Neurodegenerative Course Research Articles

Cognitive synaptopathy: synaptic and dendritic spine dysfunction in age-related cognitive disorders.

Cognitive impairment is a leading component of several neurodegenerative and neurodevelopmental diseases, profoundly impacting on the individual, the family, and society at large. Cognitive pathologies are driven by a multiplicity of factors, from genetic mutations and genetic risk factors, neurotransmitter-associated dysfunction, abnormal connectomics at the level of local neuronal circuits and broader brain networks, to environmental influences able to modulate some of the endogenous factors. Otherwise healthy older adults can be expected to experience some degree of mild cognitive impairment, some of which fall into the category of subjective cognitive deficits in clinical practice, while many neurodevelopmental and neurodegenerative diseases course with more profound alterations of cognition, particularly within the spectrum of the dementias. Our knowledge of the underlying neuropathological mechanisms at the root of this ample palette of clinical entities is far from complete. This review looks at current knowledge on synaptic modifications in the context of cognitive function along healthy ageing and cognitive dysfunction in disease, providing insight into differential diagnostic elements in the wide range of synapse alterations, from those associated with the mild cognitive changes of physiological senescence to the more profound abnormalities occurring at advanced clinical stages of dementia. I propose the term "cognitive synaptopathy" to encompass the wide spectrum of synaptic pathologies associated with higher brain function disorders.

Delineation of ADPRHL2 Variants: Report of Two New Patients with Review of the Literature.

ADPRHL2 is involved in posttranslational modification and is known to have a role in physiological functions such as cell signaling, DNA repair, gene control, cell death, and response to stress. Recently, a group of neurological disorders due to ADPRHL2 variants is described, characterized by childhood-onset, stress-induced variable movement disorders, neuropathy, seizures, and neurodegenerative course. We present the diagnostic pathway of two pediatric patients with episodic dystonia and ataxia, who later had a neurodegenerative course complicated by central hypoventilation syndrome due to the same homozygous ADPRHL2 variant. We conducted a systematic literature search and data extraction procedure following the Preferred Reporting Items for Systematic Review and Meta-Analysis 2020 statement in terms of patients with ADPRHL2 variants, from 2018 up to 3 February, 2023. In total, 12 articles describing 47 patients were included in the final analysis. Median age at symptom onset was 2 (0.7-25) years, with the most common presenting symptoms being gait problems (n = 19, 40.4%), seizures (n = 16, 34%), ataxia (n = 13, 27.6%), and weakness (n = 10, 21.2%). Triggering factors (28/47; 59.5%) and regression (28/43; 60.4%), axonal polyneuropathy (9/23; 39.1%), and cerebral and cerebellar atrophy with white matter changes (28/36; 77.7%) were the other clues. The fatality rate and median age of death were 44.6% (n = 21) and 7 (2-34) years, respectively. ADPRHL2 variants should be considered in the context of episodic, stress-induced pediatric and adult-onset movement disorders and seizures.

ASS1 deficiency is associated with impaired neuronal differentiation in zebrafish larvae

Citrullinemia type 1 (CTLN1) is a rare autosomal recessive urea cycle disorder caused by deficiency of the cytosolic enzyme argininosuccinate synthetase 1 (ASS1) due to pathogenic variants in the ASS1 gene located on chromosome 9q34.11. Even though hyperammenomia is considered the major pathomechanistic factor for neurological impairment and cognitive dysfunction, a relevant subset of individuals presents with a neurodegenerative course in the absence of hyperammonemic decompensations. Here we show, that ASS1 deficiency induced by antisense-mediated knockdown of the zebrafish ASS1 homologue is associated with defective neuronal differentiation ultimately causing neuronal cell loss and consecutively decreased brain size in zebrafish larvae in vivo. Whereas ASS1-deficient zebrafish larvae are characterized by markedly elevated concentrations of citrulline – the biochemical hallmark of CTLN1, accumulation of L-citrulline, hyperammonemia or therewith associated secondary metabolic alterations did not account for the observed phenotype. Intriguingly, coinjection of the human ASS1 mRNA not only normalized citrulline concentration but also reversed the morphological cerebral phenotype and restored brain size, confirming conserved functional properties of ASS1 across species. The results of the present study imply a novel, potentially non-enzymatic (moonlighting) function of the ASS1 protein in neurodevelopment.

