Some time ago, we reported a patient with progressive echolalia, supranuclear palsy (SNP), oromandibular dystonia (OMD), and brain calcifications. The patient had primary familial brain calcification (PFBC) associated with the heterozygous pathogenic variant c. 262₂66del (M88Wfs*4) in SLC20A2 and cerebrospinal fluid phosphate was elevated. 1 Here we provide an update on the disease course and the underlying neuropathological findings. Symptoms were progressive with loss of speech, repeated falls with hip and radial fractures, loss of walking ability, ataxia, hypersalivation, cognitive decline, anxiety, dysphagia, and cachexia. The patient moved to a care facility and was unable to undergo planned radiological follow-up. Upon examination, 6 months prior to her death, the phenomenology consisted of SNP, slow eye movements, broken smooth pursuit, OMD, cervical dystonia, ataxia, hyperreflexia in all extremities, anarthria, and severely unstable short-strided gait. The rest of the examination was normal. This presentation raised the suspicion of concomitant progressive supranuclear palsy (PSP). Death occurred at age 82 years and a neuropathological assessment was performed. Briefly, extensive brain parenchymal and blood vessel calcification was found on von Kossa staining. The basal ganglia and central part of the cerebellum were severely affected, many large sized vessels were involved, and calcospherites were present. Capillary calcifications were noticed, especially in the deeper layers of the occipital cortex (Fig. 1). Prominent cortical tau immunopositivity in threads and neurons was seen, but astrocytic plaques or tufted astrocytes were absent. Positivity for both three- (3R) and four-repeat (4R) tau was present, and beta-amyloid plaques, both diffuse and neuritic, were seen in the cerebral cortex which is compatible with Alzheimer's disease (AD) (Figure S1). Vessel walls in the cortex and leptomeninges contained beta-amyloid positivity. The morphological findings were consistent with PFBC, AD, and cerebral amyloid angiopathy (CAA). The neuropathology of genetically confirmed PFBC-SLC20A2 was first described by Baker et al. , 2 where the pathogenic variant consisted of a large deletion encompassing sevens genes, including THAP1 which is associated with autosomal dominant dystonia. 2 Two later publications described two Japanese men with PFBC-SLC20A2, without any other pathogenic variants than in SLC20A2. 3, 4 However, all three patients had a similar pattern of calcification. The clinical spectrum for PFBC is very wide – ranging from a variety of movement disorders (parkinsonism, ataxia, and/or hyperkinesias) to psychiatric presentations and cognitive deficits, with a proportion of mutation carriers remaining asymptomatic. 5 Both AD and CAA pathology are common in an older population, and are in this patient interpreted as coincidental findings considering the context of a complex movement disorder, but may have contributed to cognitive decline. Symptoms mimicking PSP with oculomotor disturbance have been reported rarely in PFBC-SLC20A2, 6, 7 and our report is the first to present any neuropathological findings. The absence of PSP-related and presence of typical PFBC-SLC20A2 findings strongly suggest that PFBC-SLC20A2 itself can be a PSP mimic. There is still a lack of in vivo biomarkers for PSP, and our report underscores the relevance of neuropathology in diagnosing and understanding complex movement disorders. (1) Research Project: A. Conception, B. Clinical Assessment, C. Neuropathological Analysis, D. Patient Care; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Editing. I. G.: 2A, 2B. P. S.: 1A, 2B. I. N.: 1C, 2B. M. P. 1A, 1B, 1D, 2B. The authors are grateful to the patient and her next-of-kin for consenting to their participation in follow-up evaluations and for consenting to this work. P. S. is a Wallenberg Clinical Scholar and supported by Region Stockholm. M. P. 's research is supported by Region Stockholm. I. G. and I. N. have nothing to declare. Data sharing is not applicable to this letter as no datasets were generated or analyzed during the present study. Figure S1. (A) Beta-amyloid deposits in cerebral cortex. Scale bar: 100 μm. (B) Amyloid deposits in leptomeningeal vessel walls. Scale bar: 100 μm. (C) Tau deposits in cerebral cortex. Scale bar: 100 μm. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Gugler et al. (Thu,) studied this question.