Abstract
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant hereditary disease, featured by cerebral white matter degeneration with demyelination and axonal spheroids. We collected three gene-confirmed HDLS cases in our neurodegenerative clinic. Two HDLS cases were sporadic with novel mutations, while another case had a family history with previously described mutations. All three cases suffered memory problems with white matter lesions and pyramid signs. No obvious clinical differences were observed between sporadic and familial HDLS cases. Distinct features, such as subcortical calcification in brain computed tomography and asymmetric abnormal MRI signal along the pyramid tracts throughout brainstem and spinal cord (cervical, thoracic, and lumbar segments), were observed in one sporadic case with novel mutation. Therefore, the interactions of genotype-phenotype still need to be further investigated.
Keywords
INTRODUCTION
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant hereditary disease, featured by cerebral white matter degeneration with demyelination and axonal spheroids [1]. The clinical manifestations include progressive cognitive impairment, epilepsy, and motor dysfunction [2]. HDLS is caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene, such as missense mutation, splice site, and frameshift mutation [3]. At present, more than 20 pathogenic mutations were identified via familial cases [4].
As a typical pathological feature in HDLS, neuroaxonal spheroids can be seen in white matter [5]. Mild neuronal loss with gliosis is found in frontal cortex. The atrophy of basal ganglia is present with loss of neurons in caudate, putamen, pallidum, and thalamus [6]. No amyloid-β positive plaques and few pretangles are found in transentorhinal cortex [7]. Corticospinal tracts in brainstem and spinal cord are affected with degenerated myelin sheaths and proliferation of astrocytes [8], while the peripheral nervous system is usually spared [9].
The differential diagnosis of HDLS includes late-onset metachromatic leukodystrophy, Krabbe disease, X-linked adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and adult-onset autosomal dominant leukodystrophy [10]. Although most of them can be ruled out by clinical and laboratory findings, histopathologic examination is still indispensable in certain cases. Genetic testing is probably an alterative for the diagnosis of HDLS in absent of pathological resources [11].
On the Chinese mainland, there are fewer HDLS case-reports in comparison with other neurodegenerative dementia. HDLS has not been well recognized and can be misdiagnosed with other leukodystrophy [12]. We reported three gene-confirmed HDLS cases with or without family history, to compare the characterization of sporadic cases and pedigree in HDLS.
METHODS
From March 2014 to September 2015, there were three HDLS cases coming to our neurodegenerative clinic. Two HDLS cases (case 1 & 2) were sporadic, while another case (case 3) had a clear family history. All three cases were confirmed by genetic analysis of the CSF1R gene. We collected demographic characteristics, neurological examination, neuropsychological testing, laboratory findings, and neuroimaging for analysis and comparison.
RESULTS
Case 1
This patient was a 28-year-old male, with no family history in neurological diseases. He was admitted to our clinic due to progressive impairment in cognition for two years. At the beginning, his relative found that he was prone to forgetting something. Six months later, he failed to go to work by himself with bad orientation. He gradually could not manage his daily life and suffered urinary or constipation incontinence. Moreover, he walked slowly and complained of fatigue. In the local hospital, he was diagnosed with inflammatory demyelination with regard to the white matter changes seen in brain magnetic resonance imaging (MRI). He was treated with cortisol, but the symptoms still progressed and he came to our clinic for the further diagnosis. On neurologicalexamination (24 months after onset), impaired cognition in orientation, memory, calculation, comprehension, and executive ability was found. He was also unable to dress himself. With the exception of jaw and tendon hyperreflexia, there were no other positive signs. Brain MRI (24 months after onset) showed patchy abnormal signal in periventricular white matter with an equal signal in T1 weighted imaging (T1WI), and high signal in T2 weighted imaging (T2WI), fluid attenuated inversion recovery (FLAIR), and diffusion weighted imaging (DWI), as well as the thinning of the corpus callosum and bilateral frontal lobe atrophy. Specific oligoclonal bands were not detected in cerebrospinal fluid. Genetic testing revealed that this patient was heterozygous for a G–>T mutation at the splice-donor site in the exon, between exon 2 and intron 3 (c. 49G>T) of CSF1R gene. To our knowledge, this mutation has not been previously reported and included in any genetic databases (Fig. 1A). Considering that the signal peptide in the CSF1;R gene, which is encoded by exon 2,is necessary for its surface localization, it is reasonable to predict that this splice site mutation could result in the production of a nonfunctional/mislocated protein.