B - 104 Late-Onset Multiple Sclerosis: a Neuropsychological Case Study.

A neuropsychological case study of Late-Onset Multiple Sclerosis (LOMS). Cognitive impairment often accompanies Multiple Sclerosis (MS). Depending on disease phase/type, 40-65% of MS patients develop various degrees of cognitive impairment. LOMS is a rare branch of Multiple Sclerosis with an onset of 50years or older. Like MS it has demyelinating qualities, however it typically has a neurodegenerative course rather than inflammatory properties. Additionally, unlike traditional MS, LOMS presents with greater motor and cognitive dysfunction. The patient, a 61-year-old, Caucasian, right-handed male, 18years of education initially presented with acute onset of vague cognitive changes along with significant motor dysfunction. A cerebral MRI revealed white matter disease in the cerebral hemispheres with the largest lesion adjacent to the right frontal horn. Lesions involved bifrontal/parietal lobes, specific lesion posteriorly in the left centrum and right caudate head. Patient was administered the Meyers Neuropsychological Battery (MNB). Findings were consistent with level one central processing deficits with attention/concentration and processing speed. Deficits were noted with primary and psychomotor abilities. Patient's premorbid estimate was T-58. Overall Test Battery Mean (T-52) and Domain Test Battery Mean (T-51) were generally within the expected range. Remaining neuropsychological abilities were relatively intact (e.g., memory, abstraction, language, spatial). Consistent with the literature, higher-order cognitive abilities were relatively intact. LOMS mirrored early-onset MS in this case. However, a significant risk factor for LOMS is the possibility of co-occurring neurodegenerative disease. This underscores the need for comprehensive neuropsychological assessment that includes motor testing for MS.

Life-Limiting Peripheral Organ Dysfunction in Feline Sandhoff Disease Emerges after Effective CNS Gene Therapy.

GM2 gangliosidosis is usually fatal by 5 years of age in its 2 major subtypes, Tay-Sachs and Sandhoff disease. First reported in 1881, GM2 gangliosidosis has no effective treatment today, and children succumb to the disease after a protracted neurodegenerative course and semi-vegetative state. This study seeks to further develop adeno-associated virus (AAV) gene therapy for human translation. Cats with Sandhoff disease were treated by intracranial injection of vectors expressing feline β-N-acetylhexosaminidase, the enzyme deficient in GM2 gangliosidosis. Hexosaminidase activity throughout the brain and spinal cord was above normal after treatment, with highest activities at the injection sites (thalamus and deep cerebellar nuclei). Ganglioside storage was reduced throughout the brain and spinal cord, with near complete clearance in many regions. While untreated cats with Sandhoff disease lived for 4.4 ± 0.6 months, AAV-treated cats lived to 19.1 ± 8.6 months, and 3 of 9 cats lived >21 months. Correction of the central nervous system was so effective that significant increases in lifespan led to the emergence of otherwise subclinical peripheral disease, including megacolon, enlarged stomach and urinary bladder, soft tissue spinal cord compression, and patellar luxation. Throughout the gastrointestinal tract, neurons of the myenteric and submucosal plexuses developed profound pathology, demonstrating that the enteric nervous system was inadequately treated. The vector formulation in the current study effectively treats neuropathology in feline Sandhoff disease, but whole-body targeting will be an important consideration in next-generation approaches. ANN NEUROL 2023;94:969-986.

