Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.

Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes-CACNA1A, ITPR1, SPTBN2, and KCNC3-were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1-associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A, ITPR1, and SPTBN2, the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist.

Ataxia and Hypogonadism: a Review of the Associated Genes and Syndromes.

The association of hypogonadism and cerebellar ataxia was first recognized in 1908 by Gordon Holmes. Since the seminal description, several heterogeneous phenotypes have been reported, differing for age at onset, associated features, and gonadotropins levels. In the last decade, the genetic bases of these disorders are being progressively uncovered. Here, we review the diseases associating ataxia and hypogonadism and the corresponding causative genes. In the first part of this study, we focus on clinical syndromes and genes (RNF216, STUB1, PNPLA6, AARS2, SIL1, SETX) predominantly associated with ataxia and hypogonadism as cardinal features. In the second part, we mention clinical syndromes and genes (POLR3A, CLPP, ERAL1, HARS, HSD17B4, LARS2, TWNK, POLG, ATM, WFS1, PMM2, FMR1) linked to complex phenotypes that include, among other features, ataxia and hypogonadism. We propose a diagnostic algorithm for patients with ataxia and hypogonadism, and we discuss the possible common etiopathogenetic mechanisms.

A Review of Brain and Pituitary Gland MRI Findings in Patients with Ataxia and Hypogonadism.

The association of cerebellar ataxia and hypogonadism occurs in a heterogeneous group of disorders, caused by different genetic mutations often associated with a recessive inheritance. In these patients, magnetic resonance imaging (MRI) plays a pivotal role in the diagnostic workflow, with a variable involvement of the cerebellar cortex, alone or in combination with other brain structures. Neuroimaging involvement of the pituitary gland is also variable. Here, we provide an overview of the main clinical and conventional brain and pituitary gland MRI imaging findings of the most common genetic mutations associated with the clinical phenotype of ataxia and hypogonadism, with the aim of helping neuroradiologists in the identification of these disorders.

CHARON: An Imaging-Based Diagnostic Algorithm to Navigate Through the Sea of Hereditary Degenerative Ataxias.

The complexity in diagnosing hereditary degenerative ataxias lies not only in their rarity, but also in the variety of different genetic conditions that can determine sometimes similar and overlapping clinical findings. In this light, Magnetic Resonance Imaging (MRI) plays a key role in the evaluation of these conditions, being a fundamental diagnostic tool needed not only to exclude other causes determining the observed clinical phenotype, but also to proper guide to an adequate genetic testing. Here, we propose an MRI-based diagnostic algorithm named CHARON (Characterization of Hereditary Ataxias Relying On Neuroimaging), to help in disentangling among the numerous, and apparently very similar, hereditary degenerative ataxias. Being conceived from a neuroradiological standpoint, it is based primarily on an accurate evaluation of the observed MRI findings, with the first and most important being the pattern of cerebellar atrophy. Along with the evaluation of the presence, or absence, of additional signal changes and/or supratentorial involvement, CHARON allows for the identification of a small groups of ataxias sharing similar imaging features. The integration of additional MRI findings, demographic, clinical and laboratory data allow then for the identification of typical, and in some cases pathognomonic, phenotypes of hereditary ataxias.

Power of NGS-based tests in HSP diagnosis: analysis of massively parallel sequencing in clinical practice.

Hereditary spastic paraplegia (HSP) refers to a group of heterogeneous neurological disorders mainly characterized by corticospinal degeneration (pure forms), but sometimes associated with additional neurological and extrapyramidal features (complex HSP). The advent of next-generation sequencing (NGS) has led to huge improvements in knowledge of HSP genetics and made it possible to clarify the genetic etiology of hundreds of "cold cases," accelerating the process of reaching a molecular diagnosis. The different NGS-based strategies currently employed as first-tier approaches most commonly involve the use of targeted resequencing panels and exome sequencing, whereas genome sequencing remains a second-tier approach because of its high costs. The question of which approach is the best is still widely debated, and many factors affect the choice. Here, we aim to analyze the diagnostic power of different NGS techniques applied in HSP, by reviewing 38 selected studies in which different strategies were applied in different-sized cohorts of patients with genetically uncharacterized HSP.

Screening for Fabry disease in a series of Parkinson's disease patients and literature review.

