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author:("holden, Henry")
1.  Extended phenotypic spectrum of KIF5A mutations 
Neurology  2014;83(7):612-619.
Objective:
To establish the phenotypic spectrum of KIF5A mutations and to investigate whether KIF5A mutations cause axonal neuropathy associated with hereditary spastic paraplegia (HSP) or typical Charcot-Marie-Tooth disease type 2 (CMT2).
Methods:
KIF5A sequencing of the motor-domain coding exons was performed in 186 patients with the clinical diagnosis of HSP and in 215 patients with typical CMT2. Another 66 patients with HSP or CMT2 with pyramidal signs were sequenced for all exons of KIF5A by targeted resequencing. One additional patient was genetically diagnosed by whole-exome sequencing.
Results:
Five KIF5A mutations were identified in 6 unrelated patients: R204W and D232N were novel mutations; R204Q, R280C, and R280H have been previously reported. Three patients had CMT2 as the predominant and presenting phenotype; 2 of them also had pyramidal signs. The other 3 patients presented with HSP but also had significant axonal neuropathy or other additional features.
Conclusion:
This is currently the largest study investigating KIF5A mutations. By combining next-generation sequencing and conventional sequencing, we confirm that KIF5A mutations can cause variable phenotypes ranging from HSP to CMT2. The identification of mutations in CMT2 broadens the phenotypic spectrum and underlines the importance of KIF5A mutations, which involve degeneration of both the central and peripheral nervous systems and should be tested in HSP and CMT2.
doi:10.1212/WNL.0000000000000691
PMCID: PMC4141994  PMID: 25008398
2.  The analysis of C9orf72 repeat expansions in a large series of clinically and pathologically diagnosed cases with atypical parkinsonism☆ 
Neurobiology of Aging  2015;36(2):1221.e1-1221.e6.
A GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. There is suggestion that these expansions may be a rare cause of parkinsonian disorders such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD). Screening the C9orf72 gene in 37 patients with features of corticobasal syndrome (CBS) detected an expansion in 3 patients, confirmed by Southern blotting. In a series of 22 patients with clinically diagnosed PSP, we found 1 patient with an intermediate repeat length. We also screened for the C9orf72 expansion in a large series of neuropathologically confirmed samples with MSA (n = 96), PSP (n = 177), and CBD (n = 18). Patients were found with no more than 22 GGGGCC repeats. Although these results still need to be confirmed in a larger cohort of CBS and/or CBD patients, these data suggest that in the presence of a family history and/or motor neuron disease features, patients with CBS or clinical PSP should be screened for the C9orf72 repeat expansion. In addition, we confirm that the C9orf72 expansions are not associated with pathologically confirmed MSA, PSP, or CBD in a large series of cases.
doi:10.1016/j.neurobiolaging.2014.08.024
PMCID: PMC4321829  PMID: 25308964
C9orf72; Parkinsonism; Multiple system atrophy (MSA); Progressive supranuclear palsy (PSP); Corticobasal degeneration (CBD) and corticobasal syndrome (CBS)
3.  Novel HSAN1 Mutation in Serine Palmitoyltransferase Resides at a Putative Phosphorylation Site That Is Involved in Regulating Substrate Specificity 
Neuromolecular Medicine  2015;17(1):47-57.
1-Deoxysphingolipids (1-deoxySL) are atypical sphingolipids that are formed by the enzyme serine palmitoyltransferase (SPT) due to a promiscuous use of l-alanine over its canonical substrate l-serine. Several mutations in SPT are associated with the hereditary sensory and autonomic neuropathy type I (HSAN1). The current hypothesis is that these mutations induce a permanent shift in the affinity from l-serine toward l-alanine which results in a pathologically increased 1-deoxySL formation in HSAN1 patients. Also, wild-type SPT forms 1-deoxySL under certain conditions, and elevated levels were found in individuals with the metabolic syndrome and diabetes. However, the molecular mechanisms which control the substrate shift of the wild-type enzyme are not understood. Here, we report a novel SPTLC2–S384F variant in two unrelated HSAN1 families. Affected patients showed elevated plasma 1-deoxySL levels and expression of the S384F mutant in HEK293 cells increased 1-deoxySL formation. Previously, S384 has been reported as one of the two (S384 and Y387) putative phosphorylation sites in SPTLC2. The phosphorylation of wild-type SPTLC2 was confirmed by isoelectric focusing. The impact of an S384 phosphorylation on SPT activity was tested by creating mutants mimicking either a constitutively phosphorylated (S384D, S384E) or non-phosphorylated (S384A, Y387F, Y387F+S384A) protein. The S384D but not the S384E variant was associated with increased 1-deoxySL formation. The other mutations had no influence on activity and substrate affinity. In summary, our data show that S384F is a novel mutation in HSAN1 and that the substrate specificity of wild-type SPT might by dynamically regulated by a phosphorylation at this position.
