Hereditary motor and sensory neuropathy Okinawa type mimicking proximal myopathy.

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), or, Okinawa type, is a rare neuromuscular disorder characterized by proximal dominant neurogenic atrophy and distal sensory alterations with an autosomal dominant inheritance pattern. We present a case of a Brazilian woman of Okinawan ancestry, with symmetrical proximal weakness, fasciculations, absent patellar reflexes and positive familial history for the same symptoms. These findings led to genetic testing, which identified a variant in the TFG gene (c.854 C>T;p.(Pro285Leu), confirming the diagnosis of HMSN-P. HMSN-P seemed to be restricted to populations in Okinawa, however, other HMSN-P cases were described in several parts of the world, especially in South America. This case report emphasizes the importance of considering HMSN-P in patients presenting with clinical features resembling proximal myopathy, especially in individuals with Okinawan ancestry.

Hereditary Neuropathy with Liability to Pressure Palsy and Vocal Cord Paralysis After Pulmonary Lobectomy: A Case Report.

Hereditary neuropathy with liability to pressure palsy (HNPP) is a rare peripheral neurological disorder that manifests with increased sensitivity to pressure. In people with this disorder, the peripheral nerves are unusually sensitive to pressure. Minor trauma or compression causing paralysis in the extremities is a hallmark of this disorder. Ensuring there is no pressure on the extremities is recommended as a preventive measure. We describe for the first time, postoperative vocal cord paralysis in a patient with HNPP due to left recurrent laryngeal nerve palsy. Anesthesiologists and surgeons should be aware of this possible complication in patients with HNPP.

Determination of free fatty acids in edible oil based on hollow mesoporous silica nanoparticles.

In our study, ammoniated hollow mesoporous silica nanoparticles (NH2-HMSN) with uniform diameter and stable structure were successively prepared via SiO2 core hard template method. Fourier transformed infrared spectroscopy revealed that amino group was effectively modified. Adsorption experiments showed that adsorption capacity of NH2-HMSN towards free fatty acids (FFAs) was superior to aminated mesopores or silica microspheres. Following through optimization of extraction conditions, FFAs from edible oil samples were successfully gathered by NH2-HMSN and showed favorable linearities (0.2-90 µg g-1), remarkably low limit of detections (0.03-0.15 nmol g-1), acceptable recoveries (85.08-96.82 %) and relatively accurate precisions (1.64-4.99 %). In comparison to existing adsorbent, NH2-HMSN could be successfully prepared via the chemical reaction of common raw materials under normal pressure and temperature. Furthermore, NH2-HMSN with hollow and mesoporous structure was more effective than the current adsorbents aimed at FFAs analysis in aspect of surface area and adsorption capacity.

Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases.

Haplo-insufficiency of the gene encoding the myelin protein PMP22 leads to focal myelin overgrowth in the peripheral nervous system and hereditary neuropathy with liability to pressure palsies (HNPP). Conversely, duplication of PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A), characterized by hypomyelination of medium to large caliber axons. The molecular mechanisms of abnormal myelin growth regulation by PMP22 have remained obscure. Here, we show in rodent models of HNPP and CMT1A that the PI3K/Akt/mTOR-pathway inhibiting phosphatase PTEN is correlated in abundance with PMP22 in peripheral nerves, without evidence for direct protein interactions. Indeed, treating DRG neuron/Schwann cell co-cultures from HNPP mice with PI3K/Akt/mTOR pathway inhibitors reduced focal hypermyelination. When we treated HNPP mice in vivo with the mTOR inhibitor Rapamycin, motor functions were improved, compound muscle amplitudes were increased and pathological tomacula in sciatic nerves were reduced. In contrast, we found Schwann cell dedifferentiation in CMT1A uncoupled from PI3K/Akt/mTOR, leaving partial PTEN ablation insufficient for disease amelioration. For HNPP, the development of PI3K/Akt/mTOR pathway inhibitors may be considered as the first treatment option for pressure palsies.