BACKGROUND: So far, mutations in genes encoding lysosomal enzymes have been associated with Parkinson's disease (PD). Fabry disease (FD) is an X-linked lysosomal storage disease caused by alpha-galactosidase A (α-GAL) deficiency, leading to deposition of globotriaosylceramide in the nervous system and other organs. We aimed to screen for FD a case series of PD patients from Southern Italy and to review the literature. METHODS: One hundred and forty-four consecutive unrelated PD subjects were enrolled. The α-GAL activity was measured in all men and, in case of pathological values, subsequent determination of globotriaosylsphingosine (lyso-Gb3) and GLA gene sequencing were also performed. All the women underwent GLA gene sequencing. RESULTS: α-GAL levels resulted low in fifteen men, whereas lyso-Gb3 testing showed values within the reference range in all of them. GLA gene variants were not detected in any tested subjects. One pathological study, six case series, and five case reports are currently reported in literature. CONCLUSIONS: The few studies reviewed are heterogeneous, and the results are controversial. An unknown significance variant in GLA gene was detected in PD patients in one large study, whereas decreased α-GAL activity was observed in PD subjects in two other researches, but without confirmation by lyso-Gb3 assessment or genetic analysis. Vascular parkinsonism was associated to FD in five case reports. We found no association between PD and FD in our population. However, it is not possible to draw definitive conclusions due to limited sample size. Furthermore, controls would have been missing in case of a positive finding.

De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia.

BACKGROUND: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy. OBJECTIVES: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia. METHODS: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants. RESULTS: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat. CONCLUSIONS: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society.

POLR3A variants in hereditary spastic paraparesis and ataxia: clinical, genetic, and neuroradiological findings in a cohort of Italian patients.

Mutations in POLR3A are characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes to milder and later-onset gait disorders with central hypomyelination, with or without additional non-neurological signs. Recently, a milder phenotype consisting of late-onset spastic ataxia without hypomyelinating leukodystrophy has been suggested to be specific to the intronic c.1909 + 22G > A mutation in POLR3A. Here, we present 10 patients from 8 unrelated families with POLR3A-related late-onset spastic ataxia, all harboring the c.1909 + 22G > A variant. Most of them showed an ataxic-spastic picture, two a "pure" cerebellar phenotype, and one a "pure" spastic presentation. The non-neurological findings typically associated with POLR3A mutations were absent in all the patients. The main findings on brain MRI were bilateral hyperintensity along the superior cerebellar peduncles on FLAIR sequences, observed in most of the patients, and cerebellar and/or spinal cord atrophy, found in half of the patients. Only one patient exhibited central hypomyelination. The POLR3A mutations present in this cohort were the c.1909 + 22G > A splice site variant found in compound heterozygosity with six additional variants (three missense, two nonsense, one splice) and, in one patient, with a novel large deletion involving exons 14-18. Interestingly, this patient had the most "complex" presentation among those observed in our cohort; it included some neurological and non-neurological features, such as seizures, neurosensory deafness, and lipomas, that have not previously been reported in association with late-onset POLR3A-related disorders, and therefore further expand the phenotype.

Cutaneous sensory and autonomic denervation in progressive supranuclear palsy.

AIM: Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative tauopathy characterised by motor, behavioural and cognitive dysfunction. While in the last decade, sensory and autonomic disturbances as well as peripheral nerve involvement are well-recognised in Parkinson's Disease (PD), little is known in this regard for PSP. Herein, we aim to assess peripheral sensory and autonomic nerve involvement in PSP and to characterise possible differences in morpho-functional pattern compared to PD patients. METHODS: We studied 27 PSP and 33 PD patients without electrophysiological signs of neuropathy, and 33 healthy controls (HC). In addition to motor impairment, evaluated by means of UPDRS-III and the PSP rating scale, all patients underwent clinical, functional and morphological assessment of sensory-autonomic nerves through dedicated questionnaires, sympathetic skin response, dynamic sweat test and skin biopsies. The analysis of cutaneous sensory and autonomic innervation was performed using indirect immunofluorescence and confocal microscopy. RESULTS: PSP patients displayed a length-dependent loss of sensory and autonomic nerve fibres associated with functional impairment compared to HC and, overall, a more severe picture than in PD patients. The disease severity correlated with the loss of intraepidermal nerve fibre density in the leg of PSP patients (p < 0.05). CONCLUSION: We demonstrated a length-dependent small fibre pathology in PSP, more severe compared to PD, and paralleling disease severity. Our findings suggest the morphological and functional study of cutaneous nerves as possible biomarkers to monitor disease progression and response to new treatments.

Conventional MRI findings in hereditary degenerative ataxias: a pictorial review.