Electronic supplementary material
The online version of this article (doi:10.1007/s12017-014-8339-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s12017-014-8339-1
PMCID: PMC4326654  PMID: 25567748
Serine palmitoyltransferase; 1-Deoxysphingolipids; Sensory neuropathy; HSAN1; Sphingolipids
4.  Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion☆ 
Neurobiology of Aging  2015;36(1):546.e1-546.e7.
An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Although 0–30 hexanucleotide repeats are present in the general population, expansions >500 repeats are associated with C9ALS/FTD. Large C9ALS/FTD expansions share a common haplotype and whether these expansions derive from a single founder or occur more frequently on a predisposing haplotype is yet to be determined and is relevant to disease pathomechanisms. Furthermore, although cases carrying 50–200 repeats have been described, their role and the pathogenic threshold of the expansions remain to be identified and carry importance for diagnostics and genetic counseling. We present clinical and genetic data from a UK ALS cohort and report the detailed molecular study of an atypical somatically unstable expansion of 90 repeats. Our results across different tissues provide evidence for the pathogenicity of this repeat number by showing they can somatically expand in the central nervous system to the well characterized pathogenic range. Our results support the occurrence of multiple expansion events for C9ALS/FTD.
doi:10.1016/j.neurobiolaging.2014.07.037
PMCID: PMC4270445  PMID: 25179228
Frontotemporal dementia; Somatic instability; Amyotrophic lateral sclerosis
5.  Alpha-synuclein mRNA expression in oligodendrocytes in MSA 
Glia  2014;62(6):964-970.
Multiple system atrophy (MSA) is a progressive neurodegenerative disease presenting clinically with parkinsonian, cerebellar, and autonomic features. α-Synuclein (αsyn), encoded by the gene SNCA, is the main constituent of glial cytoplasmic inclusion (GCI) found in oligodendrocytes in MSA, but the methods of its accumulation have not been established. The aim of this study is to investigate alterations in regional and cellular SNCA mRNA expression in MSA as a possible substrate for GCI formation. Quantitative reverse transcription polymerase chain reaction (qPCR) was performed on postmortem brain samples from 15 MSA, 5 IPD, and 5 control cases to investigate regional expression in the frontal and occipital regions, dorsal putamen, pontine base, and cerebellum. For cellular expression analysis, neurons and oligodendrocytes were isolated by laser-capture microdissection from five MSA and five control cases. SNCA mRNA expression was not significantly different between the MSA, IPD and control cases in all regions (multilevel model, P = 0.14). After adjusting for group effect, the highest expression was found in the occipital cortex while the lowest was in the putamen (multilevel model, P < 0.0001). At the cellular level, MSA oligodendrocytes expressed more SNCA than control oligodendrocytes and expression in MSA neurons was slightly lower than that in controls, however, these results did not reach statistical significance. We have demonstrated regional variations in SNCA expression, which is higher in cortical than subcortical regions. This study is the first to demonstrate SNCA mRNA expression by oligodendrocytes in human postmortem tissue using qPCR and, although not statistically significant, could suggest that this may be increased in MSA compared to controls.
doi:10.1002/glia.22653
PMCID: PMC4238782  PMID: 24590631
α-synuclein; multiple system atrophy; oligodendrocytes; glial cytoplasmic inclusions; laser-capture microdissection
6.  Neuropathological features of genetically confirmed DYT1 dystonia: investigating disease-specific inclusions 
Introduction
Early onset isolated dystonia (DYT1) is linked to a three base pair deletion (ΔGAG) mutation in the TOR1A gene. Clinical manifestation includes intermittent muscle contraction leading to twisting movements or abnormal postures. Neuropathological studies on DYT1 cases are limited, most showing no significant abnormalities. In one study, brainstem intraneuronal inclusions immunoreactive for ubiquitin, torsinA and lamin A/C were described. Using the largest series reported to date comprising 7 DYT1 cases, we aimed to identify consistent neuropathological features in the disease and determine whether we would find the same intraneuronal inclusions as previously reported.
