This study aimed to unravel the genetic factors underlying missing heritability in spinocerebellar ataxia type 17 (SCA17) caused by polyglutamine-encoding CAG/CAA repeat expansions in the TBP gene. ...Alleles with >49 CAG/CAA repeats are fully penetrant. Most patients, however, carry intermediate TBP41-49 alleles that show incomplete penetrance.
Using next-generation sequencing approaches, we investigated 40 SCA17/TBP41-54 index patients, their affected (n = 55) and unaffected (n = 51) relatives, and a cohort of patients with ataxia (n = 292).
All except 1 (30/31) of the index cases with TBP41-46 alleles carried a heterozygous pathogenic variant in the STUB1 gene associated with spinocerebellar ataxias SCAR16 (autosomal recessive) and SCA48 (autosomal dominant). No STUB1 variant was found in patients carrying TBP47-54 alleles. TBP41-46 expansions and STUB1 variants cosegregate in all affected family members, whereas the presence of either TBP41-46 expansions or STUB1 variants individually was never associated with the disease.
Our data reveal an unexpected genetic interaction between STUB1 and TBP in the pathogenesis of SCA17 and raise questions on the existence of SCA48 as a monogenic disease with crucial implications for diagnosis and counseling. They provide a convincing explanation for the incomplete penetrance of intermediate TBP alleles and demonstrate a dual inheritance pattern for SCA17, which is a monogenic dominant disorder for TBP≥47 alleles and a digenic TBP/STUB1 disease (SCA17-DI) for intermediate expansions.
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In Italy, rainfall represents the most common triggering factor for landslides; thus, many Italian Regional Departments of Civil Protection are setting up warning systems based on rainfall ...recordings. Common methods are mainly based on empirical relationships that provide the rainfall thresholds above which the occurrence of landslide phenomena is likely to be expected. In recent years, the use of machine learning approaches has gained popularity in landslide susceptibility analysis and prediction. To support the operational early warning system of Liguria Civil Protection Department for landslides hazard, we propose the implementation of a polynomial Kernel regularized least squares regression (KRLS) algorithm, for predicting the daily occurrence of shallow landslides in the five Alert Zones in Liguria (North Western Italy). The model provides an estimate of the number of landslides associated with the set of three different hydrological features, also used for the Hydrological Assessment procedure: the soil moisture, the accumulated precipitation over 12 h and the precipitation peak over 3 h. Results of the model are converted to an Alert Scenario of landslide occurrence, based on the magnitude of the expected event and identified according to the National and Regional legislation (Regional Civil Protection guidelines D.G.R. n. 1116, 23/12/2020). The performance of the predictive model (e.g. accuracy of 93%) is deemed satisfactory and the methodology is considered a valuable support to the operational early warning system of Liguria Civil Protection Department. The choice of predictive variables allows, in future development, the values obtained from historical data to be replaced by those obtained from meteorological forecast models, introducing the use of the developed model in the operational forecasting chain.
Introduction
Spastic paraplegia type 46 (SPG46) is a rare autosomal recessive hereditary spastic paraplegia, caused by mutations in the non-lysosomal glucosylceramidase β2 (GBA2) gene. Worldwide, ...approximately twenty SPG46 families have been identified so far.
Case report
We describe a compound heterozygous Italian patient carrying a novel (p.Arg879Gln) and a recurrent (p.Arg399 *)
GBA2
gene variant. The patient presented unsteady gait at age 2, and progressively manifested spastic-ataxia, scoliosis, mild intellectual decline, and bilateral cataract.
Discussion
Clinical manifestations associated with GBA2 gene variants encompass a spectrum of overlapping phenotypes including cerebellar ataxia, spastic paraplegia, and Marinesco-Sjogren-like syndrome. We review previously reported cases of SPG46 and discuss possible genetic differential diagnosis.
Autosomal dominant spinocerebellar ataxias (SCAs) are genetically heterogeneous neurological disorders characterized by cerebellar dysfunction mostly due to Purkinje cell degeneration. Here we show ...that AFG3L2 mutations cause SCA type 28. Along with paraplegin, which causes recessive spastic paraplegia, AFG3L2 is a component of the conserved m-AAA metalloprotease complex involved in the maintenance of the mitochondrial proteome. We identified heterozygous missense mutations in five unrelated SCA families and found that AFG3L2 is highly and selectively expressed in human cerebellar Purkinje cells. m-AAA-deficient yeast cells expressing human mutated AFG3L2 homocomplex show respiratory deficiency, proteolytic impairment and deficiency of respiratory chain complex IV. Structure homology modeling indicates that the mutations may affect AFG3L2 substrate handling. This work identifies AFG3L2 as a novel cause of dominant neurodegenerative disease and indicates a previously unknown role for this component of the mitochondrial protein quality control machinery in protecting the human cerebellum against neurodegeneration.
