Screening for GFAP rearrangements in a cohort of Alexander disease and undetermined leukoencephalopathy patients

Ferreira, Marie-Céleste; Dorboz, Imen; Tanguy, Odile Boespflug

doi:10.1016/j.ejmg.2015.07.002

Cited by 7 publications

(6 citation statements)

References 27 publications

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“…In fact, phenotypically comparable presentations of adult onset ataxia, dementia, and typical MRI findings (tadpole sign) have been described in GFAP mutation-negative patients [19]. …”

Section: Discussionmentioning

confidence: 99%

Stroke-like onset of brain stem degeneration presents with unique MRI sign and heterozygous NMNAT2 variant: a case report

Schulz

Wagner

Ungelenk

et al. 2016

Transl Neurodegener

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BackgroundAcute-onset neurodegenerative diseases in older patients are rare clinical cases, especially when the degeneration only affects specific regions of the nervous system. Several neurological disorders have been described in which the degeneration of brain parenchyma originates from and/or primarily affects the brain stem. Clinical diagnosis in these patients, however, is often complicated due to a poor understanding of these diseases and their underlying mechanisms.Case presentationIn this manuscript we report on a 73-year-old female who had experienced a sudden onset of complex neurological symptoms that progressively worsened over a period of 2 years. Original evaluation had suggested a MRI-negative stroke as underlying pathogenesis. The combination of patient’s medical history, clinical examination and exceptional pattern of brain stem degeneration presenting as “kissing swan sign” in MR imaging was strongly suggestive of acute onset of Alexander’s disease. This leukoencephalopathy is caused by GFAP (glial fibrilary acidic protein) gene mutations and may present with brain stem atrophy and stroke-like onset of symptoms in elderly individuals. However, a pathognomonic GFAP gene mutation could not be identified by Sanger sequencing.ConclusionsAfter an extended differential diagnosis and exclusion of other diseases, a definite diagnosis of the patient’s condition presently remains elusive. However, whole-exome sequencing performed from patient’s blood revealed 12 potentially disease-causative heterozygous variants, amongst which several have been associated with neurological disorders in vitro and in vivo – in particular the axon degeneration-related NMNAT2 gene.

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“…In fact, phenotypically comparable presentations of adult onset ataxia, dementia, and typical MRI findings (tadpole sign) have been described in GFAP mutation-negative patients [19]. …”

Section: Discussionmentioning

confidence: 99%

Stroke-like onset of brain stem degeneration presents with unique MRI sign and heterozygous NMNAT2 variant: a case report

Schulz

Wagner

Ungelenk

et al. 2016

Transl Neurodegener

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“…Clearly some aspects of the disease are replicated simply by increased levels of normal protein, such as formation of Rosenthal fibers and activation of multiple stress response pathways. However, no patients have yet been identified with disease caused by excess GFAP of normal sequence, such as might be produced by GFAP duplications [20]. We believe, but do not yet have proof, that the threshold for toxicity is lower when mutant protein is involved.…”

Section: Main Textmentioning

confidence: 91%

Refining the concept of GFAP toxicity in Alexander disease

Messing

2019

J Neurodevelop Disord

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BackgroundAlexander disease is caused by dominantly acting mutations in glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes in the central nervous system.Main bodyIn addition to the sequence variants that represent the origin of disease, GFAP accumulation also takes place, together leading to a gain-of-function that has sometimes been referred to as “GFAP toxicity.” Whether the nature of GFAP toxicity in patients, who have mixtures of both mutant and normal protein, is the same as that produced by simple GFAP excess, is not yet clear.ConclusionThe implications of these questions for the design of effective treatments are discussed.

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“…The time-and cost-effective method of quantitative multiplex PCR of short fluorescent fragments (QMPSF) has been widely used in the identification of copy number variations (CNV) [10][11][12][13][14][15][16][17][18]. We adapted it for the NPHP1 deletion screening, and here we show its perfect sensitivity and specificity, and the importance of the screening in clinical practice.…”

Section: Introductionmentioning

confidence: 93%

“…Two more unrelated patients were compound heterozygous for the classical whole-gene deletion and a novel 3′ partial deletion (c.(1810 + 1_1811-1)_(*1_? )del) involving the last three [18][19][20]…”

Section: High Rate Of Nphp1 Deletion In Juvenile Nephronophthisismentioning

confidence: 99%

QMPSF is sensitive and specific in the detection of NPHP1 heterozygous deletions

Jávorszky

Morinière

Kerti

et al. 2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Screening for GFAP rearrangements in a cohort of Alexander disease and undetermined leukoencephalopathy patients

Cited by 7 publications

References 27 publications

Stroke-like onset of brain stem degeneration presents with unique MRI sign and heterozygous NMNAT2 variant: a case report

Stroke-like onset of brain stem degeneration presents with unique MRI sign and heterozygous NMNAT2 variant: a case report

Refining the concept of GFAP toxicity in Alexander disease

QMPSF is sensitive and specific in the detection of NPHP1 heterozygous deletions

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