbers refer to the cDNA sequence reported in Brenner et al. (1990).Amino Acid Changed* = Novel mutations.Restriction SiteParentsenl = Normal for the mutation in question.14…4 mo3++Dead (5.4)+11A240C→TL76F*SacINAfNA = Not available. Parental DNA was not available; however, the mutation was absent in 50 control samples.248…1…Alive (1.5)…11A243A→TN77Y*…2 nl3BirthBirth7 years1+Alive (7.5)…11A250G→AR79HAciI2 nl488…1.5+Alive (2.6)…11A250G→AR79HAciI…566…0.5+Alive (4.7)…11A250G→AR79HAciI2 nl6668 years1.5+Alive (20)…11A250G→AR79HAciI…736…3++Alive (5.5)…11A276C→TR88C*…2 nl8BirthBirth…3++Alive (2.5)…11A276C→TR88C*…2 nl911…1…Alive (3.5)…11A276C→AR88S*……1066…3+Alive (2.2)…42A729C→TR239CAciI2 nl1166…3.5…Alive (2)…42A729C→TR239CAciI2 nl1291213 mo1++Dead (4.5)+42A729C→TR239CAciI2 nl1318186 years1.5+Alive (8)…42A729C→TR239CAciI1 nl143…3 mo3+Dead (1.2)+42A730G→AR239HAciI2 nl15448 mo4+++Dead (2.5)+……None………a Expressed as standard deviations above the mean.b + = Occasional seizures; ++ = recurrent seizures; and +++ = severe seizures.c Nucleotide numbers refer to the cDNA sequence reported in Brenner et al. (Brenner et al., 1990Brenner M Lampel K Nakatani Y Mill J Banner C Mearow K Dohadwala M Lipsky R Freese E Characterization of human cDNA and genomic clones for glial fibrillary acidic protein.Mol Brain Res. 1990; 7: 277-286Crossref PubMed Scopus (69) Google Scholar).d * = Novel mutations.e nl = Normal for the mutation in question.f NA = Not available. Parental DNA was not available; however, the mutation was absent in 50 control samples. Open table in a new tab In six patients (patients 1, 7, 8, 10, 14, and 15), the diagnosis of infantile Alexander disease was suspected on the basis of typical clinical presentation characterized by onset at age 2 SD above the mean; NA = not available.Disease Duration (years)StatusSeverityc+ = Death after >10 years of disease or patient still alive without macrocephaly after 5 years of disease; ++ = death after 5–10 years of disease or patient still alive with macrocephaly after 1 year of disease; +++ = death after 1–5 years of disease; ++++ = death after 2 SD above the mean; NA = not available.c + = Death after >10 years of disease or patient still alive without macrocephaly after 5 years of disease; ++ = death after 5–10 years of disease or patient still alive with macrocephaly after 1 year of disease; +++ = death after 1–5 years of disease; ++++ = death after <1 year of disease; NR = not rated because of short duration of disease. Open table in a new tab All the mutations we have identified involve amino acids that are identical among human, rat, and mouse GFAP, as well as many other intermediate filaments. Each occurs within the helical-rod domain of GFAP (fig. 2C), which is highly conserved among intermediate filaments and is essential for dimerization and organization into a filament network (Fuchs and Cleveland Fuchs and Cleveland, 1998Fuchs E Cleveland DW A structural scaffolding of intermediate filaments in health and disease.Science. 1998; 279: 514-519Crossref PubMed Scopus (793) Google Scholar). It has been noted that there are disease-associated mutations in other intermediate filaments homologous to each of those previously reported for GFAP (Quinlan Quinlan, 2001Quinlan R Cytoskeletal catastrophe causes brain degeneration.Nature Genet. 2001; 27: 10-11Crossref PubMed Scopus (22) Google Scholar). This is also the case for the new L76 and N77 mutations reported in the present study (e.g., Bonifas et al. Bonifas et al., 1994Bonifas JM Matsumura K Chen MA Berth-Jones J Hutchison PE Zloczower M Fritsch PO Epstein Jr, EH Mutations of keratin 9 in two families with palmoplantar epidermolytic hyperkeratosis.J Invest Dermatol. 1994; 103: 474-477Crossref PubMed Scopus (68) Google Scholar; Endo et al. Endo et al., 1997Endo H Hatamochi A Shinkai H A novel mutation of a leucine residue in coil 1A of keratin 9 in epidermolytic palmoplantar keratoderma.J Invest Dermatol. 1997; 109: 113-115Crossref PubMed Scopus (36) Google Scholar). We have not found any report of a mutation in an arginine homologous to R88; but keratin 9 (MIM 144200), which has a Q at this position, does have a disease-associated mutation at this site (Hennies et al. Hennies et al., 1994Hennies HC Zehender D Kunze J Kuster W Reis A Keratin 9 gene mutational heterogeneity in patients with epidermolytic palmoplantar keratoderma.Hum Genet. 