Allan McCarthy

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance

Progressive external ophthalmoplegia (PEO) is a canonical feature of mitochondrial disease, but in many patients its genetic basis is unknown. Using exome sequencing, Pfeffer et al. identify mutations in SPG7 as an important cause of PEO associated with spasticity and ataxia, and uncover evidence of disordered mtDNA maintenance in patients.

Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders

Objective: To assess the role of CHCHD2 variants in patients with Parkinson disease (PD) and Lewy body disease (LBD) in Caucasian populations. Methods: All exons of the CHCHD2 gene were sequenced in a US Caucasian patient-control series (878 PD, 610 LBD, and 717 controls). Subsequently, exons 1 and 2 were sequenced in an Irish series (355 PD and 365 controls) and a Polish series (394 PD and 350 controls). Immunohistochemistry and immunofluorescence studies were performed on pathologic LBD cases with rare CHCHD2 variants. Results: We identified 9 rare exonic variants of unknown significance. These variants were more frequent in the combined group of PD and LBD patients compared to controls (0.6% vs 0.1%, p = 0.013). In addition, the presence of any rare variant was more common in patients with LBD (2.5% vs 1.0%, p = 0.050) compared to controls. Eight of these 9 variants were located within the genes mitochondrial targeting sequence. Conclusions: Although the role of variants of the CHCHD2 gene in PD and LBD remains to be further elucidated, the rare variants in the mitochondrial targeting sequence may be a risk factor for Lewy body disorders, which may link CHCHD2 to other genetic forms of parkinsonism with mitochondrial dysfunction.

DNAJC13 p.Asn855Ser mutation screening in Parkinson's disease and pathologically confirmed Lewy body disease patients

Recently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinsons disease (PD) in a multi‐incident Mennonite family.

Role for the microtubule-associated protein tau variant p.A152T in risk of α-synucleinopathies

Objective: To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies. Methods: In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls. Results: The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63–2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62–20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04–12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85–25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution. Conclusions: Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies.

Teaching NeuroImages: longitudinally extensive transverse myelitis in neuro-Behcet disease.

A 25-year-old man presented with subacute spastic paraparesis. He reported 2 previous episodes of spastic paraparesis with partial recovery. Recurrent oral and genital ulceration, pustular skin eruptions, and fever coexisted. Profound motor weakness, a sensory level at T10, oral ulceration, and a pustular eruption on the anterior abdominal wall were noted. Marked neutrophilia was noted in both blood and CSF. Neuromyelitis optica–immunoglobulin G autoantibody was negative. MRI (figure) demonstrated marked inflammatory changes. IV and oral steroids, followed by 6 months of pulsed IV cyclophosphamide, resulted in marked clinical improvement. Neuro-Behçet disease lies within the clinical differential for longitudinally extensive transverse myelitis.1,2

Failure of Sequential Pallidal and Motor Thalamus DBS for Rapid-Onset Dystonia-Parkinsonism (DYT12)

