An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)>300 and a further nine individuals with (GAA)>250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)>300 and only 2/311 control individuals (0.6%) had a pure (GAA)>250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)>335 and a further six had (GAA)>250, whereas 10/190 (5.3%) control subjects had (GAA)>250 but none were (GAA)>335. The combined data suggest (GAA)>335 are disease causing and fully penetrant (p = 6.0 × 10-8, OR = 72 [95% CI = 4.3-1,227]), while (GAA)>250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2 = 0.44, p = 0.00045, slope = -0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.

A patient with neuropathy and ataxia: what do I have to consider?

PURPOSE OF REVIEW: An increasing number of peripheral neuro(no)pathies are identified as involving other components of the neurological system, particularly those that further impair balance. Here we aim to outline an evidence-based approach to the diagnosis of patients who present with a somatosensory disorder which also involves at least one other area of neurological impairment such as the vestibular, auditory, or cerebellar systems. RECENT FINDINGS: Detailed objective investigation of patients who present with sensory impairment, particularly where the degree of imbalance is greater than would be expected, aids the accurate diagnosis of genetic, autoimmune, metabolic, and toxic neurological disease. SUMMARY: Diagnosis and management of complex somatosensory disorders benefit from investigation which extends beyond the presenting sensory impairment.

Optimizing the technique for eliciting antidromic sural and superficial fibular sensory nerve action potentials.

INTRODUCTION/AIMS: Lower limb sensory nerve action potentials are an important component of nerve conduction studies. Most testing of the sural and superficial fibular nerves involves antidromic techniques above the ankle, which result in a falsely unobtainable response in 2%-6% of healthy people. Cadaver, surgical, and more recent ultrasound series suggest this may relate to the site of fascia penetration of the nerve, and it is hypothesized that a modified technique may be more likely to produce reliable responses and reduce false-negative errors. METHODS: This article evaluates a variety of recording distances for both nerves in 100 healthy controls, including varying recording electrode positions and techniques, to provide the optimal electrodiagnostic information in healthy control subjects. RESULTS: Shorter stimulation distances produce higher-amplitude responses but become confounded by increasing stimulation artifact at very short distances, with the best balance found at around 10 cm. In both sural and superficial fibular nerves, amplitude increases by approximately 10%/cm compared with the standard 14 cm distance. The Daube superficial fibular technique produced a higher amplitude than the Izzo Intermediate technique (by 22.46%, p < .001). The calculated upper limit of normal for side-to-side variation in amplitude was around 50% in the sural nerve but over 70% in the superficial fibular nerve. DISCUSSION: It is proposed that the 10 cm recording distance for both nerves is optimal, with minimal false-negatives and a higher amplitude elicited than with existing techniques.

Long latency reflexes of the median nerves in healthy adults.

INTRODUCTION/AIMS: Long latency reflexes (LLRs) are late responses in nerve conduction studies seen after peripheral nerve stimulation during submaximal muscle contraction. They follow a short latency reflex, also known as the H reflex, and are thought to involve transcortical pathways, providing a measure of proximal nerve and central conduction. For this reason, they have been evaluated in several central nervous system diseases, but reference values are not widely published and are mostly based on old studies with very small numbers of participants. Therefore, in this work we aim to provide comprehensive reference values for LLR testing. METHODS: LLRs were tested in a cohort of 100 healthy participants, testing the median nerve bilaterally. RESULTS: Mean latencies for short latency reflex (SLR), LLR1, LLR2, and LLR3 were 27.00, 38.50, 47.60, and 67.34 milliseconds, respectively. The allowable side-to-side difference was approximately 3 to 4 milliseconds. No significant sex-related differences were seen. Height correlated moderately with the SLR latency, but only weakly with LLR1, LLR2, and LLR3. DISCUSSION: This work provides normal LLR values for comparison with future studies in disease. The technique used may allow for improved evaluation of central nervous system or proximal peripheral nerve disorders.

Reducing glucose variability with continuous subcutaneous insulin infusion is associated with reversal of axonal dysfunction in type 1 diabetes mellitus.

