A 3.9-Mb Deletion on 2p11.2 Comprising the REEP1 Gene Causes Early-Onset Atypical Parkinsonism
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ABSTRACT:
SUBMITTER: Baviera-Munoz R
PROVIDER: S-EPMC8610491 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We identified an identical and recurrent 9.4-Mbp deletion at chromosome bands 2p11.2-2p12, which occurred de novo in two unrelated patients. It is flanked at the distal and proximal breakpoints by two homologous segmental duplications consisting of low copy repeat (LCR) blocks in direct orientation, which have >99% sequence identity. Despite the fact that the deletion was almost 10?Mbp in size, the patients showed a relatively mild clinical phenotype, that is, mild-to-moderate intellectual disability, a happy disposition, speech delay and delayed motor development. Their phenotype matches with that of previously described patients. The 2p11.2-2p12 deletion includes the REEP1 gene that is associated with spastic paraplegia and phenotypic features related to this are apparent in most 2p11.2-2p12 deletion patients, but not in all. Other hemizygous genes that may contribute to the clinical phenotype include LRRTM1 and CTNNA2. We propose a recurrent but rare 2p11.2-2p12 deletion syndrome based on (1) the identical, non-random localisation of the de novo deletion breakpoints in two unrelated patients and a patient from literature, (2) the patients' phenotypic similarity and their phenotypic overlap with other 2p deletions and (3) the presence of highly identical LCR blocks flanking both breakpoints, consistent with a non-allelic homologous recombination (NAHR)-mediated rearrangement.
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Project description:Mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative disorders such as ataxia and Parkinson's disease. We describe an extended Belgian pedigree where seven individuals presented with adult-onset cerebellar ataxia, axonal peripheral ataxic neuropathy, and tremor, in variable combination with parkinsonism, seizures, cognitive decline, and ophthalmoplegia. We sought to identify the underlying molecular etiology and characterize the mitochondrial pathophysiology of this neurological syndrome.Clinical, neurophysiological, and neuroradiological evaluations were conducted. Patient muscle and cultured fibroblasts underwent extensive analyses to assess mitochondrial function. Genetic studies including genome-wide sequencing were conducted.Hallmarks of mitochondrial dysfunction were present in patients' tissues including ultrastructural anomalies of mitochondria, mosaic cytochrome c oxidase deficiency, and multiple mtDNA deletions. We identified a splice acceptor variant in POLG2, c.970-1G>C, segregating with disease in this family and associated with a concomitant decrease in levels of POLG2 protein in patient cells.This work extends the clinical spectrum of POLG2 deficiency to include an overwhelming, adult-onset neurological syndrome that includes cerebellar syndrome, peripheral neuropathy, tremor, and parkinsonism. We therefore suggest to include POLG2 sequencing in the evaluation of ataxia and sensory neuropathy in adults, especially when it is accompanied by tremor or parkinsonism with white matter disease. The demonstration that deletions of mtDNA resulting from autosomal-dominant POLG2 variant lead to a monogenic neurodegenerative multicomponent syndrome provides further evidence for a major role of mitochondrial dysfunction in the pathomechanism of nonsyndromic forms of the component neurodegenerative disorders.
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Project description:This update discusses novel aspects on genetics, diagnosis, and treatments of atypical parkinsonism published over the past 2 years.A genome-wide association study identified new genetic risk factors for progressive supranuclear palsy and new genetic conditions presenting with atypical parkinsonism have been described. The clinical criteria for diagnosis of corticobasal degeneration have been revised, and for progressive supranuclear palsy are under revision. Novel molecular techniques to identify possible biomarkers, as in other neurodegenerative disorders, have started being studied on atypical parkinsonian conditions, and although preliminary results seem promising, further studies are urgently warranted. Therapeutic trials based on disease-specific targets have shown no clinical improvement.The knowledge obtained recently on atypical parkinsonian conditions points out the major deficits in this field. With the expanding phenotypical spectrum of atypical parkinsonian conditions, the early identification of patients has become difficult. The inability of conventional methods to identify these disorders earlier and better than clinicians, and the recent failure of promising therapeutic compounds, highlight the fact that the lack of biomarkers is probably the greatest limitation for developing treatments for these disorders. Thus, current and future research in this direction will be crucial.
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Project description:PURPOSE OF REVIEW:Atypical parkinsonian disorders (APDs) comprise a heterogenous group of disorders including multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Based on literature published in 2010, we here review recent advances in the APD field. RECENT FINDINGS:Genome-wide association studies have provided robust evidence of increased disease risk conferred by synuclein and tau gene variants in MSA and PSP. Furthermore, advanced imaging tools have been established in the differential diagnosis and as surrogate markers of disease activity in patients with APDs. Finally, although therapeutic options are still disappointing, translational research into disease-modifying strategies has accelerated with the increasing availability of transgenic animal models, particularly for MSA. SUMMARY:Remarkable progress has been achieved in the field of APDs, and advances in the genetics, molecular biology and neuroimaging of these disorders will continue to facilitate intensified clinical trial activity.
