A novel CSF-1R mutation in a family with hereditary diffuse leukoencephalopathy with axonal spheroids misdiagnosed as hydrocephalus
- 403 Downloads
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disease caused by mutations in the colony stimulating factor 1 receptor (CSF1R) gene that often results in cognitive impairment, psychiatric disorders, motor dysfunction and seizure. We report familial cases of a novel CSF1R mutation causing HDLS similar to hydrocephalus. The patients initially presented with a gait disturbance and then developed progressive cognitive decline, urinary incontinence, epileptic seizures and became bedridden as the disease progressed. A brain magnetic resonance imaging (MRI) scan revealed striking ventricular enlargement and diffuse brain atrophy with frontotemporal predominance, which was later accompanied by white matter changes. Genetic testing in this family showed a novel c.2552T>C (p.L851P) mutation in exon 19 of the CSF1R gene. However, three gene carriers in the family remained clinically asymptomatic. Because of its heterogeneous clinical phenotypes, HDLS patients are often misdiagnosed with other diseases. This is the first genetically proven HDLS case resembling hydrocephalus, and the clinical symptoms of HDLS may be related to the specific genetic mutation.
KeywordsHereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) Novel mutation Hydrocephalus Gait disturbance
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a progressive neurodegenerative disease first described and pathologically defined in a large Swedish family in 1984 by Axelsson R et al. . Typically, HDLS results in personality changes and is often associated with cognitive impairment, motor dysfunction and other clinical presentations, such as stroke-like episodes, sensory disturbance, dizziness, fatigue and epilepsy . Spotty calcification detected on computer tomography (CT) in the frontal pericallosal regions has been reported as a specific finding in patients with HDLS  and brain magnetic resonance imaging (MRI) shows asymmetric deep white matter lesions with frontoparietal predominance, followed by brain atrophy [4, 5]. Since HDLS was identified as a rare autosomal dominant disease caused by a mutation of the colony stimulating factor 1 receptor (CSF1R) gene located on chromosome 5 (5q32) , more than 70 pathogenic mutations have been reported in both hereditary and sporadic cases . Due to the significant variability in genotypes and phenotypes, patients with HDLS have often been misdiagnosed with other diseases [8, 9, 10, 11, 12].
Here, we report a new HDLS family with a novel CSF1R mutation, in which the prominent clinical characteristics are associated with hydrocephalus.
At age 32, the patient gradually became bedridden and unable to manage herself due to dysphagia, urinary and bowel incontinence, rigidity, apathy and dementia. She was finally diagnosed with HDLS, as confirmed by genetic analyses, which revealed a heterozygous mutation (c.2552T>C) in exon 19 of the CSF-1R gene on chromosome 5, resulting in an amino acid substitution of leucine (L) to proline (P) at codon position 851 (p.L851P).
This patient was a 27-year-old female and the youngest sister of patient III-1.
At age 26, the patient was admitted to our institution due to progressive gait disturbance and slight cognitive decline. Her MMSE score had decreased to 18/30. A neurological examination showed muscular hypertonia and ataxia of the right limbs. Hyperreflexia and ankle clonus were presented in the right leg. Because of the location of the ventriculoperitoneal shunt, subsequent MRI was not performed. Repeated CT scans showed diffuse cerebral atrophy with enlargement of the ventricles, and a small calcification located near the anterior horns of the right lateral ventricles is seen (shown in Fig. 2—CT). An 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan showed a reduction in glucose uptake in the cerebral lobes, especially the frontal lobes. DNA sequencing of the patient revealed genome revealed a heterozygous mutation (c.2552T>C) in exon 19 of the CSF-1R gene on chromosome 5, which is the same as the patient III-1.
At present, the patient is wheelchair-bound because of spasticity in the right limbs and has urinary and bowel incontinence and progressive cognitive impairment.
Genomic DNA was extracted from peripheral blood leukocytes after obtaining informed consent. The fragments of limited exons and adjacent intron areas were amplified by polymerase chain reaction (PCR) and subjected to Sanger sequencing.
