Michelle Farrar - Academia.edu (original) (raw)
Papers by Michelle Farrar
Current Molecular Medicine, 2009
Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder c... more Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder characterised by muscle weakness and atrophy due to degeneration of motor neurons of the spinal cord and cranial motor nuclei. The clinical phenotype incorporates a wide spectrum. No effective treatment is currently available and patients may experience severe physical disability which is often life limiting. The most common type of SMA is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by deletion, conversion or mutation and results in insufficient levels of survival motor neuron (SMN) protein in motor neurons. While diagnosis is usually achieved by genetic testing, an illustrative clinical case is described that highlights the molecular and diagnostic complexities. While there is an emerging picture concerning the function of the SMN protein and the molecular pathophysiological mechanisms underpinning the disease, a number of substantial issues remain unresolved. The selective vulnerability of the motor neuron and the site and timing of the primary pathogenesis are not yet determined. Utilising the organisation of the SMN genomic region, recent advances have identified a number of potential therapeutic targets. As such, this review incorporates discussion of the clinical manifestations, molecular genetics, diagnosis, mechanisms of disease pathogenesis and development of novel treatment strategies.
Neurotherapeutics, 2014
Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron... more Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron loss in the spinal cord and lower brainstem, muscle weakness, and atrophy. The clinical and genetic phenotypes incorporate a wide spectrum that is differentiated based on age of onset, pattern of muscle involvement, and inheritance pattern. Over the past several years, rapid advances in genetic technology have accelerated the identification of causative genes and provided important advances in understanding the molecular and biological basis of SMA and insights into the selective vulnerability of the motor neuron. Common pathophysiological themes include defects in RNA metabolism and splicing, axonal transport, and motor neuron development and connectivity. Together these have revealed potential novel treatment strategies, and extensive efforts are being undertaken towards expedited therapeutics. While a number of promising therapies for SMA are emerging, defining therapeutic windows and developing sensitive and relevant biomarkers are critical to facilitate potential success in clinical trials. This review incorporates an overview of the clinical manifestations and genetics of SMA, and describes recent advances in the understanding of mechanisms of disease pathogenesis and development of novel treatment strategies.
Pediatrics, 2010
The pathophysiology of stroke-like episodes in MELAS (mitochondrial myopathy, encephalopathy, lac... more The pathophysiology of stroke-like episodes in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) remains unresolved. Possible mechanisms include mitochondrial angiopathy, cytopathy, or both, collectively resulting in cellular energy depletion. To clarify disease mechanisms, axonal excitability properties were investigated in a 10-year-old child with MELAS. Serial assessments during a stroke-like episode revealed reversible depolarization of the axonal membrane consistent with disruption of energy-dependent processes. Axonal parameters correlated with the clinical assessment of central dysfunction and biochemical measures of acidosis. Novel axonal excitability techniques have established acute, reversible ischemic-like depolarization that may serve as a surrogate marker of central events that develop during stroke-like episodes in MELAS.
Muscle & nerve, 2014
Patients with hereditary neuropathy with liability to pressure palsies (HNPP) manifest with episo... more Patients with hereditary neuropathy with liability to pressure palsies (HNPP) manifest with episodes of focal paresis when exposed to mechanical stress, although the basis for vulnerability to conduction block remains relatively unexplained. Axonal excitability techniques were utilized to provide insights into pathophysiological mechanisms in 13 HNPP patients, stimulating median motor and sensory axons at the wrist. In HNPP, distal latencies were prolonged, and motor and sensory amplitudes were reduced. Threshold was increased. Depolarizing and hyperpolarizing electrotonus was greater, and resting current-threshold slope was reduced. There were greater threshold changes in superexcitability, and refractoriness was decreased. Taken together, excitability testing in patients with HNPP established axonal hyperpolarization in both motor and sensory axons that may be attributable to changes in nerve architecture. In turn, the hyperpolarized resting membrane potential in HNPP may be a maj...
The Journal of Physiology, 2013
• The evolution of human peripheral nerve function after birth to facilitate more complex neural ... more • The evolution of human peripheral nerve function after birth to facilitate more complex neural tasks has not been fully elucidated. • The present study has established the changes that occur in nerve function in developing humans using specialized non-invasive excitability techniques in infants, children, adolescents and young adults for the first time. • The activity of axonal K + conductances reduces with formation of the axo-glial junction.