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Project description:Hypotonia-cystinuria syndrome (HCS) and 2p21 deletion syndrome are two recessive contiguous gene deletion syndromes associated with cystinuria type I. In HCS patients, only SLC3A1 and PREPL are disrupted. In the 2p21 deletion syndrome, two additional genes (C2orf34 and PPM1B) are lost. Molecular analysis of the SLC3A1/PREPL locus was performed in the patients using quantitative polymerase chain reaction (PCR) methods. HCS in both siblings was confirmed with the deletion screen of the SLC3A1/PREPL locus. Fine mapping of the breakpoint revealed a deletion of 77.4 kb, including three genes: SLC3A1, PREPL and C2orf34. Features not present in classical HCS were a mild/moderate mental retardation and a respiratory chain complex IV deficiency. We report the first patients with a deletion of SLC3A1, PREPL and C2orf34. They present with a phenotype intermediate between HCS and 2p21 deletion syndrome.
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Project description:Williams-Beuren syndrome is a rare multisystem neurodevelopmental disorder caused by a 1.55-1.84-Mb hemizygous deletion on chromosome 7q11.23. The classical phenotype consists of characteristic facial features, supravalvular aortic stenosis, intellectual disability, overfriendliness, and visuospatial impairment. So far, 26-28 genes have been shown to contribute to the multisystem phenotype associated with Williams-Beuren syndrome. Among them, haploinsufficiency of the ELN gene has been shown to cause the cardiovascular anomalies. Identification of patients with atypical deletions has provided valuable information for genotype-phenotype correlation, in which other genes such as LIMK1,CLIP2, GTF2IRD1, or GTF2I have been correlated with specific cognitive profiles or craniofacial features. Here, we report the clinical and molecular characteristics of a patient with an atypical deletion that does not include the GTF2I gene and only partially includes the GTF2IRD1 gene.
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Project description:In a 2 and a half-year-old girl with onset of puberty before the age of 5 months, short stature, hand anomalies and severe mental retardation, an 8.9 Mb interstitial 19p13 duplication containing 215 predicted genes was detected. It was initially assumed that the duplication involved the kisspeptin receptor gene, GPR54, known to stimulate induction of puberty, but more refined duplication mapping excluded this possibility. In an attempt to further understand the genotype-phenotype correlation, global gene expression was measured in skin fibroblasts. The overall expression pattern was quite similar to controls, and only about 25% of the duplicated genes had an expression level that was increased by more than 1.3-fold, with no obvious changes that could explain the precocious puberty. The proband's mother carried a balanced between-arm insertion of the duplicated segment that resembled a pericentric inversion. The same insertion was found in several other family members, including one who had lost a daughter with severe mental retardation and menarche at the age of 10 years. Another close relative was severely mentally retarded, but neither dysmorphic nor microcephalic. His phenotype was initially ascribed to a presumed cryptic chromosome 19 imbalance caused by the 19p-into19q insertion, but subsequent array-CGH detected a 3.9-Mb deletion of 2q23.3q24.1. This novel microdeletion involves seven genes, of which FMNL2, a suggested regulator of Rho-GTPases, and NR4A2, an essential gene for differentiation of dopaminergic neurons, may be critical genes for the proposed 2q23q24 microdeletion syndrome.
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Project description:In recent decades, genetic research has nominated promising pathways and biological insights contributing to the etiological landscape of parkinsonism-related dystonias and atypical parkinsonism-related syndromes. Several disease-causing mutations and genetic risk factors have been unraveled, providing a deeper molecular understanding of the complex genetic architecture underlying these conditions. These disorders are difficult to accurately diagnose and categorize, thus making genetics research challenging. On one hand, dystonia is an umbrella term linked to clinically heterogeneous forms of disease including dopa-responsive dystonia, myoclonus-dystonia, rapid-onset dystonia-parkinsonism and dystonia-parkinsonism, often viewed as a precursor to Parkinson's disease. On the other hand, atypical parkinsonism disorders, such as progressive supranuclear palsy, multiple system atrophy and corticobasal degeneration, are rare in nature and represent a wide range of diverse and overlapping phenotypic variabilities, with genetic research limited by sample size availability. The current review summarizes the plethora of available genetic information for these diseases, outlining limits and future directions.
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Project description:Atypical hemolytic uremic syndrome (aHUS) is a complex complement-mediated disease that progresses to end-stage renal failure (ESRF) in 50% of cases. Dysregulation of the alternative pathway (AP) of the complement cascade manifests as microangiopathic anaemia and thrombocytopenia. Multiple genes in the AP have been implicated in disease pathogenesis. Here, we report the clinical presentation of an affected patient that was inconsistent with genotype-phenotype data for carriers of CD46 mutations. Tests of AP function in this patient suggested additional genetic factors, and in-depth studies revealed a de novo heterozygous deletion that creates a novel CFH/CFHR1 fusion protein.
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