Microneedle-assisted percutaneous delivery of methotrexate-loaded nanoparticles enabling sustained anti-inflammatory effects in psoriasis therapy.

Methotrexate (MTX) is one of the first-line drugs used for the treatment of moderate to severe psoriasis. However, low bioavailability and systemic side effects of traditional oral and injectable MTX greatly limit its clinical application. Delivering MTX using dissolving microneedles (MNs) into psoriasis-like skin lesion could improve the in situ therapeutic effects with higher bioavailability and less side effects. Here, we propose a novel therapeutic approach for psoriasis involving MN-assisted percutaneous delivery of chitosan-coated hollow mesoporous silica nanoparticles containing MTX (MTX@HMSN/CS). The MTX@HMSN/CS-loaded MNs were strong enough to successfully penetrate the psoriasiform thickened epidermis, allowing MTX@HMSN/CS to be accurately delivered to the site of skin lesion following the rapid dissolution of MNs. MTX was then released continuously from HMSN/CS for at least one week to maintain effective therapeutic drug concentration for skin lesion with long-term anti-proliferative and anti-inflammatory effects. Incubation with MTX@HMSN/CS not only inhibited the proliferation of human immortalized keratinocytes (HaCaT cells), but also significantly reduced the expression of proinflammatory cytokines and chemokines. In addition, MTX@HMSN/CS-loaded MNs showed better efficacy in alleviating psoriasis-like skin inflammation than MTX-loaded MNs at the same dose. Compared to psoriasiform mice treated with 15.8 µg MTX-loaded MNs every day, 47.4 µg MTX@HMSN/CS-loaded MNs reduce the frequency of treatment to once every 3 days and achieve comparable amelioration. Therefore, MTX@HMSN/CS loaded MNs are a promising treatment strategy for psoriasis due to their durability, efficacy, convenience, and safety in relieving psoriasis-like skin inflammation.

A dual catalytic functionalized hollow mesoporous silica-based nanocarrier coated with bacteria-derived exopolysaccharides for targeted delivery of irinotecan to colorectal cancer cells.

In this study, we introduced a multifunctional hollow mesoporous silica-based nanocarrier (HMSN) for the targeted delivery of irinotecan (IRT) to colorectal cancer cells. Due to their large reservoirs, hollow mesoporous silica nanoparticles are suitable platforms for loading significant amounts of drugs for sustained drug release. To respond to pH and redox, HMSNs were functionalized with cerium and iron oxides. Additionally, they were coated with bacterial-derived exopolysaccharide (EPS) as a biocompatible polymer. In vitro analyses revealed that cytotoxicity induced in cancer cells through oxidative stress, mediated by mature nanocarriers (EPS.IRT.Ce/Fe.HMSN), was surprisingly greater than that caused by free drugs. Cerium and iron ions, in synergy with the drug, were found to generate reactive oxygen species when targeting the acidic pH within lysosomes and the tumor microenvironment. This, in turn, triggered cascade reactions, leading to cell death. In vivo experiments revealed that the proposed nanocarriers had no noticeable effect on healthy tissues. These findings indicate the selective delivery of the drug to cancerous tissue and the induction of antioxidant effects due to the dual catalytic properties of cerium in normal cells. Accordingly, this hybrid drug delivery system provides a more effective treatment for colorectal cancer with the potential for cost-effective scaling up.

An Elderly Woman with Complaints of Pain and Hearing Loss, Diagnosed with CMT1A with PMP22 Duplication.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous hereditary motor and sensory neuropathy of the peripheral nervous system, with CMT1A in particular being the most common form. We encountered a 76-year-old woman with CMT1A who had a history of pain attacks and hearing loss from a young age, with motor symptoms manifesting late in life. Her pain and hearing loss may have been related to CMT. Our case also raises the possibility that neuropathic pain and hearing loss may precede the classic motor symptoms of CMT1A.