Natural history of neuronopathic form of Hunter syndrome in children: observational cohort study

Introduction. Mucopolysaccharidosis type II (MPS II, Hunter syndrome) (mucopolysaccharidosis type II, MPS II) is a progressive multisystem disorder. Neurodegenerative course characterizes the severe (neuronopathic) form of MPS II. Pathogenetic therapy for the severe form of the disease is under development, and symptomatic neurological treatment is to be improved. Natural history data are required for rationalization of symptomatic care and assessment of emergent treatment effectiveness.
 The aim of the study. To describe the course of neurodegenerative disease in children with neuronopathic form of MPS II. 
 Materials and methods. Fifty eight boys with established diagnosis of MPS II were included in the study. The course of the disease in 42 patients was classified as neuronopathic. Data on complaints, anamnesis and neurological examination obtained from medical documentation and within the framework of this study, as well as descriptions of video-EEG monitorings, performed in National Medical Research Center of Children’s Health, were used.
 Results. The spectrum and chronology of neurological symptoms in children with severe Hunter syndrome were described. 64% of patients were found to achieve the level of phrasal speech at any time of the development. Laughter or crying paroxysms in children with neuronopathiс MPS II were judged to be a manifestation of pseudobulbar affect. Burden of sleep disorder was demonstrated to increase through the course of the disease. Absence of epileptic seizure was significantly more frequent than epilepsy manifestation during the first two years after epiactivity appears on EEG (75 vs 25%; p = 0.046).
 Conclusion. Obtained natural history descriptions of severe MPS II cases are intended to be used in optimization of neurological care for patients and in assessment of emergent treatments’ effectiveness in real clinical practice.

5-Methylcytosine and 5-Hydroxymethylcytosine in Scrapie-Infected Sheep and Mouse Brain Tissues.

Scrapie is a neurodegenerative disorder belonging to the group of transmissible spongiform encephalopathies or prion diseases, which are caused by an infectious isoform of the innocuous cellular prion protein (PrPC) known as PrPSc. DNA methylation, one of the most studied epigenetic mechanisms, is essential for the proper functioning of the central nervous system. Recent findings point to possible involvement of DNA methylation in the pathogenesis of prion diseases, but there is still a lack of knowledge about the behavior of this epigenetic mechanism in such neurodegenerative disorders. Here, we evaluated by immunohistochemistry the 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels in sheep and mouse brain tissues infected with scrapie. Expression analysis of different gene coding for epigenetic regulatory enzymes (DNMT1, DNMT3A, DNMT3B, HDAC1, HDAC2, TET1, and TET2) was also carried out. A decrease in 5mC levels was observed in scrapie-affected sheep and mice compared to healthy animals, whereas 5hmC displayed opposite patterns between the two models, demonstrating a decrease in 5hmC in scrapie-infected sheep and an increase in preclinical mice. 5mC correlated with prion-related lesions in mice and sheep, but 5hmC was associated with prion lesions only in sheep. Differences in the expression changes of epigenetic regulatory genes were found between both disease models, being differentially expressed Dnmt3b, Hdac1, and Tet1 in mice and HDAC2 in sheep. Our results support the evidence that DNA methylation in both forms, 5mC and 5hmC, and its associated epigenetic enzymes, take part in the neurodegenerative course of prion diseases.

Association Between Body Mass Index and Response to Disease-Modifying Therapies in Patients With Relapsing-Remitting Multiple Sclerosis at King Abdulaziz University Hospital: A Retrospective Study.

