Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the farnesoid X receptor (FXR). TUDCA was predicted to bind to the GR, in a similar fashion to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction being restored by TUDCA treatment. Analysis of a SCA3 clinical cohort showed intriguing correlations between the peripheral expression of GR and the predicted age at disease onset in presymptomatic subjects and FKBP5 expression with disease progression, suggesting this pathway as a potential source of biomarkers for future study. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3 and propose this readily available drug for clinical trials in SCA3 patients.

Diagnostic accuracy and the first genotype-phenotype correlation in glycogen storage disease type V.

BACKGROUND: Glycogen storage disease type V (GSDV) is an autosomal recessive metabolic condition caused by pathogenic PYGM variants. This is an underdiagnosed condition as it presents with exercise intolerance in children. We reviewed the GSDV cases of a tertiary hospital center to assess diagnostic timing/accuracy, as well as potential clinical/analytical predictors of such factors. METHODS: We retrospectively reviewed all GSDV cases with follow-up in both Pediatric and Adult Metabolic Diseases consultations. We included 28 cases and assessed their hospital record for clinical information. RESULTS: Over 90% of our cases had late diagnoses, with more than 50% being diagnosed in adulthood despite symptom onset in preschool (very late diagnosis). Diagnostic age was lower in patients exhibiting myoglobinuria. Interestingly, patients with a positive family history of GSDV had similar rates of very late diagnoses, likely since the index case was already detected very late in life. Finally, we observe that the R50* variant is associated with increased myoglobinuria and CK elevation, in a dosage-dependent manner. CONCLUSION: We concluded that GSDV is severely underdiagnosed, and that some clinical and analytical aspects of the condition can be more indicative of this diagnosis. Furthermore, we propose for the first time a genotype-phenotype correlation in GSDV. IMPACT: GSDV is a pediatric-onset metabolic disorder that is mostly diagnosed late in the adult age and commonly misdiagnosed. We observed the first genotype-phenotype correlation in GSDV, regarding the common R50* variant. Awareness of GSDV for pediatricians and the overall medical community is vital.

Impact of Structural GLA Protein Changes on Peripheral GLA Activity and Substrate Accumulation in Fabry Disease Patients.

INTRODUCTION: Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, leading to decreased/absent α-galactosidase activity. In clinical practice, enzyme activity and substrate/byproduct accumulation play a role in diagnosis and disease-monitoring biomarkers. However, interpreting biomarker levels is not straightforward and can change according to the underlying GLA protein abnormality. OBJECTIVE: Our goals were to understand how disrupting specific protein regions changes biomarker behaviour and to establish specific patterns for individual variants. METHODOLOGY: We analysed data from the Biochemical Genetics Laboratory regarding GLA variants, GLA enzyme activity (in dried blood spots, plasma or white blood cells), plasma LysoGb3 accumulation, and urinary Gb3 excretion. We assessed correlations, trends, and potential predictor models of biomarker behaviour. RESULTS: We assessed 169 hemizygous male and 255 heterozygous female patients. For both groups, substrate accumulation correlates inversely with GLA activity. Variants affecting residues buried within the protein core or the active site were associated with more severe biomarker changes, while those affecting residues that establish disulfide bonds or are glycosylated were similar to other variants. For each non-truncating variant, we also established specific profiles of biomarker behaviour. Finally, we also designed predictor models of biomarker behaviour based on structural variant information. This study provides the groundwork for the impact of GLA protein variation on GLA activity and substrate accumulation. CONCLUSION: This knowledge is of extreme relevance for diagnostic labs and clinicians, as some genetic variants are challenging to interpret regarding pathogenicity. Assessing whether biomarker changes are in the expected range for a specific variant may help diagnostic evaluation. This study also contributes to recognising non-disease-causing variants, considering their overall biochemical impact, and providing a comparative reference for biomarker discovery studies. In the future, the correlation of these findings with disease severity may be of great relevance for diagnosis and monitoring progression.

An SPG7 mutation as a novel cause of monogenic progressive muscular atrophy.

BACKGROUND: Progressive muscular atrophy (PMA) is a rare adult-onset neurological disease that is characterized by isolated lower motor neuron degeneration. While it is still disputable whether PMA is a subtype of amyotrophic lateral sclerosis (ALS) or an isolated disorder, it is well-established as a clinically defined entity. About 5% of PMA cases are monogenic, and the implicated genes largely overlap with those causing monogenic ALS. CASE DESCRIPTION: Here we describe a 68-year-old female patient with progressive and asymmetric upper-limb weakness throughout an 18-month period, with muscle atrophy, dysphagia and slurring of speech. The lower limbs were unaffected, and there was no sign of upper motor neuron dysfunction. Comprehensive genetic testing for single nucleotide and copy-number variants revealed a pathogenic monoallelic variant c.1529C>T, p.(Ala510Val) in the SPG7 gene. DISCUSSION: Pathogenic biallelic SPG7 variants have been originally associated with hereditary spastic paraplegia, but other phenotypes are nowadays known to be linked to these variants, such as ALS. However, there is no report of this (or any) other SPG7 variant in association with PMA, whether it progressed to ALS or not. In conclusion, we present the first known case of PMA associated with a monoallelic SPG7 mutation.

