Matthew T. Lorincz

Neurologic Wilson's disease

Despite a long history, Wilsons disease, an autosomal recessive disease caused by mutations in the ATP7B gene, remains a commonly misdiagnosed import disease. Mutations in ATP7B result in abnormal copper metabolism and subsequent toxic accumulation of copper. Clinical manifestations of neurologic Wilsons disease include variable combinations of dysarthria, dystonia, tremor, and choreoathetosis. Among neurodegenerative diseases, it is unusual in that misdiagnosis and delay in treatment are clinically relevant because treatments can prevent and cure Wilsons disease, if they are given appropriately. If left untreated, Wilsons disease progresses to hepatic failure or severe neurologic disability and death, while those adequately treated have normal life spans. This review focuses on the neurologic features of Wilsons disease, its diagnosis, and treatment options.

Expanded CAG repeats in the murine Huntington's disease gene increases neuronal differentiation of embryonic and neural stem cells.

Huntingtons disease is an uncommon autosomal dominant neurodegenerative disorder caused by expanded polyglutamine repeats. Increased neurogenesis was demonstrated recently in Huntingtons disease post-mortem samples. In this manuscript, neuronally differentiated embryonic stem cells with expanded CAG repeats in the murine Huntingtons disease homologue and neural progenitors isolated from the subventricular zone of an accurate mouse Huntingtons disease were examined for increased neurogenesis. Embryonic stem cells with expanded CAG repeats in the murine Huntingtons disease homologue were demonstrated to undergo facilitated differentiation first into neural progenitors, then into more mature neurons. Neural progenitor cells isolated from the subventricular zone of a Huntingtons disease knock-in animal displayed increased production of neural progenitors and increased neurogenesis. These findings suggested that neuronally differentiating embryonic stem cells with expanded CAG repeats is a reasonable system to identify factors responsible for increased neurogenesis in Huntingtons disease. Expression profiling analysis comparing neuronally differentiating embryonic stem cells with expanded CAG repeats to neuronally differentiating embryonic stem cells without expanded CAG repeats identified transcripts involved in development and transcriptional regulation as factors possibly mediating increased neurogenesis in response to expanded CAG repeats.

A Clinical Approach to the Diagnosis of Traumatic Encephalopathy Syndrome: A Review

IMPORTANCE Chronic traumatic encephalopathy (CTE) refers to pathologic changes that have been found in some individuals with a history of repetitive traumatic impact to the head (hereinafter referred to as head trauma). These changes cannot be assessed during the clinical evaluation of a living patient. OBSERVATIONS The neuropathologic features, taxonomy, history, role of biomarkers in diagnosis, and existing criteria of CTE are reviewed. Previous criteria have been proposed to approach the living patient; however, a unified, specific approach is needed for the practicing clinician. We propose a new diagnostic construct for the clinical syndrome associated with repetitive exposure to head trauma: traumatic encephalopathy syndrome. This clinical paradigm will provide the framework for a diagnosis of probable, possible, and unlikely traumatic encephalopathy syndrome, with included discussion regarding the minimum exposure, nature of the clinical course, and additional clinical features needed for diagnosis. CONCLUSIONS AND RELEVANCE While prospective longitudinal studies are ongoing to further elucidate the association of exposure to head trauma, clinical features, and the development of pathologic changes, a corresponding clinical construct for diagnosis is necessary.

Recognition and treatment of neurologic Wilson's disease.

As Wilsons disease is both preventable and treatable, the diagnosis must not be missed. Despite this, it is usually misdiagnosed. Misdiagnosis and delay in treatment are clinically relevant because if left untreated, Wilsons disease progresses to hepatic failure or severe neurologic disability, and death. Those adequately treated have a normal life span. Wilsons disease is an autosomal recessive disease caused by mutations in the ATP7B gene. Mutations in ATP7B result in abnormal copper metabolism and subsequent toxic accumulation of copper. The clinical manifestations of neurologic Wilsons disease include variable combinations of dysarthria, dystonia, tremor, parkinsonism, ataxia, and choreoathetosis. Once the possibility of Wilsons disease is considered, diagnosis is straight forward. Currently available treatments, including zinc acetate and trientine, are generally well tolerated and effective.

Optimized Neuronal Differentiation of Murine Embryonic Stem Cells

Neuronally differentiated embryonic stem (ES) cells offer a flexible and extremely potent model to study nervous system development and disease. A variety of protocols have been described to facilitate neuronal differentiation. The density of ES cells used for neuronal differentiation has striking effects on the proportion and purity of the derived neuronal cells. Here, the protocols used to optimize ES cell density in neuronal differentiation with and without an initial aggregation step are described.

Embryonic stem cells expressing expanded CAG repeats undergo aberrant neuronal differentiation and have persistent Oct-4 and REST/NRSF expression

Nine neurodegenerative disorders are caused by CAG/polyglutamine (polyQ) repeat expansions. The molecular mechanisms responsible for disease-specific neurodegeneration remain elusive. We developed an embryonic stem (ES) cell-based model to probe the role of polyQ tract expansion in neuronal degeneration. ES cells containing expanded CAG repeats in the hypoxanthine phosphoribosyltransferase (Hprt) gene develop features typical of CAG-mediated neuropathology, exhibit length-dependent decrease in survival, undergo aberrant neuronal differentiation as well as persistent Oct-4 and Repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF) expression. This novel model will allow analysis of the molecular pathogenesis of neuronal degeneration and can be used to rapidly screen therapeutic interventions for these fatal diseases.