Background Multiple sclerosis (MS) is an immune-mediated inflammatory disease that attacks myelinated axons in the central nervous system, destroying the myelin and axon to varying degrees and producing significant physical disability. So far, many studies have found that having a high body mass index (BMI) is associated with severe autoimmune and neurodegenerative disease course. However, the impact of BMI on disease-modifying therapy (DMT) response in terms of decreasing relapses and improving overall health remains unknown. Aims and objectives The study aimed to demonstrate the effect of BMI on DMT responsiveness in patients with relapse-remitting MS at a tertiary hospital. Methods and material A single-center retrospective study was conducted at a tertiary care center in Jeddah, Saudi Arabia. The study included 89 individuals with relapsing-remitting MS who had their BMI measured within six months of their first clinical relapse, as well as their clinical response to the DMT (number of relapses on a single DMT after six months of initiation) and MRI changes (development of new T2 lesions or gadolinium-enhancing lesions on single DMT six months after DMT initiation). Results Demographic data revealed a female predominance of 71.9%, and 51.7% of the patients had a normal weight. The most commonly prescribed DMT was Gilenya at 47.2%. A significant relationship was found between BMI and the total number of clinical relapses (p=0.038), with the co-existence of a positive correlation between BMI and the number of relapses after at least six months of initiation of DMT. Additionally, MS patients who had both positive MRI changes and obesity had a significantly higher BMI mean than non-obese. Conclusion Increased BMI appeared to be associated with a lower response to DMT, as overweight patients had a worse course than normal and underweight patients. Pharmacokinetic differences are the most likely factors implicated in medication responsiveness.

Early lysosome defects precede neurodegeneration with Aβ and tau aggregation

AbstractBackgroundLoss‐of‐function mutations in the X‐linked endosomal Na+/H+ Exchanger 6 (NHE6) cause Christianson syndrome (CS) in males. CS involves endosome dysfunction leading to early cerebellar degeneration, as well as later‐onset cortical and subcortical neurodegeneration, potentially including tau deposition as reported in postmortem studies. In addition, there is reported evidence of modulation of amyloid beta (Aβ) levels in experimental models wherein NHE6 expression was targeted. For in vivo studies, rat models may have an advantage over mouse models for the study of neurodegeneration, as rat brain can demonstrate robust deposition of endogenously‐expressed Aβ and tau in certain pathological states. Mouse models generally do not show the accumulation of insoluble, endogenously‐expressed (non‐transgenic) tau or Aβ.MethodWe generated an NHE6‐null rat model of CS using CRISPR‐Cas9 genome‐editing technologies to study neurodegeneration in CS and the possibility of Aβ and tau pathology.ResultUsing this novel rat model, we were able to follow the sequence of pathogenic events in CS. NHE6‐null rats demonstrate an early and rapid loss of Purkinje cells in the cerebellum, as well as a more protracted neurodegenerative course in the cerebrum. In both the cerebellum and cerebrum, lysosome deficiency is an early pathogenic event, preceding autophagic dysfunction. Microglial and astrocyte activation also occur early. In the hippocampus and cortex, lysosome defects precede loss of pyramidal cells. Importantly, we subsequently observe biochemical and in situ evidence of both Aβ and tau aggregation in the aged NHE6‐null hippocampus and cortex (but not in the cerebellum). Tau deposition is widely distributed, including cortical and subcortical distributions. Interestingly, we observe tau deposition in both neurons and glia, as has been reported in CS postmortem studies previously.ConclusionThis new model is among very few examples of a genetically modified animal that exhibits neurodegeneration with deposition of endogenously‐expressed Aβ and tau. This NHE6‐null rat will serve as a new robust model for CS. Furthermore, these studies provide evidence for linkages between endo‐lysosome dysfunction and neurodegeneration involving protein aggregations, including Aβ and tau. Therefore these studies may provide insight into mechanisms of more common neurodegenerative disorders, including Alzheimer’s Disease and related dementias.