Case 2
This is a 32-year-old male patient, presenting with personality changes and memory decline for two years and left hemiparesis for nine months. There was no family history of neurological diseases. At first, he was irritable and incompetent at work. He often forgot and lost items and became alcoholic with urinary incontinence after drinking. Then his mother found him with left hemiparesis and walking slowly. Moreover, he had slow and slurred speech. On neurological examination (25 months after onset), hyperreflexia was found in the left limbs with ankle clonus. Left Hoffman and Chaddock signs, as well as clumsy rapid alternating movements, were present. No other positive findings were detected. In neuropsychological testing, he was found to have mild cognitive impairment (Mini-Mental State Examination = 29, Montreal Cognitive Assessment = 22, Clinical Dementia Rating = 0.5). The result of 24-h monitoring electroencephalogram (20 months after onset) was in the normal range. Brain computed tomography (20 months after onset) showed bilateral spotty periventricular and subcortical calcifications (Fig. 2A). In the follow-up at 38 months after onset, the periventricular MRI abnormal signal (high signal in T2WI and DWI, Fig. 2B, C) was becoming more symmetric in comparison with the images at 25 months after onset. Brain fluorodeoxyglucose (FDG)-positron emission tomography (PET) (25 months after onset) demonstrated prominent hypometabolism in bilateral parietal lobes and right frontal and right temporal lobe. Right basal ganglia and thalamus showed mild hypometabolism (Fig. 2D). Brain MRI (25 months after onset) showed abnormal signal in right frontal and corpus callosum, as well as asymmetric abnormal signal along the pyramid tracts with equal signal in T1WI and high signal in T2WI (Fig. 2E-I) and DWI. No specific oligoclonal bands were found in cerebrospinal fluid. Genetic analysis revealed a novel frameshift mutation (c.2909_2910insATCA) in exon 22 of CSF1R gene that would alter the original stop codon (Fig. 1B, C).These mRNAs that lack stop codon would cause translation to continue into the next in-frame stop codon (TGA), which led to an additional translation of 108 non-function amino acids at C-terminal of CSF1R gene. Whether it would disrupt normal functions of CSF1R gene needs further investigation.
Case 3
A 43-year-old female patient was admitted to our clinic due to apathy, slow behavior, urinary incontinence, and memory impairment for one year with a clear familial background of a similar condition. Her mother experienced slow reactiveness and impaired memory at 61 years of age. Then she gradually became bedridden with dysphagia and epilepsy. She died within four years after disease onset. Her sister complained of similar problems as her mother at 35-year-old. She had apathy, memory decline, urinary incontinence, epilepsy, and was bedridden, and finally died within three years after disease onset. So far, other members of this family are free of symptoms. On neurological examination (12 months after onset), cognition including calculation, memory, and orientation were impaired. Tendon hyperreflexia was found, but pathological signs were negative. No other positive signs were observed. Brain MRI (12 months after onset) illustrated symmetric patchy abnormal signal in periventricular white matter and centrum semiovale with equal signal in T1WI, and high signal in T2WI, apparent diffusion coefficient (ADC), and DWI. Brain PET imaging with11C-labelled Pittsburgh Compound-B (12 months after onset) suggested negative amyloid-β deposition. The cerebrospinal fluid was normal without specific oligoclonal bands.A nonsense mutation (c.238T>C, p.I794T) in exon18 of CSF1R gene was found in genetic testing. This mutation has been previously described in association with familial HDLS (Fig. 1D).
DISCUSSION
All three cases complained of memory problems and showed changes in white matter. The abnormal signal was an equal signal in T1WI, and high signal in T2WI, ADC, and DWI. The corpus callosum was affected in cases 1 and 2, and atrophy of the corpus callosum is regarded as an early feature of HDLS [13]. Atrophy of the frontal lobe was reported incase 1, while abnormal signal in the right frontal was found in case 2. Actually, psychiatric symptoms and executive disability are likely to correlate with frontal lobe dysfunction. Motor dysfunction and pyramid signs could be observed, which was attributed to the involvement of pyramid tracts. Although the involvement of the spinal cord in HDLS is uncommon, there have been several reports [8, 14]. Thus, spinal lesions in HDLS should be considered and differentiated with other diseases.
All three cases were confirmed by CSF1R gene analysis. Although the mutation in case 1 is supposed to destroy a splice donor site of the CSF1R gene, it cannot be tested for mRNA levels because a fresh blood sample from case 1 was not available. Considering that mutations outside the tyrosine kinase domain have not been shown previously to be pathogenic, further functional studies are still needed to confirm our genetic findings. In case 2, a novel mutation in the CSF1R gene (c.2909_2910insATCA) was detected with clinical features. Actually, subcortical calcification is not rare in HLDS, and has been seen in up to half of the cases [15]. Left parietal lobe showed hypometabolism in FDG-PET, although no lesions were found in the related regions of brain MRI. FDG-PET can reflect the metabolic level, which is more sensitive and occurs prior to the structural changes in MRI. The pathological changes of consecutive MRI asymmetric abnormal signal along the pyramid tracts were probably Wallerian degeneration. The degeneration is usually asymmetric in the early stage and gradually became bilateral with disease progression [16, 17]. The interactions of genotype-phenotype in HDLS still need to be further investigated.
For cases 1 and 2, there was lack of clear family history, which was probably the de novo mutations or reduced penetrance. However, there was no obvious difference noticed in age of onset, chief complaint, neuroimaging, and laboratory findings, between sporadic and familial HDLS cases. In the pedigree of case 3, clear family history was reported. Her mother had onset at 61 years of age and died within four years, while her sister had onset at 35 years of age and died within three years. Case 3 was affected at age 42, which was much earlier than her mother and comparable to her sister.
The sporadic HDLS cases were prone to be misdiagnosed, because of unclear family history and autosomal dominant inheritance with incomplete penetrance. However, sporadic HDLS cases are not rare and need to be considered, when white matter lesions emerge together with cognitive decline, neuropsychiatric disorders, and pyramid signs. Although no positive findings were detected in the cerebrospinal fluid of all the three cases, it has been confirmed that specific oligoclonal bands can be seen in certain HDLS cases [18]. Therefore, primary progressive multiple sclerosis should also be excluded, with regard to the white matter changes, mimic symptoms, monophase course, and lack of family history.
DISCLOSURE STATEMENT
Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/16-1193r1).