Amit Batla - Academia.edu (original) (raw)
Papers by Amit Batla
Parkinsonism & Related Disorders
European Journal of Neurology, 2021
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Glucocerebrosidase (GCase) deficiency due to mutations of the glucosidase acid beta (GBA) gene ca... more Glucocerebrosidase (GCase) deficiency due to mutations of the glucosidase acid beta (GBA) gene causes autosomal-recessive Gaucher’s disease, the most frequent lysosomal storage disorder. Over the past two decades,GBAmutations have been established as the most frequent genetic risk factor to develop Parkinson’s Disease. In dystonia, the underlying aetiology in a relevant proportion of cases remains unknown, hampering the development of causative treatment strategies. Here, we explored the possible role of lysosomal dysfunction in clinical (n=130) and post mortem (n=10) patients with dystonia.As part of extensive diagnostic evaluations (screening for structural, acquired and degenerative causes of dystonia), lysosomal enzyme activity was measured in n=79 retrospectively collected cases of patients with combined dystonia and n=51 prospectively collected cases of patients with cervical dystonia using a clinically validated, fluorescence-based assay. Clinical information on all cases was...
Brain, 2019
Cervical dystonia is a neurological disorder characterized by sustained, involuntary movements of... more Cervical dystonia is a neurological disorder characterized by sustained, involuntary movements of the head and neck. Most cases of cervical dystonia are idiopathic, with no obvious cause, yet some cases are acquired, secondary to focal brain lesions. These latter cases are valuable as they establish a causal link between neuroanatomy and resultant symptoms, lending insight into the brain regions causing cervical dystonia and possible treatment targets. However, lesions causing cervical dystonia can occur in multiple different brain locations, leaving localization unclear. Here, we use a technique termed 'lesion network mapping', which uses connectome data from a large cohort of healthy subjects (resting state functional MRI, n = 1000) to test whether lesion locations causing cervical dystonia map to a common brain network. We then test whether this network, derived from brain lesions, is abnormal in patients with idiopathic cervical dystonia (n = 39) versus matched controls (n = 37). A systematic literature search identified 25 cases of lesion-induced cervical dystonia. Lesion locations were heterogeneous, with lesions scattered throughout the cerebellum, brainstem, and basal ganglia. However, these heterogeneous lesion locations were all part of a single functionally connected brain network. Positive connectivity to the cerebellum and negative connectivity to the somatosensory cortex were specific markers for cervical dystonia compared to lesions causing other neurological symptoms. Connectivity with these two regions defined a single brain network that encompassed the heterogeneous lesion locations causing cervical dystonia. These cerebellar and somatosensory regions also showed abnormal connectivity in patients with idiopathic cervical dystonia. Finally, the most effective deep brain stimulation sites for treating dystonia were connected to these same cerebellar and somatosensory regions identified using lesion network mapping. These results lend insight into the causal neuroanatomical substrate of cervical dystonia, demonstrate convergence across idiopathic and acquired dystonia, and identify a network target for dystonia treatment.
Journal of Neurology, Neurosurgery & Psychiatry, 2019
ObjectivesTo evaluate the effectiveness of introducing a pain scale to improve cervical dystonia ... more ObjectivesTo evaluate the effectiveness of introducing a pain scale to improve cervical dystonia (CD) patient satisfaction rates in the National Hospital for Neurology and Neurosurgery (NHNN) Botox clinic.DesignCase control study.SubjectsSubjects included CD patients attending the NHNN Botox clinic to receive injections.MethodsInjectors were educated about the Toronto Western Spasmodic Torticollis Rating pain subscale (TWSTRS) and subsequently incorporated it into their standard assessment of CD patients prior to injections. Surveys were created and disseminated to patients immediately following their appointment to assess their opinions of the clinical team. Information was entered into Microsoft Excel and analysed using appropriate statistical methods. Results were compared with a previous NHNN Botox clinic audit.Results42 surveys were collected in total from CD patients over a 4 week period. 36 patients (85.7%) reported pain associated with the condition. In comparison to an audi...