PURPOSE: Cerebellar ataxias are a large and heterogeneous group of disorders. The evaluation of brain parenchyma via MRI plays a central role in the diagnostic assessment of these conditions, being mandatory to exclude the presence of other underlying causes in determining the clinical phenotype. Once these possible causes are ruled out, the diagnosis is usually researched in the wide range of hereditary or sporadic ataxias. METHODS: We here propose a review of the main clinical and conventional imaging findings of the most common hereditary degenerative ataxias, to help neuroradiologists in the evaluation of these patients. RESULTS: Hereditary degenerative ataxias are all usually characterized from a neuroimaging standpoint by the presence, in almost all cases, of cerebellar atrophy. Nevertheless, a proper assessment of imaging data, extending beyond the mere evaluation of cerebellar atrophy, evaluating also the pattern of volume loss as well as concomitant MRI signs, is crucial to achieve a proper diagnosis. CONCLUSION: The integration of typical neuroradiological characteristics, along with patient's clinical history and laboratory data, could allow the neuroradiologist to identify some conditions and exclude others, addressing the neurologist to the more appropriate genetic testing.

Othello syndrome in Parkinson's disease: a systematic review and report of a case series.

INTRODUCTION: Psychosis in Parkinson's disease (PD) is common and consists of hallucinations, illusions, and delusions. Among the latter, delusional jealousy, also named Othello syndrome (OS), might impair the quality of life of both patients and their partners. We aimed to perform a systematic review and report a series of PD patients presenting with OS. METHODS: A systematic review research was performed in PubMed database, excluding non-English articles, single case reports, reviews and neuropathology articles, comments, and articles concerning OS associated with deep brain stimulation (DBS) and levodopa-carbidopa intestinal gel infusion. We also described eleven PD patients (9 M and 2 F) with OS, identified in a cohort of consecutive 153 patients, comparing them with eleven matched no OS (nOS) PD subjects taken from the same cohort. RESULTS: We included eight articles (four case series and four cross-sectional studies). OS resulted more common among males than females. We did not find higher levodopa dose and levodopa equivalent dose for dopamine agonists and for all anti-parkinsonian drugs in our OS group. In our case series, OS patients showed visual hallucinations (p=0.001) and a trend to have depression (p=0.080) more frequently than nOS ones. CONCLUSIONS: OS is not a rare disorder in PD, probably due not only to abnormal dopaminergic stimulation but also to serotonergic dysfunction in biologically predisposed subjects. Visual hallucinations and other concomitant psychiatric diseases, in particular depression, might represent a risk factor for the OS development.

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

Magnetic resonance parkinsonism indices and interpeduncular angle in idiopathic normal pressure hydrocephalus and progressive supranuclear palsy.

PURPOSE: The clinical presentation of idiopathic normal pressure hydrocephalus (iNPH) may overlap with progressive supranuclear palsy (PSP). The Magnetic Resonance Parkinsonism Index (MRPI), MRPI 2.0, and the interpeduncular angle (IPA) have been investigated to differentiate PSP from healthy controls (HC) and other parkinsonisms. We aimed to assess equivalences and differences in MRPI, MRPI 2.0, and IPA in iNPH, PSP, and HC groups. METHODS: We retrospectively recruited 99 subjects (30 iNPH, 32 PSP, 37 HC) from two institutions. MRI exams, acquired on either 1.5 T or 3 T scanners, included 3D T1-weighted images to measure MRPI, MRPI 2.0, and IPA. Inter- and intra-rater reliability was investigated with the intra-class correlation coefficient (ICC), and the two one-sided t tests (TOST) procedure was used to assess these markers in iNPH, PSP, and HC. RESULTS: For all the three measures, intra-rater and inter-rater ICC were excellent (range = 0.91-0.93). In the comparison of iNPH and PSP with HC, differences for MRPI and MRPI 2.0 (p < 0.01 in all cases) and no equivalence (p = 1.00 in all cases) were found at TOST. iNPH and PSP MRPI showed no difference (p = 0.06) and no equivalence (p = 0.08). MRPI 2.0 was not equivalent (p = 0.06) and not different (p = 0.09) in the same two populations. PSP and HC IPA proved equivalent (p < 0.01) while iNPH IPA was different (p < 0.01) and not equivalent (p = 0.96 and 0.82) from both PSP and HC. CONCLUSION: MRPI and MRPI 2.0 significantly overlap in iNPH and PSP, with risk of misdiagnosis, and for this reason may not be helpful in the differential diagnosis.

The "crab sign": an imaging feature of spinocerebellar ataxia type 48.