Differences in respiratory function, depressive symptoms and quality of life between patients with hereditary motor and sensory neuropathy and myotonic dystrophy undergoing maintenance rehabilitation.

Hereditary motor and sensory neuropathy (HMSN) and myotonic dystrophy (MD) are chronic neuromuscular diseases that cause progressive muscular impairment and impact patient's quality of life. Conflicting findings in existing literature underscore the need for focussed research on specific health aspects in these patients. The aim of the study was to explore the differences in respiratory function, depressive symptoms and quality of life between patients with HMSN and MD undergoing maintenance rehabilitation. Our prospective observational study included 62 HMSN patients (median age 53.5, range 19-79 years; 38 women) and 50 MD patients (median age 54.0, range 18-77 years; 34 women) undergoing maintenance rehabilitation. They performed respiratory function tests (vital capacity, forced vital capacity, forced expiratory volume and peak expiratory flow) and respiratory muscle strength tests (maximum inspiratory pressure, maximum expiratory pressure and sniff nasal inspiratory force). The Center for Epidemiological Studies-Depression Scale was used to evaluate depression, and their health-related quality of life was assessed using the Quality of Life in Genetic Neuromuscular Disease Questionnaire. Using logistic regression, we examined group-difference in presence of depressive symptoms while accounting for age, symptoms duration, and marital status. Multiple linear regression was used to assess the difference in quality-of-life scores, adjusting for age, gender, and symptoms' duration. The HMSN group achieved statistically significantly better results than the MD group on all respiratory measures (about 17% absolute difference in the respiratory function measures and 30% relative difference in the respiratory muscle strength measures on average). Both groups exhibited a high level of depression symptoms (HMSN 24%, MD 44%; estimated adjusted odds-ratio MD vs. HMSN 1.9, 95% CI 0.8-4.5, P  = 0.127). We did not find a statistically significant difference between the groups regarding quality-of-life domains, though a trend towards better quality-of-life among the HMSN patients could be observed. The implication for future practice is that the MD patients would potentially benefit the most from targeted respiratory-rehabilitation interventions, and both groups could benefit from focussed mental-health interventions.

Nanocatalytic theranostics with intracellular mutual promotion for ferroptosis and chemo-photothermal therapy.

The reactive oxygen species (ROS) produced through the Fenton reaction, induces lipid peroxide (LPO), causing cellular structural damage and ultimately triggering ferroptosis. However, the generation of ROS in the tumor microenvironment (TME) is limited by the catalytic efficiency of the Fenton reaction. Herein, a novel hollow mesoporous silica nanoparticle (HMSN) combined with multi-metal sulfide-doped mesoporous silica nanocatalyzers (NCs) was developed, namely MxSy-HMSN NCs (M represents Cu Mn and Fe, S denotes sulfur). The MxSy-HMSN can dramatically enhanced the ferroptosis by: (1) facilitating the conversion of H2O2 to ·OH through Fenton or Fenton-like reactions through co-catalysis; (2) weakening ROS scavenging systems by depleting the over expressed glutathione (GSH) in TME; (3) providing exceptional photothermal therapy to augment ferroptosis. The MxSy-HMSN can also act as smart cargos for anticancer drug-doxorubicin (DOX). The release of DOX is responsive to GSH/pH/Near-infrared Light (NIR) irradiation at the tumor lesion, significantly improving therapeutic outcomes while minimizing side effects. Additionally, the MxSy-HMSN has demonstrated excellent magnetic resonance imaging (MRI) potential. This smart MxSy-HMSN offer a synergetic approach combining ferroptosis with chemo-photothermal therapy and magnetic resonance imaging (MRI) diagnose, which could be an informative guideline for the design of future NCs.

Glutathione Consumptive Dual-Sensitive Lipid-Composite Nanoparticles Induce Immunogenic Cell Death for Enhanced Breast Tumor Therapy.

