Monia Ginevrino

Impulsive-compulsive behaviors in parkin-associated Parkinson disease

Objective: The aim of this multicenter, case-control study was to investigate the prevalence and severity of impulsive-compulsive behaviors (ICBs) in a cohort of patients with parkin-associated Parkinson disease (PD) compared to a group of patients without the mutation. Methods: We compared 22 patients with biallelic parkin mutations (parkin-PD) and 26 patients negative for parkin, PINK1, DJ-1, and GBA mutations (PD-NM), matched for age at onset, disease duration, levodopa, and dopamine agonist equivalent daily dose. A semistructured interview was used to diagnose each of the following ICBs: compulsive sexual behavior, compulsive buying, binge eating, punding, hobbyism, and compulsive medication use. The Questionnaire for Impulsive-Compulsive Disorders in Parkinsons Disease–Rating Scale (QUIP-RS) was adopted to rate ICB severity. Results: Frequency of patients with at least one ICB was comparable between parkin-PD and PD-NM. Nevertheless, when analyzing the distribution of specific ICBs, a higher frequency of compulsive shopping, binge eating, and punding/hobbyism was found in the parkin-PD group. Compared to PD-NM, parkin-PD patients with ICB had younger onset age and higher frequency of smokers; in 5 patients, ICB had predated PD onset. Total and partial (compulsive buying, compulsive sexual behavior, binge eating, hobbyism/punding) QUIP-RS scores were higher in patients with parkin-PD compared to patients with PD-NM. Logistic regression analysis showed that the presence of parkin mutations was associated with smoking status and higher QUIP-RS total score. Conclusions: Our data expand the parkin-associated phenotypic spectrum demonstrating higher frequency and severity of specific ICBs, and suggesting an association between the parkin genotype, smoking status, and ICB severity.

The Contursi Family 20 Years Later: Intrafamilial Phenotypic Variability of the SNCA p.A53T Mutation

The SNCA/alpha-synuclein p.A53T mutation segregating in the Contursi kindred was the first mutation ever described in inherited Parkinson’s disease (PD). We directly examined 10 subjects (4 PD patients and 6 asymptomatic relatives) of a branch of the Contursi kindred. We also collected data on 11 members affected by history, through interviews and inspection of available medical records. Nine had died in the fourth to seventh decade diagnosed with PD (plus psychiatric features in 3), whereas 2 were reported to have severe psychiatric disturbances and were unavailable for examination. After obtaining ethics approval and written informed consent, all subjects underwent a complete neurological examination (see Video 1) and SNCA p.A53T mutation testing. The 4 PD patients (age, 42 6 9.8 years), and 2 unaffected individuals (age, 29.5 6 2.1 years) resulted as heterozygous for the mutation. Two affected (III:1, IV:1) and 2 unaffected (IV:2, IV:6) carriers also underwent extensive neuropsychological and psychiatric assessment, olfaction evaluation, and dopamine transporter imaging with single-photon emission computed tomography (DAT-SPECT); 3T brain MRI was performed in 3 subjects (III:1, IV:2, and IV:6; Fig. 1). Although the overall phenotype in the 4 patients was typical of SNCA-related PD with early, asymmetric onset, initial good response to dopaminergic therapy and early motor complications, a relevant variability was observed in the combination and severity of motor symptoms (partially responding to levodopa and DBS in III-9) and nonmotor features (Table 1). Age at onset varied from 26 to 48 years (mean, 32.7 6 10.5), with longer disease duration than previously reported (from 2 to 19 years; mean, 9.26 8.5). Cognitive deficits were present in all 4 patients, ranging from frank dementia in those with longer disease duration (III-8, III-9) to moderate cognitive impairment (III-1) or slight isolated executive dysfunction (IV-1) in those with a shorter one. Depression and anxiety were detected in 3 patients, behavioral disorders in 2, and dysautonomia in 2. Olfaction was impaired in both tested patients. Although the variable severity could depend on the different disease duration, the wide range of ages at onset among carriers of the same genetic mutation remains unexplained, suggesting the existence of yet unknown environmental, genetic, and/or epigenetic modifiers. Interestingly, 2 asymptomatic carriers, ages 31 and 28 years, were clinically unaffected. Their general cognitive functions were normal and they did not refer any sleep or mood disorder. However, the younger one (IV:2) presented an objective olfactory deficit and an abnormal DAT scan, suggesting an underlying, still subclinical, neurodegenerative process. The existence of SNCA mutation carriers who remain clinically asymptomatic at ages beyond the expected age of onset has been reported, implying reduced penetrance. However, our carriers were still younger than the latest age of onset in the family; therefore, any conclusion would be merely speculative and further clinical follow-up is necessary. In conclusion, our data further highlight the relevant intrafamilial phenotypic variability in carriers of the SNCA p.A53T mutation, suggesting a role for yet unknown genetic or environmental modifiers. Follow-up studies are encouraged to better define the clinical spectrum of PD caused by SNCA gene mutations.

Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti-Boltshauser syndrome).

Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti–Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS.

Brain connectivity changes in autosomal recessive Parkinson Disease: a model for the sporadic form

Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessive PD. Carriers of single heterozygous mutations may manifest subtle signs of disease, thus providing a unique model of preclinical PD. One emerging hypothesis suggests that non-motor symptom of PD, such as cognitive impairment may be due to a distributed functional disruption of various neuronal circuits. Using resting-state functional MRI (RS-fMRI), we tested the hypothesis that abnormal connectivity within and between brain networks may account for the patients’ cognitive status. Eight homozygous and 12 heterozygous carriers of either PINK1 or Park2 mutation and 22 healthy controls underwent RS-fMRI and cognitive assessment. RS-fMRI data underwent independent component analysis to identify five networks of interest: default-mode network, salience network, executive network, right and left fronto-parietal networks. Functional connectivity within and between each network was assessed and compared between groups. All mutation carriers were cognitively impaired, with the homozygous group reporting a more prominent impairment in visuo-spatial working memory. Changes in functional connectivity were evident within all networks between homozygous carriers and controls. Also heterozygotes reported areas of reduced connectivity when compared to controls within two networks. Additionally, increased inter-network connectivity was observed in both groups of mutation carriers, which correlated with their spatial working memory performance, and could thus be interpreted as compensatory. We conclude that both homozygous and heterozygous carriers exhibit pathophysiological changes unveiled by RS-fMRI, which can account for the presence/severity of cognitive symptoms.

Between SCA5 and SCAR14: delineation of the SPTBN2 p.R480W-associated phenotype

We read with interest the article by Elsayed et al. [1] describing a family with autosomal recessive congenital ataxia due to a homozygous 5-bp deletion in the β3-spectrin gene (SPTBN2). In-frame heterozygous variants of this gene had previously been identified as the cause of autosomal dominant adult-onset SCA5 (MIM#600224) (Suppl.Tab.1) [2–4]. The authors postulated the existence of SPTBN2 genotype-phenotype correlates, suggesting that loss of function mutations would act recessively, producing a severe congenital ataxic phenotype associated with cognitive impairment and variable additional neurological signs. This hypothesis was partially supported by three subsequent studies, reporting homozygous missense, nonsense and splicing SPTBN2 variants, all resulting in an analogous congenital ataxia syndrome, defined as SCAR14 (MIM#615386) (Suppl.Tab.1) [5–7]. Elsayed and colleagues [1] also mentioned a previously reported patient affected by a severe infantile-onset cerebellar ataxia with developmental delay, carrying the heterozygous missense variant c.1438C>T (p.R480W) in the SPTBN2 gene [8]. Based on previous literature data on heterozygous SPTBN2 mutation carriers (presenting the typical SCA5 phenotype of adult-onset, slowly progressive pure cerebellar ataxia), they speculated that either a second-site SCA5 modifier or an undetected SPTBN2 variant in trans (e.g., deep intronic or in a non-coding regulatory region) should contribute to the phenotypic manifestation. In this regard, we would like to report an additional case of congenital severe cerebellar ataxia and intellectual impairment carrying the same SPTBN2 p.R480W variant. This is a 2-year-old girl, the third child of healthy nonconsanguineous parents. She was born by cesarean section after an uncomplicated full-term pregnancy and was referred to the neuropsychiatric clinic because of generalized hypotonia, global developmental delay, and alternating esotropia. At age 12 months, she said her first words and got head control, but could not sit without support. Two months later, her developmental quotient was calculated to be 56. She progressively developed a cerebellar syndrome with gait ataxia and dysarthria. Brain MRI performed at age 1 year 10 months showed global cerebellar hypoplasia with enlarged interfolial spaces, in the absence of any brainstem or supratentorial abnormalities (Suppl.Fig.1A). Molecular analysis consisted of a next-generation sequencing (NGS) panel of 50 genes causative of different forms of nonprogressive cerebellar ataxia (with the exclusion of Joubert Syndrome genes), using TruSeq Custom Amplicon (TSCA) technology on a MiSeq platform (Illumina, San Diego, CA, USA). As in the case reported by Jacob et al. [8], this child was heterozygous for SPTBN2 p.R480W missense variant (NM_006946). This variant was not detected in either of the unaffected parents, suggesting de novo occurrence (Suppl. Fig.1B). Potential heterozygous deletions involving one or more exons were ruled out using a custom script tool aimed at detecting significant differences in read depth from NGS data. The p.R480W variant (rs397514749) is not present in population databases, affects a highly conserved amino acid, and multiple in silico tools consistently predict it as Sara Nuovo and Alessia Micalizzi contributed equally to this work.