PEBAT, an Intriguing Neurodegenerative Tubulinopathy Caused by a Novel Homozygous Variant in TBCD: A Case Series and Literature Review

Progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT) is a severe and rare progressive neurodegenerative disease (OMIM 617913). This condition has been described in individuals with pathogenic variants affecting tubulin-specific chaperone protein D (TBCD), which is responsible for proper folding and assembly of tubulin subunits. Here we describe two unrelated infants from Central America presenting with worsening neuromuscular weakness, respiratory failure, polyneuropathy, and neuroimaging findings of severe cerebral volume loss with thin corpus callosum. These individuals harbored the same homozygous variant of uncertain significance in the TBCD gene on whole exome sequencing (WES). Predicted protein modeling of this variant confirmed disruption of the protein helix at the surface of TBCD. The goal of this report is to emphasize the importance of rapid WES, careful interpretation of uncertain variants, prognostication, and family counseling especially when faced with a neurodegenerative clinical course.

Somewhere out there in a place no one knows: Yoko Ogawa’s The Memory Police and the literature of forgetting

Yoko Ogawa’s The Memory Police was published in Japanese in 1994. Since the release of its first English translation in 2019, the text has attracted a handful of responses from...

Newborn Screening for X-Linked Adrenoleukodystrophy in Nebraska: Initial Experiences and Challenges.

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease caused by pathogenic variants in ABCD1 resulting in defective peroxisomal oxidation of very long-chain fatty acids. Most male patients develop adrenal insufficiency and one of two neurologic phenotypes: a rapidly progressive demyelinating disease in mid-childhood (childhood cerebral X-ALD, ccALD) or an adult-onset spastic paraparesis (adrenomyeloneuropathy, AMN). The neurodegenerative course of ccALD can be halted if patients are treated with hematopoietic stem cell transplantation at the earliest onset of white matter disease. Newborn screening for X-ALD can be accomplished by measuring C26:0-lysophosphatidylcholine in dried blood spots. In Nebraska, X-ALD newborn screening was instituted in July 2018. Over a period of 3.3 years, 82,920 newborns were screened with 13 positive infants detected (4 males, 9 females), giving a birth prevalence of 1:10,583 in males and 1:4510 in females. All positive newborns had DNA variants in ABCD1. Lack of genotype-phenotype correlations, absence of predictive biomarkers for ccALD or AMN, and a high proportion of ABCD1 variants of uncertain significance are unique challenges in counseling families. Surveillance testing for adrenal and neurologic disease in presymptomatic X-ALD males will improve survival and overall quality of life.

Clinical and molecular findings in 6 Turkish cases with Krabbe disease.

Krabbe disease is a rare lysosomal storage disorder with a neurodegenerative course that occurs because of the deficiency of the beta-galactocerebrosidase (GALC) enzyme activity. The genetic basis of Krabbe disease consists of biallelic mutations in the GALC gene, but the genetic spectrum in the Turkish population is poorly defined. We aimed to present a Turkish case-series with infantile-onset Krabbe disease, define the clinical and molecular findings and compare the genetic spectrum with the mutations previously reported in the literature. Six cases, who were referred to our clinic between 2015-2019, with a definite diagnosis of infantileonset Krabbe disease were included in the study. The family history, clinical information, biochemical and radiological examinations of the patients were screened and evaluated. All encoded exons and exon-intron regions of the GALC gene were sequenced using next generation sequencing technology. Multiplex ligationdependent probe amplification analysis was used for deletion type mutations that could not be detected by sequence analysis. GALC gene sequence analysis revealed four known mutations including c.1394C > T (p.Thr465Ile), c.411_413delTAA (p.Lys139del), c.820G > C (p.Glu274Gln), and 30 kilobase deletion mutation among the exons 11-17 (IVS10del30kbp). Moreover, the c.1623G > A (p.Trp541Ter) variant, which was not previously reported in the literature, was detected in two cases. We believe that the demonstration of the genetic spectrum of infantile-onset Krabbe disease in Turkish patients will be an important contribution to the GALC mutation data in our country. More importantly, two novel variants were defined. This knowledge may enable early detection and treatment with the advent of a carrier or newborn screening tests.

Early lysosome defects precede neurodegeneration with amyloid-β and tau aggregation in NHE6-null rat brain.