Rapid-onset dystonia-parkinsonism (DYT12) is an autosomal dominant combined dystonia associated with mutations of the ATP1A3 gene. Onset is precipitated abruptly by physical/psychological stressors. Dystonia displays a rostrocaudal distribution with prominent orofacial and upper limb involvement, with symptoms remaining refractory to dopaminomimetic or GABA-mimetic agents. It is also the preeminent movement disorder in DYT12, with little parkinsonism, including bradykinesia (possibly reflecting dystonic slowing without decrement). We describe the response to sequential deep brain stimulation (DBS) of the globus pallidus internus (GPI) and, subsequently, the thalamic zona incerta and nucleus ventralis oralis posterior (VOP) in a patient from the Irish DYT12, which was described in detail by Pittock and colleagues. The 8-year-old patient, while playing in a playground, fell to the ground after hanging upside-down. After several minutes she began to whisper. Over the next fortnight, her speech deteriorated, and she subsequently became anarthric. She developed significant upper limb dystonia and dystonic posturing of the left foot. Slow rapidly alternating movements and facial dystonia were noted. MRI brain, neurometabolic bloods, and CSF were normal. Genetic analysis identified a C1838T point mutation in exon 14 of the ATP1A3 gene, co-segregating with disease phenotype in the family. There was no response to pharmacotherapy with levodopa, benzodiazepines, or acetazolamide. Bilateral GPI DBS was performed. Postoperatively, serial assessments identified objective deterioration in communication and feeding; verbal communication was eventually lost and she developed jaw opening dystonia. With optimization of her DBS parameters, she had fluctuating improvement of left arm function. Paradoxically, despite worsening oromandibular dystonia, it was easier to bring food to her mouth. Over time, it became apparent that DBS adjustments to improve orofacial symptoms were consistently coupled with deterioration in upper limb dystonia. Having failed to optimize GPI stimulation, she had further surgery to target the nucleus ventralis oralis posterior (VOP; a pallidal receiving area) and zona incerta (ZI). The previous pallidal system was removed. Postoperative imaging confirmed satisfactory lead placement (Fig. 1). After initial stimulation, she noticed increased difficulty swallowing, which improved with down-titration. There has been little improvement in either the orofacial or upper limb dystonia (Video S1). DYT12 remains a formidable disorder to treat and lack of response to medical therapy makes DBS appealing as a therapeutic option, however evidence is limited. Given the favorable outcomes seen in other primary dystonias, including DYT1 or similarly combined dystonias, including Lubag, it is disappointing that DBS of GPI or motor thalamus (VOP and ZI) has not resulted in significant improvements in this patient. One previous report of DBS in genetically confirmed DYT12 (GPI satisfactorily targeted) showed a reduction in dystonia severity of “borderline” clinical significance. Previous reports of pallidal +/STN-DBS in non-genetically defined, rapid-onset dystonic, and parkinsonian syndromes did not demonstrate benefit. We describe the second case of GPI DBS and the first case of VOP/ZI DBS in DYT12. There was no significant

Commentary: Parkinson's Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on α-Synuclein

Several loci and genes are associated with Parkinsons disease (IPD) with some interacting at a cellular level. For example PINK1 activates Parkin through phosphorylation of ubiquitin and enhances Parkin-mediated elimination of damaged mitochondria (mitophagy). Mutations in both may result in deregulation of mitochondrial homeostasis leading to neurodegeneration (Olszewska et al., 2014). Intimate knowledge of the interplay between gene products will be crucial for targeted-therapeutic development and pathway-based treatment initiatives (e.g., Parkin activators to enhance its housekeeping abilities in PD; Kazlauskaite et al., 2014).

Neurological picture. Neurological ornithology.