1994; 93: 649-654Crossref PubMed Scopus (67) Google Scholar). Clinical heterogeneity (including patients without macrocephaly and those with less-severe courses) has been described elsewhere in patients with Alexander disease diagnosed according to neuropathological criteria or, more recently, according to MRI criteria (Russo et al. Russo et al., 1976Russo LS Aron A Anderson PJ Alexander's disease: a report and reappraisal.Neurology. 1976; 26: 607-614Crossref PubMed Google Scholar; Borrett and Becker Borrett and Becker, 1985Borrett D Becker LE Alexander's disease, a disease of astrocytes.Brain. 1985; 108: 367-385Crossref PubMed Scopus (108) Google Scholar; Pridmore et al. Pridmore et al., 1993Pridmore CL Baraitser M Harding B Boyd SG Kendall B Brett EM Alexander's disease: clues to diagnosis.J Child Neurol. 1993; 8: 134-144Crossref PubMed Scopus (74) Google Scholar; Springer et al. Springer et al., 2000Springer S Erlewein R Naegele T Becker I Auer D Grodd W Krageloh-Mann I Alexander disease: classification revisited and isolation of a neonatal form.Neuropediatrics. 2000; 31: 86-92Crossref PubMed Scopus (43) Google Scholar; van der Knaap et al. van der Knaap et al., 2001van der Knaap MS Naidu S Breiter SN Blaser S Stroink H Springer S Begeer JC van Coster R Barth PG Thomas NH Valk J Powers JM Alexander disease: diagnosis with MR imaging.Am J Neuroradiol. 2001; 22: 541-552PubMed Google Scholar). Our results validate these diagnoses by finding GFAP mutations in a large percentage of patients who had heterogeneous clinical symptoms but were candidates for Alexander disease on the basis of suggestive neuroimaging abnormalities. Many of these mutations were identical to those previously found for pathologically diagnosed Alexander disease, and the others fell into the same pattern observed in the neuropathologically proved cases: missense mutations that are heterozygous and nonconservative and that arise de novo. A genotype-phenotype correlation can be discerned for the two most frequently mutated arginine residues (R79 [8 patients] and R239 [10 patients]), with the phenotype of the R79 mutations appearing much less severe than that of the R239 mutations (table 2). The number of patients with other mutations is too small to determine a phenotypic pattern (table 1 and 2); however, the four patients we found with R79 mutations appear to be the least-severely affected: none developed macrocephaly, three achieved independent walking, and, at the time of writing, all are alive at age 2.5–20 years. Similarly, among the four patients with R79 mutations who were reported by Brenner et al. (Brenner et al., 2001Brenner M Johnson AB Boespflug-Tanguy O Rodriguez D Goldman JE Messing A Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.Nature Genet. 2001; 27: 117-120Crossref PubMed Google Scholar), two lived until the ages of 14 and 48 years, and the other two were still alive, at ages 7 and 8 years, when the article was published. In sharp contrast, our five patients with R239 mutations had a marked impairment of psychomotor development, and three had progressive macrocephaly. Similarly severe phenotypes were displayed by the patients with R239 who were reported by Brenner et al. (Brenner et al., 2001Brenner M Johnson AB Boespflug-Tanguy O Rodriguez D Goldman JE Messing A Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.Nature Genet. 2001; 27: 117-120Crossref PubMed Google Scholar). Interestingly, the single patient in the present study and the single patient reported by Brenner et al. (Brenner et al., 2001Brenner M Johnson AB Boespflug-Tanguy O Rodriguez D Goldman JE Messing A Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.Nature Genet. 2001; 27: 117-120Crossref PubMed Google Scholar) who carried an R239H mutation had especially severe clinical courses. Our patient (patient 14) acquired only reactive smiling and head control, with early regression and feeding and respiratory difficulties that led to death at age 15 mo. Similarly, the single patient of Brenner et al. (Brenner et al., 2001Brenner M Johnson AB Boespflug-Tanguy O Rodriguez D Goldman JE Messing A Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.Nature Genet. 2001; 27: 117-120Crossref PubMed Google Scholar) who had R239H died at age 11 mo. In the two studies, the eight patients who had the R239C mutation had a less-severe clinical course than that of the two patients with the R239H mutation, and none of the eight patients has died before the age of 4 years (tables 1 and 2). Both patients who had Alexander disease without identified GFAP mutations (patient 11 of Brenner et al. [Brenner et al., 2001Brenner M Johnson AB Boespflug-Tanguy O Rodriguez D Goldman JE Messing A Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.Nature Genet. 