Journal of Clinical Neuroscience, 2010
Background: Neuronal ion channel disorders can manifest as epilepsy, migraine, ataxia and neuromy... more Background: Neuronal ion channel disorders can manifest as epilepsy, migraine, ataxia and neuromyotonia. Clinical diagnosis is challenging as features may be paroxysmal. Structural assessment is unhelpful because channelopathies predominantly affect neuronal function. Nerve excitability studies provide multidimensional information about the function of ion channels expressed in peripheral axons. The aim of this study was to test the hypothesis that the genetic channelopathy Benign Familial Neonatal Convulsions (BFNC) due to mutations of KCNQ2 encoding the Kv7.2 subunit of slow axonal potassium channels is associated with characteristically abnormal peripheral nerve excitability, even in the absence of peripheral nerve signs.
Clinical Neurophysiology, 2010
Clinical Neurophysiology, Volume 121, Issue 4, Pages e2, April 2010, Authors:Michelle A. Farrar; ... more Clinical Neurophysiology, Volume 121, Issue 4, Pages e2, April 2010, Authors:Michelle A. Farrar; Cindy S.-Y. Lin; Arun Krishnan; Susanna B. Park; Peter Ian Andrews; Matthew C. Kiernan.
Brain, 2011
Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with ... more Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with onset in developing and maturing patients. Furthermore, the rate of degeneration appears to slow over time, at least in the milder forms. To investigate disease pathophysiology and potential adaptations, the present study utilized axonal excitability studies to provide insights into axonal biophysical properties and explored correlation with clinical severity. Multiple excitability indices (stimulus-response curve, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle) were investigated in 25 genetically characterized adolescent and adult patients with spinal muscular atrophy, stimulating the median motor nerve at the wrist. Results were compared with 50 age-matched controls. The Medical Research Council sum score and Spinal Muscular Atrophy Functional Rating Scale were used to define the strength and motor functional status of patients with spinal muscular atrophy. In patients with spinal muscular atrophy, there were reductions in compound muscle action potential amplitude (P 5 0.0005) associated with reduction in stimulus response slope (P 5 0.0005), confirming significant axonal loss. In the patients with mild or ambulatory spinal muscular atrophy, there was reduction of peak amplitude without alteration in axonal excitability; in contrast, in the non-ambulatory or severe spinal muscular atrophy cohort prominent changes in axonal function were apparent. Specifically, there were steep changes in the early phase of hyperpolarization in threshold electrotonus (P 5 0.0005) that correlated with clinical severity. Additionally, there were greater changes in depolarizing threshold electrotonus (P 5 0.0005) and prolongation of the strength-duration time constant (P = 0.001). Mathematical modelling of the excitability changes obtained in patients with severe spinal muscular atrophy supported a mixed pathology comprising features of axonal degeneration and regeneration. The present study has provided novel insight into the pathophysiology of spinal muscular atrophy, with identification of functional abnormalities involving axonal K + and Na + conductances and alterations in passive membrane properties, the latter linked to the process of neurodegeneration.
Archives of Neurology, 2012
To gain further insight into disease pathophysiologic process and potential adaptations through i... more To gain further insight into disease pathophysiologic process and potential adaptations through investigating whether cortical dysfunction or plasticity is a feature of spinal muscle atrophy (SMA). Prospective, double-center study. Outpatient clinics and research institute. Clinical assessments, combined with threshold-tracking transcranial magnetic stimulation techniques, were completed in 11 genetically characterized patients with SMA. Clinical, functional, and neurophysiologic variables were compared between the 11 patients with SMA types 2 and 3, 24 healthy control participants, and 81 patients with amyotrophic lateral sclerosis (ALS) serving as disease controls. Maximal motor-evoked potential amplitude as a percentage of the compound muscle action potential was significantly increased in patients with SMA compared with the healthy controls but was similar to that in ALS (SMA, mean [SE], 39.7% [4.0%]; ALS, 38.8% [2.8%]; controls, 20.3% [2.5%]; F = 10.1; P < .001). In contrast, short-interval intracortical inhibition (SMA, 14.4% [1.6%]; ALS, 4.3% [1.8%]; controls, 17.0% [2.3%]; F = 11.4; P < .001) and cortical silent-period duration (SMA, 204.4 [9.8] milliseconds; ALS, 182.7 [5.2] milliseconds; controls, 208.8 [3.7] milliseconds; F = 4.8; P = .01), similar between SMA patients and healthy controls, were significantly larger when compared with the findings in ALS. Of relevance, peripheral disease burden as measured by the compound muscle action potential amplitude (SMA, 6.3 [0.8] mV; ALS, 5.9 [0.4] mV; controls, 11.8 [0.5] mV; F = 35.5; P < .001) and Neurophysiological Index (SMA, 0.7 [0.2]; ALS, 0.7 [0.1]; controls, 3.1 [0.2]; F = 108.2; P < .001), were significantly reduced in both SMA and ALS patients when compared with healthy controls. Taken together, findings from the present study suggest that despite spinal motoneuron degeneration there remains preservation of corticomotoneuronal function in SMA. The greater corticomotoneuronal projections to surviving spinal motoneurons likely represent an adaptive response to spinal motoneuron degeneration in SMA.