Movement disorders : official journal of the Movement Disorder Society, 2018
The onset of multiple system atrophy (MSA) before age 40 years is referred to as "young-onse... more The onset of multiple system atrophy (MSA) before age 40 years is referred to as "young-onset MSA." We identified clinical and pathological characteristics that might help with its early diagnosis and distinction from young-onset Parkinson's disease and late-onset MSA. We reviewed the available clinical and pathological features in cases that fulfilled consensus criteria for diagnosis of probable MSA or had autopsy confirmed MSA with an onset before age 40 years and compared the clinical features with 16 autopsy confirmed cases with young-onset Parkinson's disease and a large published series of late-onset MSA from the European MSA Study Group. We identified 22 patients with young-onset MSA, 8 of whom had available pathology. The mean age of onset was 36.7 years (standard deviation 2.3). Levodopa-induced dyskinesia was more common, whereas myoclonus and pyramidal signs were less common in young-onset Parkinson's disease when compared with young-onset MSA. Dysto...
Parkinsonism & related disorders, Jan 10, 2018
To characterise the distinctive eye movement disorder and the sleep-related dyskinesia in Adenyla... more To characterise the distinctive eye movement disorder and the sleep-related dyskinesia in Adenylate cyclase 5 (ADCY5) related disease. Formal eye movement examination and video-polysomnography in a cohort of patients with ADCY5 mutations. All three patients had an eye movement disorder characterised by oculomotor apraxia with gaze limitation most prominently in the vertical plane. All patients had disrupted sleep architecture with reduced sleep efficiency due to frequent and prolonged arousals and awakenings in the context of dyskinesia, which could arise from any sleep stage. The nocturnal movements could last up to 30 min and be more severe than those seen during day-time. Nocturnal exacerbations of dyskinesia ("ballistic bouts") seem to be a characteristic feature of the disease, affect the quality of life of patients and therefore require awareness and symptomatic treatment approaches. Apraxia of eye movements, with predominant difficulties in the vertical plane, was a...
Current treatment options in neurology, 2016
Urogenital dysfunction is commonly reported in Parkinson's disease (PD), and history taking a... more Urogenital dysfunction is commonly reported in Parkinson's disease (PD), and history taking and a bladder diary form the cornerstone of evaluation. The assessment of lower urinary tract (LUT) symptoms include urinalysis, ultrasonography, and urodynamic studies and help to evaluate concomitant urological pathologies such as benign prostate enlargement. Antimuscarinic medications are the first line treatment for overactive bladder (OAB) symptoms and solifenacin has been specifically studied in PD. Antimuscarininc drugs may exacerbate PD-related constipation and xerostomia, and caution is advised when using these medications in individuals where cognitive impairment is suspected. Desmopressin is effective for the management of nocturnal polyuria which has been reported to be common in PD. Intradetrusor injections of botulinum toxin have been shown to be effective for detrusor overactivity, however, are associated with the risk of urinary retention. Neuromodulation is a promising, m...
Parkinsonism & Related Disorders, 2017
Introduction: There are now a number genes, known to be associated with familial primary brain ca... more Introduction: There are now a number genes, known to be associated with familial primary brain calcification (PFBC), causing the so called 'Fahr's' disease or syndrome. These are SCL20A2, PDGF-B, PDGFRB and XPR1. In this systematic review, we analyse the clinical and radiological features reported in genetically confirmed cases with PFBC. We have additionally reviewed pseudohypoparathyroidism which is a close differential diagnosis of PFBC in clinical presentation and is also genetically determined. Methods: We performed a Medline search, from 1 st Jan 2012 through to 7 th November 2016, for publications with confirmed mutations of SCL20A2, PDGF-B, PDGFRB, and XPR1 and found twenty papers with 137 eligible cases. A second search was done for publications of cases with Pseudohypoparathyroidism or pseudopseudohypoparathyroidism, and found 18 publications with 20 eligible cases. Results: SLC20A2 was the most common gene involved with 75 out of 137 cases included with PFBC (55%) followed by PDGFB (31%) and PDGFRB (11%). Statistically significant correlation was found between the presence of parkinsonism with SLC20A2 mutations, headache in PDGFB and generalised tonic-clonic seizures in patients with pseudohypoparathyroidism. Conclusion: We combine statistical analysis and clinical inference to suggest a diagnostic algorithm based on the observations in this study to help with investigation of a patient with neurological features and brain calcification.
