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Inherited diseases caused by unstable repeated DNA sequences are rare, but together represent a substantial cause of morbidity. Trinucleotide repeat disorders are severe, usually life-shortening, neurological disorders caused by nucleotide expansions, and most have no disease-modifying treatments. Longer repeat expansions are associated with genetic anticipation (ie, earlier disease onset in successive generations), although the differences in age at onset are not entirely accounted for by repeat length. Such phenotypic variation within disorders implies the existence of additional modifying factors in pathways that can potentially be modulated to treat disease. A genome-wide association study detected genetic modifiers of age at onset in Huntington's disease. Similar findings were seen in the spinocerebellar ataxias, indicating an association between DNA damage-response and repair pathways and the age at onset of disease. These studies also suggest that a common genetic mechanism modulates age at onset across polyglutamine diseases and could extend to other repeat expansion disorders. Genetic defects in DNA repair underlie other neurodegenerative disorders (eg, ataxia-telangiectasia), and DNA double-strand breaks are crucial to the modulation of early gene expression, which provides a mechanistic link between DNA repair and neurodegeneration. Mismatch and base-excision repair are important in the somatic expansion of repeated sequences in mouse models of trinucleotide repeat disorders, and somatic expansion of the expanded CAG tract in HTT correlates with age at onset of Huntington's disease and other trinucleotide repeat disorders. To understand the common genetic architecture of trinucleotide repeat disorders and any further genetic susceptibilities in individual disorders, genetic analysis with increased numbers of variants and sample sizes is needed, followed by sequencing approaches to define the phenotype-modifying variants. The findings must then be translated into cell biology analyses to elucidate the mechanisms through which the genetic variants operate. Genes that have roles in the DNA damage response could underpin a common DNA repeat-based mechanism and provide new therapeutic targets (and hence therapeutics) in multiple trinucleotide repeat disorders.

Hereditary spastic paraplegia (HSP) describes a heterogeneous group of genetic neurodegenerative diseases characterised by progressive spasticity of the lower limbs. The pathogenic mechanism, associated clinical features, and imaging abnormalities vary substantially according to the affected gene and differentiating HSP from other genetic diseases associated with spasticity can be challenging. Next generation sequencing-based gene panels are now widely available but have limitations and a molecular diagnosis is not made in most suspected cases. Symptomatic management continues to evolve but with a greater understanding of the pathophysiological basis of individual HSP subtypes there are emerging opportunities to provide targeted molecular therapies and personalised medicine.

There has been tremendous progress toward understanding the genetic basis of Parkinson’s disease and related movement disorders. We summarize the genetic, clinical and pathological findings of autosomal dominant disease linked to mutations in SNCA , LRRK2 , ATXN2 , ATXN3 , MAPT, GCH1, DCTN1 and VPS35 . We then discuss the identification of mutations in PARK2 , PARK7 , PINK1 , ATP13A2 , FBXO7 , PANK2 and PLA2G6 genes. In particular we discuss the clinical and pathological characterization of these forms of disease, where neuropathology has been important in the likely coalescence of pathways highly relevant to typical PD. In addition to the identification of the causes of monogenic forms of PD, significant progress has been made in defining genetic risk loci for PD; we discuss these here, including both risk variants at LRRK2 and GBA , in addition to discussing the results of recent genome-wide association studies and their implications for PD. Finally, we discuss the likely path of genetic discovery in PD over the coming period and the implications of these findings from a clinical and etiological perspective.

Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 ( RFC1 ) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG) 11 allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia. Biallelic expansion of an intronic AAGGG repeat in RFC1 is identified here as a common cause of late-onset ataxia. This expansion occurs in the poly(A) tail of an AluSx3 element and is observed at a carrier frequency of 0.7% in populations of European ancestry.

Charcot–Marie–Tooth disease (CMT) encompasses a group of inherited motor and sensory neuropathies. Over the past two decades, considerable advances have been made in identification of the causative genes. Here, Rossor et al . outline the role of next-generation sequencing in enabling rapid, parallel screening of multiple CMT-associated genes, and propose a diagnostic algorithm for application of genetic screening when CMT is suspected. Charcot–Marie–Tooth disease (CMT) refers to a group of inherited neuropathies with a broad range of phenotypes, inheritance patterns and causative genes. The number of disease genes identified in CMT has expanded rapidly over the past few decades, such that more than 60 CMT-associated genes have now been discovered. This rise in genetic discovery can be attributed to the development of next-generation sequencing (NGS) technology, which allows the entire exome or genome to be sequenced in a matter of days. In this Review, we discuss how NGS is being employed in the diagnostic evaluation of patients with CMT and how the genetic advances in CMT are influencing clinical practice. In particular, we explore how genetic advances have broadened the phenotype of CMT and related disorders and how NGS allows a large number of CMT genes to be screened simultaneously early in the evaluation of an unexplained neuropathy. Finally, we discuss the different methods of NGS that can be used in CMT and related disorders, and propose a simple diagnostic algorithm in which clinical assessment and neurophysiology are used to guide the application of phenotype specific 'panels'. Key Points Charcot–Marie–Tooth disease (CMT) should be considered as a differential diagnosis in an increasingly wide range of neuropathy phenotypes In patients with autosomal dominant or sporadic demyelinating genetic neuropathy, screening for the chromosome 17p duplication should be performed first, before proceeding to a disease-specific panel Disease-specific next-generation sequencing in which all known disease-causing genes are sequenced in parallel (disease-specific panels) is now the most efficient method of genetic testing in CMT Incomplete coverage of whole-exome sequencing and whole-genome sequencing mean that their use is mainly restricted to research-led discovery of new genes Genetic testing for appropriate CMT mutations should be considered in treatment-resistant inflammatory demyelinating neuropathies

Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder caused by CAG repeat expansions in the atrophin-1 gene and is inherited in an autosomal dominant fashion. There are currently no disease-modifying treatments available. The broad development of therapies for DRPLA, as well as other similar rare diseases, has hit a roadblock due to the rarity of the condition and the wide global distribution of patients and families, consequently inhibiting biomarker development and therapeutic research. Considering the shifting focus towards diverse populations, widespread genetic testing, rapid advancements in the development of clinical and wet biomarkers for Huntington’s disease (HD), and the ongoing clinical trials for antisense oligonucleotide (ASO) therapies, the prospect of developing effective treatments in rare disorders has completely changed. The awareness of the HD ASO program has prompted global collaboration for rare disorders in natural history studies and the development of biomarkers, with the eventual goal of undergoing treatment trials. Here, we discuss DRPLA, which shares similarities with HD, and how in this and other repeat expansion disorders, neurogenetics groups like ours at UCL are gearing up for forthcoming natural history studies to accelerate future ASO treatment trials to hopefully emulate the progress seen in HD.

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca 2+ -impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca 2+ transport and AMPAR currents.”

In the last 6 years, following the first pathological description of presumed amyloid-beta (Aβ) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of iatrogenic cerebral amyloid angiopathy (CAA)—attributed to the transmission of Aβ seeds—have been increasingly recognised and reported. This newly described form of CAA is associated with early disease onset (typically in the third to fifth decade), and often presents with intracerebral haemorrhage, but also seizures and cognitive impairment. Although assumed to be rare, it is important that clinicians remain vigilant for potential cases, particularly as the optimal management, prognosis, true incidence and public health implications remain unknown. This review summarises our current understanding of the clinical spectrum of iatrogenic CAA and provides a diagnostic framework for clinicians. We provide clinical details for three patients with pathological evidence of iatrogenic CAA and present a summary of the published cases to date (n=20), identified following a systematic review. Our aims are: (1) To describe the clinical features of iatrogenic CAA, highlighting important similarities and differences between iatrogenic and sporadic CAA; and (2) To discuss potential approaches for investigation and diagnosis, including suggested diagnostic criteria for iatrogenic CAA.

High temperature requirement protein A1 (HtrA1) is a primarily secreted serine protease involved in a variety of cellular processes including transforming growth factor β (TGF-β) signaling. Loss of its activity causes cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), an inherited form of cerebral small vessel disease leading to early-onset stroke and premature dementia. Dysregulated TGF-β signaling is considered to promote CARASIL pathogenesis, but the underlying molecular mechanisms are incompletely understood. Here we present evidence from mouse brain tissue and embryonic fibroblasts as well as patient skin fibroblasts for a facilitating role of HtrA1 in TGF-β pathway activation. We identify latent TGF-β binding protein 1 (LTBP-1), an extracellular matrix protein and key regulator of TGF-β bioavailability, as a novel HtrA1 target. Cleavage occurs at physiological protease concentrations, is prevented under HtrA1-deficient conditions as well as by CARASIL mutations and disrupts both LTBP-1 binding to fibronectin and its incorporation into the extracellular matrix. Hence, our data suggest an attenuation of TGF-β signaling caused by a lack of HtrA1-mediated LTBP-1 processing as mechanism underlying CARASIL pathogenesis. Significance Cerebral small vessel disease (SVD) is a major cause of stroke and dementia. Hereditary forms, such as cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), may provide insights into key molecular mechanisms and pathways. The serine protease HtrA1, whose activity is impaired in CARASIL, has been proposed to attenuate TGF-β signaling leading to increased pathway activity in diseased arteries. We analyzed HtrA1-deficient mouse brain tissue and mouse and CARASIL patient fibroblasts and found a reduction in signaling activity on various pathway levels suggesting a facilitating role of HtrA1. Moreover, we identified LTBP-1 as a novel HtrA1 substrate and provide evidence for its functional modulation by HtrA1-dependent proteolysis. Our data suggest down-regulation of TGF-β signaling as a key mechanism underlying CARASIL pathogenesis.

A pathogenic hexanucleotide repeat expansion within the C9orf72 gene has been identified as the major cause of two neurodegenerative syndromes, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation is known to have incomplete penetrance, with some patients developing disease in their twenties and a small portion of carriers surviving to their ninth decade without developing symptoms. Describing penetrance by age among C9orf72 carriers and identifying parameters that alter onset age are essential to better understanding this locus and to enhance predictive counseling. To do so, data from 1,170 individuals were used to model penetrance. Our analysis showed that the penetrance was incomplete and age-dependent. Additionally, familial and sporadic penetrance did not significantly differ from one another; ALS cases exhibited earlier age of onset than FTD cases; and individuals with spinal-onset exhibited earlier age of onset than those with bulbar-onset. The older age of onset among female cases in general, and among female bulbar-onset cases in particular, was the most striking finding, and there may be an environmental, lifestyle, or hormonal factor that is influencing these penetrance patterns. These results will have important applications for future clinical research, the identification of disease modifiers, and genetic counseling.