Background and purpose
Mutations in DNAJB2 are associated with autosomal recessive hereditary motor neuropathies/ Charcot‐Marie‐Tooth disease type 2 (CMT2). We describe an Italian family with CMT2 ...due to a homozygous DNAJB2 mutation and provide insight into the pathomechanisms.
Methods
Patients with DNAJB2 mutations were characterized clinically, electrophysiologically and by means of skin biopsy. mRNA and protein levels were studied in lymphoblastoid cells (LCLs) from patients and controls.
Results
Three affected siblings were found to carry a homozygous DNAJB2 null mutation segregating with the disease. The disease manifested in the second to third decade of life. Clinical examination showed severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles. Sensation was reduced in the lower limbs. All patients had severe hearing loss and the proband also had Parkinson’s disease (PD). Nerve conduction studies showed an axonal motor and sensory length‐dependent polyneuropathy. DNAJB2 expression studies revealed reduced mRNA levels and the absence of the protein in the homozygous subject in both LCLs and skin biopsy. Interestingly, we detected phospho‐alpha‐synuclein deposits in the proband, as already seen in PD patients, and demonstrated TDP‐43 accumulation in patients’ skin.
Conclusions
Our results broaden the clinical spectrum of DNAJB2‐related neuropathies and provide evidence that DNAJB2 mutations should be taken into account as another causative gene of CMT2 with hearing loss and parkinsonism. The mutation likely acts through a loss‐of‐function mechanism, leading to toxic protein aggregation such as TDP‐43. The associated parkinsonism resembles the classic PD form with the addition of abnormal accumulation of phospho‐alpha‐synuclein.
We report a family with Charcot‐Marie‐Tooth disease type 2 (CMT2), with hearing loss and parkinsonism, who harbor a novel homozygous DNAJB2 mutation, expanding the phenotype associated with the disease and providing new insights into its pathomechanism.
Earth Observation (EO) from satellites has the potential to provide comprehensive, rapid and inexpensive information about water bodies, integrating in situ measurements. Traditional methods to ...retrieve optically active water quality parameters from satellite data are based on semi-empirical models relying on few bands, which often revealed to be site and season specific. The use of machine learning (ML) for remotely sensed water quality estimation has spread in recent years thanks to the advances in algorithm development and computing power. These models allow to exploit the wealth of spectral information through more flexible relationships and are less affected by atmospheric and other background factors. The present study explores the use of Sentinel-2 MultiSpectral Instrument (MSI) Level-1C Top of Atmosphere spectral radiance to derive water turbidity, through application of machine learning techniques. A dataset of 222 combination of turbidity measurements, collected in the North Tyrrhenian Sea – Italy from 2015 to 2021, and values of the 13 spectral bands in the pixel corresponding to the sample location was used. Two regression techniques were tested and compared: a Stepwise Linear Regression (SLR) and a Polynomial Kernel Regression. The two models show accurate and similar performance (R2 = 0.736, RMSE = 2.03 NTU, MAE = 1.39 NTU for the SLR and R2 = 0.725, RMSE = 2.07 NTU, MAE = 1.40 NTU for the Kernel). A band importance analysis revealed the contribution of the different spectral bands and the main role of the red-edge range. The work shows that it is possible to reach a good accuracy in turbidity estimation from MSI TOA reflectance using ML models, fed by the whole spectrum of available bands, although the possible generation of errors related to atmospheric effect in turbidity estimates was not evaluated. Comparison between turbidity estimates obtained from the models with turbidity data from Copernicus CMEMS dataset named ‘Mediterranean Sea, Bio-Geo-Chemical, L3, daily observation’ produced consistent results. Finally, turbidity maps from satellite imagery were produced for the study area, showing the ability of the models to catch extreme events.
•Machine Learning algorithms were used to predict turbidity from Sentinel-2 data.•Stepwise Linear Regression and a Kernel model were applied and results compared.•Atmospheric correction can be avoided when using machine learning algorithms.•Full turbidity maps were produced in the North Tyrrhenian Sea using the two models.
Inherited peripheral neuropathies (IPNs) represent a broad group of genetically and clinically heterogeneous disorders, including axonal Charcot-Marie-Tooth type 2 (CMT2) and hereditary motor ...neuropathy (HMN). Approximately 60%-70% of cases with HMN/CMT2 still remain without a genetic diagnosis. Interestingly, mutations in HMN/CMT2 genes may also be responsible for motor neuron disorders or other neuromuscular diseases, suggesting a broad phenotypic spectrum of clinically and genetically related conditions. Thus, it is of paramount importance to identify novel causative variants in HMN/CMT2 patients to better predict clinical outcome and progression.
We designed a collaborative study for the identification of variants responsible for HMN/CMT2. We collected 15 HMN/CMT2 families with evidence for autosomal recessive inheritance, who had tested negative for mutations in 94 known IPN genes, who underwent whole-exome sequencing (WES) analyses. Candidate genes identified by WES were sequenced in an additional cohort of 167 familial or sporadic HMN/CMT2 patients using next-generation sequencing (NGS) panel analysis.
