Hereditary Neuropathy With Liability To Pressure Palsies Research Articles

Anesthetic Considerations for Patients with Hereditary Neuropathy with Liability to Pressure Palsies: A Narrative Review.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant demyelinating neuropathy characterized by an increased susceptibility to peripheral nerve injury from trauma, compression, or shear forces. Patients with this condition are unique, necessitating distinct considerations for anesthesia and surgical teams. This review describes the etiology, prevalence, clinical presentation, and management of HNPP and presents contemporary evidence and recommendations for optimal care for HNPP patients in the perioperative period. While the incidence of HNPP is reported at 7-16:100,000, this figure may be an underestimation due to underdiagnosis, further complicating medicolegal issues. With the subtle nature of symptoms associated with HNPP, patients with this condition may remain unrecognized during the perioperative period, posing significant risks. Several aspects of caring for this population, including anesthetic choices, intraoperative positioning, and monitoring strategy, may deviate from standard practices. As such, a tailored approach to caring for this unique population, coupled with meticulous preoperative planning, is crucial and requires a multidisciplinary approach.

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.

An Uncommon Disease with a Common Presentation: Severe Back pain and Diffuse Neuropathy in Two Cases of Hereditary Neuropathy with Liability to Pressure Palsy

Introduction: Hereditary Neuropathy with liability to Pressure Palsy (HNPP) is an autosomal dominant genetic disorder characterized by multiple episodes of focal weakness and sensory loss caused by compression or trauma. HNPP is rare disorder and often exhibits cranial nerve involvement, sensorineural deafness and scoliosis. Individuals diagnosed with this condition typically exhibit a primary deficit of a single nerve palsy that can result in numbness, paresthesias, or weakness. Case Presentation: Two unrelated individuals with HNPP were evaluated with clinical, laboratory, electrophysiological and genetic testing. Case 1 was a 32-year-old man who presented with an episode of transient right arm weakness and severe back pain. Case 2 was a 46-year-old woman who presented with severe back pain and diffuse paresthesias, which was diagnosed as HNPP. Discussion: These cases present common symptoms that are uncommon for the typical HNPP patient. This report serves to contribute new information to the body of evidence describing HNPP. Conclusion: Although HNPP typically presents with transient compressive mononeuropathies, this study suggests that HNPP can present with various broad clinical presentations, including severe back pain. Neurologists need to broaden their spectrum of clinical presentations to help diagnose these rare conditions.

Hereditary Neuropathy With Liability to Pressure Palsy Detected During the Use of Recreational Drugs.

Background: Nitrous oxide (N2O) has been an increasingly popular recreational drug over the past few years. Abuse is associated with severe neurological complications and even fatal outcomes. Purpose: Here we present a case of chronic nitric oxide abuse in a teenager presenting with rapidly progressive mixed sensory and motor polyneuropathy. Results: The initial diagnostic workup excluded electrolyte derangement, heavy metal intoxication, autoimmune neuropathy, myopathy, hematological disorders, and thyroid disease. On further questioning, patient reported 8-months of inhalation of nitrous oxide, commonly known as "whippets". Subsequent tests revealed low Vitamin B12 and elevated homocysteine level. Eventual genetic test demonstrated a heterozygous deletion in the gene that encodes the peripheral myelin protein 22 (PMP22), consistent with a diagnosis of Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). Conclusion: The association of neurologic and genetic findings with the timeline of nitrous oxide inhalation suggests a multifactorial etiology of her symptoms, with the N2O acting as a trigger to the axonal degeneration and demyelination detected on electrodiagnostic studies.

A CASE REPORT OF HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES

Hereditary neuropathy with liability to pressure palsy is an autosomal dominant demyelinating disorder. In individuals with numerous compressive neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP) should be taken into consideration.Here We present a case of 49-year-old man who exhibited right upper and lower extremity weakness with tingling and numbness of right upper limb and lower limb. Electrophysiological studies showed widespread, multifocal, motor > sensory, chronic peripheral neuropathy affecting the upper and lower limbs.Type: demyelinating >> axonal.Genetic studies showed Heterozygous deletion of PMP22 gene (upstream, exons 1-5) along with anking regions encompassing TEKT3 and COX10 genes were detected.Treatment for this usually self-limiting illness is debatable, in this instance, patient was managed conservatively following which there is an improvement in patient condition

Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.