HDLS is a hereditary cerebral white matter degenerative disease caused by mutations of CSF1R and results in personality changes, followed by cognitive decline and motor impairment, particularly affecting the gait . The family we report here is consistent with previous descriptions in some aspects. The onset ages of our patients were 28 and 25 years old, which is consistent with the typical onset age (ranging from 8 to 78 years old) [6, 10, 14]. Both patients developed motor dysfunction, cognitive decline and epileptic seizures in the final disease stage. Spotty calcification in the white matter was observed by CT scan which was considered a common manifestation in patients with HDLS [3, 15]. The final MRI changes were similar to those of classical HDLS, with asymmetrical lesions predominant in the anterior deep white matter along with thinning of the corpus callosum and brain atrophy [4, 5].
However, there are some unique features in our report.
The patients we reported initially presented with motor dysfunction, a symptom that often develops as the disease progresses. For most HDLS patients, the first clinical symptom is cognitive impairment or psychiatric disorder, including all six cases described in the Chinese mainland [16, 17, 18]. Stabile  reported that motor dysfunction had a high incidence rate as the first symptom among women in their 20s, who then developed seizures, dementia and other pyramidal dysfunctions as the disease progressed , which supports our findings.
Although the MRI results in the late phase of the disease were similar to previously reported neuroimaging findings, our patients’ first brain MRI results revealed markedly diffuse brain atrophy and enlargement of the lateral and third ventricles. Additionally, patient III-3 showed spotty bright DWI signals in the left frontoparietal lobe and left lateral ventricle, which led to an initial diagnosis of multiple lacunar cerebral infarctions. A previous report showed that strong DWI signals could be observed in the early stage of HDLS, but unlike cerebral infarctions, these abnormal signals would persist . We hypothesised that this imaging manifestation might be related to the mutation of CSF1R gene. These types of noticeable imaging changes combined with the clinical manifestations of gait instability, cognitive impairment and urinary incontinence show a strong resemblance to hydrocephalus , thus leading to ineffective treatment.
The family in this study was found to have a novel CSF1R gene mutation c.2552T>C (p.L851P), which has not been previously reported worldwide. The gene carriers in the family were found to have different phenotypes. The patients were severely affected at 28 and 25 years old, whereas their mother, who carried the same CSF1R mutation remained healthy at 64 years, and their uncle (58 years) and cousin (30 years) also remained healthy. This pattern of asymptomatic mutation might represent a lack of penetrance or a late-onset phenotype that had not yet manifested, as previously reported in the literature . Due to the broad age of onset and various clinical manifestations, it is not certain whether the asymptomatic carriers will develop symptoms with age. We will closely monitor this family to improve our understanding of the disease.
In terms of treatment, there are no effective drugs currently known to halt or alter the course of HDLS. Patient III-1 was treated with HSCT, but it did not improve any of her symptoms. A previous report described an affected individual who successfully underwent an allogenic bone marrow transplantation from her healthy sibling and maintained a stable condition for the following 15 years . Thus, therapies need to be explored for HDLS patients.
The c.2552T>C missense mutation identified in this family has not been previously reported. The clinical and neuroimaging features of the family reported here resembled hydrocephalus. HDLS was verified by genetic testing. In contrast to previous reports, the initial symptom of HDLS can be motor dysfunction. Brain atrophy may be the prominent finding on MRI. The clinical features of the family may be related to the novel mutation of p.L851P. HDLS should be considered a differential diagnosis when a patient presents with the clinical characteristics as mentioned above.
