Molecular findings in symptomatic and pre-symptomatic Alexander disease patients

Gorospe, J. Rafael; Naidu, Sakkubai; Johnson, Anne B.; Puri, Vandana; Raymond, Gerald V.; Jenkins, Simon; Pedersen, Robert C.; Lewis, Diana; Knowles, Paul D.; Fernández, Rafael Ramos; Vivo, Darryl De; Knaap, Marjo S. van der; Messing, Albee; Brenner, Michael; Hoffman, Eric P.

doi:10.1212/wnl.58.10.1494

Cited by 95 publications

(75 citation statements)

References 21 publications

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“…Recently, mutations in the glial fibrillary acidic protein (GFAP) gene were identified in AD patients [3][4][5]. This has facilitated the genetic diagnosis of mild AD patients, and the discovery of different clinical manifestations of AD [4][5][6][7][8][9]. However, genotype-phenotype correlations have yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

An infantile–juvenile form of Alexander disease caused by a R79H mutation in GFAP

Asahina

Okamoto

Sudo

et al. 2006

Brain and Development

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Alexander disease is a degenerative white matter disorder due to mutations in the glial fibrillary acidic protein (GFAP) gene. It has been classified into three forms based on the age of onset and severity: an infantile, a juvenile, and an adult form. In a six-yearold patient with a relatively mild form of Alexander disease, we detected a common R79H mutation in GFAP previously only described in the infantile form. These results suggest the need for further studies of the genotype-phenotype correlation.

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Section: Introductionmentioning

confidence: 99%

An infantile–juvenile form of Alexander disease caused by a R79H mutation in GFAP

Asahina

Okamoto

Sudo

et al. 2006

Brain and Development

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“…Clinically, Alexander disease is classified into three subtypes: infantile, juvenile, and adult forms, based on the age at disease onset. Recently, GFAP mutations have been reported in various forms of Alexander disease Aoki et al 2001;Rodriguez et al 2001;Shiroma et al 2001;Gorospe et al 2002;Li et al 2002;Meins et al 2002;Namekawa et al 2002;Probst et al 2003;Sawaishi et al 2002;Shiihara et al 2002;Shiroma et al 2003;Suzuki et al 2004) and we have identified juvenile and adult forms of Alexander disease with three different GFAP mutations: V87G (Okamoto et al 2002), R88C (Nobuhara et al 2004) and R416W (Kinoshita et al 2003). To date, there had been few reports investigating the properties of mutant GFAP (Li et al 2005;Hsiao et al 2005;Perng et al 2006).…”

Section: Introductionmentioning

confidence: 84%

The functional alteration of mutant GFAP depends on the location of the domain: morphological and functional studies using astrocytoma-derived cells

et al. 2007

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To clarify the functional effects of mutant glial fibrillary acidic protein (GFAP), we examined the expression patterns of mutant GFAPs (V87G, R88C, and R416W) in astrocytoma-derived cells and performed migration assay. The morphological change was found in mutant GFAP cells, although the number of changes was small. On migration assay, the migration rate in cells with the V87G or R88C mutation, which are located in the helical rod domain in GFAP, was significantly higher than those of wild-type and R416W. These findings suggest that the functional abnormalities of astrocytes might be induced prior to aggregation of GFAP in Alexander disease and that the functional alteration depends on the location of the domain.

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“…Gorospe et al, reported 12 genetically confirmed cases of AD including seven with infantile onset. All had megalencephaly at presentation [8]. Li et al, studied 26 infantile AD out of 44 patients with AD and found macrocephaly in 62 % cases.…”

Section: Discussionmentioning

confidence: 99%

Infantile Onset Alexander Disease with Normal Head Circumference: A Genetically Proven Case Report

Goyal¹

2014

JCDR

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A 16-month-old boy presented to our genetic OPD for evaluation of developmental regression and seizures. He was second in birth order, born to non consanguineous couple at term after normal vaginal delivery with birth weight of 2.8 kg. Mother's antenatal and perinatal history was uneventful. There was no history of any drug intake during pregnancy. He had attained social smile and neck holding at appropriate ages. He developed seizure at four months of age followed by significant regression in motor and cognitive skills whereby he lost neck holding and unable to recognise parents. Seizure was continuous and difficult to manage. Presently, at 16 monthss of age, he has partial neck holding, has no speech or interaction or recognition of parents. Parents gave a history of generalized spasticity of the body since six months of age. The patient has a six year old elder brother, intelligent, with normal development. There was no similar history in any family members from both sides of parents. On examination at 16 months of age, there were no dysmorphic features. Spasticity of upper and lower limbs with peripheral contractures at ankles was noted [Table/ Fig-1]. His weight, length and head circumference were 7.5 kg (between -2 and -3 SD), 72 cm (between -2 to -3 SD) and 46 cm (between 0 to -1 SD), respectively. There was no hepato-splenomegaly or any neurocutaneous stigmata. His body tone was increased with intermittent tightening. Deep tendon reflexes were exaggerated in both upper and lower limbs with extensor planter at ankle joints.Blood investigations including high performance liquid chromatography (HPLC) of serum amino acids, urine organic acid profile, serum ammonia and lactate level and thyroid function tests were within normal limit. Renal function tests, liver function test, hearing evaluation, ultrasonography abdomen were normal. Visual evoked potential (VEP) was subnormal with increased latencies. Magnetic resonance imaging ( MRI) brain showed signal alteration of white matter, predominantely in the bilateral frontal regions also involving basal ganglia. There was hypointense line along the ventricular margin and areas of diffusion restriction in the bilateral lentiform nucleus and frontal white matter with cystic dilatation of cavum septum pellucidum [Table/ Fig-2a&b]. Features were suggestive of Infantile form of Alexander disease (AD). Mutation analysis was advised. Consent was obtained from each of the participating members of the family in this study for genetic evaluation. A standard salting out protocol was followed for DNA isolation from the peripheral venous whole blood. The coding portion of the GFAP was amplified by polymerase chain reactions using nine set of primers. primer designing was done by Primer-3 software. The Paediatrics SectionInfantile Onset Alexander Disease with Normal Head Circumference: A Genetically Proven Case Report aBstRaCt Alexander disease (AD) is an autosomal dominant leukodystrophy which predominantly affects infants and children. The infantile form comprises the most c...

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Molecular findings in symptomatic and pre-symptomatic Alexander disease patients

Abstract: In symptomatic and asymptomatic patients with a predominantly frontal leukoencephalopathy by MRI, GFAP gene mutation analysis should be included in the initial diagnostic evaluation process for Alexander disease.

Cited by 95 publications

References 21 publications

An infantile–juvenile form of Alexander disease caused by a R79H mutation in GFAP

An infantile–juvenile form of Alexander disease caused by a R79H mutation in GFAP

The functional alteration of mutant GFAP depends on the location of the domain: morphological and functional studies using astrocytoma-derived cells

Infantile Onset Alexander Disease with Normal Head Circumference: A Genetically Proven Case Report

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