Result
The pathological changes of brainstem inclusions reported in DYT1 dystonia were not replicated in our case series. Other anatomical regions implicated in dystonia showed no disease-specific pathological intracellular inclusions or evidence of more than mild neuronal loss.
Conclusion
Our findings suggest that the intracellular inclusions described previously in DYT1 dystonia may not be a hallmark feature of the disorder. In isolated dystonia, DYT1 in particular, biochemical changes may be more relevant than the morphological changes.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-014-0159-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s40478-014-0159-x
PMCID: PMC4247124  PMID: 25403864
DYT1; Neuropathology; Isolated dystonia; Inclusions
7.  Ongoing Developments in Sporadic Inclusion Body Myositis 
Sporadic inclusion body myositis (IBM) is an acquired muscle disorder associated with ageing, for which there is no effective treatment. Ongoing developments include: genetic studies that may provide insights regarding the pathogenesis of IBM, improved histopathological markers, the description of a new IBM autoantibody, scrutiny of the diagnostic utility of clinical features and biomarkers, the refinement of diagnostic criteria, the emerging use of MRI as a diagnostic and monitoring tool, and new pathogenic insights that have led to novel therapeutic approaches being trialled for IBM, including treatments with the objective of restoring protein homeostasis and myostatin blockers. The effect of exercise in IBM continues to be investigated. However, despite these ongoing developments, the aetiopathogenesis of IBM remains uncertain. A translational and multidisciplinary collaborative approach is critical to improve the diagnosis, treatment, and care of patients with IBM.
doi:10.1007/s11926-014-0477-9
PMCID: PMC4233319  PMID: 25399751
Inclusion body myositis; Myositis; Myopathy; Neuromuscular; Genetics; Whole-exome sequencing; Aetiopathogenesis; Diagnosis; Treatment; Magnetic resonance imaging; Histology; Autoantibodies; Protein aggregates; Inflammation; Exercise; Disability; Myostatin; Monoclonal antibodies; Gene therapy; Heat shock proteins; Chaperones; Clinical trial
8.  Exome sequencing identifies a significant variant in methionyl-tRNA synthetase (MARS) in a family with late-onset CMT2 
Charcot–Marie–Tooth (CMT) disease is a genetically heterogeneous condition with >50 genes now being identified. Thanks to new technological developments, namely, exome sequencing, the ability to identify additional rare genes in CMT has been drastically improved. Here we present data suggesting that MARS is a very rare novel cause of late-onset CMT2. This is supported by strong functional and evolutionary evidence, yet the absence of additional unrelated cases warrant future studies to substantiate this conclusion.
doi:10.1136/jnnp-2013-305049
PMCID: PMC3796032  PMID: 23729695
9.  The Glucocerobrosidase E326K Variant Predisposes to Parkinson’s Disease, But Does Not Cause Gaucher’s Disease 
Background
Heterozygous loss-of-function mutations in the acid beta-glucocerebrosidase (GBA1) gene, responsible for the recessive lysosomal storage disorder, Gaucher’s disease (GD), are the strongest known risk factor for Parkinson’s disease (PD). Our aim was to assess the contribution of GBA1 mutations in a series of early-onset PD.
Methods
One hundred and eighty-five PD patients (with an onset age of ≤50) and 283 age-matched controls were screened for GBA1 mutations by Sanger sequencing.
Results
We show that the frequency of GBA1 mutations is much higher in this patient series than in typical late-onset patient cohorts. Furthermore, our results reveal that the most prevalent PD-associated GBA1 mutation is E326K, a variant that does not, when homozygous, cause GD.