Although chemotherapy remains the standard therapy for tumor treatment, serious side effects can occur because of nontargeted distribution and damage to healthy tissues. Hollow mesoporous silica nanoparticles (HMSNs) modified with lipids offer potential as delivery systems to improve therapeutic outcomes and reduce adverse effects. Herein, we synthesized HMSNs with integrated disulfide bonds (HMSN) for loading with the chemotherapeutic agent oxaliplatin (OXP) which were then covered with the synthesized hypoxia-sensitive lipid (Lip) on the surface to prepare the dual-sensitive lipid-composite nanoparticles (HMSN-OXP-Lip). The empty lipid-composite nanoparticles (HMSN-Lip) would consume glutathione (GSH) in cells because of the reduction of disulfide bonds in HMSN and would also inhibit GSH production because of NADPH depletion driven by Lip cleavage. These actions contribute to increased levels of ROS that induce the immunogenic cell death (ICD) effect. Simultaneously, HMSN-Lip would disintegrate in the presence of high concentrations of GSH. The lipid in HMSN-OXP-Lip could evade payload leakage during blood circulation and accelerate the release of the OXP in the tumor region in the hypoxic microenvironment, which could significantly induce the ICD effect to activate an immune response for an enhanced therapeutic effect. The tumor inhibitory rate of HMSN-OXP-Lip was almost twice that of free OXP, and no apparent side effects were observed. This design provides a dual-sensitive and efficient strategy for tumor therapy by using lipid-composite nanoparticles that can undergo sensitive drug release and biodegradation.

Charcot-Marie-Tooth disease: from historical landmarks in Brazil to current care perspectives.

Hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease (CMT), traditionally refers to a group of genetic disorders in which neuropathy is the main or sole feature. Its prevalence varies according to different populations studied, with an estimate between 1:2,500 to 1:10,000. Since the identification of PMP22 gene duplication on chromosome 17 by Vance et al., in 1989, more than 100 genes have been related to this group of disorders, and we have seen advances in the care of patients, with identification of associated conditions and better supportive treatments, including clinical and surgical interventions. Also, with discoveries in the field of genetics, including RNA interference and gene editing techniques, new treatment perspectives begin to emerge. In the present work, we report the most import landmarks regarding CMT research in Brazil and provide a comprehensive review on topics such as frequency of different genes associated with CMT in our population, prevalence of pain, impact on pregnancy, respiratory features, and development of new therapies.

A neuropatia sensitivo-motora hereditária, também conhecida como doença de Charcot-Marie-Tooth (CMT), tradicionalmente se refere a um grupo de doenças genéticas em que a neuropatia é a principal ou única manifestação. Sua prevalência varia de acordo com as diferentes populações estudadas, com estimativa entre 1:2.500 a 1:10.000. Desde a identificação da duplicação do gene PMP22 no cromossomo 17, por Vance et al., em 1989, mais de 100 genes foram relacionados a esse grupo de doenças e temos visto avanços no atendimento aos pacientes, com identificação de condições associadas e melhores tratamentos de suporte, incluindo intervenções clínicas e cirúrgicas. Além disso, com as descobertas no campo da genética, incluindo técnicas de interferência de RNA e de edição genética, novas perspectivas de tratamento começaram a surgir. No presente trabalho, relatamos os marcos mais importantes sobre a pesquisa de CMT no Brasil e fornecemos uma revisão abrangente sobre tópicos como frequência de diferentes genes associados à CMT em nossa população, prevalência de dor, impacto na gravidez, alterações respiratórias e desenvolvimento de novas terapias.

Expanding the genetic and clinical spectrum of SORD-related peripheral neuropathy by reporting a novel variant c.210T>G and evidence of subclinical muscle involvement.