Loss-of-function mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome in males. Christianson syndrome involves endosome dysfunction leading to early cerebellar degeneration, as well as later-onset cortical and subcortical neurodegeneration, potentially including tau deposition as reported in post-mortem studies. In addition, there is reported evidence of modulation of amyloid-β levels in experimental models wherein NHE6 expression was targeted. We have recently shown that loss of NHE6 causes defects in endosome maturation and trafficking underlying lysosome deficiency in primary mouse neurons in vitro. For in vivo studies, rat models may have an advantage over mouse models for the study of neurodegeneration, as rat brain can demonstrate robust deposition of endogenously-expressed amyloid-β and tau in certain pathological states. Mouse models generally do not show the accumulation of insoluble, endogenously-expressed (non-transgenic) tau or amyloid-β. Therefore, to study neurodegeneration in Christianson syndrome and the possibility of amyloid-β and tau pathology, we generated an NHE6-null rat model of Christianson syndrome using CRISPR-Cas9 genome-editing. Here, we present the sequence of pathogenic events in neurodegenerating NHE6-null male rat brains across the lifespan. NHE6-null rats demonstrated an early and rapid loss of Purkinje cells in the cerebellum, as well as a more protracted neurodegenerative course in the cerebrum. In both the cerebellum and cerebrum, lysosome deficiency is an early pathogenic event, preceding autophagic dysfunction. Microglial and astrocyte activation also occur early. In the hippocampus and cortex, lysosome defects precede loss of pyramidal cells. Importantly, we subsequently observed biochemical and in situ evidence of both amyloid-β and tau aggregation in the aged NHE6-null hippocampus and cortex (but not in the cerebellum). Tau deposition is widely distributed, including cortical and subcortical distributions. Interestingly, we observed tau deposition in both neurons and glia, as has been reported in Christianson syndrome post-mortem studies previously. In summary, this experimental model is among very few examples of a genetically modified animal that exhibits neurodegeneration with deposition of endogenously-expressed amyloid-β and tau. This NHE6-null rat will serve as a new robust model for Christianson syndrome. Furthermore, these studies provide evidence for linkages between endolysosome dysfunction and neurodegeneration involving protein aggregations, including amyloid-β and tau. Therefore these studies may provide insight into mechanisms of more common neurodegenerative disorders, including Alzheimer's disease and related dementias.

Blood markers of neuronal/axonal and glial injury for clinical progression in a predominately Hispanic cohort: The Texas Alzheimer’s Research and Care Consortium

AbstractBackgroundThe clinical translation of biofluid markers for Alzheimer’s disease and related dementias (ADRDs) requires validation in diverse cohorts. The goal of the study was to evaluate if blood biomarkers of neuronal/axonal and glial injury predict cognitive decline and clinical disease progression in a predominately Hispanic cohort from the Texas Alzheimer’s Research and Care Consortium.MethodParticipants included 745 Hispanic and 274 non‐Hispanic white participants, aged 55‐89 years, who annually completed cognitive assessments, the Clinical Dementia Rating scale (CDR), and dementia consensus reviews. Serum from the baseline examination was assayed to quantify levels of total tau (t‐tau), neurofilament light (NFL), ubiquitin carboxyl‐terminal hydrolase LI (UCHLI), and glial fibrillary acidic protein (GFAP) using the Simoa Neurology 4‐Plex Kit (Quanterix), as well as soluble CD14 (sCD14) and chitinase‐3‐like protein 1 (YKL‐40) using commercial ELISAs (R&D Systems). Generalized estimating equations were used to evaluate the associations between serum biomarkers and longitudinal cognitive outcomes, as well as disease progression (CDR Sum of Boxes), adjusting for covariates of age, sex, ethnicity, education, body mass index, systolic blood pressure, diabetes, APOE ε4 status, and clinical diagnosis. Cox proportional hazard models were used to evaluate the associations between serum biomarkers and incident mild cognitive impairment (MCI) and dementia with adjustment for the covariates listed above.ResultAcross the average four‐year follow‐up period, 162 individuals developed MCI and 96 developed dementia (Table 1). As displayed in Table 2, serum GFAP levels predicted cognitive decline across most cognitive domains. Serum t‐tau levels were associated with declines in global cognition, learning, and memory. Serum GFAP (b=0.154, SE=0.028, p<0.001), NFL (b=0.069, SE=0.026, p=0.007), and t‐tau (b=0.065, SE=0.023, p=0.004) predicted clinical progression. Higher GFAP levels at baseline were associated with increased risk of incident dementia (HR=1.485, p=0.009). None of the biomarkers predicted incident MCI.ConclusionSerum GFAP levels were associated with multi‐domain cognitive decline, clinical progression, and incident dementia risk. The results suggest that reactive astrogliosis may be an important mechanism underlying a progressive neurodegenerative disease course in our predominately Hispanic sample. With further validation, serum GFAP may hold utility for predicting disease progression and monitoring the efficacy of newly emerging treatments.

