Toward a new nosology of neurodegenerative diseases
New “omic” technologies are revealing shared and distinct biological pathways within and across neurodegenerative diseases (NDDs), allowing a better understanding of endophenotypes that exceeds the boundaries of the current diagnostic criteria. Moreover, a diagnostic framework is needed that can accommodate the co-pathology and the clinical overlap and heterogeneity of NDDs. Apart from dissecting the reasons for a revolution in how we conceive NDD, this article aims to prompt a change in how we diagnose and classify NDD, drafting a general scheme for a new nosology. As identifying a cause is the key to using the term “disease” properly, we propose using a tridimensional classification based on three axes: (1) etiology or pathogenic mechanism, (2) pathology markers and molecular biomarkers, (3) anatomic–clinical; and three hierarchical levels of etiology: (1) genetic/sporadic (2) cellular pathways and processes, and function of fluidic brain systems, and (3) risk factors.
Reference: . Toward a new nosology of neurodegenerative diseases. Alzheimer's Dement. 2023; 1- 7. https://doi.org/10.1002/alz.13041
Intrathecal Pseudodelivery of Drugs in the Therapy of Neurodegenerative Diseases: Rationale, Basis and Potential Applications
Intrathecal pseudodelivery is a specialized drug delivery method where the therapeutic agent is introduced into a reservoir connected to the intrathecal space rather than being directly released into the cerebrospinal fluid (CSF). In this approach, the drug remains within the reservoir, where it interacts with its target, thus altering the composition of the CSF without systemic release of the drug into the body.
Key Points:
- Localized Interaction: The drug interacts with its target within the reservoir, potentially allowing for more controlled and localized treatment effects.
- Minimal Systemic Exposure: By confining the drug to the reservoir and avoiding its release into the broader CSF, this method can reduce systemic side effects and toxicity.
- Enhanced Efficacy: It aims to maximize the efficacy of the drug by ensuring it is delivered precisely where needed while avoiding dispersion throughout the central nervous system (CNS) that might dilute its effectiveness.
Overall, intrathecal pseudodelivery can be advantageous in achieving targeted drug effects within the CNS while minimizing unintended systemic impacts.
Intrathecal pseudodelivery of drugs is a novel route to administer medications to treat neurodegenerative diseases based on the CSF-sink therapeutic strategy by means of implantable devices. While the development of this therapy is still in the preclinical stage, it offers promising advantages over traditional routes of drug delivery. In this paper, we describe the rationale of this system and provide a technical report on the mechanism of action, that relies on the use of nanoporous membranes enabling selective molecular permeability. On one side, the membranes do not permit the crossing of certain drugs; whereas, on the other side, they permit the crossing of target molecules present in the CSF. Target molecules, by binding drugs inside the system, are retained or cleaved and subsequently eliminated from the central nervous system. Finally, we provide a list of potential indications, the respective molecular targets, and the proposed therapeutic agents.
Reference: Manuel, M.-G.; Tamba, B.-I.; Leclere, M.; Mabrouk, M.; Schreiner, T.-G.; Ciobanu, R.; Cristina, T.-Z. Intrathecal Pseudodelivery of Drugs in the Therapy of Neurodegenerative Diseases: Rationale, Basis and Potential Applications. Pharmaceutics 2023, 15, 768. https://doi.org/10.3390/pharmaceutics15030768
A variant in GRN of Spanish origin presenting with heterogeneous phenotypes
A. Marked depletion of motor neurons from the anterior horn of the spinal cord (H&E). B. Motor neuron filiform cytoplasmic inclusion is revealed by anti-TDP-43 in the spinal cord (black arrow). Other remaining motor neurons show loss of normal nuclear staining (red arrows). C. Many cortical neuronal small para nuclear inclusions are detected with antibodies to TDP-43 (black arrows). Short cortical dystrophic neurites are observed with anti-TDP-43 (black arrowheads) Loss of normal nuclear staining of TDP-43 is noted (red arrows). D. Some hippocampal neuronal cytoplasmic inclusions in dentate granule cells are displayed (black arrows). Loss of normal nuclear staining of TDP-43 is noted (red arrow). Magnification x400.
Introduction
The variant c.1414-1G > T in theGRN gene has been previously reported as probably pathogenic in subjects of Hispanic origin in the American continent.
Methods
We report five families of Spanish origin carrying this variant, including the clinical, neuroimaging, and laboratory findings.