A 69-year-old man with a 10-year history of localisation-related epilepsy with secondary generalisation, and a 1-year history of right occipital haemorrhage presented with cognitive impairment, insomnia, visual hallucinosis and shortened stride. Examination suggested encephalopathy with subtle appendicular myoclonus and left hand postural and classical rest tremor, asymmetrical bradykinesia, neck and limb rigidity and left-sided neglect. Saccadic eye movements were entirely normal for approximately 5 years of follow-up. Sagittal T1 imaging (see figure 1A) demonstrated midbrain atrophy suggestive of the ‘hummingbird’ sign of Progressive Supranuclear Palsy (PSP) in the context of diffuse hemispheric foci of susceptibility artefact (see figure 1B) secondary to microhaemorrhages from cerebral amyloid angiopathy (CAA). I-Ioflupane single-photon emission computed tomography (SPECT) (DaTSCAN) was performed and demonstrated significant reduction in radiotracer uptake in the striatum bilaterally. Significant reduction in radiotracer uptake in the posterior striatum, particularly on the right was noted. The DaTSCAN was graded as upper range of grade 2 out of 3 by qualitative assessment according to the Catafau classification. This case of CAA with Parkinsonism is noteworthy in that the Parkinsonian phenomenology described is more suggestive of an idiopathic or symptomatic aetiology rather than PSP, and challenges the apparent 100% specificity of the ‘hummingbird sign’ for PSP as demonstrated recently in a clinical, radiological and pathological study of 41 cases of atypical Parkinsonism. The degree of midbrain atrophy seen in this case may reflect chronic Wallerian degeneration secondary to extensive cortical involvement in CAA, and cortical involvement is the likely cause of the appendicular myoclonus seen on clinical examination. The hummingbird appearance in PSP relates to atrophy of the midbrain tegmentum. Additionally, there is a relative lengthening of the interpeduncular fossa compared with the anteroposterior diameter of the midbrain tegmentum itself. To further demonstrate the diagnostic utility of MRI brain imaging in PSP, and supplementing the hummingbird sign which is essentially a qualitative finding, studies have looked at regional MRI measurements of brainstem structures in order to identify quantitative indicators of PSP. Various brainstem measurements have been studied in subjects with PSP, versus idiopathic Parkinson’s disease (IPD) and controls. Kato et al performed a morphometric analysis of midsagittal MRI images in patients with PSP and noted that all had the hummingbird sign. Additionally, there was a significant reduction in the areas (mm) of the midbrain tegmentum, inferior colliculus and pontine tegmentum compared with IPD and controls. Such areas may not be practically quantified on routine conventional MRI, however, the authors did note that the mean length (mm) of the anteroposterior diameter of the midbrain tegmentum in PSP patients was significantly shorter than in IPD patients and controls. The anteroposterior diameter of the midbrain is a measurement that could be relatively easily performed on routine diagnostic imaging, and Warmuth–Metz et al have studied this in addition to the anteroposterior diameter of the pons and collicular plate in 50 individuals with a variety of Parkinsonian syndromes including PSP, IPD and the striatonigral variant of multiple-system atrophy (MSA-P). They identified that patients with PSP had significantly lower midbrain diameters (mean 13.4 mm, range 11–15 mm, p<0.001) compared with patients with IPD (mean 18.5 mm, range 17–19 mm) and controls (mean 18.2 mm, range 17–20 mm). The anteroposterior diameter of the pons was defined as the largest distance perpendicular to the floor of the fourth ventricle, and this was significantly smaller in patients with PSP and MSA-P compared with those with IPD or control subjects (p<0.001). There was, however, significant overlap in individual values between all four groups of patients such that the authors concluded that measuring pontine diameter did not add significant information to the measurement of midbrain diameter alone in patients with PSP. In the case we describe, the anteroposterior diameter of the midbrain measured 14.7 mm within the range described in PSP Figure 1 (A) Sagittal T1 image demonstrating midbrain atrophy with preserved pontine volume suggestive of the ‘hummingbird sign’. (B) Axial susceptibility weighted image demonstrating multiple foci suggestive of microhaemorrhages in the setting of cerebral amyloid angiopathy.

The inherent susceptibility of dorsal motor nucleus cholinergic neurons to the neurodegenerative process in Parkinson's Disease

