A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.

Deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR), the very rare methionine synthase reductase (CblE) and methionine synthase (CblG) defects, and the recently identified CblD-variant-1 defect are primary remethylation defects characterized by an isolated defect in methionine synthesis without methylmalonic aciduria. The clinical signs are mainly neurological, and hematological signs are seen in CblE, CblG, and CblD-variant-1 defects. Patients with neonatal or early-onset disease exhibit acute neurological distress. Infants and children have unspecific mental retardation, often with acquired microcephaly. Without appropriate therapy, they may experience acute or rapidly progressive neurological deterioration, which may be fatal. Adolescents and adults show normal development or mild developmental delay initially and then experience rapid neurological or behavioral deterioration. A few patients may have signs of subacute combined degeneration of the spinal cord. Adults may be asymptomatic or present with isolated thromboembolism. All patients with suspected remethylation disorders should receive emergency treatment with parenteral administration of hydroxocobalamin and folate supplements combined with betaine orally. The long-term treatment of CblE, CblG, and CblD-variant-1 defects consists of parenterally administered hydroxocobalamin and orally administered folate and betaine supplements, whereas patients with MTHFR deficiency require long-term oral folate and betaine supplements. Long-term oral methionine therapy should also be considered. Early treatment may lead to a favorable outcome with developmental recovery and prevention of further neurological deterioration. In contrast, most late-treated patients have severe and irreversible neuromotor impairments. Hematological abnormalities are easily corrected.

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Introduction: Females have been shown to experience less neuromuscular fatigue than males in knee extensors (KE) and less peripheral fatigue in plantar flexors (PF) following ultra-trail running, but it is unknown if these differences exist for shorter trail running races and whether this may impact running economy. The purpose of this study was to characterize sex differences in fatigability over a range of running distances and to examine possible differences in the postrace alteration of the cost of running (Cr).Methods: Eighteen pairs of males and females were matched by performance after completing different races ranging from 40 to 171 km, divided into SHORT vs LONG races (< 60 and > 100 km, respectively). NM function and Cr were tested before and after each race. NM function was evaluated on both KE and PF with voluntary and evoked contractions using electrical nerve (KE and PF) and transcranial magnetic (KE) stimulation. Oxygen uptake, respiratory exchange ratio and ventilation were measured on a treadmill and used to calculate Cr.Results: Compared to males, females displayed a smaller decrease in maximal strength in KE (−36% vs −27%, respectively, p < 0.01), independent of race distance. In SHORT only, females displayed less peripheral fatigue in PF compared to males (Δ peak twitch: −10% vs −24%, respectively, p < 0.05). Cr increased similarly in males and females.Conclusion: Females experience less neuromuscular fatigue than men following both 'classic' and 'extreme' prolonged running exercises but this does not impact the degradation of the energy cost of running.