- 3.Konno T, Broderick DF, Mezaki N, Isami A, Kaneda D, Tashiro Y, Tokutake T, Keegan BM, Woodruff BK, Miura T, Nozaki H, Nishizawa M, Onodera O, Wszolek ZK, Ikeuchi T (2017) Diagnostic value of brain calcifications in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. AJNR Am J Neuroradiol 38(1):77–83. https://doi.org/10.3174/ajnr.A4938
- 4.Sundal C, Van Gerpen JA, Nicholson AM, Wider C, Shuster EA, Aasly J, Spina S, Ghetti B, Roeber S, Garbern J, Borjesson-Hanson A, Tselis A, Swerdlow RH, Miller BB, Fujioka S, Heckman MG, Uitti RJ, Josephs KA, Baker M, Andersen O, Rademakers R, Dickson DW, Broderick D, Wszolek ZK (2012) MRI characteristics and scoring in HDLS due to CSF1R gene mutations. Neurology 79(6):566–574. https://doi.org/10.1212/WNL.0b013e318263575a CrossRefPubMedGoogle Scholar
- 5.Sundal C, Jönsson L, Ljungberg M, Zhong J, Tian W, Zhu T, Linden T, Börjesson-Hanson A, Andersen O, Ekholm S (2014) Different stages of white matter changes in the original HDLS family revealed by advanced MRI techniques. J Neuroimaging 24(5):444–452. https://doi.org/10.1111/jon.12037 CrossRefPubMedGoogle Scholar
- 6.Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, Lash J, Wider C, Wojtas A, DeJesus-Hernandez M, Adamson J, Kouri N, Sundal C, Shuster EA, Aasly J, MacKenzie J, Roeber S, Kretzschmar HA, Boeve BF, Knopman DS, Petersen RC, Cairns NJ, Ghetti B, Spina S, Garbern J, Tselis AC, Uitti R, Das P, Van Gerpen JA, Meschia JF, Levy S, Broderick DF, Graff-Radford N, Ross OA, Miller BB, Swerdlow RH, Dickson DW, Wszolek ZK (2011) Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 44(2):200–205. https://doi.org/10.1038/ng.1027 CrossRefPubMedGoogle Scholar
- 9.Terada S, Ishizu H, Yokota O, Ishihara T, Nakashima H, Kugo A, Tanaka Y, Nakashima T, Nakashima Y, Kuroda S (2004) An autopsy case of hereditary diffuse leukoencephalopathy with spheroids, clinically suspected of Alzheimer’s disease. Acta Neuropathol 108(6):538–545. https://doi.org/10.1007/s00401-004-0920-5 CrossRefPubMedGoogle Scholar
- 12.Kim EJ, Shin JH, Lee JH, Kim JH, Na DL, Suh YL, Hwang SJ, Lee JH, Lee YM, Shin MJ, Lee MJ, Kim SJ, Yoon U, Park DY, Jung DS, Ahn JW, Sung S, Huh GY (2015) Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia linked CSF1R mutation: report of four Korean cases. J Neurol Sci 349(1–2):232–238. https://doi.org/10.1016/j.jns.2014.12.021 CrossRefPubMedGoogle Scholar
- 13.Sundal C, Lash J, Aasly J, Øygarden S, Roeber S, Kretzschman H, Garbern JY, Tselis A, Rademakers R, Dickson DW, Broderick D, Wszolek ZK (2012) Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity. J Neurol Sci 314(1–2):130–137. https://doi.org/10.1016/j.jns.2011.10.006 CrossRefPubMedGoogle Scholar
- 17.Cheng X, Shen W, Zou H, Shen L, Gu X, Huang D, Sun Y, Wang B, Tian Q, Xu J (2015) Analysis of CSF1R gene mutation in a Chinese family with hereditary diffuse leukoencephalopathy with neuroaxonal spheroids. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 32(2):208–212. https://doi.org/10.3760/cma.j.issn.1003-9406 PubMedGoogle Scholar
- 19.Karle KN, Biskup S, Schüle R, Schweitzer KJ, Krüger R, Bauer P, Bender B, Nägele T, Schöls L (2013) De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS). Neurology 81(23):2039–2044. https://doi.org/10.1212/01.wnl.0000436945.01023.ac CrossRefPubMedGoogle Scholar
- 20.Mateen FJ, Keegan BM, Krecke K, Parisi JE, Trenerry MR, Pittock SJ (2010) Sporadic leucodystrophy with neuroaxonal spheroids: persistence of DWI changes and neurocognitive profiles: a case study. J Neurol Neurosurg Psychiatry 81(6):619–622. https://doi.org/10.1136/jnnp.2008.169243 CrossRefPubMedGoogle Scholar
- 22.Konno T, Yoshida K, Mizuno T, Kawarai T, Tada M, Nozaki H, Ikeda SI, Nishizawa M, Onodera O, Wszolek ZK, Ikeuchi T (2017) Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation. Eur J Neurol 24(1):37–45. https://doi.org/10.1111/ene.13125 CrossRefPubMedGoogle Scholar
- 23.Eichler FS, Li J, Guo Y, Caruso PA, Bjonnes AC, Pan J, Booker JK, Lane JM, Tare A, Vlasac I, Hakonarson H, Gusella JF, Zhang J, Keating BJ, Saxena R (2016) CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids. BRAIN 139(Pt 6:1666–1672. https://doi.org/10.1093/brain/aww066 CrossRefPubMedGoogle Scholar
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.