A commentary on Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinsons disease by Goldberg, J. A., Guzman, J. N., Estep, C. M., Ilijic, E., Kondapalli, J., Sanchez-Padilla, J., et al. (2012). Nat. Neurosci. 15, 1414–1421. What is it about the dopaminergic neurones of the substantia nigra pars compacta (SNpc) and the cholinergic neurones of the dorsal motor nucleus of the vagus (DMV) that makes them particularly prone to the neurodegenerative changes found in Parkinsons disease? If mitochondrial oxidant stress is accepted as an important step in the pathogenesis or Parkinsons disease, are these cell groups inherently prone to this? If they are, is this a potential target for future therapy? Recent work with the neurons of the SNpc has demonstrated that they are slow autonomous pacemakers with broad spikes (Grace and Bunney, 1984) and that this self-generated activity creates a metabolic stress that may prime these cells for to the deleterious effects of mitochondrial toxins and genetic alterations seen in familial forms of Parkinsons. This form of pacemaking promotes sustained calcium entry through L-type voltage-dependent calcium channels (Nedergaard et al., 1993; Puopolo et al., 2007; Guzman et al., 2010) that is, only weakly buffered by calcium-binding proteins (CaBPs) (Foehring et al., 2009). Goldberg et al. (2012) set out to identify if other neuron subsets might also be vulnerable in this way. They focused their attention on the neurons of the DMV, as it is known that these neurons are amongst the first to show Lewy Body Neurites (LBN) in Parkinsons disease. This marries well with the known early involvement of gut motility in many Parkinsons disease patients and recent experimental work that has demonstrated that alpha-synuclein accumulation in the DMV can be induced by slow gastric lavage of rotenone in rodents (Pan-Montojo et al., 2010). Perforated patch recordings of DMV neurons, taken from the medulla oblongata of choline acetyltransferase-enhanced green fluorescent protein (ChAT-eGFP) BAC transgenic mice, demonstrated autonomous pacemaking activity with broad spikes. This activity continued in the presence of cholinergic, glutamatergic, GABAergic, serotonergic, and adrenergic receptor antagonists. Following on from this, the authors demonstrated that this autonomous pacemaking elevates intracellular calcium concentration. They demonstrated rapid intracellular rise in calcium concentration following a spike and exponential fall in concentration during the interspike interval. A linear relationship between spike duration and calcium concentration was seen. Abolishing spike formation, with the addition of the sodium channel blocker tetrodotoxin (TTX), removed this intracellular calcium fluctuation and provided further evidence against a subthreshold, calcium channel-dependent oscillation. DMV neurons were then demonstrated to have a low intrinsic buffering capacity, meaning their ability to provide an energy neutral means of buffering intracellular calcium is poor. DMV neurons are not known to express detectable levels of calbindin or parvalbumin, two common CaBPs. The authors determined the intrinsic buffering capacity of DMV neurons using the added buffer method (Maravall et al., 2000), to allow for the possibility that these neurons may express other less well-characterized CaBPs. The matrix of DMV mitochondria was shown to be relatively oxidized. When isradipine (L-type calcium channel antagonist) was added, this oxidant stress was diminished, without altering the cells inherent spiking or pacemaking activity. Antagonizing Nav1 sodium channels with TTX (eliminates spiking and calcium entry) and lowering cell ambient temperature (reduces firing rate), both resulted in significantly lower mitochondrial oxidant stress. Increasing spike duration with tetraethylammonium [TEA, an antagonist of the large conductance voltage- and calcium-activated (BK) potassium channel] resulted in a significant increase in mitochondrial oxidant stress. Therefore, spike duration and rate directly influence calcium entry and subsequently the level of mitochondrial oxidant stress. Mutations in DJ-1 are linked with early onset autosomal recessive Parkinsons disease. DJ-1 helps to organize mitochondrial oxidant defences. The authors employed DJ-1−/− mice to explore the effect on mitochondrial oxidant stress. While basal pacemaking, spike width and rate were normal in these mice, basal mitochondrial oxidant stress levels were elevated. This basal mitochondrial stress was improved with pre-incubation with isradipine. In this important study the authors have highlighted the physiologic similarities between DMV cholinergic neurons and SNpc dopaminergic neurons, proposing a common neuronal phenotype underlying neurodegenerative risk in Parkinsons disease. The inherent pacemaking activity of these cells, via enhanced calcium entry, provides a first “hit” to their mitochondria, which may then be exacerbated further by exposure to environmental toxins or the individuals genetic makeup in rare familial cases of disease. However, DMV cholinergic neurons and SNc dopaminergic neurons appear to differ in their ability to withstand the pathological changes they acquire in Parkinsons disease. Cholinergic neurons appear to meet with this challenge better and animal models suggest they are more resistant to neuronal loss despite accumulation of alpha synuclein pathology (Nedergaard et al., 1993). Therefore, the physiologic similarities described here, do not on their own fully explain neuronal cell death in Parkinsons disease. The study provides further insight as to why individuals using L-type calcium channel blockers for hypertension may be protected from developing Parkinsons disease (Ritz et al., 2010) and points to a potential target for future preventative therapy.

A Wolf in Sheep’s Clothing: An “Alien Leg” in Corticobasal Syndrome

Background Alien limb phenomenon occurs in 50–60% of patients with corticobasal syndrome (CBS) and usually presents with an “alien hand” phenomenon. The “alien foot” presentation is rarer and may be misdiagnosed, as foot involvement can lead to erroneous localization of the clinical problem to the knee, hip, or back. Subsequently misdiagnoses such as myelopathy, radiculopathy, functional disorder, stiff leg syndrome, neuromyotonia, and painful leg moving toes syndrome may occur. Case report We describe two patients with alien foot symptoms that resulted in multiple opinions from different specialists, multiple diagnostic and therapeutic procedures, and delayed diagnosis. Eventually a diagnosis of CBS was made in both. Alien foot symptoms may be more common than initially thought and can result in a delayed diagnosis of CBS. Conclusion The inclusion of this clinical finding in recently proposed diagnostic criteria highlights the need for increased clinical awareness.