Bioinformatic analyses led to the identification of novel or very rare variants in genes, which have not been previously associated with HMN/CMT2 (
,
,
and
); in genes previously associated with HMN/CMT2 but in combination with different clinical phenotypes (
and
), and in the
gene, which has been linked to HMN/CMT2 in only a few cases. These findings were further validated by Sanger sequencing, segregation analyses and functional studies.
These results demonstrate the broad spectrum of clinical phenotypes that can be associated with a specific disease gene, as well as the complexity of the pathogenesis of neuromuscular disorders.
Background and purpose
Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among ...undefined leukoencephalopathies in adulthood.
Methods
We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near‐normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy‐targeted next generation sequencing panel.
Results
We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the POLR3A (n = 2), POLR1C (n = 1), RARS1 (n = 1), and TUBB4A (n = 1) genes, which are typically associated with severe early‐onset HLDs, and in the GJA1 gene (n = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing PLP1 and a pathogenic GJC2 variant were found in two patients, both females, with early‐onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in PEX3 (n = 1) and PEX13 (n = 1) and potentially relevant variants of unknown significance in TBCD (n = 1), which are genes associated with severe, early‐onset diseases with central hypomyelination/dysmyelination.
Conclusions
A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease‐causing genes, including genes associated with severe early‐onset HLDs, and genes causing peroxisome biogenesis disorders.
A brain MRI pattern suggestive of hypomyelination can be the prominent feature of adult‐onset genetic conditions. Adult neurologists should be trained in recognizing this pattern, as its presence implies different diagnostic work‐up and prognosis. An inclusive genetic screening can allow diagnosis in almost half of cases.
•Different mutations of the HCN channels can predispose to the development of epilepsy.•HCN1 mutations account for the majority of patients, but also the alteration of HCN2 and HCN4 can have a role ...in epilepsy.•Several rare variants of unknown significance (VUS) are found in genes coding for HCN channels and accessory proteins.•It would be wise to include the genetic screening of HCN channels as a standard diagnostic tool for epilepsy.
The Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are highly expressed in the Central Nervous Systems, where they are responsible for the Ih current. Together with specific accessory proteins, these channels finely regulate neuronal excitability and discharge activity. In the last few years, a substantial body of evidence has been gathered showing that modifications of Ih can play an important role in the pathogenesis of epilepsy. However, the extent to which HCN dysfunction is spread among the epileptic population is still unknown. The aim of this work is to evaluate the impact of genetic mutations potentially affecting the HCN channels’ activity, using a NGS approach. We screened a large cohort of patients with epilepsy of unknown etiology for mutations in HCN1, HCN2 and HCN4 and in genes coding for accessory proteins (MiRP1, Filamin A, Caveolin-3, TRIP8b, Tamalin, S-SCAM and Mint2). We confirmed the presence of specific mutations of HCN genes affecting channel function and predisposing to the development of the disease. We also found several previously unreported additional genetic variants, whose contribution to the phenotype remains to be clarified. According to these results and data from literature, alteration of HCN1 channel function seems to play a major role in epilepsy, but also dysfunctional HCN2 and HCN4 channels can predispose to the development of the disease. Our findings suggest that inclusion of the genetic screening of HCN channels in diagnostic procedures of epileptic patients should be recommended. This would help pave the way for a better understanding of the role played by Ih dysfunction in the pathogenesis of epilepsy.
Resolving the genetic architecture of painful neuropathy will lead to better disease management strategies. We aimed to develop a reliable method to re-sequence multiple genes in a large cohort of ...painful neuropathy patients at low cost. In this study, we compared sensitivity, specificity, targeting efficiency, performance and cost effectiveness of Molecular Inversion Probes-Next generation sequencing (MIPs-NGS) and TruSeq® Custom Amplicon-Next generation sequencing (TSCA-NGS). Capture probes were designed to target nine sodium channel genes (SCN3A, SCN8A-SCN11A, and SCN1B-SCN4B). One hundred sixty-six patients with diabetic and idiopathic neuropathy were tested by both methods, 70 patients were validated by Sanger sequencing. Sensitivity, specificity and performance of both techniques were comparable, and in agreement with Sanger sequencing. The average targeted regions coverage for MIPs-NGS was 97.3% versus 93.9% for TSCA-NGS. MIPs-NGS has a more versatile assay design and is more flexible than TSCA-NGS. The cost of MIPs-NGS is >5 times cheaper than TSCA-NGS when 500 or more samples are tested. In conclusion, MIPs-NGS is a reliable, flexible, and relatively inexpensive method to detect genetic variations in a large cohort of patients. In our centers, MIPs-NGS is currently implemented as a routine diagnostic tool for screening of sodium channel genes in painful neuropathy patients.
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