Leukoencephalopathy, cerebral calcifications, and cysts: Case report

The triad of leukoencephalopathy, cerebral calcifications, and ysts (LCC) represents a very rare, and distinct clinico-radiologic ntity of unknown etiology, first described in children by Labrune t al. [1] in 1996. The onset ranges from infancy to adults 1–5], with varying clinical presentations including a combinaion of mild cognitive dysfunction or normal intelligence, seizures, erebellar, pyramidal and extrapyramidal signs. The disorder s characterized by diffusely progressive basal ganglia, brain tem and subcortical white matter calcifications, cerebellar, and upratentorial parenchymal cysts, as well as diffusely abnormal 2-weighted sequences on MRI [1–4]. The white matter abnoralities were described as a leukoencephalopathy rather than demyelinating process (leukodystrophy) [2]. Histopathologic xamination reveals angiomatous-like blood vessels, gliosis, and eaded, corkscrew-shaped intracytoplasmic inclusions typically ssociated with highly gliotic tissue surrounding cysts and vascuar malformations (Rosenthal fiber formation) in the white matter 1,3,4]. Complications are typically a consequence of mass effect ncluding cerebral edema leading to intracranial hypertension, apilledema, syringomyelia and eventually tonsillar herniation [4].

Wilson disease and related copper disorders

Copper is a required cofactor for enzymes in critical metabolic pathways. Mutations in copper metabolism genes or abnormalities in copper metabolism result in disease from copper excess or deficiency. Wilson disease (WD) is an autosomal-recessive disease caused by mutations in the ATP7B gene which encodes a copper-transporting ATPase. Over 500 different WD mutations throughout the ATP7B gene have been described, most of which are missense mutations. Mutations in both ATP7B alleles result in abnormal copper metabolism and subsequent toxic accumulation of copper. The clinical manifestations of neurologic WD include variable combinations of dysarthria, dystonia, tremor, and choreoathetosis. Misdiagnosis and delay in treatment are clinically relevant because untreated WD progresses to hepatic failure or severe neurologic disability and death. Treatment can prevent and cure WD. Mutations in a second, closely related copper-transporting ATPase, ATP7A, cause a spectrum of copper deficiency disorders that include Menkes disease, occipital horn syndrome, and ATP7A-related distal motor neuropathy. Two important, nongenetic causes of copper deficiency myeloneuropathy are copper deficiency following gastric bypass or due to excess zinc ingestion, both of which can cause a myeloneuropathy similar to vitamin B12 deficiency. Copper deficiency following gastric bypass is preventable, and identification and elimination of the excess zinc source, most commonly dental cream, can result in recovery.

Characterization of cervical neuromuscular response to head-neck perturbation in active young adults

BACKGROUND The majority of studies examining the role of cervical muscles on head-neck kinematics focused on musculoskeletal attributes (e.g. strength). Cervical neuromuscular response to perturbation may represent a divergent construct that has not been examined under various perturbation conditions. This study examined the association between cervical musculoskeletal attributes and cervical neuromuscular response of the sternocleidomastoid (SCM) to perturbation. Furthermore, this study examined the effect of anticipation and preload on the SCM neuromuscular response. METHODS Nineteen participants completed measurement of SCM muscle size, cervical flexion maximal voluntary isometric contraction, and the neuromuscular response of the SCM to cervical perturbation. Cervical perturbation was delivered by dropping a 1.59 kg mass from a loading apparatus. The impulsive load was delivered under four conditions: (1) Anticipated perturbation with no preload (A-NP), (2) Unanticipated perturbation with no preload (U-NP), (3) Anticipated perturbation with preload (A-P), and (4) Unanticipated perturbation with preload (U-P). RESULTS None of the cervical musculoskeletal attributes were correlated with the SCM cervical neuromuscular response. This study demonstrated significant effect of preloading and anticipation on baseline EMG amplitude and EMG onset latency for the SCM. Furthermore, there was a significant effect of preloading on average EMG response amplitude for the SCM. DISCUSSION The findings of this study indicate that cervical neuromuscular response of the SCM is different from musculoskeletal attributes and is influenced by perturbation conditions. These findings provide conceptual support to examine the neuromuscular response of the SCM in mitigating head-neck kinematics.

Online postconcussion return-to-play instructions

OBJECTIVE The authors of recent concussion guidelines have sought to form a consensus on injury management, but it is unclear if they have been effective in conveying this information to the public. Many parents and athletes obtain medical recommendations via the Internet. This review is aimed at evaluating consistency between online resources and published guideline statements in postconcussion return-to-play (RTP) decisions. METHODS Five websites were selected through a Google search for RTP after concussion, including a federal government institution (Centers for Disease Control and Prevention) website, a national high school association (National Federation of State High School Associations) website, a popular nationally recognized medical website for patients (WebMD), a popular parent-driven website for parents of children who participate in sports (MomsTeam), and the website of a private concussion clinic (Sports Concussion Institute), along with a university hospital website (University of Michigan Medicine). Eight specific items from the Zurich Sport Concussion Consensus Statement 2012 were used as the gold standard for RTP recommendations. Three independent reviewers graded each website for each of the 8 recommendations (A = states guideline recommendations appropriately; B = mentions guideline recommendation; C = does not mention guideline recommendation; F = makes inappropriate recommendation). RESULTS A grade of A was assigned for 45.8% of the recommendations, B for 25.0%, C for 25.0%, and F for 4.2%. All the websites were assigned an A grade for the recommendation of no RTP on the day of injury. Only 1 website (WebMD) mentioned medication usage in conjunction with the Zurich statement, and only 2 websites (Sports Concussion Institute and University of Michigan Medicine) mentioned appropriate management of persistent symptoms. None of these websites commented correctly on all 8 guideline recommendations. CONCLUSIONS Online resources are inconsistent in relaying guideline recommendations for RTP and provide a potential source of confusion in the management of concussion for athletes and their parents, which can result in inappropriate RTP decisions.