ObjectivesLeigh syndrome is a progressive encephalopathy characterized by symmetrical lesions in brain. This study aimed to investigate the clinicopathologic and genetic characteristics of a family with Leigh syndrome and hereditary neuropathy with liability to pressure palsy (HNPP).MethodsData from a Japanese family's clinical features, MRIs, muscle biopsy, and an autopsy were analyzed. A whole-exome sequence was performed, as well as real-time PCR analysis to determine copy number variations and Western blot analyses.ResultsThe proband and her 2 siblings developed spastic paraplegia and mental retardation during childhood. The proband and her sister had peripheral neuropathy, whereas their father developed compression neuropathy. Leigh encephalopathy was diagnosed neuropathologically. Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum. Muscle biopsy revealed type 2 fiber uniformity and decreased staining of cytochrome c oxidase. The COX10 missense mutation was identified through whole-exome sequence. A 1.4-Mb genomic deletion extending from intron 5 of COX10 to PMP22 was detected.DiscussionThese findings suggest that in this family, Leigh syndrome is associated with a mitochondrial respiratory chain complex IV deficiency caused by biallelic COX10 mutations coexisting with HNPP caused by heterozygous PMP22 deletion.

Utility of Carpal Tunnel Release and Ulnar Decompression in CMT1A and HNPP.

Carpal and cubital tunnel syndrome (CTS, CuTS) are common among patients with hereditary neuropathy with liability to pressure-palsies (HNPP) and Charcot-Marie-Tooth type 1A (CMT1A) and may impact quality of life. We aimed to evaluate the utility of nerve decompression surgeries in these patients. Medical records were reviewed for patients with PMP22 mutations confirmed in Mayo Clinic laboratories from January 1999 to December 2020, who had CTS and CuTS and underwent surgical decompression. CTS occurred in 53.3% of HNPP and 11.5% of CMT1A, while CuTS was present in 43.3% of HNPP and 5.8% of CMT1A patients. CTS decompression occurred in 10-HNPP and 5-CMT1A patients, and CuTS decompression with/without transposition was performed in 5-HNPP and 1-CMT1A patients. In HNPP, electrodiagnostic studies identified median neuropathy at the wrist in 9/10 patients and ultrasound showed focal enlargements at the carpal and cubital tunnels. In CMT1A, median and ulnar sensory responses were all absent, and the nerves were diffusely enlarged. After CTS surgery, pain, sensory loss, and strength improved in 4/5 CMT1A, and 6/10 HNPP patients. Of clinical, electrophysiologic and ultrasound findings, only activity-provoked features significantly correlated with CTS surgical benefit in HNPP patients (odds ratio=117.0:95% confidence interval, 1.94 > 999.99, p=0.01). One CMT1A and one HNPP patient improved with CuTS surgery while 2 HNPP patients worsened. CTS symptom improvement post-surgery can be seen in CMT1A and (less frequent) in HNPP patients. CuTS surgery commonly worsened course in HNPP. Activity-provoked symptoms in HNPP best informed benefits from CTS surgery.

Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients.

Duplication and deletion of the peripheral myelin protein 22 (PMP22) gene cause Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively, while point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP. This study was performed to identify PMP22 mutations and to analyze the genotype–phenotype correlation in Korean CMT families. By the application of whole-exome sequencing (WES) and targeted gene panel sequencing (TS), we identified 14 pathogenic or likely pathogenic PMP22 mutations in 21 families out of 850 CMT families who were negative for 17p12 (PMP22) duplication. Most mutations were located in the well-conserved transmembrane domains. Of these, eight mutations were not reported in other populations. High frequencies of de novo mutations were observed, and the mutation sites of c.68C>G and c.215C>T were suggested as the mutational hotspots. Affected individuals showed an early onset-severe phenotype and late onset-mild phenotype, and more than 40% of the CMT1E patients showed hearing loss. Physical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A while similar to CMT1B caused by MPZ mutations. Our results will be useful for the reference data of Korean CMT1E and the molecular diagnosis of CMT1 with or without hearing loss.

Hereditary neuropathy with liability to pressure palsies (HNPP): Intrafamilial phenotypic variability and early childhood refusal to walk as the presenting symptom