PURPOSE: A new form of autosomal dominant hereditary spinocerebellar ataxia (SCA) has been recently described (SCA48), and here we investigate its conventional MRI findings to identify the presence of a possible imaging feature of this condition. METHODS: In this retrospective observational study, we evaluated conventional MRI scans from 10 SCA48 patients (M/F = 5/5; 44.7 ± 7.8 years). For all subjects, atrophy of both supratentorial and infratentorial compartments were recorded, as well as the presence of possible T2-weighted imaging (T2WI) signal alterations. RESULTS: In SCA48 patients, no meaningful supratentorial changes were found, both in terms of volume loss or MRI signal changes. Atrophy of the cerebellum was present in all cases, involving both the vermis and the hemispheres, but particularly affecting the postero-lateral portions of the cerebellar hemispheres. In all patients, with the exception of only one subject (90.0% of the cases), a T2WI hyperintensity of both dentate nuclei was found. The association of such signal alteration with the pattern of cerebellar atrophy resembled the appearance of a crab ("crab sign"). CONCLUSION: Our findings suggest that SCA48 patients are characterized by cerebellar atrophy, mainly involving the postero-lateral hemisphere areas, along with a T2WI hyperintensity of dentate nuclei. We propose that the association of such signal change, along with the atrophy of the lateral portion of the cerebellar hemispheres, resembled the appearance of a crab, and therefore, we propose the "crab sign" as a neuroradiological sign present in SCA48 patients.

Spinocerebellar ataxia type 48: last but not least.

INTRODUCTION: Biallelic mutations in STUB1, which encodes the E3 ubiquitin ligase CHIP, were originally described in association with SCAR16, a rare autosomal recessive spinocerebellar ataxia, so far reported in 16 kindreds. In the last 2 years, a new form of spinocerebellar ataxia (SCA48), associated with heterozygous mutations in the same gene, has been described in 12 kindreds with autosomal dominant inheritance. METHODS: We reviewed molecular and clinical findings of both SCAR16 and SCA48 described patients. RESULTS AND CONCLUSION: SCAR16 is characterized by early onset spastic ataxia and a wide disease spectrum, including cognitive dysfunction, hyperkinetic disorders, epilepsy, peripheral neuropathy, and hypogonadism. SCA48 is an adult-onset syndrome characterized by ataxia and cognitive-psychiatric features, variably associated with chorea, parkinsonism, dystonia, and urinary symptoms. SCA48, the last dominant ataxia to be described, could emerge as the most frequent among the SCAs due to conventional mutations. The overlap of several clinical signs between SCAR16 and SCA48 indicates the presence of a continuous clinical spectrum among recessively and dominantly inherited mutations of STUB1. Different kinds of mutations, scattered over the three gene domains, have been found in both disorders. Their pathogenesis and the relationship between SCA48 and SCAR16 remain to be clarified.

Primary familial brain calcification caused by a novel homozygous MYORG mutation in a consanguineous Italian family.

Primary familial brain calcification (PFBC) is a rare disorder mostly characterized by calcium deposits in the basal ganglia and a wide spectrum of neurologic and psychiatric symptoms, typically inherited as an autosomal dominant trait. Recently, MYORG was reported as the first autosomal recessive causal gene in PFBC patients of Chinese and Middle Eastern origin. Herein, we describe the first PFBC patient of European descent found to carry a novel homozygous MYORG mutation (p.N511Tfs*243). Interestingly, the patient's father, a heterozygous carrier of the same mutation, showed diffuse bilateral cerebral calcifications with no symptoms other than very mild postural tremor.

Degenerative and acquired sporadic adult onset ataxia.

The diagnosis of sporadic adult onset ataxia is a challenging task since a large collection of hereditary and non-hereditary disorders should be taken into consideration. Sporadic adult onset ataxias include degenerative non-hereditary, hereditary, and acquired ataxias. Multiple system atrophy and idiopathic late cerebellar ataxia are degenerative non-hereditary ataxias. Late-onset Friedreich's ataxia, spinocerebellar ataxia type 6 and 2, and fragile X-associated tremor/ataxia syndrome account for most sporadic hereditary ataxias. Alcoholic cerebellar degeneration, paraneoplastic and other autoimmune cerebellar degeneration, vitamin deficiencies, and toxic-induced and infectious cerebellar syndrome are the main causes of acquired cerebellar degeneration. The diagnostic approach should include a history taking, disease progression, general and neurological examination, brain MRI, and laboratory and genetic tests. Novel opportunities in massive gene sequencing will increase the likelihood to define true etiologies.

A new genetic cause of spastic ataxia: the p.Glu415Lys variant in TUBA4A.

Tubulinopathies encompass neurodevelopmental disorders caused by mutations in genes encoding for different isotypes of α- and ß-tubulins, the structural components of microtubules. Less frequently, mutations in tubulins may underlie neurodegenerative disorders. In the present study, we report two families, one with 11 affected individuals and the other with a single patient, carrying a novel, likely pathogenic, variant (p. Glu415Lys) in the TUBA4A gene (NM_006000). The phenotype, not previously described, is that of spastic ataxia. Our findings widen the phenotypic and genetic manifestations of TUBA4A variants and add a new type of spastic ataxia to be taken into consideration in the differential diagnosis.