Journal of Inherited Metabolic Disease, 2012
Recessive LPIN1 mutations were identified as a cause of severe rhabdomyolysis in pediatric patien... more Recessive LPIN1 mutations were identified as a cause of severe rhabdomyolysis in pediatric patients. The human lipin family includes two other closely related members, lipin-2 and 3, which share strong homology and similar activity. The study aimed to determine the involvement of the LPIN family genes in a cohort of pediatric and adult patients (n = 171) presenting with muscular symptoms, ranging from severe (CK >10 000 UI/L) or moderate (CK <10 000 UI/L) rhabdomyolysis (n = 141) to exercise-induced myalgia (n = 30), and to report the clinical findings in patients harboring mutations. Coding regions of LPIN1, LPIN2 and LPIN3 genes were sequenced using genomic or complementary DNAs. Eighteen patients harbored two LPIN1 mutations, including a frequent intragenic deletion. All presented with severe episodes of rhabdomyolysis, starting before age 6 years except two (8 and 42 years). Few patients also suffered from permanent muscle symptoms, including the eldest ones (≥ 40 years). Around 3/4 of muscle biopsies showed accumulation of lipid droplets. At least 40% of heterozygous relatives presented muscular myalgia. Nine heterozygous SNPs in LPIN family genes were identified in milder phenotypes (mild rhabdomyolysis or myalgia). These variants were non-functional in yeast complementation assay based on respiratory activity, except the LPIN3-P24L variant. LPIN1-related myolysis constitutes a major cause of early-onset rhabdomyolysis and occasionally in adults. Heterozygous LPIN1 mutations may cause mild muscular symptoms. No major defects of LPIN2 or LPIN3 genes were associated with muscular manifestations.
Current Molecular Medicine, 2009
Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder c... more Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder characterised by muscle weakness and atrophy due to degeneration of motor neurons of the spinal cord and cranial motor nuclei. The clinical phenotype incorporates a wide spectrum. No effective treatment is currently available and patients may experience severe physical disability which is often life limiting. The most common type of SMA is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by deletion, conversion or mutation and results in insufficient levels of survival motor neuron (SMN) protein in motor neurons. While diagnosis is usually achieved by genetic testing, an illustrative clinical case is described that highlights the molecular and diagnostic complexities. While there is an emerging picture concerning the function of the SMN protein and the molecular pathophysiological mechanisms underpinning the disease, a number of substantial issues remain unresolved. The selective vulnerability of the motor neuron and the site and timing of the primary pathogenesis are not yet determined. Utilising the organisation of the SMN genomic region, recent advances have identified a number of potential therapeutic targets. As such, this review incorporates discussion of the clinical manifestations, molecular genetics, diagnosis, mechanisms of disease pathogenesis and development of novel treatment strategies.
Neurotherapeutics, 2014
Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron... more Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron loss in the spinal cord and lower brainstem, muscle weakness, and atrophy. The clinical and genetic phenotypes incorporate a wide spectrum that is differentiated based on age of onset, pattern of muscle involvement, and inheritance pattern. Over the past several years, rapid advances in genetic technology have accelerated the identification of causative genes and provided important advances in understanding the molecular and biological basis of SMA and insights into the selective vulnerability of the motor neuron. Common pathophysiological themes include defects in RNA metabolism and splicing, axonal transport, and motor neuron development and connectivity. Together these have revealed potential novel treatment strategies, and extensive efforts are being undertaken towards expedited therapeutics. While a number of promising therapies for SMA are emerging, defining therapeutic windows and developing sensitive and relevant biomarkers are critical to facilitate potential success in clinical trials. This review incorporates an overview of the clinical manifestations and genetics of SMA, and describes recent advances in the understanding of mechanisms of disease pathogenesis and development of novel treatment strategies.
