Myotonic dystrophy type 1 (DM1), commonly known as Steinert’s disease (OMIM #160900), is the most common muscular dystrophy among adults, caused by an unstable expansion of a CTG trinucleotide repeat in the 3′ untranslated region (UTR) of DMPK. Besides skeletal muscle, central nervous system (CNS) involvement is one of the core manifestations of DM1, whose relevant cognitive, behavioral, and affective symptoms deeply affect quality of life of DM1 patients, and that, together with muscle and heart, may profoundly influence the global disease burden and overall prognosis. Therefore, CNS should be also included among the main targets for future therapeutic developments in DM1, and, in this regard, identifying a cost-effective, easily accessible, and sensitive diagnostic and monitoring biomarker of CNS involvement in DM1 represents a relevant issue to be addressed. In this mini review, we will discuss all the papers so far published exploring the usefulness of both cerebrospinal fluid (CSF) and blood-based biomarkers of CNS involvement in DM1. Globally, the results of these studies are quite consistent on the value of CSF and blood Neurofilament Light Chain (NfL) as a biomarker of CNS involvement, with less robust results regarding levels of tau protein or amyloid-beta.

Neurological involvement is relatively common in Erdheim–Chester disease (ECD), a rare clonal disorder of histiocytic myeloid precursors characterized by multisystem involvement. In ECD patients, neurological symptoms can occur either at onset or during the disease course and may lead to various degrees of neurological disability or affect patients’ life expectancy. The clinical neurological presentation of ECD often consists of cerebellar symptoms, showing either a subacute or progressive course. In this latter case, patients manifest with a slowly progressive cerebellar ataxia, variably associated with other non-specific neurological signs, infratentorial leukoencephalopathy, and cerebellar atrophy, possibly mimicking either adult-onset degenerative or immune-mediated ataxia. In such cases, diagnosis of ECD may be particularly challenging, yet some peculiar features are helpful to address it. Here, we retrospectively describe four novel ECD patients, all manifesting cerebellar symptoms at onset. In two cases, slow disease progression and associated brain MRI features simulated a degenerative cerebellar ataxia. Three patients received a definite diagnosis of histiocytosis, whereas one case lacked histology confirmation, although clinical diagnostic features were strongly suggestive. Our findings regarding existing literature data focused on neurological ECD will be also discussed to highlight those diagnostic clues helpful to address diagnosis.

Background/Objectives: Fabry disease (FD) is an inborn error of the glycosphingolipid metabolism with variable kidney, heart, and central nervous system (CNS) involvement. CNS-related FD manifestations include early ischemic stroke and white matter lesions (WMLs) related to cerebral small-vessel disease (CSVD), possibly resulting in cognitive impairment. We studied 40 adult FD patients (17 male) to assess: (i) prevalence of cerebrovascular and cognitive manifestations in FD and their correlation with heart and renal involvement; and (ii) the potential value of serum neurofilament light chain (NfL) levels as an indicator of WMLs in FD. Methods: Patients underwent detailed diagnostic assessment related to FD, also including Mainz Severity Score Index (MSSI), neuropsychological tests, brain MRI to assess WMLs by the modified Fazekas score (mFS), and NfL determination by single-molecule array (SiMoA) (n = 22 FD patients vs. 15 healthy controls). Results: Overall, 4 FD patients had a history of ischemic stroke and 13/32 patients (40.6%) had an mFS ≥ 1. Almost two-thirds of FD patients (27/39, 69.2%) showed impairment on at least one cognitive test. On univariate analysis, only a reduction in estimated glomerular filtration rate was associated with an increased likelihood of having WMLs on brain MRI. Serum NfL levels were higher in FD patients vs. controls, with a trend toward significance (p = 0.08). Conclusions: Mild-to-moderate CSVD is a characteristic brain “signature” in FD patients. Both cardiac and renal involvement correlate with WML load, but only renal involvement appears to be predictive of CNS damage. Brain microvascular damage is associated with mild cognitive impairment in FD, and serum NfL might represent a potential biomarker of CSVD in FD.

We describe the complex case of a 44-year-old man with polycystic kidney disease, mild cognitive impairment, and tremors in the upper limbs. Brain MRI showed lesions compatible with leukodystrophy. The diagnostic process, which included clinical exome sequencing (CES) and chromosomal microarray analysis (CMA), revealed a triple diagnosis: autosomal dominant polycystic kidney disease (ADPKD) due to a pathogenic variant, c.2152C>T-p.(Gln718Ter), in the PKD1 gene; late-onset phenylketonuria due to the presence of two missense variants, c.842C>T-p.(Pro281Leu) and c.143T>C-p.(Leu48Ser) in the PAH gene; and a 915 Kb duplication on chromosome 15. Few patients with multiple concurrent genetic diagnoses are reported in the literature; in this ADPKD patient, genome-wide analysis allowed for the diagnosis of adult-onset phenylketonuria (which would have otherwise gone unnoticed) and a 15q11.2 duplication responsible for cognitive and behavioral impairment with incomplete penetrance. This case underlines the importance of clinical genetics for interpreting complex results obtained by genome-wide techniques, and for diagnosing concurrent late-onset monogenic conditions.

Background: Krabbe disease (KD) is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in GALC . Despite accounting only for 5% of forms, reports of adult-onset KD cases are increasingly described. Methods: A female patient manifesting KD after the age of 60 years, presenting with spastic paraplegia and cognitive decline, is described. The scientific literature of KD with onset > 10 years has been extensively reviewed to refine the spectrum of later-onset KD manifestations. Results: Including ours, we identified 84 KD adolescent/adult-onset patients (mean age at onset 28.7 ± 14.2 years). Most patients had limb spasticity as main characterizing neurological feature (58/84, 70.2%), followed by polyneuropathy (11/ 84, 13.1%), both upper and lower motor neuron signs (2/84, 2.4%), and epilepsy (2/84, 2.4%). Five out of 84 patients (6.0%) were asymptomatic. Most patients had cortico-spinal tracts involvement at brain MRI. The most common pathogenic GALC variants were the c.1901 T > C (18 patients), the c.857G > A (13 patients), and the c.1161 + 6532_polyA + 9kbdel (13 patients). Conclusions: Complicated spastic paraplegia is the most common manifestation in later-onset KD, rarely with normal brain MRI. KD should be always considered also in cases with very late-onset spastic paraplegia.

Background: Fabry Disease (FD) is an X-linked lysosomal disease, in which, unlike other X-linked disorders, most female carriers manifest signs or symptoms for unknown reasons. Objectives: Herein, we aimed to test the potential role of X-chromosome inactivation (XCI) in leukocytes as a prognostic biomarker of disease in FD female carriers. Moreover, we explored if levels of X-inactive-specific transcript (Xist), a long non-coding RNA driving XCI, were detectable in the leukocytes of FD female carriers. Methods: We tested the XCI pattern in leukocytes on 33 consecutive females carrying pathogenic GLA variants. Disease severity was defined using the Mainz Severity Score Index (MSSI). Xist levels in leukocytes were assessed by real-time PCR and compared to the levels of 22 controls. Results: XCI was obtained for 31 female patients, finding 16 skewed (51.6%) individuals. Global MSSI did not differ in skewed vs. non-skewed FD carriers. In skewed FD females, the renal function and mean cardiologic MSSI subscore were significantly worse, and systemic arterial hypertension was more frequent. Xist levels detected in leukocytes were similar between female patients and controls, and did not differ by phenotype or XCI status. Conclusions: A skewed XCI pattern in leukocytes may represent a prognostic biomarker of worse renal and cardiac outcomes in female FD carriers.