BackgroundLimping and/or refusal to walk is a common complaint in the setting of the pediatric department, with a widely diverse differential diagnosis. An unusual etiology, is that of a hereditary neuropathy.Hereditary neuropathy with liability to pressure palsies (HNPP) is a recurrent, episodic demyelinating neuropathy, most commonly caused by a 17p11.2 chromosomal deletion encompassing the PMP22 gene.MethodsWe pursued chromosomal microarray analysis (CMA) in multiple affected individuals of a single extended family, manifesting a range of phenotypic features consistent with HNPP.ResultsA 4.5 years-old boy presented for in-patient evaluation due to refusal to walk. Initial investigations including spine MRI and bone scan failed to yield a conclusive diagnosis. Following family history, which implied an autosomal dominant mode of inheritance, CMA was pursued and confirmed a 17p11.2 deletion in the proband consistent with HNPP. Importantly, following this diagnosis, four additional affected family members were demonstrated to harbor the deletion. Their variable phenotypic features, ranging from a prenatal diagnosis of a 6 months-old sibling, to recurrent paresthesias manifesting in the fourth decade of life, are discussed.ConclusionsOur experience with the family reported herein demonstrates how a thorough anamnesis can lead to a rare genetic etiology with a favorable prognosis and prevent unnecessary investigations, and underscores HNPP as an uncommon diagnostic possibility in the limping child.

Candidate imaging biomarkers for PMP22-related inherited neuropathies.

ObjectiveCharcot–Marie–Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP) are caused by mutations to the peripheral myelin protein 22 (PMP22) gene. A need exists for sensitive and reliable biomarkers of progression and treatment response. Magnetic resonance imaging (MRI) metrics of nerve pathology and morphology were investigated for this purpose.MethodsMRI was performed at 3.0 T in the thigh of CMT1A (N = 11) and HNPP patients (N = 12) and controls (N = 23). Three potential imaging biomarkers of the sciatic nerve were investigated: 1) magnetization transfer ratio (MTR), which assays myelin content, and 2) cross‐sectional area (CSA) and 3) circularity, which assay morphological changes. Potential imaging biomarkers were compared across cohorts and assessed for relationships with disability in the legs (CMTESL), compound motor action potentials (CMAP), and motor conduction velocities (MCV). Inter‐rater reliability and test–retest repeatability were established for each imaging metric.ResultsSignificant differences in MTR, CSA, and circularity were observed in CMT1A relative to controls (p = 0.02, p < 0.001, and p = 0.003, respectively, via Wilcoxon rank‐sum tests). Differences were not observed in the HNPP cohort. Significant relationships were observed between MTR and clinical metrics (CMTESL: p = 0.003, CMAP: p = 0.03, MCV: p = 0.01); and between CSA and electrophysiology (CMAP: p = 0.002, MCV: p < 0.001). All metrics were reliable and repeatable with MTR the most reliable (intraclass correlation coefficient [ICC] >0.999, CV = 0.30%) and repeatable (ICC = 0.84, CV = 3.16%).InterpretationMTR, CSA, and circularity showed promise as reliable and sensitive biomarkers of CMT1A, but not HNPP. These warrant longitudinal investigation as response biomarkers in upcoming clinical trials of CMT1A, while other methods should be considered for HNPP.

Dosage effects of PMP22 on nonmyelinating Schwann cells in hereditary neuropathy with liability to pressure palsies

Focal thickening of the myelin sheath, also known as tomacula, is a characteristic pathological feature of patients with hereditary neuropathy with liability to pressure palsies (HNPP). However, a deeper understanding of the pathology underlying unmyelinated fibers and nonmyelinating Schwann cells is required. Electron microscopic examination of sural nerve biopsy specimens was performed for 14 HNPP patients with peripheral myelin protein 22 (PMP22) deletion, and their results were compared to 12 normal controls and 14 Charcot–Marie–Tooth disease type 1A (CMT1A) patients with PMP22 duplication. The number of unmyelinated axons in a single axon-containing nonmyelinating Schwann cell subunit in the HNPP group significantly increased compared with that in normal controls (1.99 ± 0.66 vs. 1.57 ± 0.52, p < 0.05). Conversely, these numbers significantly decreased in the CMT1A group compared with those in normal controls (1.16 ± 0.16, p < 0.05). Some unmyelinated axons in patients with HNPP were incompletely surrounded by the cytoplasm of Schwann cells, almost as if the Schwann cells failed to form mesaxons; such failure in mesaxon formation was not observed in normal controls or in patients with CMT1A. These findings suggest that PMP22 dosage affects nonmyelinating as well as myelinating Schwann cells.

Facial Paresthesia, a Rare Manifestation of Hereditary Neuropathy With Liability to Pressure Palsies: A Case Report

Trigeminal sensory neuropathy can be caused by a variety of conditions, including local, traumatic, iatrogenic, or systemic causes. Diagnosis and management remain a challenge for maxillofacial surgeons and neurologists. Therefore, a good clinical examination and objective tests and imaging are needed when diagnosing patients who present with facial numbness. We present a case with spontaneous episodes of facial paresthesia. He was diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), a rare condition that affects the peripheral nerves. Only a few case reports that describe involvement of the cranial nerves in patients with HNPP were found in the literature, and facial paresthesia has not been previously reported.