Pediatrics, 2010
The pathophysiology of stroke-like episodes in MELAS (mitochondrial myopathy, encephalopathy, lac... more The pathophysiology of stroke-like episodes in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) remains unresolved. Possible mechanisms include mitochondrial angiopathy, cytopathy, or both, collectively resulting in cellular energy depletion. To clarify disease mechanisms, axonal excitability properties were investigated in a 10-year-old child with MELAS. Serial assessments during a stroke-like episode revealed reversible depolarization of the axonal membrane consistent with disruption of energy-dependent processes. Axonal parameters correlated with the clinical assessment of central dysfunction and biochemical measures of acidosis. Novel axonal excitability techniques have established acute, reversible ischemic-like depolarization that may serve as a surrogate marker of central events that develop during stroke-like episodes in MELAS.
Muscle & nerve, 2014
Patients with hereditary neuropathy with liability to pressure palsies (HNPP) manifest with episo... more Patients with hereditary neuropathy with liability to pressure palsies (HNPP) manifest with episodes of focal paresis when exposed to mechanical stress, although the basis for vulnerability to conduction block remains relatively unexplained. Axonal excitability techniques were utilized to provide insights into pathophysiological mechanisms in 13 HNPP patients, stimulating median motor and sensory axons at the wrist. In HNPP, distal latencies were prolonged, and motor and sensory amplitudes were reduced. Threshold was increased. Depolarizing and hyperpolarizing electrotonus was greater, and resting current-threshold slope was reduced. There were greater threshold changes in superexcitability, and refractoriness was decreased. Taken together, excitability testing in patients with HNPP established axonal hyperpolarization in both motor and sensory axons that may be attributable to changes in nerve architecture. In turn, the hyperpolarized resting membrane potential in HNPP may be a maj...
The Journal of Physiology, 2013
• The evolution of human peripheral nerve function after birth to facilitate more complex neural ... more • The evolution of human peripheral nerve function after birth to facilitate more complex neural tasks has not been fully elucidated. • The present study has established the changes that occur in nerve function in developing humans using specialized non-invasive excitability techniques in infants, children, adolescents and young adults for the first time. • The activity of axonal K + conductances reduces with formation of the axo-glial junction.
Journal of Clinical Neuroscience, 2010
Background: Neuronal ion channel disorders can manifest as epilepsy, migraine, ataxia and neuromy... more Background: Neuronal ion channel disorders can manifest as epilepsy, migraine, ataxia and neuromyotonia. Clinical diagnosis is challenging as features may be paroxysmal. Structural assessment is unhelpful because channelopathies predominantly affect neuronal function. Nerve excitability studies provide multidimensional information about the function of ion channels expressed in peripheral axons. The aim of this study was to test the hypothesis that the genetic channelopathy Benign Familial Neonatal Convulsions (BFNC) due to mutations of KCNQ2 encoding the Kv7.2 subunit of slow axonal potassium channels is associated with characteristically abnormal peripheral nerve excitability, even in the absence of peripheral nerve signs.
Clinical Neurophysiology, 2010
Clinical Neurophysiology, Volume 121, Issue 4, Pages e2, April 2010, Authors:Michelle A. Farrar; ... more Clinical Neurophysiology, Volume 121, Issue 4, Pages e2, April 2010, Authors:Michelle A. Farrar; Cindy S.-Y. Lin; Arun Krishnan; Susanna B. Park; Peter Ian Andrews; Matthew C. Kiernan.
Brain, 2011
Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with ... more Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with onset in developing and maturing patients. Furthermore, the rate of degeneration appears to slow over time, at least in the milder forms. To investigate disease pathophysiology and potential adaptations, the present study utilized axonal excitability studies to provide insights into axonal biophysical properties and explored correlation with clinical severity. Multiple excitability indices (stimulus-response curve, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle) were investigated in 25 genetically characterized adolescent and adult patients with spinal muscular atrophy, stimulating the median motor nerve at the wrist. Results were compared with 50 age-matched controls. The Medical Research Council sum score and Spinal Muscular Atrophy Functional Rating Scale were used to define the strength and motor functional status of patients with spinal muscular atrophy. In patients with spinal muscular atrophy, there were reductions in compound muscle action potential amplitude (P 5 0.0005) associated with reduction in stimulus response slope (P 5 0.0005), confirming significant axonal loss. In the patients with mild or ambulatory spinal muscular atrophy, there was reduction of peak amplitude without alteration in axonal excitability; in contrast, in the non-ambulatory or severe spinal muscular atrophy cohort prominent changes in axonal function were apparent. Specifically, there were steep changes in the early phase of hyperpolarization in threshold electrotonus (P 5 0.0005) that correlated with clinical severity. Additionally, there were greater changes in depolarizing threshold electrotonus (P 5 0.0005) and prolongation of the strength-duration time constant (P = 0.001). Mathematical modelling of the excitability changes obtained in patients with severe spinal muscular atrophy supported a mixed pathology comprising features of axonal degeneration and regeneration. The present study has provided novel insight into the pathophysiology of spinal muscular atrophy, with identification of functional abnormalities involving axonal K + and Na + conductances and alterations in passive membrane properties, the latter linked to the process of neurodegeneration.
