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Objective: To provide clinical data on a cohort of 6 patients with massive expansion (>200 CAG repeats) of spinocerebellar ataxia type 2 (SCA2) and investigate possible pathways of pathogenesis using bioinformatics analysis of ATXN2 networks. Methods: We present data on 6 patients with massive expansion of SCA2 who presented in infancy with variable combinations of hypotonia, global developmental delay, infantile spasms, and retinitis pigmentosa. ATXN2 is known to interact with a network of synaptic proteins. To investigate pathways of pathogenesis, we performed bioinformatics analysis on ATXN2 combined with known genes associated with infantile spasms, retinitis pigmentosa, and synaptic function. Results: All patients had a progressive encephalopathy with autonomic dysfunction, 4 had retinitis pigmentosa, and 3 had infantile spasms. The bioinformatics analysis led to several interesting findings. First, an interaction between ATXN2 and SYNJ1 may account for the development of retinitis pigmentosa. Second, dysfunction of postsynaptic vesicle endocytosis may be important in children with this progressive encephalopathy. Infantile spasms may be associated with interactions between ATXN2 and the postsynaptic structural proteins MAGI2 and SPTAN1. Conclusions: Severe phenotype in children with massive expansion of SCA2 may be due to a functional deficit in protein networks in the postsynapse, specifically involving vesicle endocytosis.

Objective: To examine the potential validity of performance measures and examination-based scales in Friedreich ataxia (FA) by examining their correlation with disease characteristics. Methods: The authors assessed the properties of a candidate clinical outcome measure, the Friedreich Ataxia Rating Scale (FARS), and simple performance measures (9-hole peg test, the timed 25-foot walk, PATA test, and low-contrast letter acuity) in 155 patients with FA from six institutions, and correlated the scores with disease duration, functional disability, activity of daily living scores, age, and shorter GAA repeat length to assess whether these measures capture the severity of neurologic dysfunction in FA. Results: Scores for the FARS and performance measures correlated significantly with functional disability, activities of daily living scores, and disease duration, showing that these measures meet essential criteria for construct validity for measuring the progressive nature of FA. In addition, the FARS and transformed performance measures scores were predicted by age and shorter GAA repeat length in linear regression models accounting for sex and testing site. Correlations between performance measures were moderate in magnitude, suggesting that each test captures separate yet related dimensions of neurologic function in FA and that a composite measure might better predict disease status. Composite measures created using cohort means and standard deviations predicted disease status better than or equal to single performance measures or examination-based measures. Conclusions: The Friedreich Ataxia Rating Scale, performance measures, and performance measure composites provide valid assessments of disease progression in Friedreich ataxia.

Objective: To provide clinical, electrophysiologic, and ultrastructural findings in three patients with a presynaptic congenital myasthenic syndrome (CMS). Background: Familial infantile myasthenia and paucity of synaptic vesicles are the only two fully characterized CMS. We are describing here three patients with another form of presynaptic CMS characterized by deficiency of the action potential–dependent release without reduction of the spontaneous release of neurotransmitter from the nerve terminal. Methods: The authors performed electromyography and anconeus muscle biopsies that included intracellular recordings and electron microscopy of the neuromuscular junction in three patients with presynaptic CMS. They also sequenced part of the P/Q-calcium α1-subunit gene (CACNA1A) and the acetylcholine receptor subunit (AChR) genes in these patients. Results: In these patients there were additional neurologic findings including nystagmus and ataxia. In all three patients the end-plate potential quantal content (m) was markedly reduced but neither the amplitudes nor the frequencies of miniature end-plate potentials were diminished. Ultrastructurally, postsynaptic end-plate folds, nerve terminal size, and synaptic vesicle number were normal but double-membrane-bound sacs containing synaptic vesicles were present in the nerve terminal of all three patients. The screening of reported pathogenic mutations in the CACNA1A and a mutational analysis of AChR subunit genes were negative. Conclusion: This form of CMS appears to result only from a deficiency of the quantal release of neurotransmitter that may be due to an abnormal calcium mechanism or impaired endocytosis and recycling of synaptic vesicles.