Hereditary neuropathy with liability to pressure palsy presenting as bilateral foot drop

Hereditary neuropathy with liability to pressure palsy (HNPP) is a rare, autosomal dominant disorder that typically present with episodic, multifocal neuropathy and recurrent transient pressure palsies. However HNPP can be underdiagnosed or misdiagnosed due to its heterogeneity in clinical and electrophysiological presentation. We herein present a case of HNPP presenting with bilateral foot drop.

Management of anesthesia for surgery in prone position for a patient with hereditary neuropathy with liability to pressure palsies. A case report and narrative literature review

The reported case describes a patient with hereditary neuropathy with liability to pressure palsies (HNPP) requiring a neurosurgical laminotomy procedure for an arachnoid cyst with medullary compression. HNPP is a rare pathology requiring meticulous anesthetic and surgical management. We give a detailed overview of the planning, simulation, and performance of the anesthesia procedure in order to minimize all potential risk factors for perioperative nerve injury. During the preparation of this case, where the positioning was extremely challenging, we reviewed the available literature for guidance. A few papers report the use of neuraxial anesthesia in patients previously diagnosed with HNPP. No reports could be found on the management of general anesthesia and positioning for major surgery in those patients.

Hereditary neuropathy with liability to pressure palsies: a case report

Hereditary neuropathy with liability to pressure palsies (HNPP) is a rare hereditary disorder characterized by recurrent episodes of nerve compression. The first attack usually occurs in the second or third decade of life. In the majority of cases, HNPP is associated with a mutation at chromosome 17 p11.2-12 comprising the gene encoding peripheral myelin protein 22 (PMP22). Here we present a case report of a 43-year-old male with HNPP confirmed by DNA testing. The patient complained of recurrent episodes of bilateral foot extensor muscles weakness and/or hyperesthesia on the outer surface of the hands and forearms, which started after a prolonged posture maintaining and without evident precipitating factors. We also describe typical clinical, electrophysiological, and nerve ultrasound characteristics of the disease.

Health-related Quality of Life and Satisfaction with German Health Care Services in Patients with Charcot-Marie-Tooth Neuropathy.

BackgroundCharcot-Marie-Tooth (CMT) neuropathies entail a large group of diseases with different gene mutation patterns, which produce heterogeneous phenotypes. Although health-related quality of life (HRQOL) is significantly impaired, a comprehensive assessment of HRQOL in CMT patients in Germany considering phenotypical heterogeneity represented a research gap.ObjectiveThe aim was to assess HRQOL and the satisfaction with health care in CMT patients in Germany.MethodsCMT patients > 15 years with a genetically confirmed CMT subtype were recruited through a national CMT patient registry. HRQOL was assessed using the EQ-5D-5L questionnaire. Furthermore, subjective impairments in daily or work activities and satisfaction with health care were assessed using 4-point scales.ResultsHRQOL in CMT patients (n = 385) was impaired compared to the German population. Most patients reported problems in the dimension mobility (89.6%), pain/discomfort (89.4%) and usual activities (81.0%). Except for patients with hereditary neuropathy with liability to pressure palsy (HNPP), we found no differences in HRQOL between the CMT subtypes. 72.0%of CMT patients were satisfied with available health care services. However, patients reported to expect more CMT-specific knowledge and support as well as easier prescription and cost coverage procedures from health professionals and insurances.ConclusionsThe patient-reported outcomes in the assessed CMT cohort elucidate the need for more specific health care services that also address the heterogeneous phenotypes. Although the assessment has been limited to the German health services setting, insights may be applicable to CMT-specific care in other national settings.