Telehealth in genetic counselling consultations: the impact of COVID-19 in a Portuguese genetic healthcare service.

The already increasing use of telemedicine in the last few years has risen significantly after the onset of the COVID-19 pandemic. With a fast implementation, it is important to understand the experience of genetic counselling patients using telehealth. To this end, we developed a study to understand the impact of the pandemic on genetics consultations, using a mixed-method approach through a questionnaire to collect the patients' opinions. The largest group included in the study was 26-45 years old (65%), and 33.6% had completed year 12 of secondary education. Due to the impact of the pandemic, we observed an increase of 84.5% in teleconsultations. The participants' satisfaction was quite significant, 67.3% felt comfortable discussing personal and family health, 53.6% were well-enlightened, and 59.1% did not find it difficult to build a doctor-patient relationship. However, 64.5% of our participants indicated using the service only for subsequent consultations but supported the idea of continuing with telemedicine in the future. Undoubtedly, this service is essential for better quality and healthcare support. The professionals involved must be increasingly trained to provide adequate genetic counselling and comfort to the patient. Training automatically influences the improvement of the service regarding the barriers encountered and consequently provides a better experience and satisfaction to the patient and their families.

Refining the Clinical Spectrum of the 17p13.3 Microduplication Syndrome: Case-Report of a Familial Small Microduplication.

The chromosomal region 17p13.3 contains extensive repetitive sequences and is a well-recognized region of genomic instability. The 17p13.3 microduplication syndrome has been associated with a clinical spectrum of moderately non-specific phenotypes, including global developmental delay/intellectual disability, behavioral disorders, autism spectrum disorder and variable dysmorphic features. Depending on the genes involved in the microduplication, it can be categorized in two subtypes with different phenotypes. Here, we report a case of a 7-year-old boy with global developmental delay, speech impairment, hypotonia, behavioral conditions (ADHD and ODD), non-specific dysmorphic features and overgrowth. Genetic testing revealed a small 17p13.3 chromosomal duplication, which included the BHLHA9, CRK and YWHAE genes. Additionally, we observed that this was maternally inherited, and that the mother presented with a milder phenotype including mild learning disabilities, speech impairment and non-specific dysmorphic features, which did not significantly affect her. In conclusion, we present a clinical case of a 17p13.3 duplication that further delineates the clinical spectrum of this syndrome, including its intrafamilial/intergenerational variability.

Aripiprazole Offsets Mutant ATXN3-Induced Motor Dysfunction by Targeting Dopamine D2 and Serotonin 1A and 2A Receptors in C. elegans.

The atypical antipsychotic aripiprazole is a Food and Drug Administration-approved drug for the treatment of psychotic, mood, and other psychiatric disorders. Previous drug discovery efforts pinpointed aripiprazole as an effective suppressor of Machado-Joseph disease (MJD) pathogenesis, as its administration resulted in a reduced abundance and aggregation of mutant Ataxin-3 (ATXN3) proteins. Dopamine partial agonism and functional selectivity have been proposed as the main pharmacological mechanism of action of aripiprazole in the treatment of psychosis; however, this mechanism remains to be determined in the context of MJD. Here, we focus on confirming the efficacy of aripiprazole to reduce motor dysfunction in vivo, using a Caenorhabditis elegans (C. elegans) model of MJD, and on unveiling the drug targets required for its positive action against mutant ATXN3 pathogenesis. We employed pharmacogenetics and pharmacological approaches to identify which dopamine and serotonin receptors are critical for aripiprazole-mediated improvements in motor function. We demonstrated that dopamine D2-like and serotonin 5-HT1A and 5-HT2A receptors play important roles in this process. Our findings strengthen the relevance of dopaminergic and serotoninergic signaling modulation against mutant ATXN3-mediated pathogenesis. The identification of aripiprazole's cellular targets, relevant for MJD and perhaps other neurodegenerative diseases, may pave the way for prospective drug discovery and development campaigns aiming to improve the features of this prototypical compound and reduce side effects not negligible in the case of aripiprazole.

A Novel Frameshift CHD4 Variant Leading to Sifrim-Hitz-Weiss Syndrome in a Proband with a Subclinical Familial t(17;19) and a Large dup(2)(q14.3q21.1).