Lysosomal dysfunction impairs mitochondrial quality control and is associated with neurodegeneration in TBCK encephaloneuronopathy.

Biallelic variants in the TBCK gene cause intellectual disability with remarkable clinical variability, ranging from static encephalopathy to progressive neurodegeneration (TBCK-Encephaloneuronopathy). The biological factors underlying variable disease penetrance remain unknown. Since previous studies had suggested aberrant autophagy, we tested whether mitophagy and mitochondrial function are altered in TBCK−/− fibroblasts derived from patients exhibiting variable clinical severity. Our data show significant accumulation of mitophagosomes, reduced mitochondrial respiratory capacity and mitochondrial DNA content, suggesting impaired mitochondrial quality control. Furthermore, the degree of mitochondrial dysfunction correlates with a neurodegenerative clinical course. Since mitophagy ultimately depends on lysosomal degradation, we also examined lysosomal function. Our data show that lysosomal proteolytic function is significantly reduced in TBCK−/− fibroblasts. Moreover, acidifying lysosomal nanoparticles rescue the mitochondrial respiratory defects in fibroblasts, suggesting impaired mitochondrial quality control secondary to lysosomal dysfunction. Our data provide insight into the disease mechanisms of TBCK Encephaloneuronopathy and the potential relevance of mitochondrial function as a biomarker beyond primary mitochondrial disorders. It also supports the benefit of lysosomal acidification strategies for disorders of impaired lysosomal degradation affecting mitochondrial quality control.

The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease.

Recent reports have identified rare, biallelic damaging variants of the AGTPBP1 gene that cause a novel and documented human disease known as childhood-onset neurodegeneration with cerebellar atrophy (CONDCA), linking loss of function of the AGTPBP1 protein to human neurodegenerative diseases. CONDCA patients exhibit progressive cognitive decline, ataxia, hypotonia or muscle weakness among other clinical features that may be fatal. Loss of AGTPBP1 in humans recapitulates the neurodegenerative course reported in a well-characterised murine animal model harbouring loss-of-function mutations in the AGTPBP1 gene. In particular, in the Purkinje cell degeneration (pcd) mouse model, mutations in AGTPBP1 lead to early cerebellar ataxia, which correlates with the massive loss of cerebellar Purkinje cells. In addition, neurodegeneration in the olfactory bulb, retina, thalamus and spinal cord were also reported. In addition to neurodegeneration, pcd mice show behavioural deficits such as cognitive decline. Here, we provide an overview of what is currently known about the structure and functional role of AGTPBP1 and discuss the various alterations in AGTPBP1 that cause neurodegeneration in the pcd mutant mouse and humans with CONDCA. The sequence of neuropathological events that occur in pcd mice and the mechanisms governing these neurodegenerative processes are also reported. Finally, we describe the therapeutic strategies that were applied in pcd mice and focus on the potential usefulness of pcd mice as a promising model for the development of new therapeutic strategies for clinical trials in humans, which may offer potential beneficial options for patients with AGTPBP1 mutation-related CONDCA.

Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary.

Ufmylation is a relatively newly discovered type of post-translational modification when the ubiquitin-fold modifier 1 (UFM1) protein is covalently attached to its target proteins in a three-step enzymatic reaction involving an E1 activating enzyme (UBA5), E2 conjugating enzyme (UFC1), and E3 ligase enzyme (UFL1). The process of ufmylation is essential for normal brain development and function in humans. Mutations in the UFM1 gene are associated with Hypomyelinating leukodystrophy type 14, presenting with global developmental delay, failure to thrive, progressive microcephaly, refractive epilepsy, and hypomyelination, with atrophy of the basal ganglia and cerebellum phenotypes. The c.-155_-153delTCA deletion in the promoter region of UFM1 is considered to be a founding mutation in the Roma population. Here we present four index patients with homozygous UFM1:c.-155_-153delTCA mutation detected by next-generation sequencing (whole genome/exome sequencing) or Sanger sequencing. This mutation may be more common in the Roma population than previously estimated, and the targeted testing of the UFM1:c.-155_-153delTCA mutation may have an indication in cases of hypomyelination and neurodegenerative clinical course in pediatric patients of Roma descent.

Congenital metabolic diseases. Lysosomal storage diseases

The classification and epidemiology of hereditary metabolic disorders are presented. That is a large group consisting from more them 800 monogenic diseases, each of which caused by inherited deficiency of certain metabolic fate. Many of these disorders are extremely rare, but their total incidence in the population is close to 1:10005000. Lysosomal storage diseases (LSD) resulting from inherited deficiency in lysosomal functions occupy a special place among hereditary metabolic disorders. The defects of catabolism cause the accumulation of undigested or partially digested macromolecules in lysosomes (that is, storage), which can result in cellular damage. About 60 diseases take part in this group with total incidence of about 1:70008000. LSDs typically present in infancy and childhood, although adult-onset forms also occur. Most of them have a progressive neurodegenerative clinical course, although symptoms in other organ systems are frequent. The etiology and pathogenetic aspects of their main clinical entities: mucopolysaccharidosis, glycolipidosis, mucolipidosis, glycoproteinosis, etc, are presented. Mucopolysaccharidoses caused by malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans are more frequent among LSD. Sphingolipidoses caused by defects of lipid catabolism are second for frequency group of LSD. The state-of-art in field of newborn screening. clinical, biochemical and molecular diagnostics of these grave diseases are discussed. The main directions of modern lysosomal storage diseases therapy are characterized: transplantation of hematopoietic stem cells; enzyme replacement therapy; therapy with limitation of substrate synthesis (substrate-reducing therapy); pharmacological chaperone therapy. Perspective directions for LSD therapy are gene therapy and genome editing which are at advanced preclinical stages.

Defective Autophagy and Mitophagy in Alzheimer's Disease: Mechanisms and Translational Implications.

The main histopathology of Alzheimer's disease (AD) is featured by the extracellular accumulation of amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles (NFT) in the brain, which is likely to result from co-pathogenic interactions among multiple factors, e.g., aging or genes. The link between defective autophagy/mitophagy and AD pathologies is still under investigation and not fully established. In this review, we consider how AD is associated with impaired autophagy and mitophagy, and how these impact pathological hallmarks as well as the potential mechanisms. This complicated interplay between autophagy or mitophagy and histopathology in AD suggests that targeting autophagy or mitophagy probably is a promising anti-AD drug candidate. Finally, we review the implications of some new insights for induction of autophagy or mitophagy as the new therapeutic way that targets processes upstream of both NFT and Aβ plaques, and hence stops the neurodegenerative course in AD.