INTRODUCTION: We assess whether improvement in control of type 1 diabetes mellitus (T1DM) with continuous subcutaneous insulin infusion (CSII) can protect peripheral nerve function. METHODS: Twelve patients with T1DM treated with multiple daily insulin injections were assessed with nerve excitability testing prior to and 3 months after initiation of CSII. RESULTS: Although commencing treatment with CSII for 3 months improved mean glycosylated hemoglobin, it did not significantly alter nerve excitability or glycemic variability (GV). In four patients, some deterioration in GV was observed, while eight patients had improvement in SD and mean amplitude of glycemic excursions. For these eight patients, there was normalization of depolarizing and hyperpolarizing threshold electrotonus and recovery cycle superexcitablity. DISCUSSION: When CSII initiation is able to reduce glycemic variability in T1DM, reversal of axonal dysfunction is seen, likely due to normalization of sodium-potassium pump function and restoration of transaxonal membrane potential.

Single-fiber F waves compared with conventional surface F waves, and their utility in detecting early diabetic neuropathy.

INTRODUCTION: The single-fiber F-wave (SFF-wave) technique assesses the entire length of single motor fibers using a concentric needle. Herein we investigated the utility of this approach in the detection of early diabetes-related neuropathy, and compared it with the use of conventional surface F waves (CF waves). METHODS: Sixteen patients with diabetes and either no neuropathy or mild neuropathy were assessed and compared with 16 age- and height-matched control participants. RESULTS: Both CF and SFF waves were abnormal in all 5 patients who had mild neuropathy. However, SFF waves demonstrated subclinical abnormalities in 7 of 11 patients (64%) with no neuropathy, whereas only 2 of these patients (18%) had prolonged CF waves. Minimum F-wave latency was comparable between techniques, but maximum SFF-wave latency was more frequently prolonged, as these delayed motor units were better isolated, rather than buried among summated CF-wave responses. DISCUSSION: SFF waves highlight the segmental involvement in diabetic neuropathy, and use of the SFF-wave technique detects more abnormalities than with CF waves. Muscle Nerve 58: 665-670, 2018.

Monitoring and reporting attacks on education in the Democratic Republic of the Congo and Somalia.

The United Nations' Monitoring and Reporting Mechanism is charged with documenting six grave violations against children in a time of conflict, including attacks on schools. Many of these incidents, however, remain unreported across the globe. This study explores whether or not a local knowledge base of education and child protection actors in North and South Kivu Provinces, Democratic Republic of the Congo, and in Mogadishu, Somalia, could contribute to a more complete record of attacks on education in those areas. Hundreds of semi-structured interviews were conducted with key informants across the three settings, and in total 432 attacks on education were documented. Purposive samples of these reports were verified and a large majority was confirmed. Local non-governmental organisations and education institutions were most knowledgeable about these incidents, but most never reported them to a monitoring authority. The study concludes that attack surveillance and response were largely insufficient, and recommends investing in mechanisms that utilise local knowledge to address these shortcomings.

Estimating the size of the homeless adolescent population across seven cities in Cambodia.

BACKGROUND: The Government of Cambodia has committed to supporting family care for vulnerable children, including homeless populations. Collecting baseline data on the numbers and characteristics of homeless adolescents was prioritized to illuminate the scope of the issue, mobilize resources and direct the response. METHODS: Administrative zones across seven cities were purposively selected to cover the main urban areas known to have homeless populations in Cambodia. A complete enumeration of homeless individuals between the ages of 13 and 17 was attempted in the selected areas. In addition, a second independent count was conducted to enable a statistical estimation of completeness based on overlap across counts. This technique is known as capture-recapture. Adolescents were also interviewed about their schooling, health and other circumstances. RESULTS: After adjustment by the capture-recapture corrective multipliers (range: 3.53 -27.08), the study yielded an estimate of 2,697 13-17 year old homeless adolescents across all seven cities. The total number of homeless boys counted was significantly greater than homeless girls, especially in older ages. CONCLUSIONS: To the authors' knowledge, this is the first time capture-recapture methods have been applied to a homeless estimation of this scale in a resource-limited setting. Findings suggest the number of homeless adolescents in Cambodia is much greater than one would expect if relying on single count data alone and that this population faces many hardships.