Results
Phenotypes were strikingly different, including cases presenting with behavioral variant of frontotemporal dementia, with semantic variant of primary progressive aphasia, with rapidly progressive motor neuron disease (pathologically documented), and with tremor-dominant parkinsonism. Retinal degeneration has been found in homozygous carriers only. Ex vivo splicing assays confirmed that the mutation c.1414-1G > T affects the splicing of the exon, causing a loss of 20 amino acids in exon 11.
Conclusions
We conclude that variant c.1414-1G > Tn the GRN gene is pathogenic, can lead to a variety of clinical presentations and to gene dosage effect, and probably has a Spanish founder effect.
Full text: https://doi.org/10.1016/j.nrleng.2022.10.001
New, Fully Implantable Device for Selective Clearance of CSF-Target Molecules: Proof of Concept in a Murine Model of Alzheimer’s Disease
Intermediate and Expanded HTT Alleles and the Risk for α-Synucleinopathies
Background
Previous studies suggest a link between CAG repeat number in the HTT gene and non-Huntington neurodegenerative diseases.
Objective
The aim is to analyze whether expanded HTT CAG alleles and/or their size are associated with the risk for developing α-synucleinopathies or their behavior as modulators of the phenotype.
Methods
We genotyped the HTT gene CAG repeat number and APOE-Ɛ isoforms in a case-control series including patients with either clinical or neuropathological diagnosis of α-synucleinopathy.
Results
We identified three Parkinson's disease (PD) patients (0.30%) and two healthy controls (0.19%) carrying low-penetrance HTT repeat expansions whereas none of the dementia with Lewy bodies (DLB) or multisystem atrophy (MSA) patients carried pathogenic HTT expansions. In addition, a clear increase in the number of HTT CAG repeats was found among DLB and PD groups influenced by the male gender and also by the APOE4 allele among DLB patients. HTT intermediate alleles' (IAs) distribution frequency increased in the MSA group compared with controls (8.8% vs. 3.9%, respectively). These differences were indeed statistically significant in the MSA group with neuropathological confirmation. Two MSA HTT CAG IAs carriers with 32 HTT CAG repeats showed isolated polyQ inclusions in pons and basal nuclei, which are two critical structures in the neurodegeneration of MSA.
Conclusions
Our results point to a link between HTT CAG number, HTT IAs, and expanded HTT CAG repeats with other non-HD brain pathology and support the hypothesis that they can share common neurodegenerative pathways.
Reference: Pérez-Oliveira, S., Álvarez, I., Rosas, I., Menendez-González, M., Blázquez-Estrada, M., Aguilar, M., Corte, D., Buongiorno, M., Molina-Porcel, L., Aldecoa, I., Martí, M.J., Sánchez-Juan, P., Infante, J., González-Aramburu, I., García-González, P., Rosende-Roca, M., Boada, M., Ruiz, A., Periñán, M.T., Macías-García, D., Muñoz-Delgado, L., Gómez-Garre, P., Mir, P., Clarimón, J., Lleo, A., Alcolea, D., De la Casa-Fages, B., Duarte, I., Álvarez, V. and Pastor, P. (2022), Intermediate and Expanded HTT Alleles and the Risk for α-Synucleinopathies. Mov Disord. https://doi.org/10.1002/mds.29153
The “Cerebrospinal Fluid Sink Therapeutic Strategy” in Alzheimer’s Disease—From Theory to Design of Applied Systems
Alzheimer’s disease (AD) is a global health problem, with incidence and prevalence considered to increase during the next decades. However, no currently available effective treatment exists despite numerous clinical trials in progress. Moreover, although many hypotheses are accepted regarding the pathophysiological mechanisms of AD onset and evolution, there are still many unknowns about the disorder. A relatively new approach, based on the amyloid-beta dynamics among different biological compartments, is currently intensely discussed, as it seems to offer a promising solution with significant therapeutic impact. Known as the “cerebrospinal-fluid-sink therapeutic strategy”, part of the “three-sink therapeutic strategy”, this theoretical model focuses on the dynamics of amyloid-beta among the three main liquid compartments of the human body, namely blood, cerebrospinal fluid, and the (brain) interstitial fluid. In this context, this article aims to describe in detail the abovementioned hypothesis, by reviewing in the first part the most relevant anatomical and physiological aspects of amyloid-beta dynamics. Subsequently, explored therapeutic strategies based on the clearance of amyloid-beta from the cerebrospinal fluid level are presented, additionally highlighting their limitations. Finally, the originality and novelty of this work rely on the research experience of the authors, who focus on implantable devices and their utility in AD treatment.