Conclusions
Our results confirm recent reports that the mutation, E326K, predisposes to PD and suggest that, in addition to reduced GBA1 activity, other molecular mechanisms may contribute to the development of the disease.
doi:10.1002/mds.25248
PMCID: PMC4208290  PMID: 23225227
GBA; E326K; Parkinson’s disease; Gaucher’s disease; early onset
10.  Dystonic Opisthotonus: A “Red Flag” for Neurodegeneration With Brain Iron Accumulation Syndromes? 
Back arching was reported in one of the very first patients with neurodegeneration with brain iron accumulation syndrome (NBIAs) published in 1936. However, recent reports have mainly focused on the genetic and imaging aspects of these disorders, and the phenotypic characterization of the dystonia has been lost. In evaluating patients with NBIAs in our centers, we have observed that action-induced dystonic opisthotonus is a common and characteristic feature of NBIAs. Here, we present a case series of patients with NBIAs presenting this feature demonstrated by videos. We suggest that dystonic opisthotonus could be a useful “red flag” for clinicians to suspect NBIAs, and we discuss the differential diagnosis of this feature. This would be particularly useful in identifying patients with NBIAs and no iron accumulation as yet on brain imaging (for example, as in phospholipase A2, group IV (cytosolic, calcium-independent) [PLA2G6]-related disorders), and it has management implications.
doi:10.1002/mds.25490
PMCID: PMC4208296  PMID: 23736975
neurodegeneration with brain iron accumulation; NBIA; opisthotonus; retrocollis; extensor axial dystonia; PLA2G6; PANK2
11.  Analysis of Parkinson’s Disease Brain–Derived DNA for Alpha-Synuclein Coding Somatic Mutations 
Background
Although alpha-synuclein (SNCA) is crucial to the pathogenesis of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), mutations in the gene appear to be rare. We have recently hypothesized that somatic mutations in early development could contribute to PD.
Methods
Expanding on our recent negative small study, we used high-resolution melting (HRM) analysis to screen SNCA coding exons for somatic point mutations in DNA from 539 PD and DLB cerebellar samples, with two additional regions (frontal cortex, substantia nigra) for 20 PD cases. We used artificial mosaics to determine sensitivity where possible.
Results
We did not detect any evidence of somatic coding mutations. Three cases were heterozygous for known silent polymorphisms. The protocol we used was sensitive enough to detect 5% to 10% mutant DNA.
Conclusion
Using DNA predominantly from cerebellum, but also from frontal cortex and substantia nigra (n=20 each), we have not detected any somatic coding SNCA point mutations.
doi:10.1002/mds.25883
PMCID: PMC4190821  PMID: 24752924
SNCA; alpha-synuclein; somatic mutation; mosaicism; etiology of Parkinson’s disease
12.  Genetic Analysis of Inherited Leukodystrophies 
JAMA neurology  2013;70(7):875-882.
Importance
The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. Recently, Rademakers and colleagues identified mutations in the CSF1R gene as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), offering the possibility for an in-life diagnosis. The detection of mutations in this gene in cases diagnosed with different clinical entities further demonstrated the difficulties in the clinical diagnosis of HDLS.
Objective
To better understand the genetic role of mutations in this gene, we sequenced a large cohort of adult-onset leukodystrophy cases.
Design
Whole-exome sequencing and follow up-screening by Sanger sequencing.
Setting
Collaborative study between the Institute of Neurology, University College London and the Inserm, Paris, France.
Participants
A total of 114 probands, mostly European patients, with a diagnosis of adult-onset leukodystrophy or atypical cases that could fit within a picture of leukodystrophy. These included 3 extended families within the spectrum of leukodystrophy phenotype.
Interventions
Whole-exome sequencing in a family and Sanger sequencing of CSF1R.
Main Outcomes and Measures
Mutations in CSF1R.
Results
We identified 12 probands with mutations in CSF1R. The clinical diagnoses given to these patients included dementia with spastic paraplegia, corticobasal degeneration syndrome, and stroke disorders. Our study shows that CSF1R mutations are responsible for a significant proportion of clinically and pathologically proven HDLS.
Conclusions and Relevance
These results give an indication of the frequency of CSF1R mutations in a European leukodystrophy series and expand the phenotypic spectrum of disorders that should be screened for this gene.
doi:10.1001/jamaneurol.2013.698
PMCID: PMC4204151  PMID: 23649896
13.  The Pallidopyramidal Syndromes: nosology, aetiology and pathogenesis 
Current opinion in neurology  2013;26(4):381-394.
Purpose of review
The aims of this review are to suggest a new nomenclature and classification system for the diseases currently categorised as NBIA or dystonia-parkinsonism, and to discuss the mechanisms implicated in the pathogenesis of these diseases.
