Recurrent Sensory-Motor Neuropathy Mimicking CIDP as Predominant Presentation of PDH Deficiency.

INTRODUCTION: Pyruvate dehydrogenase complex (PDH) deficiency (Online Mendelian Inheritance in Man # 312170) is a relatively common mitochondrial disorder, caused by mutations in the X-linked PDHA1 gene and presenting with a variable phenotypic spectrum, ranging from severe infantile encephalopathy to milder chronic neurological disorders.Isolated peripheral neuropathy as predominant clinical presentation is uncommon. RESULTS: We report on a patient, now 21 years old, presenting at the age of 2 years with recurrent symmetric weakness as first symptom of a PDH deficiency. Neurophysiological evaluation proving a sensory-motor polyneuropathy with conduction blocks and presence of elevated cerebrospinal fluid proteins, suggested a chronic inflammatory demyelinating polyneuropathy. The evidence of high serum lactate and the alterations in oxidative metabolism in muscle biopsy pointed toward the final diagnosis. After starting nutritional supplements, no further episodes occurred. A hemizygous mutation in PDHA1 (p.Arg88Cys) was identified. This mutation has been previously described in five patients with a similar phenotype. A three-dimensional reconstruction demonstrated that mutations affecting this arginine destabilize the interactions between the subunits of the E1 complex. CONCLUSION: We summarize the clinical and genetic characteristics of one patient with PDH deficiency presenting isolated peripheral nervous system involvement. This study highlights that the diagnosis of PDH deficiency should be considered in children with unexplained peripheral neuropathy, even with features suggestive of acquired forms, especially in case of early onset and limited response to treatment. A simple analysis of lactic acid could help to target the diagnosis.In addition, we suggest that the residue Arg88 is the most frequently involved in this specific phenotype of PDH deficiency.

Evaluation of Adult and Pediatric Chiari Type 1 Malformation Patients: Do Consensus Documents Fit Everyday Practice?

The management of Chiari 1 malformation (CM1) and Syringomyelia (Syr) has shown many changes in surgical indications and techniques over time. The dedicated neurosurgical and neurological community recently planned to analyze the state of the art and find conduct uniformity. This led to international consensus documents on diagnostic criteria and therapeutic strategies. We aimed to evaluate, in a large, monocentric surgical series of adult and children CM1 patients, if the daily clinical practice reflects the consensus documents. Our series comprises 190 pediatric and 220 adult Chiari patients submitted to surgery from 2000 to 2021. The main indications for the treatment were the presence of Syr and symptoms related to CM1. While there is great correspondence with the statements derived from the consensus documents about what to do for Syr and symptomatic CM1, the accordance is less evident in CM1 associated with craniosynostosis or hydrocephalus, especially when considering the early part of the series. However, we think that performing such studies could increase the homogeneity of surgical series, find a common way to evaluate long-term outcomes, and reinforce the comparability of different strategies adopted in different referral centers.

Near-Infrared Spectroscopy Monitoring, Superior Vena Cava Flow, and Neurodevelopmental Outcome at 2 years in a Cohort of Very Low-Birth-Weight Infants.

Objective We aimed at assessing the association between superior vena cava flow (SVCf), regional (cerebral) tissue oxygen saturation (rSO2), and cerebral fractional oxygen extraction (CFOE) during the first 48 hours of life and 2-years neurodevelopmental outcome of very low-birth-weight infants (VLBW). Methods We prospectively studied 60 VLBW infants admitted to our neonatal intensive care unit; rSO2 was continuously monitored with near-infrared spectroscopy during the first 48 hours of life, SVCf was measured at 4 to 6, 12, 24, and 48 hours, and CFOE was calculated. Neurodevelopmental outcome was assessed at 24 months corrected age. Results The mean gestational age at birth was 27.9 weeks (standard deviation: 2.4); 8 infants died in the first 3 months of life, 6 were lost to follow-up, 46 survived and were followed up. At 24 months, 6 (13%) and 7 (15.2%) infants developed minor and major sequelae, respectively. Infants who died had higher CFOE (p < 0.001) and lower SVCf (p < 0.001) than infants surviving with sequelae. In turn, these had higher SVCf between 24 and 48 hours than those without sequelae (p < 0.001). Conclusion SVCf, rSO2, and CFOE patterns in the first days of life suggest cerebral hyperperfusion, related to loss of autoregulation and/or use of inotropic drugs, as a potential mechanism of cerebral injury.

The Microcystis-microbiome interactions: origins of the colonial lifestyle.

Species of the Microcystis genus are the most common bloom-forming toxic cyanobacteria worldwide. They belong to a clade of unicellular cyanobacteria whose ability to reach high biomasses during blooms is linked to the formation of colonies. Colonial lifestyle provides several advantages under stressing conditions of light intensity, ultraviolet light, toxic substances and grazing. The progression from a single-celled organism to multicellularity in Microcystis has usually been interpreted as individual phenotypic responses of the cyanobacterial cells to the environment. Here, we synthesize current knowledge about Microcystis colonial lifestyle and its role in the organism ecology. We then briefly review the available information on Microcystis microbiome and propose that changes leading from single cells to colonies are the consequence of specific and tightly regulated signals between the cyanobacterium and its microbiome through a biofilm-like mechanism. The resulting colony is a multi-specific community of interdependent microorganisms.

