A Rare Genetic Cause of Young Onset Rapidly Progressive Dementia- First Report from India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.344666
Source of Support: None, Conflict of Interest: None
Keywords: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), CSF 1 receptor gene mutation, persistent diffusion restriction, young onset dementia
Rapidly progressive dementias are challenging diagnoses. They could be due to varied etiologies like autoimmune, vasculitis, infections, toxic-metabolic, paraneoplastic, prion diseases or due to atypical presentations of degenerative dementias. We present a rare case of genetic cause of young-onset rapidly progressive dementia.
A 40-year-old gentleman was brought by his wife with problems in attention, behavior and memory for past 9 months, calculation difficulty for past 7 months, tremulousness of hands, and change in voice, along with difficulties in activities of daily living for past 6 months.
He is a graduate working as a clerk in government office. His symptoms started in the form of attention disturbances, initially for items in the shopping list, forgetting to take money from vendor in grocery shops, forgetting his keys or wallet. He became withdrawn and had anger outbursts at work place. By next two months, he developed memory disturbances in the form of forgetting what he had for breakfast and important occasions like marriage anniversary. He was unable to handle bills. He then developed visuospatial disturbances like forgetting way around familiar places. He also developed tremulousness of both hands, left more than right while holding objects. Gradually, he stopped working as he was unable to manage office work. He became dependent on his wife for all activities of daily living including bathing, dressing, eating and became incontinent. There was history of migraine with aura and hypertension which was well controlled on regular medication for last 3 years. There was no family history of similar illness.
On examination, his vitals and blood pressure were normal. Systemic examination was unremarkable. Neurologic examination showed impairment in attention, fluency, working memory, recent memory, visuospatial functions with preserved language. Cranial nerve examination, motor, sensory examination was normal. Frontal release signs, bilateral postural tremors were present. Possibility of young onset rapidly progressive major neurocognitive disorder with hypertension was thought and differentials considered were vasculitis, vascular dementia due to multi-infarct state or infective causes.
His routine investigation, i.e. complete blood counts, liver and renal function tests, serum electrolytes, peripheral smear, thyroid function test, vitamin B12 and homocysteine were normal. HbA1c was 5.4%. ESR was 9 mm in 1st hr.
Serum autoimmune antibodies, paraneoplastic antibodies, human immunodeficiency virus (HIV) and Venereal Disease Research Laboratory (VDRL) tests were negative.
Visual evoked potentials, echocardiography, renal artery doppler were normal. Abdominal ultrasonogram showed bilateral nephrolithiasis. MRI of the brain [Figure 1] showed extensive white matter hyperintensities in bilateral subcortical, deep and periventricular region sparing U fibers with diffusion restriction and cortical atrophy without contrast enhancement. Corpus callosal atrophy was noted. Similar picture comprising FLAIR and Diffusion changes were present in the MRI done outside 9 months before as well [Figure 2]. CSF showed nil cells, 75 mg/dl protein, 84 mg/dl sugar.
Based on the MRI findings, possibilities considered were multi-infarct state and vasculitis. The persistence of diffusion restriction over 9 months raised a suspicion of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. However, he was treated with 2 pulses of methyl prednisolone (5 grams/month) with which there was no improvement. Meanwhile, patient party was counseled and genetic analysis was done.
At a follow-up visit after 2 months, his personality, memory, visuospatial disturbances worsened and he developed Parkinsonism More Details with rigidity and bradykinesia, apraxia and stimulus-sensitive myoclonus. The clinical exome sequencing revealed a pathogenic heterozygous missense variation in exon 18 of the CSF1R gene (chr5:g. 149435843A > G; Depth: 98x) that resulted in the amino acid substitution of Threonine for Isoleucine at codon 794 (p.Ile794Thr). The observed variation has been previously reported in a patient affected with hereditary diffuse leukoencephalopathy with spheroids and the functional studies suggested mutant CSF1R might assemble into non-functional homo dimers and wild-type/mutant heterodimers inducing a dominant negative disease mechanism. The p.Ile794Thr variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.0008% and 0.002% in the ExAC database. He was diagnosed with ALSP or CSF-1R related leukoencephalopathy and counseled regarding the illness. He was started on Memantine and Donepezil and is on follow up.
CSF1R is a cell surface receptor that is highly expressed in microglia. It has a regulatory role in the functioning of the microglia. Mutations in the tyrosine kinase domain of this protein are associated with disease. Mutations were first described in 2012, though the disease was pathologically identified in 1984. It is currently classified under primary microgliopathies. It has been variously termed as hereditary leukoencephalopathy with axonal spheroids (HDLS) and Pigmentary orthochromatic leukodystrophy (POLD). It is an autosomal dominant and adult onset leukodystrophy. Patients present with rapidly progressive cognitive impairment with extrapyramidal/pyramidal involvement. The mean age of onset is 43 years (15-78). Median life expectancy is 6 years. Konno et al. studied 122 cases retrospectively. The most frequent symptoms were cognitive decline (59%), psychiatric symptoms (44%), motor dysfunction, which included Parkinsonism and spasticity (38%) and speech problems (19%). Findings in MRI were dilation of the lateral ventricles (100%), bilateral white matter lesions (96%), cortical atrophy (92%), thinning of the corpus callosum (88%), abnormal signal in the corpus callosum (88%), abnormal signal in the pyramidal tracts (58%), diffusion-restricted lesions (38%), calcifications in white matter (54%). The persistence of diffusion restriction on MRI probably reflects intramyelinic edema and it may contribute to the rapid progression of dementia in such patients. Neuropathologically, it is characterized by axonal loss, axonal spheroids and pigmentary microglia. Recently alanyl-transfer RNA synthetase 2 (AARS2) mutation has been described to cause spastic paraparesis and adult-onset leukodystrophy. Patients present in young adult age with frontal behavioral syndrome, pyramidal involvement, cardiomyopathy and ovarian failure. Both the conditions (ALSP and AARS2) are clinically, radiologically and pathologically similar. Ovarian failures is seen exclusively in AARS2 mutation.
The MRI findings could be misinterpreted as small vessel disease, demyelination, vascular insult, vasculitis., Hence, knowledge of leukoencephalopathies is important. Interestingly, it is one of the rare genetically mediated diseases presenting as rapidly progressive dementia/FTD in young patients. The salient features of our case are (a) younger age at onset, (b) rapidly progressive dementia, and (c) persistent diffusion restriction on MRI with periventricular white matter hyperintensities.
CSF-1R related leukoencephalopathies are estimated to constitute about 10% of adult onset leukodystrophies. Hence, it is important to recognize the characteristic imaging pattern to narrow down the diagnosis, to avoid unnecessary treatment with immunosuppressive medications, prognostication and genetic counseling of such patients.
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[Figure 1], [Figure 2]