Parkinsonism & Related Disorders, 2017
Background: Atypical parkinsonian conditions such as multiple system atrophy (MSA), progressive s... more Background: Atypical parkinsonian conditions such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and Dementia with Lewy bodies (DLB) comprise 10-15% of parkinsonian syndromes. Misdiagnosis with Parkinson disease (PD) and within the entities is common, given the absence of reliable biomarkers. However a correct diagnosis is not only important in clinical practice, but also crucial for any trial attempting to identify biomarkers or new treatments. Methods: Consecutive patients, who were either referred with a diagnosis of a particular AP by a neurologist, or where a movement disorder specialist at Queen Square considered such a diagnosis, were included and the medical records were reviewed retrospectively. We applied each set of current diagnostic research criteria to the respective cohort to see which features fit in and if there are atypical features "outside" the classic definition. Results: Sixty-nine patients were recruited clinically presenting with one of the following phenotypes: 14 MSA, 24 PSP, 19 CBS and 12 DLB. Up to 49% showed additional "atypical" features and approximately 10% eventually received an alternative diagnosis, in half of whom this was based on genetic testing. Conclusions: In a subset of our patients, despite the final diagnosis of an AP being maintained, there were additional "atypical" features. It remains to be seen if these reflect the clinical heterogeneity of APs, or should prompt a search for an alternative diagnosis. A change in terminology using phenotypic descriptors (e.g. MSA syndrome) rather than aetiological labels, as already applied for CBS, could therefore be a consideration for all the APs.
Parkinsonism & Related Disorders, 2016
The Cerebellum, 2016
A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, ... more A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia. The following topics are discussed: The relationships between neuronal/network dysfunctions and motor abnormalities in rodent models of dystonia. Data about brain structure, cerebellar metabolism, cerebellar connections, and noninvasive cerebellar stimulation that support (or not) a role for the cerebellum in human dystonia. Connections between the cerebellum and motor cortical and sub-cortical structures that could support a role for the cerebellum in dystonia. Overall points of consensus include: Neuronal dysfunction originating in the cerebellum can drive dystonic movements in rodent model systems. Imaging and neurophysiological studies in humans suggest that the cerebellum plays a role in the pathophysiology of dystonia, but do not provide conclusive evidence that the cerebellum is the primary or sole neuroanatomical site of origin.
Movement disorders : official journal of the Movement Disorder Society, Dec 27, 2016
Linkage analyses of families with primary familial brain calcification (formerly idiopathic basal... more Linkage analyses of families with primary familial brain calcification (formerly idiopathic basal ganglia calcification [IBGC]) identified 3 candidate loci (IBGC1-3). Recently, SLC20A2 mutations were found in the IBGC1 and IBGC3 families, merging these 2 loci. We here elucidate the genetic cause of primary familial brain calcification in the 'IBGC2' kindred. We sequenced known primary familial brain calcification genes and quantified SLC20A2 and PDGFB. Moreover, CT scans of affected and unaffected family members were evaluated by 2 blinded neuroradiologists for distribution of brain calcification. A heterozygous multiexonic SLC20A2 deletion was detected in several affected family members. A reevaluation of neuroimaging data revealed a subset of mutation-negative individuals with only mild and/or unilateral calcification. The identified SLC20A2 mutation resolves the genetic cause of primary familial brain calcification in the 'IBGC2' kindred, collapsing 'IBGC2'...
Differential Diagnosis in Neurology, 2016
Parkinsonism & Related Disorders, 2016
In dystonia the formulation of a clinical syndrome is paramount to refine the list of etiologies.... more In dystonia the formulation of a clinical syndrome is paramount to refine the list of etiologies. We here describe the rare association of dystonia with anarthria/aphonia, by examining a large cohort of patients, to provide a narrow field of underlying conditions and a practical algorithmic approach to reach diagnosis. Methods We retrospectively reviewed cases, which were evaluated between 2005 and 2014, to identify those with dystonia combined with marked anarthria and/or aphonia. We reviewed demographic information, clinical characteristics, as well as clinico-genetic investigations. We evaluated video material where available. Results From 860 cases with dystonia as the predominant motor feature, we identified 32 cases (3.7%) with anarthria/aphonia. Age at neurological symptom onset was variable, but the majority of cases (n=20) developed symptoms within their first eight years of life. A conclusive diagnosis was reached in 27 cases. Monoamine neurotransmitter disorders, neurodegeneration with brain iron accumulation syndromes, hypomyelination with atrophy of the basal ganglia and cerebellum, and syndromes with inborn errors of metabolism were the most common diagnoses. Brain MRI was crucial for reaching a diagnosis by examining the structural integrity of the basal ganglia, the cerebral cortex, brain myelination and whether there was abnormal metal deposition. Pathophysiological mechanisms underlying anarthria/aphonia
Parkinsonism & Related Disorders
European Journal of Neurology, 2021
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Glucocerebrosidase (GCase) deficiency due to mutations of the glucosidase acid beta (GBA) gene ca... more Glucocerebrosidase (GCase) deficiency due to mutations of the glucosidase acid beta (GBA) gene causes autosomal-recessive Gaucher’s disease, the most frequent lysosomal storage disorder. Over the past two decades,GBAmutations have been established as the most frequent genetic risk factor to develop Parkinson’s Disease. In dystonia, the underlying aetiology in a relevant proportion of cases remains unknown, hampering the development of causative treatment strategies. Here, we explored the possible role of lysosomal dysfunction in clinical (n=130) and post mortem (n=10) patients with dystonia.As part of extensive diagnostic evaluations (screening for structural, acquired and degenerative causes of dystonia), lysosomal enzyme activity was measured in n=79 retrospectively collected cases of patients with combined dystonia and n=51 prospectively collected cases of patients with cervical dystonia using a clinically validated, fluorescence-based assay. Clinical information on all cases was...