Archives of Neurology, 2012
To gain further insight into disease pathophysiologic process and potential adaptations through i... more To gain further insight into disease pathophysiologic process and potential adaptations through investigating whether cortical dysfunction or plasticity is a feature of spinal muscle atrophy (SMA). Prospective, double-center study. Outpatient clinics and research institute. Clinical assessments, combined with threshold-tracking transcranial magnetic stimulation techniques, were completed in 11 genetically characterized patients with SMA. Clinical, functional, and neurophysiologic variables were compared between the 11 patients with SMA types 2 and 3, 24 healthy control participants, and 81 patients with amyotrophic lateral sclerosis (ALS) serving as disease controls. Maximal motor-evoked potential amplitude as a percentage of the compound muscle action potential was significantly increased in patients with SMA compared with the healthy controls but was similar to that in ALS (SMA, mean [SE], 39.7% [4.0%]; ALS, 38.8% [2.8%]; controls, 20.3% [2.5%]; F = 10.1; P < .001). In contrast, short-interval intracortical inhibition (SMA, 14.4% [1.6%]; ALS, 4.3% [1.8%]; controls, 17.0% [2.3%]; F = 11.4; P < .001) and cortical silent-period duration (SMA, 204.4 [9.8] milliseconds; ALS, 182.7 [5.2] milliseconds; controls, 208.8 [3.7] milliseconds; F = 4.8; P = .01), similar between SMA patients and healthy controls, were significantly larger when compared with the findings in ALS. Of relevance, peripheral disease burden as measured by the compound muscle action potential amplitude (SMA, 6.3 [0.8] mV; ALS, 5.9 [0.4] mV; controls, 11.8 [0.5] mV; F = 35.5; P < .001) and Neurophysiological Index (SMA, 0.7 [0.2]; ALS, 0.7 [0.1]; controls, 3.1 [0.2]; F = 108.2; P < .001), were significantly reduced in both SMA and ALS patients when compared with healthy controls. Taken together, findings from the present study suggest that despite spinal motoneuron degeneration there remains preservation of corticomotoneuronal function in SMA. The greater corticomotoneuronal projections to surviving spinal motoneurons likely represent an adaptive response to spinal motoneuron degeneration in SMA.
Journal of Inherited Metabolic Disease, 2012
Recessive LPIN1 mutations were identified as a cause of severe rhabdomyolysis in pediatric patien... more Recessive LPIN1 mutations were identified as a cause of severe rhabdomyolysis in pediatric patients. The human lipin family includes two other closely related members, lipin-2 and 3, which share strong homology and similar activity. The study aimed to determine the involvement of the LPIN family genes in a cohort of pediatric and adult patients (n = 171) presenting with muscular symptoms, ranging from severe (CK >10 000 UI/L) or moderate (CK <10 000 UI/L) rhabdomyolysis (n = 141) to exercise-induced myalgia (n = 30), and to report the clinical findings in patients harboring mutations. Coding regions of LPIN1, LPIN2 and LPIN3 genes were sequenced using genomic or complementary DNAs. Eighteen patients harbored two LPIN1 mutations, including a frequent intragenic deletion. All presented with severe episodes of rhabdomyolysis, starting before age 6 years except two (8 and 42 years). Few patients also suffered from permanent muscle symptoms, including the eldest ones (≥ 40 years). Around 3/4 of muscle biopsies showed accumulation of lipid droplets. At least 40% of heterozygous relatives presented muscular myalgia. Nine heterozygous SNPs in LPIN family genes were identified in milder phenotypes (mild rhabdomyolysis or myalgia). These variants were non-functional in yeast complementation assay based on respiratory activity, except the LPIN3-P24L variant. LPIN1-related myolysis constitutes a major cause of early-onset rhabdomyolysis and occasionally in adults. Heterozygous LPIN1 mutations may cause mild muscular symptoms. No major defects of LPIN2 or LPIN3 genes were associated with muscular manifestations.