The current policy of the American Academy of Neurology (AAN) was approved in principle by its Executive Board in December 1975: "Neuroimaging is an integral part of the practice of neurology that requires broad knowledge of neuroanatomy, neuropathology, pathophysiology, and clinical neurologic disorders. Proper interpretation of neuroimaging requires knowledge of the effects of disease on the neuroimaging examination, its indications, performance and interpretation." In addition, the American Medical Association (AMA) has clearly stated its position regarding jurisdictional disputes among medical specialists: "The AMA believes that (1) individual character, training, competence, experience, and judgment should be the criteria for granting privileges in hospitals; and(2) physicians representing several specialties can and should be permitted to perform the same procedures if they meet these criteria (Res. 26, A-77; Reaffirmed CLRPD Rep. C, A-89)."1,2 This position was ratified by the AMA House of Delegates in its interim meeting of 1994 by having approved the following resolution submitted by the AAN: WHEREAS physicians have often been denied privileges to perform a cross-specialty service primarily because the physicians' specialty is different from the specialty that has the most influence over institutional policies relating to that service area; and WHEREAS such denials may restrict patient access to care and impede improvements in quality of care by excluding physicians with adequate training and experience and who have an important perspective on a particular field, BE IT RESOLVED that the AMA supports the policy that hospitals and other institutions should allow physician staff to provide any service for which they have adequate training and experience, regardless of specialty, and should use quality of patient care as the only reason for denying privileges. The Neuroimaging Subcommittee of the Practice Committee of the AAN recognized the need to update the AAN guidelines for credentialing neurologists in the practice of neuroimaging. …

To an increasing extent, the desire to catalog and categorize neurologic disorders based on genotype–phenotype correlations is challenged by frequent departures from the syndromic categorizations that were commonplace in the pregenomic era. This challenge is not limited to the recent striking revelations concerning diseases attributable to noncoding, nonconventional mutations, such as repeat expansions in C9ORF72 . There are abundant examples of conventional mutations, identified using nonbiased, whole-exome sequencing, that lead to unanticipated phenotypes in the world of hereditary motor system disorders. The report by Pfeffer et al.1 further the supports the idea that, as targeted sequencing based on clinical phenotype moves toward nonbiased sequencing, we must be prepared to expect surprises that link genetic abnormalities to unanticipated clinical syndromes.

Measuring the severity of neurologic dysfunction in patients with inherited ataxias, including Friedreich ataxia (FA), is difficult because of the variable rate of progression, the variable age at onset and the variety of neural systems that may be affected. The authors discuss the problems related to rating scales in the ataxias, report a neurologic rating scale for FA, and demonstrate acceptable interrater reliability of the instrument.

The relevance of gluten sensitivity in sporadic and hereditary ataxia pathogenesis is unclear. The authors found high antigliadin antibody titers in 23 of 52 (44%) patients with Huntington’s disease (HD), suggesting a previously unrecognized association between HD and gluten sensitivity. The results further question “gluten ataxia” as a distinct disease entity and raise the possibility that antigliadin antibodies in ataxia and other neurodegenerative diseases may be an epiphenomenon, the mechanisms of which remain to be investigated.

Three reports in this issue of Neurology illustrate what we should expect to see as a trend for clinical neurogenetics in the future1–3⇓⇓; that is, as the genetic basis is revealed for disorders identified with a specific regional or ethnic population, allelic disorders for each will be identified worldwide. Crisculo et al.3 and Grieco et al.,1 in patients from Italy, and Ogawa et al.,2 in patients from Japan, identify a series of new mutations in the SACS gene responsible for the disease known as autosomal recessive spastic ataxia of the Charlevoix-Saguenay region (ARSACS). Another report included patients from Tunisia.4 This disorder owes its long name to its high prevalence in two small regions of Quebec where individuals bearing one point mutation settled from Europe in the mid-1800s.5,6⇓ The propagation of the descendants of these individuals within a relatively small founder population led to a high carrier frequency for this mutation.5,6⇓ By the late 1970s a series of clinical …

Article abstract—The slow-channel syndrome is one of several congenital myasthenic syndromes that result from inherited abnormalities of the ion channel of the skeletal muscle acetylcholine receptor (AChR). The ion channel is formed by the second transmembrane domains (M2) of the four AChR subunits. We screened the genomic DNA of one family with the slow-channel syndrome for mutations in the coding sequences for the M2 domains of the four AChR subunits and report the identification of a missense mutation that causes a leucine-to-phenylalanine substitution at position 269 of the E subunit in three affected members of a family with the slow-channel syndrome. We propose that this mutation may be responsible for the disease.