Very mild features of dysequilibrium syndrome associated with a novel VLDLR missense mutation

Dysequilibrium syndrome (DES) is a non-progressive congenital ataxia characterized by severe intellectual deficit, truncal ataxia and markedly delayed, quadrupedal or absent ambulation. Recessive loss-of-function mutations in the very low density lipoprotein receptor (VLDLR) gene represent the most common cause of DES. Only two families have been reported harbouring homozygous missense mutations, both with a similarly severe phenotype. We report an Italian girl with very mild DES caused by the novel homozygous VLDLR missense mutation p.(C419Y). This unusually benign phenotype possibly relates to a less disruptive effect of the mutation, falling within a domain (EGF-B) not predicted as crucial for the protein function.

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi002-A from a patient affected by the Jervell and Lange-Nielsen syndrome and carrier of two compound heterozygous mutations on the KCNQ1 gene

We report the generation of human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a female patient carrier of the two compound heterozygous mutations c.568 C>T p.R190W (maternal allele), and c.1781 G>A p.R594Q (paternal allele) on the KCNQ1 gene, causing Jervell and Lange-Nielsen Syndrome (JLNS). To obtain hiPSCs, we used the classical approach of the four retroviruses each encoding for a reprogramming factor OCT4, SOX2, KLF4, cMYC. The obtained hiPSC clones display pluripotent stem cell characteristics, and differentiate into spontaneously beating cardiomyocytes (hiPSC-CMs).

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi003-A from a patient affected by an autosomal recessive form of Long QT Syndrome type 1

We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a 51years old female patient homozygous for the mutation c.535 G>A p.G179S on the KCNQ1 gene, causing a severe form of autosomal recessive Long QT Syndrome type 1 (AR-LQT1), not associated with deafness. The hiPSCs, generated using four retroviruses each encoding for a reprogramming factor OCT4, SOX2, KLF4, cMYC, are pluripotent and can differentiate into spontaneously beating cardiomyocytes (hiPSC-CMs).

Progressive Supranuclear Palsy–Like Phenotype in a GBA E326K Mutation Carrier

Mutations in the beta-glucocerebrosidase gene (GBA OMIM *606463), encoding the lysosomal enzyme that is deficient in Gaucher’s disease (GD), are important and common risk factors for Parkinson’s disease (PD) and Lewy body dementia (LBD; i.e., a-synucleinopathies). PD patients with GBA mutations have younger age at onset and are more likely to develop cognitive dysfunction. There are approximately 300 known GBA mutations and determining accurate exact genotype-phenotype correlations is challenging. In general, GBA mutations were found to variably influence PD risk according to their impact on the protein function. For instance, the “severe” mutations L444P bears the highest risk of developing PD (OR:10–21), whereas the risk is much lower for the “mild” mutation N370S. The GBA variant, E326K, has long been considered a polymorphism, given that homozygous individuals do not develop GD. However, this variant was found to reduce GBA enzymatic activity in vitro and mildly increase the risk to develop PD (OR:1.7), with frequent development of associated dementia. The impact of GBA mutations on the risk to develop tauopathies is less defined, given that previous studies failed to report a significant association with PSP and corticobasal degeneration. Yet, more recent data suggest that the clinical phenotype of GBA-associated neurodegeneration is more heterogeneous than previously assumed, including phenotypes distinct from a-synucleinopathies. Herein, we report on a patient with an unusual phenotype characterized by supranuclear vertical gaze palsy at onset with late emergence of postural instability carrier of the GBA E326K variant.

Genetic Paradoxes in an Italian Family with PARK2 Multiexon Duplication

Biallelic mutations in the PARK2 gene encoding Parkin are the commonest cause of autosomal recessive early-onset Parkinson disease (EOPD), with frequency inversely correlated with onset age and complete penetrance. Single heterozygous PARK2 mutations are occasionally detected in PD patients and in healthy subjects, and are considered minor susceptibility factors towards the risk of sporadic later-onset PD (1). We report on a 41-year-old male patient with EOPD (Figure 1A). Motor signs and symptoms started at 36 years with slowness and rigidity of the left upper limb. This article is protected by copyright. All rights reserved.