An Autopsy Proven Case of CSF1R-mutant Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) with Premature Ovarian Failure

Abstract

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a progressive degenerative white matter disorder caused by mutations in the tyrosine kinase domain of the CSF1R gene. ALSP is often misdiagnosed as other diseases due to its rarity and various clinical presentations such as Parkinsonism, pyramidal signs, cognitive impairment and/or psychiatric symptoms. We describe an autopsy case of ALSP with a CSF1R mutation. A 61-year-old woman presented insidious-onset gait difficulty for 12 years since her age of 49, and premature ovarian failure since her age of 35. At initial hospital visit, brain magnetic resonance imaging revealed hydrocephalus. Initially, Parkinson's syndrome was diagnosed, and she was prescribed L-dopa/carbidopa because of spasticity and rigidity of extremities, which had worsened. Subsequently, severe neuropsychiatric symptoms and cognitive impairment developed and radiologically, features of leukoencephalopathy or leukodystrophy were detected. She showed a down-hill course and died, 12 years after initial diagnosis. At autopsy, the brain showed severe symmetric atrophy of bilateral white matter, paper-thin corpus callosum, thin internal capsule, and marked hydrocephalus. Microscopically, diffuse loss of white matter, relatively preserved subcortical U-fibers, and many eosinophilic bulbous neuroaxonal spheroids were noted, but there was no calcification. Pigmented glia with brown cytoplasmic pigmentation were readily found in the white matter, which were positive for Periodic acid-Schiff, p62, and CD163 stains, but almost negative for CD68. Whole-exome and Sanger sequencing revealed a CSF1R mutation (c.2539G>A, p.Glu847Lys) which was reported in prior one ALSP case. This example demonstrates that ALSP could be associated with premature ovarian failure.

Granulocyte Colony Stimulating Factor causes cerebellar deficits and anxiety in a mouse model of CSF-1 receptor-related leukoencephalopathy

“…Females tend to be more severely affected by CRL and exhibit a higher prevalence of gait disorders (5). Furthermore, ataxia and cerebellar involvement have also been reported predominantly in female CRL patients (13 out of 15 documented cases) (42,45,(47)(48)(49)(50)(51)(52)(53)(54)(55). These findings raise the possibility that estrogens and/or androgens might specifically regulate subpopulations of microglia such as the cerebellar microglia, or those interacting with motor neurons.…”

Microglial replacement therapy: a potential therapeutic strategy for incurable CSF1R-related leukoencephalopathy

“…Expression of the CSF1R signaling ligands CSF-1 (predominant in the cerebellum) and interleukin (IL)-34 (predominant in the cortex) are important for microglial homeostasis in both mice and humans, indicating brain region-specific effects [ 29 ]. It is acknowledged that CSF1R -related leukoencephalopathy is caused by dysfunctional microglia, and that different mutation locations of the CSF1R gene lead to different clinical phenotypes of CSF1R -related leukoencephalopathy, with both disease presentation and progression varying significantly among family members [ 30 , 31 ]. Although CSF1R -related leukoencephalopathy is a genetic disease inherited in an autosomal dominant pattern, approximately 36% of cases are sporadic [ 11 ].…”

“…Neuropathological features of CSF1R -related leukoencephalopathy include a widespread loss of myelin and axons, astrogliosis and macrophage accumulation in the presence of swollen and spherical axons [ 31 ]. Microglia are adapted to the CNS microenvironment and express specific gene signatures ( P2ry12 , Tmem119 and SiglecH ) in order to perform tissue-specific functions [ 39 ].…”

“…Infiltrating Iba1 + P2ry12 − macrophages are detectable on histopathological examinations [ 4 , 41 ], particularly in the degenerating corpus callosum, and most express CD68, CD163 and CD204 [ 41 ]. There is a dominance of CD163 + over CD68 + subpopulations present in the pigmented cells [ 31 ]. Interestingly, macrophages are evident in areas with sparsely distributed microglia, suggesting that macrophages are recruited to the degenerated white matter and might contribute to pathology.…”

Protective roles and mechanisms of rosmarinic acid in cyclophosphamide‐induced premature ovarian failure

“…[ 1 ] The loss of fertility and the clinical effects of low estrogen are two important consequences of POF. [ 2 ] There are many factors that cause POF, including autoimmune disease, chemotherapy, and some gene mutations, and it is believed that it is mainly related to permanent damage to the ovaries. [ 3,4 ] Recently, research has shown that approximately 30% of POF cases are related to immune abnormalities.…”