Autosomal recessive MFN2-related Charcot-Marie-Tooth disease with diaphragmatic weakness: Case report and literature review

Pathogenic variants in the mitofusin 2 gene (MFN2) are the most common cause of autosomal dominant Charcot-Marie-Tooth (CMT2) disease, which is typically characterized by axonal sensorimotor neuropathy. We report on a 7-month-old white female with hypotonia, motor delay, distal weakness, and motor/sensory axonal neuropathy in which next-generation sequencing analysis identified compound heterozygous pathogenic variants (c.2054_2069_1170del and c.392A>G) in MFN2. A review of the literature reveals that sporadic and familial cases of compound heterozygous or homozygous pathogenic MFN2 variants have been infrequently described, which indicates that MFN2 can also be inherited in a recessive manner. This case highlights several clinical findings not typically associated with MFN2 pathogenic variants, including young age of onset and rapidly progressing diaphragmatic paresis that necessitated tracheostomy and mechanical ventilation, and adds to the growing list of features identified in autosomal recessive MFN2-related CMT2. Our patient with MFN2-related CMT2 expands the clinical and mutational spectrum of individuals with autosomal recessive CMT2 and identifies a new clinical feature that warrants further observation. © 2016 Wiley Periodicals, Inc.

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Does medical intervention affect outcome in infants with trisomy 18 or trisomy 13?

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Abdominal tuberculosis: experience with RNTCP category III antitubercular therapy

2016-03-08T23-05-59Z
Source: International Journal of Medical Science and Public Health
Sunit K Shukla, Govind N Srivastava, Manoj Meena, Piyush Arora, Chetan B Patil, Ram N Meena.
Background: Abdominal tuberculosis as such has been put in seriously ill category III regimen because the therapy of abdominal tuberculosis throws up many challenges, especially those presenting with immune compromised and malnourished state. To accommodate all the accompanying challenges, it is prudent to keep the regimen flexible. Objective: To study the 30- and 60-day efficacy of daily versus alternate-day self-administered therapy of abdominal tuberculosis in young adults with ileocecal tuberculosis (IC) and mesenteric tubercular lymphadenitis (ML). Materials and Methods: This study was conducted for a duration of 2 years, starting June 2013, in an outpatient setting of a tertiary referral center in north India. Patients identified during a study of causes of functional abdominal pain syndrome (FAPS) or only pain presentation in gastroenterology (GI) outpatient and diagnosed as IC or ML on the basis of contrast-enhanced computerized tomography (CECT) and/or colonoscopy with ileoscopy were given daily (weight based) versus alternate-day revised national tuberculosis control program (RNTCP) category III regimen therapy in a nonrandom manner. Result: Twelve patients of abdominal tuberculosis were identified: eight cases had IC with varying degrees of gastrointestinal disturbances whereas four had ML with no other organic disease explaining the symptoms. Groups prescribed daily versus alternate-day therapy did not differ significantly because of the presentation as FAPS in young adults. All patients received clinically significant improvement with antitubercular therapy. Four patients prescribed RNTCP category III regimen showed excellent clinical relief. Dyspepsia occurred significantly more with alternate-day therapy. Conclusion: Self-administered DOTS alternate-day therapy according to RNTCP category III regimen is equally efficacious to daily-weight-based regimen in young adults with abdominal tuberculosis.


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Interneurons contribute to the hemodynamic/metabolic response to epileptiform discharges

Interpretation of hemodynamic responses in epilepsy is hampered by an incomplete understanding of the underlying neurovascular coupling, especially the contributions of excitation and inhibition. We made simultaneous multimodal recordings of local field potentials (LFPs), firing of individual neurons, blood flow, and oxygen level in the somatosensory cortex of anesthetized rats. Epileptiform discharges induced by bicuculline injections were used to trigger large local events. LFP and blood flow were robustly coupled, as were LFP and tissue oxygen. In a parametric linear model, LFP and the baseline activities of cerebral blood flow and tissue partial oxygen tension contributed significantly to blood flow and oxygen responses. In an analysis of recordings from 402 neurons, blood flow/tissue oxygen correlated with the discharge of putative interneurons but not of principal cells. Our results show that interneuron activity is important in the vascular and metabolic responses during epileptiform discharges.