Recent findings
Neurodegeneration with brain iron accumulation (NBIA) is a disease category encompassing syndromes with iron accumulation and prominent dystonia-parkinsonism. However, as there are many diseases with similar clinical presentations but without iron accumulation and/or known genetic cause, the current classification system and nomenclature remain confusing. The pathogenetic mechanisms of these diseases and the causes of gross iron accumulation and significant burden of neuroaxonal spheroids are also elusive. Recent genetic and functional studies have identified surprising links between PPS, Parkinson’s disease (PD) and Lysosomal storage disorders (LSD) with the common theme being a combined lysosomal-mitochondrial dysfunction. We hypothesise that mitochondria and lysosomes form a functional continuum with a predominance of mitochondrial and lysosomal pathways in PPS and LSD respectively and with PD representing an intermediate form of disease.
Summary
During the past 18 months important advances have been made towards understanding the genetic and pathological underpinnings of the Pallidopyramidal syndromes with important implications for clinical practice and future treatment developments.
doi:10.1097/WCO.0b013e3283632e83
PMCID: PMC4196641  PMID: 23817214
Neurodegeneration with brain iron accumulation; Hallervordern-Spatz disease; Parkinson’s disease; lysosomal storage disorders
14.  Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia 
Brain  2014;137(12):3200-3212.
Mitochondrial ophthalmoplegia is a genetically heterogeneous disorder. Horga et al. investigate whether peripheral neuropathy can predict the underlying genetic defect in patients with progressive external ophthalmoplegia. Results indicate that neuropathy is highly predictive of a nuclear DNA defect and that it is rarely associated with single mitochondrial DNA deletions.
Progressive external ophthalmoplegia is a common clinical feature in mitochondrial disease caused by nuclear DNA defects and single, large-scale mitochondrial DNA deletions and is less frequently associated with point mutations of mitochondrial DNA. Peripheral neuropathy is also a frequent manifestation of mitochondrial disease, although its prevalence and characteristics varies considerably among the different syndromes and genetic aetiologies. Based on clinical observations, we systematically investigated whether the presence of peripheral neuropathy could predict the underlying genetic defect in patients with progressive external ophthalmoplegia. We analysed detailed demographic, clinical and neurophysiological data from 116 patients with genetically-defined mitochondrial disease and progressive external ophthalmoplegia. Seventy-eight patients (67%) had a single mitochondrial DNA deletion, 12 (10%) had a point mutation of mitochondrial DNA and 26 (22%) had mutations in either POLG, C10orf2 or RRM2B, or had multiple mitochondrial DNA deletions in muscle without an identified nuclear gene defect. Seventy-seven patients had neurophysiological studies; of these, 16 patients (21%) had a large-fibre peripheral neuropathy. The prevalence of peripheral neuropathy was significantly lower in patients with a single mitochondrial DNA deletion (2%) as compared to those with a point mutation of mitochondrial DNA or with a nuclear DNA defect (44% and 52%, respectively; P < 0.001). Univariate analyses revealed significant differences in the distribution of other clinical features between genotypes, including age at disease onset, gender, family history, progressive external ophthalmoplegia at clinical presentation, hearing loss, pigmentary retinopathy and extrapyramidal features. However, binomial logistic regression analysis identified peripheral neuropathy as the only independent predictor associated with a nuclear DNA defect (P = 0.002; odds ratio 8.43, 95% confidence interval 2.24–31.76). Multinomial logistic regression analysis identified peripheral neuropathy, family history and hearing loss as significant predictors of the genotype, and the same three variables showed the highest performance in genotype classification in a decision tree analysis. Of these variables, peripheral neuropathy had the highest specificity (91%), negative predictive value (83%) and positive likelihood ratio (5.87) for the diagnosis of a nuclear DNA defect. These results indicate that peripheral neuropathy is a rare finding in patients with single mitochondrial DNA deletions but that it is highly predictive of an underlying nuclear DNA defect. This observation may facilitate the development of diagnostic algorithms. We suggest that nuclear gene testing may enable a more rapid diagnosis and avoid muscle biopsy in patients with progressive external ophthalmoplegia and peripheral neuropathy.
doi:10.1093/brain/awu279
PMCID: PMC4240292  PMID: 25281868
mitochondrial DNA; mitochondrial DNA deletion; peripheral neuropathy; POLG; progressive external ophthalmoplegia
15.  C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies 
Neurology  2014;82(4):292-299.