The genetic complexity of neurodevelopmental disorders (NDD), combined with a heterogeneous clinical presentation, makes accurate assessment of their molecular bases and pathogenic mechanisms challenging. Our purpose is to reveal the pathogenic variant underlying a complex NDD through identification of the "full" spectrum of structural genomic and genetic variants. Therefore, clinical phenotyping and identification of variants by genome and exome sequencing, together with comprehensive assessment of these and affected candidate genes, were carried out. A maternally-inherited familial translocation [t(17;19)(p13.1;p13.3)mat] disrupting the GSG1 like 2 gene (GSG1L2), a 3.2 Mb dup(2)(q14.3q21.1) encompassing the autosomal dominant OMIM phenotype-associated PROC and HS6ST1 gene, and a novel frameshift c.4442del, p.(Gly1481Valfs*21) variant within exon 30 of the Chromodomain helicase DNA binding protein 4 (CHD4) have been identified. Considering the pathogenic potential of each variant and the proband's phenotype, we conclude that this case basically fits the Sifrim-Hitz-Weiss syndrome or CHD4-associated neurodevelopmental phenotype. Finally, our data highlight the need for identification of the "full" spectrum of structural genomic and genetic variants and of reverse comparative phenotyping, including unrelated patients with variants in same genes, for improved genomic healthcare of patients with NDD.

Case Report: A Novel GNB1 Mutation Causes Global Developmental Delay With Intellectual Disability and Behavioral Disorders.

Diseases of neurodevelopment mostly exhibit neurological and psychiatric symptoms that go from very mild to extremely severe. While the etiology of most cases of neurodevelopmental disease is still unknown, the discovery of underlying genetic causes is rapidly increasing, with hundreds of genes being currently implicated as disease-causing. Here, we report a clinical case of a patient with a previously undiagnosed syndrome comprising severe global developmental delay, intellectual disability, and behavioral disorders (such as attention-deficit/hyperactivity disorder, autism spectrum disorder and recurrent bouts of aggressive behavior). After genetic testing, a pathogenic variant was detected in the GNB1 gene, which codes for the G-protein subunit ß1. The detected variant (c.217G>A, p.A73T) has not been previously reported in any of the 58 published cases of GNB1 encephalopathy. However, it localizes to the mutational hotspot in exons 6 and 7 in which 88% of all missense mutations occur. An in silico model predicts that this mutation is likely to disrupt the WD40 domain of the GNB1 protein, which is required for its interaction with other G-proteins and, consequently, for downstream signal transduction. In conclusion, we reported an additional GNB1 encephalopathy patient, bearing a novel mutation, taking another step toward a better understanding of its clinical presentation and prospective development of treatments for the disease.

Loss of egli-1, the Caenorhabditis elegans Orthologue of a Downstream Target of SMN, Leads to Abnormalities in Sensorimotor Integration.

The connectome of Caenorhabditis elegans has been extensively studied and fully mapped, allowing researchers to more confidently conclude on the impact of any change in neuronal circuits based on behavioral data. One of the more complex sensorimotor circuits in nematodes is the one that regulates the integration of feeding status with the subsequent behavioral responses that allow animals to adapt to environmental conditions. Here, we have characterized a Caenorhabditis elegans knockout model of the egli-1 gene (previously known as tag-175). This is an orthologue of the stasimon/tmem41b gene, a downstream target of SMN, the depleted protein in spinal muscular atrophy (SMA), which partially recapitulates the SMA phenotype in fly and zebrafish models when mutated. Surprisingly, egli-1 mutants reveal no deficits in motor function. Instead, they show functional impairment of a specific neuronal circuit, leading to defects in the integration of sensorial information related to food abundance, with consequences at the level of locomotion adaptation, egg laying, and the response to aversive chemical stimuli. This work has demonstrated for the first time the relevance of egli-1 in the nervous system, as well as revealed a function for this gene, which had remained elusive so far.

From Pathogenesis to Novel Therapeutics for Spinocerebellar Ataxia Type 3: Evading Potholes on the Way to Translation.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a neurodegenerative disorder caused by a polyglutamine expansion in the ATXN3 gene. In spite of the identification of a clear monogenic cause 25 years ago, the pathological process still puzzles researchers, impairing prospects for an effective therapy. Here, we propose the disruption of protein homeostasis as the hub of SCA3 pathogenesis, being the molecular mechanisms and cellular pathways that are deregulated in SCA3 downstream consequences of the misfolding and aggregation of ATXN3. Moreover, we attempt to provide a realistic perspective on how the translational/clinical research in SCA3 should evolve. This was based on molecular findings, clinical and epidemiological characteristics, studies of proposed treatments in other conditions, and how that information is essential for their (re-)application in SCA3. This review thus aims i) to critically evaluate the current state of research on SCA3, from fundamental to translational and clinical perspectives; ii) to bring up the current key questions that remain unanswered in this disorder; and iii) to provide a frame on how those answers should be pursued.