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Quantifying the spatial extent of the corollary discharge benefit to transsaccadic visual perception

Extraretinal information, such as corollary discharge (CD), is hypothesized to help compensate for saccade-induced visual input disruptions. However, support for this hypothesis is largely for one-dimensional transsaccadic visual changes, with little comprehensive information on the spatial characteristics. Here we systematically mapped the two-dimensional extent of this compensation by quantifying the insensitivity to different displacement metrics. Human subjects made saccades to targets positioned at different amplitudes (4° or 8°) and directions (rightward, oblique, or upward). After the saccade the initial target disappeared and, after a blank period, reappeared at a shifted location—a collinear, diagonal, or orthogonal displacement. Subjects reported the perceived shift direction, and we determined the displacement detection based on the perceptual judgments. The two-dimensional insensitivity fields resulting from the perceptual thresholds had spatial features similar to the saccadic eye movement variability: 1) scaled with movement amplitude, 2) oriented (less sensitive to the change) along the saccade vector, and 3) approximately constant in shape when normalized by movement amplitude. In addition, comparing the postsaccadic perceptual estimate of the presaccadic target location to that based solely on the postsaccade visual error showed that overall the perceptual estimate was approximately 50% more accurate and 35% less variable than estimates based solely on this visual information. However, this relationship was not uniform: The benefit of extraretinal information was observed largely for displacements with a component parallel to the saccade vector. These results suggest a graded use of extraretinal information when forming the postsaccadic perceptual evaluation of transsaccadic environmental changes.

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Hyperpolarization-independent maturation and refinement of GABA/glycinergic connections in the auditory brain stem

During development GABA and glycine synapses are initially excitatory before they gradually become inhibitory. This transition is due to a developmental increase in the activity of neuronal potassium-chloride cotransporter 2 (KCC2), which shifts the chloride equilibrium potential (E_Cl) to values more negative than the resting membrane potential. While the role of early GABA and glycine depolarizations in neuronal development has become increasingly clear, the role of the transition to hyperpolarization in synapse maturation and circuit refinement has remained an open question. Here we investigated this question by examining the maturation and developmental refinement of GABA/glycinergic and glutamatergic synapses in the lateral superior olive (LSO), a binaural auditory brain stem nucleus, in KCC2-knockdown mice, in which GABA and glycine remain depolarizing. We found that many key events in the development of synaptic inputs to the LSO, such as changes in neurotransmitter phenotype, strengthening and elimination of GABA/glycinergic connection, and maturation of glutamatergic synapses, occur undisturbed in KCC2-knockdown mice compared with wild-type mice. These results indicate that maturation of inhibitory and excitatory synapses in the LSO is independent of the GABA and glycine depolarization-to-hyperpolarization transition.

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Modulation of impulsivity and reward sensitivity in intertemporal choice by striatal and midbrain dopamine synthesis in healthy adults

Converging evidence links individual differences in mesolimbic and mesocortical dopamine (DA) to variation in the tendency to choose immediate rewards ("Now") over larger, delayed rewards ("Later"), or "Now bias." However, to date, no study of healthy young adults has evaluated the relationship between Now bias and DA with positron emission tomography (PET). Sixteen healthy adults (ages 24–34 yr; 50% women) completed a delay-discounting task that quantified aspects of intertemporal reward choice, including Now bias and reward magnitude sensitivity. Participants also underwent PET scanning with 6-[¹⁸F]fluoro-l-m-tyrosine (FMT), a radiotracer that measures DA synthesis capacity. Lower putamen FMT signal predicted elevated Now bias, a more rapidly declining discount rate with increasing delay time, and reduced willingness to accept low-interest-rate delayed rewards. In contrast, lower FMT signal in the midbrain predicted greater sensitivity to increasing magnitude of the Later reward. These data demonstrate that intertemporal reward choice in healthy humans varies with region-specific measures of DA processing, with regionally distinct associations with sensitivity to delay and to reward magnitude.

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