Hereditary spastic paraplegias (HSP) are a large group of genetic diseases characterized by progressive degeneration of the long tracts of the spinal cord, namely the corticospinal tracts and dorsal columns. Genotypic and phenotypic heterogeneity is a hallmark of this group of diseases, which makes proper diagnosis and management often challenging. In this scenario, magnetic resonance imaging (MRI) emerges as a valuable tool to assist in the exclusion of mimicking disorders and in the detailed phenotypic characterization. Some neuroradiological signs have been reported in specific subtypes of HSP and are therefore helpful to guide genetic testing/interpretation. In addition, advanced MRI techniques enable detection of subtle structural abnormalities not visible on routine scans in the spinal cord and brain of subjects with HSP. In particular, quantitative spinal cord morphometry and diffusion tensor imaging look promising tools to uncover the pathophysiology and to track progression of these diseases. In the current review article, we discuss the current use and future perspectives of MRI in the context of HSP.
Objective:Protein misfolding plays a central role not only in amyotrophic lateral sclerosis (ALS), but also in other conditions, such as frontotemporal dementia (FTD), inclusion body myopathy (hIBM) or Paget's disease of bone. The concept of multisystem proteinopathies (MSP) was created to account for those rare families that segregate at least 2 out of these 4 conditions in the same pedigree. The calcium-dependent phospholipid-binding protein annexin A11 was recently associated to ALS in European pedigrees. Herein, we describe in detail 3 Brazilian families presenting hIBM (isolated or in combination with ALS/FTD) caused by the novel p.D40Y change in the gene encoding annexin A11 (ANXA11). Methods: We collected clinical, genetic, pathological and skeletal muscle imaging from 11 affected subjects. Neuroimaging was also obtained from 8 patients and 8 matched controls. Results: Clinico-radiological phenotype of this novel hIBM reveals a slowly progressive predominant limb-girdle syndrome, but with frequent axial (ptosis/dropped head) and distal (medial gastrocnemius) involvement as well. Muscle pathology identified numerous rimmed vacuoles with positive annexin A11, TDP-43 and p62 inclusions, but no inflammation. Central nervous system was also involved: two patients had FTD, but diffusion tensor imaging uncovered multiple areas of cerebral white matter damage in the whole group (including the corticospinal tracts and frontal subcortical regions). Interpretation: These findings expand the phenotypic spectrum related to ANXA11. This gene should be considered the cause of a novel multisystem proteinopathy (MSP type 6), rather than just ALS.
We read the letter titled "RFC1 Intronic Repeat Expansions Absent in Pathologically Confirmed Multiple Systems Atrophy" published online in April 2020 1 with great interest. In light of that letter, we would like to expand the phenotypic spectrum of RFC1 expansion-related disorders by reporting dopa-responsive parkinsonism in a 63-year-old woman. She developed parkinsonian symptoms in her early 50s, characterized by bradykinesia, resting tremor, and stiffness. The patient was started on levodopa as a symptomatic therapy with overt gait improvement (Video S1). Approximately 1 year later, she noticed oscillopsia and sensory complaints described as asymmetrical limb paresthesia that became confluent and associated with decreased vibration as well as proprioceptive sensation leading to gait unsteadiness. Head impulse test demonstrated absent vestibulo-ocular reflex bilaterally. A 20-year dry cough history was also reported. Brain magnetic resonance imaging and laboratory workup were unremarkable. Nerve conduction studies showed diffuse abnormalities restricted to sensory nerves, quantitative sudomotor axonal reflex was normal, and heart rate variability revealed incipient cardiac dysautonomia. Dopamine transporter scan highlighted a marked reduction of dopaminergic
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