- Repeat-associated non-AUG (RAN) translation and other molecular mechanisms in Fragile X Tremor Ataxia Syndrome. [Journal Article]
- BRBrain Res 2018 Feb 14
- Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset inherited neurodegenerative disorder characterized by progressive intention tremor, gait ataxia and dementia associated with mild b...
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset inherited neurodegenerative disorder characterized by progressive intention tremor, gait ataxia and dementia associated with mild brain atrophy. The cause of FXTAS is a premutation expansion, of 55 to 200 CGG repeats localized within the 5'UTR of FMR1. These repeats are transcribed in the sense and antisense directions into mutants RNAs, which have increased expression in FXTAS. Furthermore, CGG sense and CCG antisense expanded repeats are translated into novel proteins despite their localization in putatively non-coding regions of the transcript. Here we focus on two proposed disease mechanisms for FXTAS: 1) RNA gain-of-function, whereby the mutant RNAs bind specific proteins and preclude their normal functions, and 2) repeat-associated non-AUG (RAN) translation, whereby translation through the CGG or CCG repeats leads to the production of toxic homopolypeptides, which in turn interfere with a variety of cellular functions. Here, we analyze the data generated to date on both of these potential molecular mechanisms and lay out a path forward for determining which factors drive FXTAS pathogenicity.
- Probable Diagnosis of a Patient with Niemann-Pick Disease Type C: Managing Pitfalls of Exome Sequencing. [Journal Article]
- JRJIMD Rep 2018 Feb 17
- Here, we present a case of a 31-year-old man with progressive cognitive decline, ataxia, and dystonia. Extensive laboratory, radiographic, and targeted genetic studies over the course of several year...
Here, we present a case of a 31-year-old man with progressive cognitive decline, ataxia, and dystonia. Extensive laboratory, radiographic, and targeted genetic studies over the course of several years failed to yield a diagnosis. Initial whole exome sequencing through a commercial laboratory identified several variants of uncertain significance; however, follow-up clinical examination and testing ruled each of these out. Eventually, repeat whole exome sequencing identified a known pathogenic intronic variant in the NPC1 gene (NM_000271.4, c.1554-1009G>A) and an additional heterozygous exonic variant of uncertain significance in the NPC1 gene (NM_000271.4, c.2524T>C). Follow-up biochemical testing was consistent with a diagnosis of probable Niemann-Pick disease Type C (NP-C). This case illustrates the potential of whole exome sequencing for diagnosing rare complex neurologic diseases. It also identifies several potential common pitfalls that must be navigated by clinicians when interpreting commercial whole exome sequencing results.
- Survival strategies for mouse cerebellar Purkinje neurons lacking PMCA2. [Review]
- NLNeurosci Lett 2018 Jan 10; 663:25-28
- Expression of the fast calcium extrusion protein, PMCA2, in the cerebellum is amongst the highest found throughout the central nervous system, and unsurprisingly PMCA2 knockout mice exhibit cerebella...
Expression of the fast calcium extrusion protein, PMCA2, in the cerebellum is amongst the highest found throughout the central nervous system, and unsurprisingly PMCA2 knockout mice exhibit cerebellar ataxia or loss of controlled movement. The sole output neurons of the cerebellar cortex, Purkinje neurons, are functionally compromised in these knockout mice, yet remarkably these neurons survive. In this mini-review we review and speculate on the importance of multiple PMCA2 dependent actions at cellular and synaptic sites within the cerebellar Purkinje neuron network. We also explore how loss of PMCA2-/-can lead to the ataxic phenotype, but can paradoxically also minimise calcium rises in cerebellar Purkinje neurons, thereby ensuring their resilience and survival.
- Clival meningocele causing bilateral hearing loss in a child due to superficial siderosis of the central nervous system: case report. [Journal Article]
- JNJ Neurosurg Pediatr 2018 Feb 16; :1-6
- Superficial siderosis (SS) of the CNS is a rare and often unrecognized condition. Caused by hemosiderin deposition from chronic, repetitive hemorrhage in the subarachnoid space, it results in parench...