Brain, 2019
Cervical dystonia is a neurological disorder characterized by sustained, involuntary movements of... more Cervical dystonia is a neurological disorder characterized by sustained, involuntary movements of the head and neck. Most cases of cervical dystonia are idiopathic, with no obvious cause, yet some cases are acquired, secondary to focal brain lesions. These latter cases are valuable as they establish a causal link between neuroanatomy and resultant symptoms, lending insight into the brain regions causing cervical dystonia and possible treatment targets. However, lesions causing cervical dystonia can occur in multiple different brain locations, leaving localization unclear. Here, we use a technique termed 'lesion network mapping', which uses connectome data from a large cohort of healthy subjects (resting state functional MRI, n = 1000) to test whether lesion locations causing cervical dystonia map to a common brain network. We then test whether this network, derived from brain lesions, is abnormal in patients with idiopathic cervical dystonia (n = 39) versus matched controls (n = 37). A systematic literature search identified 25 cases of lesion-induced cervical dystonia. Lesion locations were heterogeneous, with lesions scattered throughout the cerebellum, brainstem, and basal ganglia. However, these heterogeneous lesion locations were all part of a single functionally connected brain network. Positive connectivity to the cerebellum and negative connectivity to the somatosensory cortex were specific markers for cervical dystonia compared to lesions causing other neurological symptoms. Connectivity with these two regions defined a single brain network that encompassed the heterogeneous lesion locations causing cervical dystonia. These cerebellar and somatosensory regions also showed abnormal connectivity in patients with idiopathic cervical dystonia. Finally, the most effective deep brain stimulation sites for treating dystonia were connected to these same cerebellar and somatosensory regions identified using lesion network mapping. These results lend insight into the causal neuroanatomical substrate of cervical dystonia, demonstrate convergence across idiopathic and acquired dystonia, and identify a network target for dystonia treatment.
Journal of Neurology, Neurosurgery & Psychiatry, 2019
ObjectivesTo evaluate the effectiveness of introducing a pain scale to improve cervical dystonia ... more ObjectivesTo evaluate the effectiveness of introducing a pain scale to improve cervical dystonia (CD) patient satisfaction rates in the National Hospital for Neurology and Neurosurgery (NHNN) Botox clinic.DesignCase control study.SubjectsSubjects included CD patients attending the NHNN Botox clinic to receive injections.MethodsInjectors were educated about the Toronto Western Spasmodic Torticollis Rating pain subscale (TWSTRS) and subsequently incorporated it into their standard assessment of CD patients prior to injections. Surveys were created and disseminated to patients immediately following their appointment to assess their opinions of the clinical team. Information was entered into Microsoft Excel and analysed using appropriate statistical methods. Results were compared with a previous NHNN Botox clinic audit.Results42 surveys were collected in total from CD patients over a 4 week period. 36 patients (85.7%) reported pain associated with the condition. In comparison to an audi...