Objective: To identify potential biomarkers in the cerebrospinal fluid (CSF) of patients with spinocerebellar ataxia (SCA) 1, SCA2, SCA6, and multiple system atrophy of the cerebellar type (MSA-C). Background Levels of proteins such as α-synuclein, tau, and DJ-1 have shown promise as potential type-specific and stage-specific bioimarkers of several neurodegenerative diseases, including Parkinson9s, Alzheimer9s, multiple sclerosis, and ALS. DJ-1 has recently been shown to be involved in oxidative stress and to be elevated in the early stages of Parkinson9s. α-synuclein is thought to be involved in vesicle trafficking and is decreased in the CSF of Parkinson9s patients. Tau is a general marker of neuroaxonal damage elevated in Alzheimer9s, ALS, and multiple sclerosis. Limited to no biomarker data has been previously published in regards to ataxia disorders. Design/Methods: The CSF samples were obtained for this study from 26 patients: 5 diagnosed with SCA1, 6 with SCA2, 5 with SCA6, 5 with MSA-C, and 5 controls with no neurological pathology. CSF was analyzed using commercial enzyme-linked immunoabsorption assays (ELISAs) to determine protein concentrations of α-synuclein, tau, and DJ-1. Statistical analysis was performed using a Mann-Whitney U nonparametric test with appropriate post-hoc Bonferroni corrections. Results: DJ-1 levels were unchanged in all the disease states. Levels of α-synuclein were elevated only in SCA-2 patients (p=0.004) at 0.6965 ng/mL vs. 0.4312 ng/mL in controls. Tau protein was elevated in both MSA-C (p=0.004) and SCA2 (p=0.002) patients at 76.117 pg/mL and 106.634 pg/mL respectively as compared to 44.154 pg/mL in the controls. Conclusions: Elevated levels of both tau and α-synuclein in SCA2 and none of the other SCAs examined indicate a possible differentiation between diseases that present in a clinically similar manner. Additionally, as very little is known about MSA-C, elevated levels of tau could provide insight into pathogenesis. Supported by: National Ataxia Foundation, JayD Schlueter Fund. Disclosure: Dr. Brouillette has nothing to disclose. Dr. Gomez has nothing to disclose.

Molecular discoveries of the past decade have defined many new classes of neurological disorders. Two of these, the ion channelopathies and the polyglutamine diseases, have distinct pathological mechanisms and may require different therapeutic strategies. One disorder, spinocerebellar ataxia type 6 (SCA6) is unusual: It appears to belong to both classes. Disorders of ion channel function underlie many autosomal dominant, episodic, or progressive conditions including epilepsy, periodic paralysis, migraine, and episodic ataxia.1,2⇓ Missense or truncation mutations in neurotransmitter-gated or voltage-gated ion channels disturb nerve or muscle excitability, or intracellular ionic homeostasis, and lead to neuronal dysfunction or death. The toxic effect exerted by these mutant channels occurs by a perturbing normal channel function. Polyglutamine (polyQ) expansion disorders, such as Huntington’s disease and most autosomal dominant spinocerebellar ataxias, arise from a shared mutational mechanism,3 an abnormally expanded sequence encoding a tract of glutamine residues in any of several unrelated …

Summary and critique. Advantages of method. TCD is a noninvasive test effective in monitoring blood velocities in large intracranial arteries. It uses small, potentially portable, relatively inexpensive equipment. The test can be repeated and therefore allows the detection of changes over time and after various physiologic studies or pharmacologie intervention, and during various postural and positional changes. TCD can also be used to monitor changes during surgery or other interventions.

The acute phase of experimental autoimmune myasthenia gravis (EAMG) is characterized by macrophage inflammation of muscle endplates and by muscle fiber necrosis. We induced acute EAMG by passive transfer of monoclonal antibodies (mAbs) directed against the acetylcholine receptor (AChR) to investigate this brief and self-limited disorder. After the initial acute phase, animals were refractory to induction of a second episode by subsequent injection of the same mAb, or another anti-AChR mAb of different idiotype and which binds to a separate epitope. Therefore, the refractory state was not caused by an anti-idiotypic response or elpitopic modulation. Adoptive transfer of spleen cells from refractory animals had no effect, excluding a role of suppressor lymphocytes, and there was no evidence from-experiments involving adoptive transfer of spleen cells from naive animals to refractory animals that refractory animals lacked effector cells.