Objective:
In many cases where Huntington disease (HD) is suspected, the genetic test for HD is negative: these are known as HD phenocopies. A repeat expansion in the C9orf72 gene has recently been identified as a major cause of familial and sporadic frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Our objective was to determine whether this mutation causes HD phenocopies.
Methods:
A cohort of 514 HD phenocopy patients were analyzed for the C9orf72 expansion using repeat primed PCR. In cases where the expansion was found, Southern hybridization was performed to determine expansion size. Clinical case notes were reviewed to determine the phenotype of expansion-positive cases.
Results:
Ten subjects (1.95%) had the expansion, making it the most common identified genetic cause of HD phenocopy presentations. The size of expansion was not significantly different from that associated with other clinical presentations of C9orf72 expanded cases. The C9orf72 expansion-positive subjects were characterized by the presence of movement disorders, including dystonia, chorea, myoclonus, tremor, and rigidity. Furthermore, the age at onset in this cohort was lower than previously reported for subjects with the C9orf72 expansion and included one case with pediatric onset.
Discussion:
This study extends the known phenotype of the C9orf72 expansion in both age at onset and movement disorder symptoms. We propose a revised clinico-genetic algorithm for the investigation of HD phenocopy patients based on these data.
doi:10.1212/WNL.0000000000000061
PMCID: PMC3929197  PMID: 24363131
16.  Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers 
Brain  2014;137(9):2480-2492.
Mutations in the gene encoding the dopamine-synthetic enzyme GTP cyclohydrolase-1 (GCH1) cause DOPA-responsive dystonia (DRD). Mencacci et al. demonstrate that GCH1 variants are associated with an increased risk of Parkinson's disease in both DRD pedigrees and in patients with Parkinson's disease but without a family history of DRD.
GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson’s disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson’s disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson’s disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher’s exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4–25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson’s disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson’s disease.
doi:10.1093/brain/awu179
PMCID: PMC4132650  PMID: 24993959
GCH1; DOPA-responsive-dystonia; Parkinson’s disease; dopamine; exome sequencing
17.  Sporadic inclusion body myositis: the genetic contributions to the pathogenesis 
Sporadic inclusion body myositis (sIBM) is the commonest idiopathic inflammatory muscle disease in people over 50 years old. It is characterized by slowly progressive muscle weakness and atrophy, with typical pathological changes of inflammation, degeneration and mitochondrial abnormality in affected muscle fibres. The cause(s) of sIBM are still unknown, but are considered complex, with the contribution of multiple factors such as environmental triggers, ageing and genetic susceptibility. This review summarizes the current understanding of the genetic contributions to sIBM and provides some insights for future research in this mysterious disease with the advantage of the rapid development of advanced genetic technology. An international sIBM genetic study is ongoing and whole-exome sequencing will be applied in a large cohort of sIBM patients with the aim of unravelling important genetic risk factors for sIBM.
doi:10.1186/1750-1172-9-88
PMCID: PMC4071018  PMID: 24948216
Inclusion body myositis; Inclusion body myopathy; IBM; Genes; Genetics; Exome sequencing
18.  Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation 
Brain  2013;136(6):1708-1717.
Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a ‘halo’ of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.
doi:10.1093/brain/awt095
PMCID: PMC3673459  PMID: 23687123
iron; NBIA; autophagy; basal ganglia; Rett syndrome
19.  The instability of the BTB-KELCH protein Gigaxonin causes Giant Axonal Neuropathy and constitutes a new penetrant and specific diagnostic test 
Background
The BTB-KELCH protein Gigaxonin plays key roles in sustaining neuron survival and cytoskeleton architecture. Indeed, recessive mutations in the Gigaxonin-encoding gene cause Giant Axonal Neuropathy (GAN), a severe neurodegenerative disorder characterized by a wide disorganization of the Intermediate Filament network. Growing evidences suggest that GAN is a continuum with the peripheral neuropathy Charcot-Marie-Tooth diseases type 2 (CMT2). Sharing similar sensory-motor alterations and aggregation of Neurofilaments, few reports have revealed that GAN and some CMT2 forms can be misdiagnosed on clinical and histopathological examination. The goal of this study is to propose a new differential diagnostic test for GAN/CMT2. Moreover, we aim at identifying the mechanisms causing the loss-of-function of Gigaxonin, which has been proposed to bind CUL3 and substrates as part of an E3 ligase complex.
