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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary Background 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. Recent developments 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. Where next? 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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Riboflavin transporter deficiency (RTD) is a rare neurological condition that encompasses the Brown‐Vialetto‐Van Laere and Fazio‐Londe syndromes since the discovery of pathogenic mutations in the ...SLC52A2 and SLC52A3 genes that encode human riboflavin transporters RFVT2 and RFVT3. Patients present with a deteriorating progression of peripheral and cranial neuropathy that causes muscle weakness, vision loss, deafness, sensory ataxia, and respiratory compromise which when left untreated can be fatal. Considerable progress in the clinical and genetic diagnosis of RTDs has been made in recent years and has permitted the successful lifesaving treatment of many patients with high dose riboflavin supplementation. In this review, we first outline the importance of riboflavin and its efficient transmembrane transport in human physiology. Reports on 109 patients with a genetically confirmed diagnosis of RTD are then summarized in order to highlight commonly presenting clinical features and possible differences between patients with pathogenic SLC52A2 (RTD2) or SLC52A3 (RTD3) mutations. Finally, we focus attention on recent work with different models of RTD that have revealed possible pathomechanisms contributing to neurodegeneration in patients.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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)
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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'.
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.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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