Full text: https://www.mdpi.com/2227-9059
Smoking is associated with age at disease onset in Parkinson's disease
Background
Previous studies linked disease-progression variables such as age at onset or survival to both genetic, and non-genetic factors in Parkinson's disease (PD) patients.
Objective
The aim of this study was to assess how genetic and non genetic factors act as modifiers of age at onset and survival and in a cohort of 753 PD patients, and to determine how these variables interact to define the overall risk.
Methods
We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic, gPD or idiopathic, iPD) and three genetic variants rs5848- GRN, rs1042522- TP53 and APOE. We studied two cohorts (PPMI and IPDGC) to replicate positive results.
Results
Regarding age at onset, male smokers PD had a significantly lower mean age compared to non-smoker (p = 0.001). APOE-Ɛ4 carriers had a younger onset-age compared to non-carriers (p = 0.03) in the Spanish cohort, but these results were not replicated in the other cohorts. Concerning survival, PD patients with an early onset (below 50 years) had an increased survival rate (p < 0.001).
Conclusions
Our study showed how several genetic and non-genetic risk factors influenced the age at onset and survival in PD.
Previous studies linked disease-progression variables such as age at onset or survival to both genetic, and non-genetic factors in Parkinson's disease (PD) patients.
Objective
The aim of this study was to assess how genetic and non genetic factors act as modifiers of age at onset and survival and in a cohort of 753 PD patients, and to determine how these variables interact to define the overall risk.
Methods
We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic, gPD or idiopathic, iPD) and three genetic variants rs5848- GRN, rs1042522- TP53 and APOE. We studied two cohorts (PPMI and IPDGC) to replicate positive results.
Results
Regarding age at onset, male smokers PD had a significantly lower mean age compared to non-smoker (p = 0.001). APOE-Ɛ4 carriers had a younger onset-age compared to non-carriers (p = 0.03) in the Spanish cohort, but these results were not replicated in the other cohorts. Concerning survival, PD patients with an early onset (below 50 years) had an increased survival rate (p < 0.001).
Conclusions
Our study showed how several genetic and non-genetic risk factors influenced the age at onset and survival in PD.
Reference: https://doi.org/10.1016/j.parkreldis.2022.03.005
Cancer in Parkinson Disease: an approximation to the main risk factors
Background: Many evidences suggest a pathological link between neurodegenerative diseases and cancer. In fact, several epidemiologic studies indicate a a decreased incidence of most cancer types in Parkinson's disease (PD) patients and some PD genes are involved in cancer networks. Objective : The aim of this study is to assess the influence of several factors in the risk of cancer in a cohort of 753 PD patients and to study how these variables interact with each other. Methods: We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic (gPD) or idiopathic PD (iPD)) and two genetic variants, previouly associated with cancer, rs5848- GRN, rs1042522- TP53. Results: A higher age at PD onset was observed in patients that develop cancer before PD (p<0.001). Alcohol consumption was a risk factor to develop cancer in PD patients (p=0.011) while smoking was not a cancer risk factor in our cohort(p=0.098). Among the genetic factors, the genotype TT GRN-rs5848 was statistically more frequent in PD patients without cancer (p=0.05). Conclusions: Our study identified several factors, genetic and non-genetic, which contribute to the risk for cancer in PD.
Impact of Depression and Anxiety on Dimensions of Health-Related Quality of Life in Subjects with Parkinson’s Disease Enrolled in an Association of Patients
Parkinson’s disease (PD) is a complex disorder characterized by a wide spectrum of symptoms. Depression and anxiety are common manifestations in PD and may be determinants of health-related quality of life (HRQoL). The objective of this study is to determine the association of depression and anxiety with the dimensions of HRQoL in subjects with PD enrolled in an association of patients. Ninety-five community-based patients with PD diagnosis at different disease stages were studied. HRQoL was assessed using the Parkinson’s Disease Questionnaire (PDQ-39); depression and anxiety were assessed using the Beck Depression Inventory (BDI-II) and the State-Trait Anxiety Inventory (STAI), respectively. Our results showed that depression and anxiety were negatively associated with HRQoL measured by PDSI. Higher motor dysfunction measured by Hoehn and Yahr (H&Y) staging was also associated with worse HRQoL. Depression was the most influential variable in the model. All PDQ-39 dimensions except social support and bodily discomfort were associated with depression. Anxiety was associated with the emotional well-being and bodily discomfort dimensions. These results suggest that physicians should pay attention to the presence of psychiatric symptoms and treat them appropriately.