Results
We establish that determining Gigaxonin level constitutes a very valuable diagnostic test in discriminating new GAN cases from clinically related inherited neuropathies. Indeed, in a set of seven new families presenting a neuropathy resembling GAN/CMT2, only five exhibiting a reduced Gigaxonin abundance have been subsequently genetically linked to GAN. Generating the homology modeling of Gigaxonin, we suggest that disease mutations would lead to a range of defects in Gigaxonin stability, impairing its homodimerization, BTB or KELCH domain folding, or CUL3 and substrate binding. We further demonstrate that regardless of the mutations or the severity of the disease, Gigaxonin abundance is severely reduced in all GAN patients due to both mRNA and protein instability mechanisms.
Conclusions
In this study, we developed a new penetrant and specific test to diagnose GAN among a set of individuals exhibiting CMT2 of unknown etiology to suggest that the prevalence of GAN is probably under-evaluated among peripheral neuropathies. We propose to use this new test in concert with the clinical examination and prior to the systematic screening of GAN mutations that has shown strong limitations for large deletions. Combining the generation of the structural modeling of Gigaxonin to an analysis of Gigaxonin transcripts and proteins in patients, we provide the first evidences of the instability of this E3 ligase adaptor in disease.
doi:10.1186/2051-5960-2-47
PMCID: PMC4234992  PMID: 24758703
CMT2; GAN; Diagnosis; Gigaxonin; E3 ligase; Modelization; Instability
20.  Novel single base-pair deletion in exon 1 of XK gene leading to McLeod syndrome with chorea, muscle wasting, peripheral neuropathy, acanthocytosis and haemolysis 
Journal of the Neurological Sciences  2014;339(1-2):220-222.
We present a 70-year-old male patient of Greek origin with choreatic movements of the tongue and face, lower limb muscle weakness, peripheral neuropathy, elevated creatinephosphokinase (CPK), acanthocytosis and haemolysis in the absence of Kell RBC antigens with an additional Factor IX-deficiency. Genetic testing for mutations in the three exons of the XK gene revealed a previously unreported hemizygous single base-pair frameshift deletion at exon 1 (c.229delC, p.Leu80fs). In conclusion, we hereby describe a rare phenotype of a patient with McLeod syndrome which was discovered coincidentally during routine blood group testing and consecutively genetically confirmed.
Highlights
•McLeod syndrome with chorea, muscle wasting, and peripheral neuropathy•Acanthocytosis and haemolysis in the absence of Kell RBC antigens•McLeod syndrome with an additional Factor IX deficiency•Novel hemizygous single base-pair frameshift deletion in the XK gene
doi:10.1016/j.jns.2014.01.034
PMCID: PMC3988988  PMID: 24529944
McLeod syndromes; XK gene; Novel mutation; Frameshift deletion; Acanthocytosis; Chorea; Non-CGD
21.  Mutations in gamma adducin are associated with inherited cerebral palsy 
Annals of neurology  2013;74(6):805-814.
OBJECTIVE
Cerebral palsy is estimated to affect nearly 1 in 500 children, and although prenatal and perinatal contributors have been well-characterized, at least 20% of cases are believed to be inherited. Previous studies have identified mutations in the actin-capping protein KANK1 and the adaptor protein -4 complex in forms of inherited cerebral palsy, suggesting a role for components of the dynamic cytoskeleton in the genesis of the disease.
METHODS
We studied a multiplex consanguineous Jordanian family by homozygosity mapping and exome sequencing, then used patient-derived fibroblasts to examine functional consequences of the mutation we identified in vitro. We subsequently studied the effects of adducin loss of function in drosophila.
RESULTS
We identified a homozygous c.1100G>A [p.G367D] mutation in ADD3, encoding gamma adducin in all affected members of the index family. Follow-up experiments in patient fibroblasts found that the p.G367D mutation, which occurs within the putative oligomerization critical region, impairs the ability of gamma adducin to associate with the alpha subunit. This mutation impairs the normal actin capping function of adducin, leading to both abnormal proliferation and migration in cultured patient fibroblasts. Loss of function studies of the Drosophila adducin ortholog hts confirmed a critical role for adducin in locomotion.