BACKGROUND AND AIMS: Biallelic variants in the sorbitol dehydrogenase (SORD) gene have been identified as the genetic cause of autosomal recessive (AR) peripheral neuropathy (PN) manifesting as Charcot-Marie-Tooth disease type 2 (CMT2) or distal hereditary motor neuropathy (dHMN). We aim to observe the genetic and clinical spectrum of a cohort of patients with SORD-related PN (SORD-PN). METHODS: A total of 107 patients with AR or sporadic CMT2/dHMN underwent molecular diagnosis by whole-exome sequencing and subsequent Sanger sequencing validation. Available phenotypic data for SORD-PN were collected and analyzed. RESULTS: Eleven (10.28%) of 107 patients were identified as SORD-PN, including four with CMT2 and seven with dHMN. The SORD variant c.210 T > G;p.His70Gln in F-d3 was firstly reported and subsequent analysis showed that it resulted in loss of SORD enzyme function. Evidence of subclinical muscle involvement was frequently detected in patients with SORD-PN, including mildly to moderately elevated serum creatine kinase (CK) levels in 10 patients, myogenic electrophysiological changes in one patient, and muscle edema in five patients undergoing lower extremity MRI. Fasting serum sorbitol level was 88-fold higher in SORD-PN patients (9.69 ± 1.07 mg/L) than in healthy heterozygous subjects (0.11 ± 0.01 mg/L) and 138-fold higher than in healthy controls (0.07 ± 0.02 mg/L). INTERPRETATION: The novel SORD variant c.210 T > G;p.His70Gln and evidence of subclinical muscle involvement were identified, which expanded the genetic and clinical spectrum of SORD-PN. Subclinical muscle involvement might be a common but easily overlooked clinical feature. The serum CK and fasting serum sorbitol levels were expected to be sensitive biomarkers confirmed by follow-up cohort study.

Rare PMP22 variants in mild to severe neuropathy uncorrelated to plasma GDF15 or neurofilament light.

Charcot-Marie-Tooth disease (CMT) is a heterogeneous set of hereditary neuropathies whose genetic causes are not fully understood. Here, we characterize three previously unknown variants in PMP22 and assess their effect on the recently described potential CMT biomarkers' growth differentiation factor 15 (GDF15) and neurofilament light (NFL): first, a heterozygous PMP22 c.178G > A (p.Glu60Lys) in one mother-son pair with adult-onset mild axonal neuropathy. The variant led to abnormal splicing, confirmed in fibroblasts by reverse transcription PCR. Second, a de novo PMP22 c.35A > C (p.His12Pro), and third, a heterozygous 3.2 kb deletion predicting loss of exon 4. The latter two had severe CMT and ultrasonography showing strong nerve enlargement similar to a previous case of exon 4 loss due to a larger deletion. We further studied patients with PMP22 duplication (CMT1A) finding slightly elevated plasma NFL, as measured by the single molecule array immunoassay (SIMOA). In addition, plasma GDF15, as measured by ELISA, correlated with symptom severity for CMT1A. However, in the severely affected individuals with PMP22 exon 4 deletion or p.His12Pro, these biomarkers were within the range of variability of CMT1A and controls, although they had more pronounced nerve hypertrophy. This study adds p.His12Pro and confirms PMP22 exon 4 deletion as causes of severe CMT, whereas the previously unknown splice variant p.Glu60Lys leads to mild axonal neuropathy. Our results suggest that GDF15 and NFL do not distinguish CMT1A from advanced hypertrophic neuropathy caused by rare PMP22 variants.

A Molecular Switch-Integrated Nanoplatform Enables Photo-Unlocked Antibacterial Drug Delivery for Synergistic Abscess Therapy.