Congenital myopathy associated with a novel mutation in MEGF10 gene, myofibrillar alteration and progressive course.

Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is caused by homozygous or compound heterozygous mutation in the MEGF10 gene (OMIM #614399). Phenotypic spectrum of EMARDD is variable, ranging from severe infantile forms in which patients are ventilator-dependent and die in childhood, to milder chronic disorders with a more favorable course (mild variant, mvEMARDD). Here we describe a 22 years old boy, offspring of consanguineous parents, presenting a congenital myopathic phenotype since infancy with elbow contractures and scoliosis. The patient developed a slowly progressive muscle weakness with impaired walking, rhinolalia, dysphagia, and respiratory involvement, which required noninvasive ventilation therapy since the age of 16 years. First muscle biopsy revealed unspecific muscle damage, with fiber size variation, internal nuclei and fibrosis. Myofibrillar alterations were noted at a second muscle biopsy including whorled fibres, cytoplasmic inclusion and minicores. Exome sequencing identified a homozygous mutation in MEGF10 gene, c.2096G > C (p.Cys699Ser), inherited by both parents. This variant, not reported in public databases of mutations, is expected to alter the structure of the protein and is therefore predicted to be probably damaging according to ACMG classification. In conclusion, we found a new likely pathogenic mutation in MEGF10, which is responsible for a progressive form of mvEMARDD with myofibrillar alterations at muscle biopsy. Interestingly, the presence of MEGF10 mutations has not been reported in Italian population. Early diagnosis of MEGF10 myopathy is essential in light of recent results from in vivo testing demonstrating a potential therapeutic effect of SSRIs compounds.

On the role of REM sleep microstructure in suppressing interictal spikes in Electrical Status Epilepticus during Sleep.

OBJECTIVE: Non-Rapid Eye Movement (NREM) sleep promotes the spread and propagation of Interictal Epileptiform Discharges (IEDs), while IEDs are suppressed during REM. Recently, it has been shown that the inhibitory effect on epileptic activity is mostly exerted by the phasic REM (PREM) microstate. This study aims at assessing if this holds true even in the extreme condition of IEDs activation during sleep represented by Electrical Status Epilepticus during Sleep (ESES). METHODS: eight patients affected by ESES, who underwent long-term EEG were included. REM was subdivided into phasic and tonic microstates along with the sleep scoring. IEDs count was carried out using a semi-automatic method and a Spike Index (SI) was calculated. RESULTS: The SI was significantly higher in NREM sleep than in REM. Within REM, the SI was significantly lower in PREM than in tonic REM (TREM). The SI was reduced by 84% in TREM with respect to NREM and by 97% in PREM with respect to NREM. Moreover, the SI was reduced by 87% in PREM with respect to TREM. CONCLUSIONS: PREM has a greater suppressive effect on epileptic activity even in the extreme IEDs activation during sleep typical of ESES. SIGNIFICANCE: Understanding the protective effect of PREM sleep on epileptic activity might be relevant for future therapeutic approaches.

Targeted re-sequencing in malformations of cortical development: genotype-phenotype correlations.

PURPOSE: Malformations of cortical development (MCD) are a phenotypically and genetically heterogeneous group of disorders, for which the diagnostic rate of genetic testing in a clinical setting remains to be clarified. In this study we aimed to assess the diagnostic rate of germline and pathogenic variants using a custom panel in a heterogeneous group of subjects with MCD and explore genotype-phenotype correlations. METHODS: A total of 84 subjects with different MCD were enrolled. Genomic DNA was isolated from peripheral blood. Fifty-nine tartget genes were assessed using a custom next-generation sequencing (NGS) panel. RESULTS: Genetic causes were identified in one-fourth of our cohort (21.4 %). Overall, we identified 19 pathogenic or likely pathogenic single-nucleotide variants in 11 genes among 18 subjects, including PAFAH1B1 (LIS1) (n = 3), TUBA1A (n = 3), DYNC1H1 (n = 3), ACTG1 (n = 2), TUBB2B (n = 1), TUBB3 (n = 1), DCX (n = 1), FLNA (n = 1), LAMA2 (n = 1), POMGNT2 (n = 1) and VLDLR (n = 1). The diagnostic yield was higher in patients with lissencephaly/pachygyria (60 %) (p = 0.001), cobblestone malformation (50 %), and subcortical band heterotopia (SBH) (40 %). Furthermore, five out of six subjects with suspect tubulinopathies on imaging harboured pathogenic variants in tubulin genes. Overall, germline pathogenic variants were more likely to be identified if MCD were diffuse (p = 0.002) and associated with other central nervous system malformations (p = 0.029). Moderate to severe intellectual disability was also more commonly associated with pathogenic variants (p = 0.044). CONCLUSION: Customized gene panels may support the diagnostic work-up for some specific MCD, especially when these are diffuse, bilateral and associated with other brain malformations.