Movement disorders : official journal of the Movement Disorder Society, 2018
The onset of multiple system atrophy (MSA) before age 40 years is referred to as "young-onse... more The onset of multiple system atrophy (MSA) before age 40 years is referred to as "young-onset MSA." We identified clinical and pathological characteristics that might help with its early diagnosis and distinction from young-onset Parkinson's disease and late-onset MSA. We reviewed the available clinical and pathological features in cases that fulfilled consensus criteria for diagnosis of probable MSA or had autopsy confirmed MSA with an onset before age 40 years and compared the clinical features with 16 autopsy confirmed cases with young-onset Parkinson's disease and a large published series of late-onset MSA from the European MSA Study Group. We identified 22 patients with young-onset MSA, 8 of whom had available pathology. The mean age of onset was 36.7 years (standard deviation 2.3). Levodopa-induced dyskinesia was more common, whereas myoclonus and pyramidal signs were less common in young-onset Parkinson's disease when compared with young-onset MSA. Dysto...
Parkinsonism & related disorders, Jan 10, 2018
To characterise the distinctive eye movement disorder and the sleep-related dyskinesia in Adenyla... more To characterise the distinctive eye movement disorder and the sleep-related dyskinesia in Adenylate cyclase 5 (ADCY5) related disease. Formal eye movement examination and video-polysomnography in a cohort of patients with ADCY5 mutations. All three patients had an eye movement disorder characterised by oculomotor apraxia with gaze limitation most prominently in the vertical plane. All patients had disrupted sleep architecture with reduced sleep efficiency due to frequent and prolonged arousals and awakenings in the context of dyskinesia, which could arise from any sleep stage. The nocturnal movements could last up to 30 min and be more severe than those seen during day-time. Nocturnal exacerbations of dyskinesia ("ballistic bouts") seem to be a characteristic feature of the disease, affect the quality of life of patients and therefore require awareness and symptomatic treatment approaches. Apraxia of eye movements, with predominant difficulties in the vertical plane, was a...
Current treatment options in neurology, 2016
Urogenital dysfunction is commonly reported in Parkinson's disease (PD), and history taking a... more Urogenital dysfunction is commonly reported in Parkinson's disease (PD), and history taking and a bladder diary form the cornerstone of evaluation. The assessment of lower urinary tract (LUT) symptoms include urinalysis, ultrasonography, and urodynamic studies and help to evaluate concomitant urological pathologies such as benign prostate enlargement. Antimuscarinic medications are the first line treatment for overactive bladder (OAB) symptoms and solifenacin has been specifically studied in PD. Antimuscarininc drugs may exacerbate PD-related constipation and xerostomia, and caution is advised when using these medications in individuals where cognitive impairment is suspected. Desmopressin is effective for the management of nocturnal polyuria which has been reported to be common in PD. Intradetrusor injections of botulinum toxin have been shown to be effective for detrusor overactivity, however, are associated with the risk of urinary retention. Neuromodulation is a promising, m...
Parkinsonism & Related Disorders, 2017
Introduction: There are now a number genes, known to be associated with familial primary brain ca... more Introduction: There are now a number genes, known to be associated with familial primary brain calcification (PFBC), causing the so called 'Fahr's' disease or syndrome. These are SCL20A2, PDGF-B, PDGFRB and XPR1. In this systematic review, we analyse the clinical and radiological features reported in genetically confirmed cases with PFBC. We have additionally reviewed pseudohypoparathyroidism which is a close differential diagnosis of PFBC in clinical presentation and is also genetically determined. Methods: We performed a Medline search, from 1 st Jan 2012 through to 7 th November 2016, for publications with confirmed mutations of SCL20A2, PDGF-B, PDGFRB, and XPR1 and found twenty papers with 137 eligible cases. A second search was done for publications of cases with Pseudohypoparathyroidism or pseudopseudohypoparathyroidism, and found 18 publications with 20 eligible cases. Results: SLC20A2 was the most common gene involved with 75 out of 137 cases included with PFBC (55%) followed by PDGFB (31%) and PDGFRB (11%). Statistically significant correlation was found between the presence of parkinsonism with SLC20A2 mutations, headache in PDGFB and generalised tonic-clonic seizures in patients with pseudohypoparathyroidism. Conclusion: We combine statistical analysis and clinical inference to suggest a diagnostic algorithm based on the observations in this study to help with investigation of a patient with neurological features and brain calcification.