Drug delivery systems (DDSs) capable of sequential multistage drug release are urgently needed for antibacterial applications. Herein, a molecular switch-integrated, photo-responsive nanoplatform is reported based on hollow mesoporous silica nanospheres (HMSN) loaded with silver nanoparticles (Ag NPs), vancomycin (Van), and hemin (HAVH) for bacteria elimination and abscess therapy. Upon near-infrared (NIR) light irradiation, the molecular switch, hemin, can effuse from the mesopores of HMSN, triggering the release of pre-loaded Ag+ and Van, which enables photothermal-modulated drug release and synergistic photothermal-chemo therapy (PTT-CHT). The HAVH_NIR irreversibly disrupts the bacterial cell membrane, facilitating the penetration of Ag+ and Van. It is found that these compounds restrain the transcription and translation of ribosomes and lead to rapid bacterial death. Furthermore, hemin can effectively inhibit excessive inflammatory responses associated with the treatment, promoting accelerated wound healing in a murine abscess model. This work presents a new strategy for antibacterial drug delivery with high controllability and extendibility, which may benefit the development of smart multifunctional nanomedicine for diseases not limited to bacterial infections.

Isorhamnetin and anti-PD-L1 antibody dual-functional mesoporous silica nanoparticles improve tumor immune microenvironment and inhibit YY1-mediated tumor progression.

BACKGROUND: The immune checkpoint inhibitor (ICI) anti-PD-L1 monoclonal antibody can inhibit the progress of hepatocellular carcinoma (HCC). Epithelial-mesenchymal transformation (EMT) can promote tumor migration and the formation of immune-suppression microenvironment, which affects the therapeutic effect of ICI. Yin-yang-1 (YY1) is an important transcription factor regulating proliferation, migration and EMT of tumor cells. This work proposed a drug-development strategy that combined the regulation of YY1-mediated tumor progression with ICIs for the treatment of HCC. METHODS: We first studied the proteins that regulated YY1 expression by using pull-down, co-immunoprecipitation, and duo-link assay. The active compound regulating YY1 content was screened by virtual screening and cell-function assay. Isorhamnetin (ISO) and anti-PD-L1 antibody dual-functional mesoporous silica nanoparticles (HMSN-ISO@ProA-PD-L1 Ab) were prepared as an antitumor drug to play a synergistic anti-tumor role. RESULTS: YY1 can specifically bind with the deubiquitination enzyme USP7. USP7 can prevent YY1 from ubiquitin-dependent degradation and stabilize YY1 expression, which can promote the proliferation, migration and EMT of HCC cells. Isorhamnetin (ISO) were screened out, which can target USP7 and promote YY1 ubiquitin-dependent degradation. The cell experiments revealed that the HMSN-ISO@ProA-PD-L1 Ab nanoparticles can specifically target tumor cells and play a role in the controlled release of ISO. HMSN-ISO@ProA-PD-L1 Ab nanoparticles inhibited the growth of Hepa1-6 transplanted tumors and the effect was better than that of PD-L1 Ab treatment group and ISO treatment group. HMSN-ISO@ProA-PD-L1 Ab nanoparticles also exerted a promising effect on reducing MDSC content in the tumor microenvironment and promoting T-cell infiltration in tumors. CONCLUSIONS: The isorhamnetin and anti-PD-L1 antibody dual-functional nanoparticles can improve tumor immune microenvironment and inhibit YY1-mediated tumor progression. This study demonstrated the possibility of HCC treatment strategies based on inhibiting USP7-mediated YY1 deubiquitination combined with anti-PD-L1 monoclonal Ab.

EGR2 gene-linked hereditary neuropathies present with a bimodal age distribution at symptoms onset.

