Exome sequencing reveals a novel WDR45 frameshift mutation and inherited POLR3A heterozygous variants in a female with a complex phenotype and mixed brain MRI findings

Khalifa, Mohamed M.; Naffaa, Lena

doi:10.1016/j.ejmg.2015.05.009

Cited by 24 publications

(18 citation statements)

References 31 publications

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“…They may not be comprehensively covered by some next-generation sequencing panels and include the spinocerebellar ataxias, autosomal recessive ataxias, spastic ataxias, demyelinating and hypomyelinating leukodystrophies, and other rare metabolic and neurodegenerative disorders (table 2). [46][47][48][49][50][51][52][53] Several of the diseases in these groups, such as SCA1 (ATXN1), SCA3 (ATXN3), and Friedreich's ataxia (FXN) are triplet repeat disorders and may not therefore be covered by gene panels, even if they are extended to include wider groups of monogenic diseases associated with spasticity. [54][55][56] Particular attention should however be given to atypical presentations of treatable diseases in which lower limb spasticity occurs, often in the context of other clinical features, in the absence of T2-weighted imaging abnormalities in the spinal cord.…”

Section: Genetic Testingmentioning

confidence: 99%

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Shribman

Reid

Crosby

et al. 2019

The Lancet Neurology

215

207

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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 significantly according to the affected gene. Here, we describe the clinical and imaging characteristics of the more common forms of HSP. We discuss how to approach the diagnosis and management of a suspected case of HSP in the era of next generation sequencing, before discussing treatment and the potential of emerging therapeutic options for specific causes of HSP based on their underlying molecular mechanism.

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Section: Genetic Testingmentioning

confidence: 99%

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Shribman

Reid

Crosby

et al. 2019

The Lancet Neurology

215

207

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“…A total of 64 patients were included in the analysis, comprising 55 women (85.9%) and nine men (14.1%) (Tables and ) . Mean age at diagnosis was 27.6 ± 14 years (range 1–52), and mean age at deterioration was 27.2 ± 5.7 (range 13–39).…”

Section: Literature Reviewmentioning

confidence: 99%

“…Other clinical features of BPAN include neuropsychiatric symptoms [18,22,24], "happy demeanor" [7], and excessive drooling [7,25]. Chorea has been reported in one patient [12].…”

Section: Literature Review Demographics and Clinical Spectrum Of Bpanmentioning

confidence: 99%

“…A wide range of sleep disturbances has been reported including REM sleep disorder , excessive movement during sleep , circadian rhythm sleep disorder , hypersomnolence with choreiform movements at onset of sleep , parasomnia with nocturnal screaming , and unspecified sleep disorders . Ocular/visual involvement has been reported in 17 patients and comprises myopia , astigmatism , strabismus , abnormal pupillary shade , spontaneous retinal detachment , bilateral partial retinal coloboma , patchy loss of pupillary ruff , difficulties with eyesight with intermittent double‐vision , bilateral optic disk pallor , bilateral optic atrophy , increased visual evoked potential (VEP) latency , cortical blindness , and retinitis pigmentosa .…”

Section: Literature Reviewmentioning

confidence: 99%

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Beta‐propeller protein‐associated neurodegeneration: a case report and review of the literature

Stige

Gjerde

Houge

et al. 2018

Clinical Case Reports

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Key Clinical MessageBeta‐propeller protein‐associated neurodegeneration (BPAN) is a rare disorder, which is increasingly recognized thanks to next‐generation sequencing. Due to a highly variable phenotype, patients may present to pediatrics, neurology, psychiatry, or internal medicine. It is therefore essential that physicians of different specialties are familiar with this severe and debilitating condition.

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“…Especially for conditions that can be caused by a large number of candidate genes, WES provides an unbiased approach to identify the genetic cause, precluding comprehensive analysis of all individual genes (1–4). By contrast, in some neurological conditions, clinical symptoms or additional investigations may directly point to one or a few candidate genes, enabling faster and cheaper diagnosis by targeted gene analysis (5–7).…”

Section: Introductionmentioning

confidence: 99%

Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

Theunissen

Szklarczyk

Gerards³

et al. 2016

Front. Neurol.

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In establishing a genetic diagnosis in heterogeneous neurological disease, clinical characterization and whole exome sequencing (WES) go hand-in-hand. Clinical data are essential, not only to guide WES variant selection and define the clinical severity of a genetic defect but also to identify other patients with defects in the same gene. In an infant patient with sensorineural hearing loss, psychomotor retardation, and epilepsy, WES resulted in identification of a novel homozygous CLPP frameshift mutation (c.21delA). Based on the gene defect and clinical symptoms, the diagnosis Perrault syndrome type 3 (PRLTS3) was established. The patient’s brain-MRI revealed specific abnormalities of the subcortical and deep cerebral white matter and the middle blade of the corpus callosum, which was used to identify similar patients in the Amsterdam brain-MRI database, containing over 3000 unclassified leukoencephalopathy cases. In three unrelated patients with similar MRI abnormalities the CLPP gene was sequenced, and in two of them novel missense mutations were identified together with a large deletion that covered part of the CLPP gene on the other allele. The severe neurological and MRI abnormalities in these young patients were due to the drastic impact of the CLPP mutations, correlating with the variation in clinical manifestations among previously reported patients. Our data show that similarity in brain-MRI patterns can be used to identify novel PRLTS3 patients, especially during early disease stages, when only part of the disease manifestations are present. This seems especially applicable to the severely affected cases in which CLPP function is drastically affected and MRI abnormalities are pronounced.

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Exome sequencing reveals a novel WDR45 frameshift mutation and inherited POLR3A heterozygous variants in a female with a complex phenotype and mixed brain MRI findings

Cited by 24 publications

References 31 publications

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Beta‐propeller protein‐associated neurodegeneration: a case report and review of the literature

Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

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