De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT. METHODS: We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes. RESULTS: We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes. CONCLUSION: Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.

Safe Transition to Pembrolizumab following Ipilimumab-Induced Guillain-Barré Syndrome: A Case Report and Review of the Literature.

BACKGROUND: Immune checkpoint inhibitors are novel therapies with indications for treating several solid cancers. They are associated with immune-related adverse events, which are generally well tolerated. Though rare, severe side effects may be life-threatening. One such adverse event is Guillain-Barré syndrome, which requires cessation of the immunotherapy and intravenous immunoglobulin and/or high-dose steroids to treat. No recommendations have been published regarding restarting cancer treatment after development of immunotherapy-induced Guillain-Barré syndrome. CASE PRESENTATION: A 71-year-old gentleman with recurrent, stage IIIB melanoma was started on ipilimumab (cytotoxic T lymphocyte antigen-4 inhibitor) for adjuvant treatment following radical neck dissection and radiation therapy. After completing his third cycle of ipilimumab, he developed rapidly progressive ascending paralysis. He was diagnosed with ipilimumab-induced atypical Guillain-Barré syndrome and was treated with intravenous immunoglobulin and corticosteroids. Ipilimumab was discontinued, and the patient was monitored via surveillance imaging, as there was no evidence of active disease at that time. Several months later, he was found to have recurrent disease involving the lung, requiring right lower lobectomy. Restaging revealed thoracic lymph node involvement, and he was then started on pembrolizumab (programmed cell death protein-1 inhibitor). He experienced a complete tumoral response to pembrolizumab, and he tolerated treatment well without recurrent weakness. CONCLUSIONS: Guillain-Barré syndrome is a rare but severe complication associated with immunotherapy. Our findings suggest that in patients with a history of ipilimumab-induced Guillain-Barré syndrome, pembrolizumab may possibly be a safe and effective alternative for cancer therapy.

An immune tolerance approach using transient low-dose methotrexate in the ERT-naïve setting of patients treated with a therapeutic protein: experience in infantile-onset Pompe disease.

PURPOSE: To investigate immune tolerance induction with transient low-dose methotrexate (TLD-MTX) initiated with recombinant human acid α-glucosidase (rhGAA), in treatment-naïve cross-reactive immunologic material (CRIM)-positive infantile-onset Pompe disease (IOPD) patients. METHODS: Newly diagnosed IOPD patients received subcutaneous or oral 0.4 mg/kg TLD-MTX for 3 cycles (3 doses/cycle) with the first 3 rhGAA infusions. Anti-rhGAA IgG titers, classified as high-sustained (HSAT; ≥51,200, ≥2 times after 6 months), sustained intermediate (SIT; ≥12,800 and <51,200 within 12 months), or low (LT; ≤6400 within 12 months), were compared with those of 37 CRIM-positive IOPD historic comparators receiving rhGAA alone. RESULTS: Fourteen IOPD TLD-MTX recipients at the median age of 3.8 months (range, 0.7-13.5 months) had a median last titer of 150 (range, 0-51,200) at median rhGAA duration ~83 weeks (range, 36-122 weeks). One IOPD patient (7.1%) developed titers in the SIT range and one patient (7.1%) developed titers in the HSAT range. Twelve of the 14 patients (85.7%) that received TLD-MTX remained LT, versus 5/37 HSAT (peak 51,200-409,600), 7/37 SIT (12,800-51,000), and 23/37 LT (200-12,800) among comparators. CONCLUSION: Results of TLD-MTX coinitiated with rhGAA are encouraging and merit a larger longitudinal study.

Diaphragm pacing in amyotrophic lateral sclerosis: a literature review.

Amyotrophic lateral sclerosis (ALS) remains a rapidly progressive fatal degenerative disease of motor neurons for which there are few interventions to slow disease progression or improve quality of life. A diaphragm pacing system was approved by the U.S. Food and Drug Administration in September 2011 for ALS under a Humanitarian Device Exemption. News of this approval has been met with a combination of excitement and uncertainty by members of the ALS community. We review the currently available data on the diaphragm pacing system and its use in ALS. Diaphragm pacing appears to be reasonably safe in carefully selected patients, but flaws in the reporting on it thus far preclude conclusions regarding efficacy. Further study is needed.