New evidence for secondary axonal degeneration in demyelinating neuropathies

Development of peripheral nervous system (PNS) myelin involves a coordinated series of events between growing axons and the Schwann cell (SC) progenitors that will eventually ensheath them. Myelin sheaths have evolved out of necessity to maintain rapid impulse propagation while accounting for body space constraints. However, myelinating SCs perform additional critical functions that are required to preserve axonal integrity including mitigating energy consumption by establishing the nodal architecture, regulating axon caliber by organizing axonal cytoskeleton networks, providing trophic and potentially metabolic support, possibly supplying genetic translation materials and protecting axons from toxic insults. The intermediate steps between the loss of these functions and the initiation of axon degeneration are unknown but the importance of these processes provides insightful clues. Prevalent demyelinating diseases of the PNS include the inherited neuropathies Charcot-Marie-Tooth Disease, Type 1 (CMT1) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and the inflammatory diseases Acute Inflammatory Demyelinating Polyneuropathy (AIDP) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Secondary axon degeneration is a common feature of demyelinating neuropathies and this process is often correlated with clinical deficits and long-lasting disability in patients. There is abundant electrophysiological and histological evidence for secondary axon degeneration in patients and rodent models of PNS demyelinating diseases. Fully understanding the involvement of secondary axon degeneration in these diseases is essential for expanding our knowledge of disease pathogenesis and prognosis, which will be essential for developing novel therapeutic strategies.

Charcot-Marie-Tooth disease and hereditary motor neuropathies – Update 2020

Abstract Inherited peripheral neuropathy is the most common hereditary neuromuscular disease with a prevalence of about 1:2,500. The most frequent form is Charcot-Marie-Tooth disease (CMT, or hereditary motor and sensory neuropathy [HMSN]). Other clinical entities are hereditary neuropathy with liability to pressure palsies (HNPP), distal hereditary motor neuropathies (dHMN), and hereditary sensory and autonomic neuropathies (HSAN). With the exception of HNPP, which is almost always caused by defects of the PMP22 gene, all other forms show genetic heterogeneity with altogether more than 100 genes involved. Mutation detection rates vary considerably, reaching up to 80 % in demyelinating CMT (CMT1) but are still as low as 10–30 % in axonal CMT (CMT2), dHMN, and HSAN. Based on current information, analysis of only four genes (PMP22, GJB1, MPZ, MFN2) identifies 80–90 % of CMT-causing mutations that can be detected in all known disease genes. For the remaining patients, parallel analysis of multiple neuropathy genes using next-generation sequencing is now replacing phenotype-oriented multistep gene-by-gene sequencing. Such approaches tend to generate a wealth of genetic information that requires comprehensive evaluation of the pathogenic relevance of identified variants. In this review, we present current classification systems, specific phenotypic clues, and diagnostic yields in the different subgroups of hereditary CMT and motor neuropathies.

Fatigue in patients with hereditary neuropathy with liability to pressure palsies.

ObjectiveHereditary Neuropathy with Liability to Pressure Palsies (HNPP) is caused by a heterozygous deletion of peripheral myelin protein‐22 (PMP22) gene resulting in focal sensorimotor deficits. Our lab has identified a disruption of myelin junctions in excessively permeable myelin that impairs action potential propagation. This mechanism is expected to cause fatigue in patients with HNPP. Therefore, the objective was to characterize fatigue in patients with HNPP and determine the relationship of fatigue to nerve pathology, disability, and quality of life.MethodsNine females with HNPP participated in a single visit that included genotyping, nerve conduction studies, neurological exam, quantitative magnetic resonance imaging, and a physical therapy exam incorporating upper and lower extremity function and survey measures of fatigue. This visit was followed by 2 weeks of ecological momentary assessment (wrist‐worn device) that captured fatigue ratings five times per day.ResultsParticipants demonstrated mild neurological impairment (CMTNS: 5.7 ± 2.8), yet reported high fatigue levels (average fatigue intensity over 2 weeks: 5.9 out of 10). Higher fatigue levels were associated with poorer quality of life and more pain. Higher fatigue was associated with significantly greater distal nerve proton density changes on peripheral nerve MRI, which is in line with hyper‐permeable myelin in HNPP.InterpretationFatigue is common and severe among patients with HNPP whose disabilities are minimal by conventional outcome measures. Therapeutic interventions targeting fatigue have the potential to improve quality of life and may serve as a robust outcome measure to show longitudinal changes for patients with HNPP.

Hereditary Neuropathy with Liability to Pressure Palsies: A Case Report

Background: Hereditary neuropathy with liability to pressure palsies (HNPP) is an uncommon diagnosis that should be considered in patients with multiple compressive neuropathies. This case reports highlights a relatively rare neuropathy with genetic and occupational predisposition, probably first to be reported in the united arab emirates. Case Presentation: We present the case of a 41 years old male who presented with right hand numbness and weakness. Electrodiagnostic testing revealed multifocal neuropathy. Subsequent genetic testing identified heterogeneous deletion of the PMP22 gene to confirm the diagnosis of HNPP. Conclusions: Hereditary neuropathy with liability to pressure palsies can present as a multifocal neuropathy. Occupational history along with genetic testing plays a pivotal role to make the diagnosis.