A series of cases with Huntington-like phenotype and intermediate repeats in HTT
Here we describe the larger series of clinical cases (n = 14) with HD-like phenotype and IAs published to date. MRI and FDG-PET neuroimaging findings compatible with HD can be found in some patients with IA. Larger and more detailed series are needed to assess the pathogenic role of IAs in HTT gene.
Background
Intermediate Alleles (IAs) are expansions of CAG repeats in the HTT gene between 27 and 35 repeats which pathogenic meaning remains controversial. They are present in the general population but there is an increasing number of cases with Huntington-like phenotype reported.
Methods
We reviewed the medical records of cases in our centre where the neurologist suspected Huntington's disease (HD) as one of the feasible diagnoses and genetic testing showed the number of CAG repeats was in the “intermediate range”. We gathered the type of symptoms in all cases and the main neuroimaging findings when available.
Results
We found 14 cases, 8 males and 6 females, with average age at onset at 64 years old. Most cases exhibited some type of extrapyramidal symptoms. Cognitive and/or behavioral symptoms were also present in most cases (being depression, anxiety and cognitive impairment the most frequent ones). In one case we found deposits of iron in the basal ganglia in the MRI, and in another case we found diffuse cortical hypometabolism with predominantly frontal bilateral involvement and bilateral focal deficit of both caudate and thalamus in the FDG-PET.
Conclusion
The clinical and neuroimaging findings of some cases with IA in this series are compatible with the clinical picture of HD but also with several other alternative diagnoses. Therefore we can not establish association between IA and HD. Larger series with more comprehensive diagnostic workout and neuropathological studies are needed to confirm or rule out whether IAs in the HTT gene may cause HD.
Patients with Parkinson’s Disease Show Alteration in their Visuospatial Abilities and in their Egocentric and Allocentric Spatial Orientation Measured by Card Placing Tests
Background: Visuospatial skills are impaired in Parkinson's disease (PD). Other related skills exist, such as spatial orientation have been poorly studied. The egocentric (based on internal cues) and allocentric frameworks (based on external cues) are used in daily spatial orientation. Depending on PD onset, the allocentric framework may have a higher level of impairment in tremor-dominant and the egocentric one in akinetic-rigid.
Objective: To evaluate spatial orientation and visuospatial functions in PD patients and controls, and to assess whether their performance is related to disease duration and the PD subtype (tremor-dominant and akinetic-rigid).
Methods: We evaluated egocentric and allocentric spatial orientation (Egocentric and Allocentric Spatial Memory Tasks) and visuospatial abilities, span and working memory in 59 PD patients and 51 healthy controls.
Results: Visuospatial skills, visuospatial span, and egocentric and allocentric orientation are affected in PD. Visuospatial skills and allocentric orientation undergo deterioration during the first 5 years of the disease progression, while egocentric orientation and visuospatial span do so at later stages (9-11 years). The akinetic-rigid subtype presents worse results in all the spatial abilities that were measured when compared to controls, and worse scores in visuospatial working memory, visuospatial abilities and allocentric orientation when compared to the tremor-dominant group. The tremor-dominant group performed worse than controls in egocentric and allocentric orientation.
Conclusion: PD patients show deficits in their visuospatial abilities and in their egocentric and allocentric spatial orientation compared to controls, specifically in akinetic-rigid PD. Only spatial orientation are affected in tremor-dominant PD patients. Allocentric orientation is affected earlier in the progression of the disease.
Reference: Fernandez-Baizan C, Paula Fernandez Garcia M, Diaz-Caceres E, Menendez-Gonzalez M, Arias JL, Mendez M. Patients with Parkinson's Disease Show Alteration in their Visuospatial Abilities and in their Egocentric and Allocentric Spatial Orientation Measured by Card Placing Tests. J Parkinsons Dis. 2020;10(4):1807-1816. doi: 10.3233/JPD-202122
Genetic variation in APOE, GRN and TP53 are phenotype modifiers in frontotemporal dementia
Frontotemporal dementia (FTD) is a clinical, genetic and pathological heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 frontotemporal dementia (FTD) patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p<0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (HR=4.12) and the PNFA group showed the highest onset-age (p=0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p=0.02) and survival (HR= 1.73) and rs5848 GRN with a significant shorter survival in CC homozygous patients (HR= 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 non carriers (p=0.022). Although validation of our findings is necessary, our results suggest that TP53,GRN and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials (full text).