Radial nerve palsy in Guillain-Barré syndrome.

The risk of focal compression neuropathy in the setting of an underlying inflammatory polyneuropathy is unknown. A man developed ascending weakness and severe sensory ataxia and could not walk. Electromyography was diagnostic of Guillain-Barré syndrome. He improved with gammaglobulin and was released home 1 month later. Shortly after discharge, he developed severe left arm pain followed by wrist and finger drop. He was readmitted for another round of gamma-globulin without improvement. Subsequent electromyography showed severe radial neuropathy. Only then did he disclose that he usually slept with his wife's head on his arm at home. Two years later, he had recovered from Guillain-Barré syndrome with minimal gait imbalance, but wrist and finger extension remained weak. Reduced awareness of warning paresthesias coupled with the underlying polyneuropathy may account for this case of severe radial nerve compression. Potential mechanisms underlying increased nerve susceptibility to compression in the setting of polyneuropathy are reviewed.

Does this patient have myasthenia gravis?

CONTEXT: Clinicians must be able to diagnose myasthenia gravis, since delays in establishing the diagnosis may put patients at risk for complications from this treatable disease. OBJECTIVE: To determine if items in the history and examination or results of simple tests change the likelihood of myasthenia gravis as a diagnosis. DATA SOURCES: MEDLINE search of English-language articles (January 1966-January 2005) using the terms myasthenia gravis, diagnosis, and test, and a search of bibliographies of retrieved articles. STUDY SELECTION: Studies evaluating a particular symptom or sign in patients both with and without myasthenia gravis. Of 640 articles retrieved, 33 were eligible for review. Of these, 15 met inclusion criteria and form the basis of this review. DATA EXTRACTION: Two authors independently reviewed each study to determine eligibility, abstracted data using a standardized instrument, and classified study quality using previously published criteria. DATA SYNTHESIS: A history of "speech becoming unintelligible during prolonged speaking" and the presence of the peek sign increase the likelihood of myasthenia gravis (likelihood ratio [LR], 4.5; 95% confidence interval [CI], 1.2-17.0 and LR, 30.0; 95% CI, 3.2-278.0, respectively). Their absence does not significantly reduce the likelihood of myasthenia gravis. The identified studies only assessed 1 other historical feature and sign each ("food remaining in the mouth after swallowing" and quiver eye movements, respectively), and neither of these significantly changes the likelihood of myasthenia. The ice test is useful when the response is abnormal (summary positive LR, 24.0; 95% CI, 8.5-67.0) and diminishes the likelihood of myasthenia gravis when the response is normal (summary negative LR, 0.16; 95% CI, 0.09-0.27). A positive response to an anticholinesterase medication (mainly edrophonium test) increases the probability of a diagnosis of myasthenia gravis (summary positive LR, 15.0; 95% CI, 7.5-31.0), and a negative response reduces the diagnostic probability of myasthenia (summary negative LR, 0.11; 95% CI, 0.06-0.21). An abnormal sleep test result is useful in confirming the diagnosis (LR, 53.0; 95% CI, 3.4-832.0). The rest and sleep tests make the probability of myasthenia unlikely when results are normal (LR, 0.52; 95% CI, 0.29-0.95 and LR, 0.01; 95% CI, 0.00-0.16, respectively). CONCLUSIONS: Items in the history and physical examination along with results of certain simple tests performed in the office (ice test, sleep test, and edrophonium test) are useful in predicting the likelihood of myasthenia gravis. These results must be interpreted with caution, however, given the high prevalence of disease in the populations reported in clinical studies. This review is limited by the small number of signs and symptoms scientifically studied and reported in the literature. Future studies evaluating the value of common historical features and easy maneuvers commonly known and practiced by experts in the clinical diagnosis of myasthenia are needed.