2001; 27: 117-120Crossref PubMed Google Scholar] and patient 10 of the present work) had a histologically proved diagnosis and a severe clinical form of the disease. However, we have not yet rigorously excluded (1) mutations in the promoter or intronic sequences of the GFAP gene or (2) rearrangements of the genomic region containing GFAP. On the other hand, although GFAP gene mutations appear to be the predominant cause of infantile Alexander disease, it is possible that other genes may contribute, particularly in patients with the most-severe (early infantile) or mildest (juvenile and adult) forms of the disease (reviewed in Messing et al. Messing et al., 2001Messing A Goldman JE Johnson AB Brenner M Alexander disease: new insights from genetics.J Neuropathol Exp Neurol. 2001; 60: 563-573Crossref PubMed Scopus (62) Google Scholar). In other human genetic diseases involving intermediate filaments, mutations have been found in both the intermediate filament protein and associated proteins. In all patients analyzed, the GFAP mutations are dominant and arise de novo. Affected siblings whose parents were unaffected, including one family with neuropathologically proved Alexander disease (Wohlwill et al. Wohlwill et al., 1959Wohlwill FJ Bernstein J Yakovlev PI Dysmyelinogenic leukodystrophy: report of a case of a new, presumably familial, type of leukodystrophy with megalencephaly.J Neuropathol Exp Neurol. 1959; 18: 359-383Crossref PubMed Scopus (49) Google Scholar), could result from autosomal recessive transmission or from germinal mosaicism for a dominant mutation. Therefore, in patients with Alexander disease who have de novo GFAP mutations, prenatal diagnosis should be proposed for all further pregnancies. Further GFAP analysis is needed to investigate whether the inheritable dominant forms of Alexander disease that have been described in two families, both of which had late onsets after age 25 years (Howard et al. Howard et al., 1993Howard RS Greenwood R Gawler J Scaravilli F Marsden CD Harding AE A familial disorder associated with palatal myoclonus, other brainstem signs, tetraparesis, ataxia and Rosenthal fibre formation.J Neurol Neurosurg Psychiatry. 1993; 56: 977-981Crossref PubMed Scopus (36) Google Scholar; Schwankhaus et al. Schwankhaus et al., 1995Schwankhaus JD Parisi JE Gulledge WR Chin L Currier RD Hereditary adult-onset Alexander's disease with palatal myoclonus, spastic paraparesis, and cerebellar ataxia.Neurology. 1995; 45: 2266-2271Crossref PubMed Scopus (61) Google Scholar), are also associated with GFAP mutations. In conclusion, GFAP mutations are a reliable marker for infantile Alexander disease diagnosed according to neuropathological or MRI defined criteria. MRI abnormalities with the characteristic rostrocaudal gradient in white matter signal provide a strong rationale for the analysis of the GFAP gene, even in the absence of macrocephaly or neurological deterioration, when other causes of leukodystrophies have been ruled out. The patients and their families are warmly acknowledged for their participation. We greatly thank L. Dauche and E. Eymard-Pierre (both of INSERM U384) and D. Recan (banque de cellules, Hôpital Cochin) for their help in processing blood samples. This work was supported by grants from the European Leukodystrophy Association, INSERM projet PROGRES, the Centre National de la Recherche Scientifique (to D.R., D.P.D., and A.D.), the National Institutes of Health (to M.B. and A.M.), the Jean Pierre and Nancy Boespflug Myopathic Research Foundation, and a fellowship from the Association Française de Recherche en Génétique (to D.R.). We are also indebted for a grant, to study genetic leukodystrophies, from Ricerca Finalizzata Strategica of the Italian Ministry of Health. Erratum et al.The American Journal of Human GeneticsDecember, 2001In BriefIn the November 2001 issue, in the article "Infantile Alexander Disease: Spectrum of GFAP Mutations and Genotype-Phenotype Correlation," by Rodriguez et al. 69:1134–1140), the following errors appear: (1) on the title page, the location of affiliations 11 and 12 should be Bordeaux (not Pellegrin); (2) in table 1, the title should be "Clinical Features and GFAP Mutations of Patients with Infantile Alexander Disease" (not "Progressive Fibrinoid Degeneration"), and the heading of the seventh column should be spelled "Neuropathology"; and (3) in table 2, the "Severity"-column entry for patient 3 should be "+" (not "0"). Full-Text PDF Open Archive
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