A role for ATXN1, ATXN2 and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease
We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2 and HTT genes in several neurodegenerative diseases.
The study included 1,126 Alzheimer disease (AD), 440 frontotemporal dementia (FTD) and 610 Parkinson's disease (PD) patients. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. Additionally, in the FTD cohort we determined the number of HTT CAG-repeats.
The frequency of HTT IAs was higher in FTD patients (6.9%) vs controls (2.9%) and in the C9orf72 expansion non carriers (7.2%) vs. controls (2.9%), although the difference was non-significant after correction for multiple testing. Compared to controls, progressive non-fluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs ( 13.6% vs 2.9% controls). For the ATXN2 gene, we observed an IAs increased frequency in AD cases (AD 4.1% vs controls 1.8%) and in the behavioural FTD (bvFTD) group (4.8% vs 1.8%). For the ATXN1 gene we found a significant increase of IAs in PNFA patients (18.6%) vs controls (6.7%).
In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD.
Reference: https://doi.org/10.1016/j.neurobiolaging.2019.10.017
The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population‐Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight
Background
The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.
Objectives
To perform the largest PD genome‐wide association study restricted to a single country.
Methods
We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population‐specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease‐associated loci, heritability estimates, genetic correlations, and burden analyses.
Results
We identified a novel population‐specific genome‐wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome‐wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA‐DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non‐Spanish origin. Seventeen PD‐related genes showed functional consequence by two‐sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.
Conclusions
Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine‐mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain.
Albumin Exchange in Alzheimer's Disease: Might CSF Be an Alternative Route to Plasma?
Amyloid β (Aβ) in brain parenchyma is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). Aβ is transported from the brain to the plasma via complex transport mechanisms at the blood-brain barrier (BBB). About 90–95% of plasma Aβ may be bound to albumin. Replacement of serum albumin in plasma has been proposed as a promising therapy for AD. However, the efficacy of this approach may be compromised by altered BBB Aβ receptors in AD, as well as multiple pools of Aβ from other organs in exchange with plasma Aβ, competing for albumin binding sites. The flow of interstitial fluid (ISF) into cerebrospinal fluid (CSF) is another major route of Aβ clearance. Though the concentration of albumin in CSF is much lower than in plasma, the mixing of CSF with ISF is not impeded by a highly selective barrier and, hence, Aβ in the two pools is in more direct exchange. Furthermore, unlike in plasma, Aβ in CSF is not in direct exchange with multiple organ sources of Aβ. Here we consider albumin replacement in CSF as an alternative method for therapeutic brain Aβ removal and describe the possible advantages and rationale supporting this hypothesis.
Reference: Front. Neurol., 18 October 2019 | https://doi.org/10.3389/fneur.2019.01036
Prevalence of Depression and Anxiety in Parkinson Disease and Impact on Quality of Life: A Community-Based Study in Spain
Background:
Identifying neuropsychiatric disorders is essential for prompt treatment to reduce morbidity. Among these disorders, anxiety and depression have been frequently associated with Parkinson disease (PD), particularly among elderly population.
Objective:
The objective of this study is to determine the prevalence of anxiety and depression in a series of community-based PD cases in Spain, their relationship with different clinical and sociodemographic characteristics, and quality of life.
Methods:
This is an observational, descriptive, survey-based study with 95 community-based patients with PD diagnosis at different disease stages. Anxiety and depression were assessed using the State-Trait Anxiety Inventory and the Beck Depression Inventory II, respectively. Quality of life was assessed using the Parkinson’s Disease Questionnaire 39.
Results:
The prevalence of depression and anxiety was 32.63% and 68.42%, respectively. Concomitant depression and anxiety were observed in 31.58% of patients. Patients with longer than 10 years’ PD duration had an increased risk of depression. We found a relationship between the presence of anxiety, depression, and the patient’s quality of life.
Conclusions:
Depression is present in one-third and anxiety in two-thirds of PD cases in community settings in Spain. Depression and anxiety have a very negative impact on quality of life in PD. Both anxiety and depression are independent from sociodemographic characteristics, patient’s comorbidities, or antiparkinsonian treatments; presenting as intrinsic symptoms in PD.
Full text https://doi.org/10.1177/0891988719874130
Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders
Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype–phenotype correlations.
Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene.
Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29*), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern.
Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype–phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype–phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome.
Reference: Journal of Translational Medicine volume 17, Article number: 290 (2019) Full text
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