Superficial siderosis (SS) of the CNS is a rare and often unrecognized condition. Caused by hemosiderin deposition from chronic, repetitive hemorrhage in the subarachnoid space, it results in parenchymal damage in the subpial layers of the brain and spinal cord. T2-weighted MRI shows the characteristic hypointensity of hemosiderin deposition, classically occurring around the cerebellum, brainstem, and spinal cord. Patients present with progressive gait ataxia and sensorineural hearing impairment. Although there have been several studies, case reports, and review articles over the years, the clear pathophysiology of subarachnoid space hemorrhage remains to be elucidated. The proposed causes include prior intradural surgery, prior trauma, tumors, vascular abnormalities, nerve root avulsion, and dural abnormalities. Surgical repair of a dural defect associated with SS has been shown to be efficacious at preventing symptomatic progression. There have been several reports of dural defects within the spinal canal treated with surgery. Here, the authors present the first known case of a dural defect of the ventral skull base, namely a clival meningocele, presumed to be causing SS. In this case report, a 10-year-old girl with a history of head trauma at the age of 3 years was found to have a clival meningocele 3 years after her original trauma. On follow-up imaging, the patient was found to have radiographic growth of the meningocele along with evidence of SS of the CNS. The patient was treated conservatively until she began to have progressive hearing loss. It was presumed that the growing meningocele was the source of her SS. An endoscopic endonasal transclival approach with a multilayer dural reconstruction was performed to fix the dural defect and repair the meningocele in hopes of mitigating the progression of her symptoms. At her 12-month postoperative follow-up, she was doing well, with audiometry showing a slightly decreased hearing threshold in the left ear but improved speech discrimination bilaterally. Postoperative MRI showed a stable level of hemosiderin deposition and meningocele repair. Long-term follow-up will be necessary to evaluate for continued clinical stabilization or possible improvement.
- m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration. [Review]
- CRCell Res 2018 Feb 16
- The function of mitochondria depends on ubiquitously expressed and evolutionary conserved m-AAA proteases in the inner membrane. These ATP-dependent peptidases form hexameric complexes built up of ho...
The function of mitochondria depends on ubiquitously expressed and evolutionary conserved m-AAA proteases in the inner membrane. These ATP-dependent peptidases form hexameric complexes built up of homologous subunits. AFG3L2 subunits assemble either into homo-oligomeric isoenzymes or with SPG7 (paraplegin) subunits into hetero-oligomeric proteolytic complexes. Mutations in AFG3L2 are associated with dominant spinocerebellar ataxia (SCA28) characterized by the loss of Purkinje cells, whereas mutations in SPG7 cause a recessive form of hereditary spastic paraplegia (HSP7) with motor neurons of the cortico-spinal tract being predominantly affected. Pleiotropic functions have been assigned to m-AAA proteases, which act as quality control and regulatory enzymes in mitochondria. Loss of m-AAA proteases affects mitochondrial protein synthesis and respiration and leads to mitochondrial fragmentation and deficiencies in the axonal transport of mitochondria. Moreover m-AAA proteases regulate the assembly of the mitochondrial calcium uniporter (MCU) complex. Impaired degradation of the MCU subunit EMRE in AFG3L2-deficient mitochondria results in the formation of deregulated MCU complexes, increased mitochondrial calcium uptake and increased vulnerability of neurons for calcium-induced cell death. A reduction of calcium influx into the cytosol of Purkinje cells rescues ataxia in an AFG3L2-deficient mouse model. In this review, we discuss the relationship between the m-AAA protease and mitochondrial calcium homeostasis and its relevance for neurodegeneration and describe a novel mouse model lacking MCU specifically in Purkinje cells. Our results pledge for a novel view on m-AAA proteases that integrates their pleiotropic functions in mitochondria to explain the pathogenesis of associated neurodegenerative disorders.Cell Research advance online publication 16 February 2018; doi:10.1038/cr.2018.17.
- Reversible cerebellar oedema secondary to profound hypomagnesaemia. [Journal Article]
- PNPract Neurol 2018 Feb 15
- Magnesium is the second most abundant intracellular cation. Deficiency can cause several neurological complications, including cerebellar syndromes, with various MRI findings. These include cerebella...
Magnesium is the second most abundant intracellular cation. Deficiency can cause several neurological complications, including cerebellar syndromes, with various MRI findings. These include cerebellar oedema, presumably through a similar mechanism to that in posterior reversible encephalopathy syndrome (PRES). People particularly vulnerable to deficiency include those with high alcohol consumption, excessive loss due to gastrointestinal pathology and those taking certain medications, including proton pump inhibitors. We report three patients with cerebellar syndromes associated with hypomagnesaemia. These cases support the previously reported association between hypomagnesaemia and reversible cerebellar dysfunction and illustrate the range of potential presentations. They highlight an uncommon but treatable cause of cerebellar ataxia that may present to acute neurological liaison services.