Assessment of the relationship between hypoglycaemia awareness and autonomic function following islet cell/pancreas transplantation.

BACKGROUND: This study assesses the autonomic function of patients who have regained awareness of hypoglycaemia following islet cell or whole pancreas transplant. METHODS: Five patients with type 1 diabetes and either islet cell (four patients) or whole pancreas (one patient) transplant were assessed. These patients were age-matched and gender-matched to five patients with type 1 diabetes without transplant and preserved hypoglycaemia awareness and five healthy control participants without diabetes. All participants underwent (i) a battery of five cardiovascular autonomic function tests, (ii) quantitative sudomotor axonal reflex testing, and (iii) sympathetic skin response testing. RESULTS: Total recorded hypoglycaemia episodes per month fell from 76 pre-transplant to 13 at 0- to 3-month post-transplant (83% reduction). The percentage of hypoglycaemia episodes that patients were unaware of decreased from 97 to 69% at 0-3 months (p < 0.001, Fisher's exact test) and to 20% after 12 months (p < 0.0001, Fisher's exact test). This amelioration was maintained at the time of testing (mean time: 4.1 years later, range: 2-6 years). Presence of significant autonomic neuropathy was seen in all five transplanted patients (at least 2/3 above modalities abnormal) but in only one of the patients with diabetes without transplantation. CONCLUSIONS: The long-term maintenance of hypoglycaemia awareness that returns after islet cell/pancreas transplantation in patients with diabetes is not prevented by significant autonomic neuropathy and is better accounted for by other factors such as reversal of hypoglycaemia-associated autonomic failure.

Fibular motor nerve conduction studies: Investigating the mechanism for compound muscle action potential amplitude drop with proximal stimulation.

INTRODUCTION: The compound muscle action potential (CMAP) amplitude of extensor digitorum brevis can show a drop with proximal stimulation in normal fibular nerves. METHODS: We assessed the contribution of the far-field potential recorded by the reference electrode (R-CMAP) to the fibular CMAP. Negative R-CMAP amplitude, peak-to-peak amplitude, and negative area were measured and correlated with the amplitude decrease. Fibular motor nerves from 14 healthy participants were studied. RESULTS: The mean CMAP amplitude drop with proximal stimulation was 14.0 ± 9.3%, including a >30% reduction in 1 study. All measured R-CMAP parameters correlated with the degree of amplitude drop. CONCLUSIONS: A greater R-CMAP contribution to the fibular CMAP leads to greater phase cancellation and temporal dispersion. The resulting amplitude drop seen in the proximal CMAP can be large enough to be classified incorrectly as "probable conduction block" by several different diagnostic criteria.

Neurophysiological evidence for generalized sensory neuronopathy in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome.

INTRODUCTION: Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recently described multisystem ataxia defined by the presence of cerebellar ataxia, bilateral vestibulopathy, and a somatosensory deficit. The characteristic clinical sign is an abnormal visually enhanced vestibuloocular reflex. The somatosensory deficit contributes to a significant level of disability in CANVAS. METHODS: This study was a neurophysiological investigation of 14 patients with CANVAS. RESULTS: Findings revealed uniformly absent sensory nerve action potentials in all limbs, abnormal blink reflexes in 13 of 14 patients, and abnormal masseter reflexes in 6 of 11 patients. Tibial H-reflexes were absent in 11 of 14 patients. Somatosensory evoked potentials were abnormal in 10 of the 11 patients tested, and brainstem auditory evoked responses were abnormal in 3 of 8. Cutaneous silent period responses were abnormal in 7 of 14 patients. CONCLUSIONS: We suggest that a sensory neuronopathy should be sought in cerebellar and/or vestibular ataxias, particularly where the degree of ataxia is out of proportion to the clinically identified cerebellar and/or vestibular dysfunction.

Wild poliovirus makes comeback in Afghanistan and Pakistan.

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Report offers harsh verdict on global polio vaccine switch.

Draft evaluation calls 2016 decision to change oral vaccines a "failure".