Parkinsonism & Related Disorders, 2017
Background: Atypical parkinsonian conditions such as multiple system atrophy (MSA), progressive s... more Background: Atypical parkinsonian conditions such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and Dementia with Lewy bodies (DLB) comprise 10-15% of parkinsonian syndromes. Misdiagnosis with Parkinson disease (PD) and within the entities is common, given the absence of reliable biomarkers. However a correct diagnosis is not only important in clinical practice, but also crucial for any trial attempting to identify biomarkers or new treatments. Methods: Consecutive patients, who were either referred with a diagnosis of a particular AP by a neurologist, or where a movement disorder specialist at Queen Square considered such a diagnosis, were included and the medical records were reviewed retrospectively. We applied each set of current diagnostic research criteria to the respective cohort to see which features fit in and if there are atypical features "outside" the classic definition. Results: Sixty-nine patients were recruited clinically presenting with one of the following phenotypes: 14 MSA, 24 PSP, 19 CBS and 12 DLB. Up to 49% showed additional "atypical" features and approximately 10% eventually received an alternative diagnosis, in half of whom this was based on genetic testing. Conclusions: In a subset of our patients, despite the final diagnosis of an AP being maintained, there were additional "atypical" features. It remains to be seen if these reflect the clinical heterogeneity of APs, or should prompt a search for an alternative diagnosis. A change in terminology using phenotypic descriptors (e.g. MSA syndrome) rather than aetiological labels, as already applied for CBS, could therefore be a consideration for all the APs.
Parkinsonism & Related Disorders, 2016
The Cerebellum, 2016
A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, ... more A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia. The following topics are discussed: The relationships between neuronal/network dysfunctions and motor abnormalities in rodent models of dystonia. Data about brain structure, cerebellar metabolism, cerebellar connections, and noninvasive cerebellar stimulation that support (or not) a role for the cerebellum in human dystonia. Connections between the cerebellum and motor cortical and sub-cortical structures that could support a role for the cerebellum in dystonia. Overall points of consensus include: Neuronal dysfunction originating in the cerebellum can drive dystonic movements in rodent model systems. Imaging and neurophysiological studies in humans suggest that the cerebellum plays a role in the pathophysiology of dystonia, but do not provide conclusive evidence that the cerebellum is the primary or sole neuroanatomical site of origin.
Movement disorders : official journal of the Movement Disorder Society, Dec 27, 2016
Linkage analyses of families with primary familial brain calcification (formerly idiopathic basal... more Linkage analyses of families with primary familial brain calcification (formerly idiopathic basal ganglia calcification [IBGC]) identified 3 candidate loci (IBGC1-3). Recently, SLC20A2 mutations were found in the IBGC1 and IBGC3 families, merging these 2 loci. We here elucidate the genetic cause of primary familial brain calcification in the 'IBGC2' kindred. We sequenced known primary familial brain calcification genes and quantified SLC20A2 and PDGFB. Moreover, CT scans of affected and unaffected family members were evaluated by 2 blinded neuroradiologists for distribution of brain calcification. A heterozygous multiexonic SLC20A2 deletion was detected in several affected family members. A reevaluation of neuroimaging data revealed a subset of mutation-negative individuals with only mild and/or unilateral calcification. The identified SLC20A2 mutation resolves the genetic cause of primary familial brain calcification in the 'IBGC2' kindred, collapsing 'IBGC2'...
Differential Diagnosis in Neurology, 2016
Parkinsonism & Related Disorders, 2016
In dystonia the formulation of a clinical syndrome is paramount to refine the list of etiologies.... more In dystonia the formulation of a clinical syndrome is paramount to refine the list of etiologies. We here describe the rare association of dystonia with anarthria/aphonia, by examining a large cohort of patients, to provide a narrow field of underlying conditions and a practical algorithmic approach to reach diagnosis. Methods We retrospectively reviewed cases, which were evaluated between 2005 and 2014, to identify those with dystonia combined with marked anarthria and/or aphonia. We reviewed demographic information, clinical characteristics, as well as clinico-genetic investigations. We evaluated video material where available. Results From 860 cases with dystonia as the predominant motor feature, we identified 32 cases (3.7%) with anarthria/aphonia. Age at neurological symptom onset was variable, but the majority of cases (n=20) developed symptoms within their first eight years of life. A conclusive diagnosis was reached in 27 cases. Monoamine neurotransmitter disorders, neurodegeneration with brain iron accumulation syndromes, hypomyelination with atrophy of the basal ganglia and cerebellum, and syndromes with inborn errors of metabolism were the most common diagnoses. Brain MRI was crucial for reaching a diagnosis by examining the structural integrity of the basal ganglia, the cerebral cortex, brain myelination and whether there was abnormal metal deposition. Pathophysiological mechanisms underlying anarthria/aphonia