INTERPRETATION
Although likely a rare cause of cerebral palsy, our findings indicate a critical role for adducins in regulating the activity of the actin cytoskeleton, suggesting that impaired adducin function may lead to neuromotor impairment and further implicating abnormalities of the dynamic cytoskeleton as a pathogenic mechanism contributing to cerebral palsy.
doi:10.1002/ana.23971
PMCID: PMC3952628  PMID: 23836506
22.  Defective N-linked protein glycosylation pathway in congenital myasthenic syndromes 
Brain  2013;136(3):692-695.
doi:10.1093/brain/awt042
PMCID: PMC3580274  PMID: 23436500
23.  The Parkinson’s disease genes Fbxo7 and Parkin interact to mediate mitophagy 
Nature neuroscience  2013;16(9):10.1038/nn.3489.
Compelling evidence indicates that two autosomal recessive Parkinson’s disease genes, PINK1 (PARK6) and Parkin (PARK2), co-operate to mediate the autophagic clearance of damaged mitochondria (mitophagy). Mutations in the F-box domain containing protein Fbxo7 (PARK15) also cause early onset autosomal recessive Parkinson’s disease by an unknown mechanism. Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and plays a role in Parkin-mediated mitophagy. Cells with reduced Fbxo7 expression show deficiencies in Parkin mitochondrial translocation, ubiquitination of mitofusin 1 and mitophagy. In Drosophila, ectopic overexpression of Fbxo7 rescued loss of Parkin supporting a functional relationship between the two proteins. Parkinson’s disease-causing mutations in Fbxo7 interfere with this process, emphasising the importance of mitochondrial dysfunction in Parkinson’s disease pathogenesis.
doi:10.1038/nn.3489
PMCID: PMC3827746  PMID: 23933751
Fbxo7; Parkin; PINK1; mitofusin 1; mitophagy; Drosophila; Parkinson’s disease
24.  Mutational analysis of parkin and PINK1 in multiple system atrophy 
Neurobiology of aging  2010;32(3):548.e5-548.e7.
Multiple system atrophy (MSA) and Parkinson’s disease (PD) are progressive neurodegenerative disorders with overlapping clinical, biochemical and genetic features. To test the hypothesis that the Parkinson’s disease genes parkin and PINK1 also play a role in the pathogenesis of MSA, we performed a mutational screening study involving 87 pathology-proven MSA cases. In parkin we identified eight sequence variants and four heterozygous deletions, and in PINK1 we identified nine variants of which two silent mutations have not been previously reported (p.Gly189Gly and p.Arg337Arg). The frequencies of the observed variants were not significantly different from previously published control data and none of the possibly pathogenic variants were found in a homozygous state. Our results indicate that genetic variants at the parkin and PINK1 loci do not play a critical role in the pathogenesis of MSA.
doi:10.1016/j.neurobiolaging.2009.11.020
PMCID: PMC3934211  PMID: 20034704
multiple system atrophy; Parkinson’s disease; PINK1; parkin
25.  Concomitant progressive supranuclear palsy and chronic traumatic encephalopathy in a boxer 
We report the case of a 75-year-old ex-professional boxer who developed diplopia and eye movement abnormalities in his 60’s followed by memory impairment, low mood and recurrent falls. Examination shortly before death revealed hypomimia, dysarthria, vertical supranuclear gaze palsy and impaired postural reflexes. Pathological examination demonstrated 4-repeat tau neuronal and glial lesions, including tufted astrocytes, consistent with a diagnosis of progressive supranuclear palsy. In addition, neurofibrillary tangles composed of mixed 3-repeat and 4-repeat tau and astrocytic tangles in a distribution highly suggestive of chronic traumatic encephalopathy were observed together with limbic TDP-43 pathology. Possible mechanisms for the co-occurrence of these two tau pathologies are discussed.
doi:10.1186/2051-5960-2-24
PMCID: PMC3996066  PMID: 24559032
Boxer; Dementia pugilistica; Chronic traumatic encephalopathy; Progressive supranuclear palsy; Tauopathy

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