- Novel homozygous variants in ATCAY, MCOLN1, and SACS in complex neurological disorders. [Journal Article]
- PRParkinsonism Relat Disord 2018 Feb 06
- CONCLUSIONS: We expand the phenotypic, genotypic, and ethnical spectrum of mutations in these genes. Our findings alert neurologists that rare genetic causes should be considered in complex phenotypes regardless of ethnicity.
- RNA-DNA hybrids promote the expansion of Friedreich's ataxia (GAA)n repeats via break-induced replication. [Journal Article]
- NANucleic Acids Res 2018 Feb 13
- Expansion of simple DNA repeats is responsible for numerous hereditary diseases in humans. The role of DNA replication, repair and transcription in the expansion process has been well documented. Her...
Expansion of simple DNA repeats is responsible for numerous hereditary diseases in humans. The role of DNA replication, repair and transcription in the expansion process has been well documented. Here we analyzed, in a yeast experimental system, the role of RNA-DNA hybrids in genetic instability of long (GAA)n repeats, which cause Friedreich's ataxia. Knocking out both yeast RNase H enzymes, which counteract the formation of RNA-DNA hybrids, increased (GAA)n repeat expansion and contraction rates when the repetitive sequence was transcribed. Unexpectedly, we observed a similar increase in repeat instability in RNase H-deficient cells when we either changed the direction of transcription-replication collisions, or flipped the repeat sequence such that the (UUC)n run occurred in the transcript. The increase in repeat expansions in RNase H-deficient strains was dependent on Rad52 and Pol32 proteins, suggesting that break-induced replication (BIR) is responsible for this effect. We conclude that expansions of (GAA)n repeats are induced by the formation of RNA-DNA hybrids that trigger BIR. Since this stimulation is independent of which strand of the repeat (homopurine or homopyrimidine) is in the RNA transcript, we hypothesize that triplex H-DNA structures stabilized by an RNA-DNA hybrid (H-loops), rather than conventional R-loops, could be responsible.
- Low apolipoprotein A-I levels in Friedreich's ataxia and in frataxin-deficient cells: Implications for therapy. [Journal Article]
- PlosPLoS One 2018; 13(2):e0192779
- Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of...
Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure. However, the pathophysiology of heart disease in FA is non-vascular and there are conflicting data on HDL-cholesterol in FA. Two studies have shown a decrease in HDL-cholesterol compared with controls and two have shown there was no difference between FA and controls. One also showed that there was no difference in serum Apo-A-I levels in FA when compared with controls. Using a highly specific stable isotope dilution mass spectrometry-based assay, we demonstrated a 21.6% decrease in serum ApoA-I in FA patients (134.8 mg/dL, n = 95) compared with non-affected controls (172.1 mg/dL, n = 95). This is similar to the difference in serum ApoA-I levels between non-smokers and tobacco smokers. Knockdown of frataxin by > 70% in human hepatoma HepG2 cells caused a 20% reduction in secreted ApoA-I. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor caused a 200% increase in HMG-CoA in the control HepG2 cells with a similar increase in the frataxin knockdown HepG2 cells, back to levels found in the control cells. There was a concomitant 20% increase in secreted ApoA-I to levels found in the control cells that were treated with simvastatin. This study provides compelling evidence that ApoA-I levels are reduced in FA patients compared with controls and suggest that statin treatment would normalize the ApoA-I levels.
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- Migraine Variants in Children. [Journal Article]
- PAPediatr Ann 2018 Feb 01; 47(2):e50-e54
- Migraine in children can manifest in ways that are markedly different from adult migraines. In children, migraine variants are often unaccompanied by headache and include conditions such as cyclic vo...
Migraine in children can manifest in ways that are markedly different from adult migraines. In children, migraine variants are often unaccompanied by headache and include conditions such as cyclic vomiting and abdominal migraine. Children who experience these conditions are often thought to have a disorder of the gastrointestinal tract, and when evaluation is unremarkable they may be diagnosed as having a conversion reaction. Complicated migraines, on the other hand, are often accompanied by focal neurological symptoms such as ataxia, hemiparesis, or altered level of consciousness that evoke great consternation in the examining clinician. Certain episodic syndromes that may hold interest to pediatricians are also discussed in this article, mostly to emphasize the ambiguity that still surrounds these disorders, such as migraine triggered by trauma. The cardinal rule that most of these disorders are diagnoses of exclusion and can only be confirmed after extensive evaluation, either by the pediatrician or pediatric neurologist, is emphasized. [Pediatr Ann. 2018;47(2):e50-e54.].