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Common neuropathological features underlie distinct clinical presentations in three siblings with hereditary diffuse leukoencephalopathy with spheroids caused by CSF1R p.Arg782His.

Robinson JL, Suh E, Wood EM, Lee EB, Coslett HB, Raible K, Lee VM, Trojanowski JQ, Van Deerlin VM - Acta Neuropathol Commun (2015)

Bottom Line: Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases.Similar to other cases reported in the literature, the three cases described here had varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology.Our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA.

ABSTRACT
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) presents with a variety of clinical phenotypes including motor impairments such as gait dysfunction, rigidity, tremor and bradykinesia as well as cognitive deficits including personality changes and dementia. In recent years, colony stimulating factor 1 receptor gene (CSF1R) has been identified as the primary genetic cause of HDLS. We describe the clinical and neuropathological features in three siblings with HDLS and the CSF1R p.Arg782His (c.2345G > A) pathogenic mutation. Each case had varied motor symptoms and clinical features, but all included slowed movements, poor balance, memory impairment and frontal deficits. Neuroimaging with magnetic resonance imaging revealed atrophy and increased signal in the deep white matter. Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases. Similar to other cases reported in the literature, the three cases described here had varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology. Our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.

No MeSH data available.


Related in: MedlinePlus

CSF1R protein domain and mutation schematic. Schematic diagram of the protein domain structure of CSF1R with amino acid numbers provided. Mutations previously reported in other studies are shown in black [3–5, 7–9] and the R782H mutation identified in the present study is highlighted in red. Ig: Immunoglobulin domains
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Fig1: CSF1R protein domain and mutation schematic. Schematic diagram of the protein domain structure of CSF1R with amino acid numbers provided. Mutations previously reported in other studies are shown in black [3–5, 7–9] and the R782H mutation identified in the present study is highlighted in red. Ig: Immunoglobulin domains

Mentions: Targeted next-generation sequencing was performed alongside histology, immunohistochemistry and microscopic analyses of the brain tissue [10]. A heterozygous missense mutation c.2345G > A (p.Arg782His, rs282860281) was identified in exon 18 of CSF1R (Fig. 1) in all three symptomatic siblings (Fig. 2). Other neurodegenerative disease-associated gene mutations were excluded and the mutation was confirmed by genotyping using a custom TaqMan allelic discrimination assay (Life Technologies). The family history is notable for late-onset dementia in the mother at the age of 89 (Fig. 2) and a father who died at age 62 of unrelated causes. Of note, a paternal first cousin once removed may have had symptoms similar to Case #1 (not shown in pedigree). The genetic status of four additional living siblings shown in the pedigree is not provided for privacy reasons. Because of the father’s relatively early death and the fact that neither parent’s DNA was available to test, the penetrance of the mutation cannot be fully assessed.Fig. 1


Common neuropathological features underlie distinct clinical presentations in three siblings with hereditary diffuse leukoencephalopathy with spheroids caused by CSF1R p.Arg782His.

Robinson JL, Suh E, Wood EM, Lee EB, Coslett HB, Raible K, Lee VM, Trojanowski JQ, Van Deerlin VM - Acta Neuropathol Commun (2015)

CSF1R protein domain and mutation schematic. Schematic diagram of the protein domain structure of CSF1R with amino acid numbers provided. Mutations previously reported in other studies are shown in black [3–5, 7–9] and the R782H mutation identified in the present study is highlighted in red. Ig: Immunoglobulin domains
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4491242&req=5

Fig1: CSF1R protein domain and mutation schematic. Schematic diagram of the protein domain structure of CSF1R with amino acid numbers provided. Mutations previously reported in other studies are shown in black [3–5, 7–9] and the R782H mutation identified in the present study is highlighted in red. Ig: Immunoglobulin domains
Mentions: Targeted next-generation sequencing was performed alongside histology, immunohistochemistry and microscopic analyses of the brain tissue [10]. A heterozygous missense mutation c.2345G > A (p.Arg782His, rs282860281) was identified in exon 18 of CSF1R (Fig. 1) in all three symptomatic siblings (Fig. 2). Other neurodegenerative disease-associated gene mutations were excluded and the mutation was confirmed by genotyping using a custom TaqMan allelic discrimination assay (Life Technologies). The family history is notable for late-onset dementia in the mother at the age of 89 (Fig. 2) and a father who died at age 62 of unrelated causes. Of note, a paternal first cousin once removed may have had symptoms similar to Case #1 (not shown in pedigree). The genetic status of four additional living siblings shown in the pedigree is not provided for privacy reasons. Because of the father’s relatively early death and the fact that neither parent’s DNA was available to test, the penetrance of the mutation cannot be fully assessed.Fig. 1

Bottom Line: Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases.Similar to other cases reported in the literature, the three cases described here had varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology.Our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA.

ABSTRACT
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) presents with a variety of clinical phenotypes including motor impairments such as gait dysfunction, rigidity, tremor and bradykinesia as well as cognitive deficits including personality changes and dementia. In recent years, colony stimulating factor 1 receptor gene (CSF1R) has been identified as the primary genetic cause of HDLS. We describe the clinical and neuropathological features in three siblings with HDLS and the CSF1R p.Arg782His (c.2345G > A) pathogenic mutation. Each case had varied motor symptoms and clinical features, but all included slowed movements, poor balance, memory impairment and frontal deficits. Neuroimaging with magnetic resonance imaging revealed atrophy and increased signal in the deep white matter. Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases. Similar to other cases reported in the literature, the three cases described here had varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology. Our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.

No MeSH data available.


Related in: MedlinePlus