BACKGROUND: Mutations in the Early-Growth Response 2 (EGR2) gene cause various hereditary neuropathies, including demyelinating Charcot-Marie-Tooth (CMT) disease type 1D (CMT1D), congenital hypomyelinating neuropathy type 1 (CHN1), Déjerine-Sottas syndrome (DSS), and axonal CMT (CMT2). METHODS: In this study, we identified 14 patients with heterozygous EGR2 mutations diagnosed between 2000 and 2022. RESULTS: Mean age was 44 years (15-70), 10 patients were female (71%), and mean disease duration was 28 years (1-56). Disease onset was before age 15 years in nine cases (64%), after age 35 years in four cases (28%), and one patient aged 26 years was asymptomatic (7%). All symptomatic patients had pes cavus and distal lower limbs weakness (100%). Distal lower limbs sensory symptoms were observed in 86% of cases, hand atrophy in 71%, and scoliosis in 21%. Nerve conduction studies showed a predominantly demyelinating sensorimotor neuropathy in all cases (100%), and five patients needed walking assistance after a mean disease duration of 50 years (47-56) (36%). Three patients were misdiagnosed as inflammatory neuropathy and treated with immunosuppressive drugs for years before diagnosis was corrected. Two patients presented with an additional neurologic disorder, including Steinert's myotonic dystrophy and spinocerebellar ataxia (14%). Eight EGR2 gene mutations were found, including four previously undescribed. INTERPRETATION: Our findings demonstrate EGR2 gene-related hereditary neuropathies are rare and slowly progressive demyelinating neuropathies with two major clinical presentations, including a childhood-onset variant and an adult-onset variant which may mimic inflammatory neuropathy. Our study also expands the genotypic spectrum of EGR2 gene mutations.

A case report of two Moroccan patients with hereditary neurological disorders and molecular modeling study on the S72L de novo PMP22 variant.

Hereditary neurological disorders represent a wild group of hereditary illnesses affecting mainly the nervous system, the majority of which have a Mendelian inheritance pattern. Here we present the case of two Moroccan patients each affected by a different hereditary neurological disorder. In the first patient WES analysis revealed the presence of the p.Ser72Leu de novo mutation in the PMP22 gene reported for the first time in Africa, specifically in Morocco. This variant is predicted to be in a mutation "hot-spot" region causing Dejerine-Sottas syndrome called also Charcot-Marie-Tooth type 3. The molecular modeling study suggests an important alteration of hydrogen and hydrophobic interactions between the residue in position 72 of the PMP22 protein and its surrounding amino acids. On the other hand, the p.Ala177Thr mutation on the RNASEH2B gene, responsible of Aicardi-Goutières syndrome 2, was carried in a homozygous state by the second patient descending from a consanguineous family. This mutation is common among the Moroccan population as well as in other North African countries. The present results contributed to a better follow-up of both cases allowing better symptom management with convenient treatments.

Monomelic Multifocal Neuropathy: An Unrecognized Electrophysiological Feature of Hereditary Neuropathy with Liability to Pressure Palsies in Childhood.

Hereditary neuropathy with liability to pressure palsies (HNPP) is well defined in adults, but its clinical and electrophysiological features in childhood have not been well characterized. We describe a case of HNPP in a child with the unique electrophysiological presentation, affecting only one upper extremity.

Noncanonical splice-site variant in peripheral myelin protein 22 gene (PMP22) in a patient with hereditary neuropathy with liability to pressure palsies.

AIM: Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral neuropathy with autosomal dominant inheritance. Diagnosis can be made from the characteristic abnormalities determined by nerve conduction studies (NCS), including subclinical deficits at physiological compression sites. Heterozygous deletion of the chromosome 17p11.2-p12 region including the peripheral myelin protein 22 gene (PMP22) is the cause in the majority of cases. However, the loss of function of PMP22 due to frameshift-causing insertion/deletion, missense, nonsense, or splice-site disrupting variants cause HNPP in some patients. We report a case of a patient diagnosed with HNPP on the basis of clinical features and the results of NCS. No deletions of PMP22 were detected by fluorescence in situ hybridization. METHODS: We performed direct nucleotide sequence analysis and identified a heterozygous variant, c.78 + 3G > T, in PMP22. Since this variant is located outside the canonical splice site at the exon 2-intron 2 junction, we investigated whether the variant causes aberrant splicing and leads to the skipping of exon 2 of PMP22 by in vitro minigene splicing assay. RESULTS: We demonstrated that the c.78 + 3G > T variant causes the skipping of exon 2 and leads to loss of function of the mutant allele. CONCLUSION: Searching for sequence variants located outside the canonical splice sites should also be considered even when deletion of PMP22 is not found in a patient with a clinical diagnosis suggesting HNPP.