Development and validation of a nomogram to predict the risk of residual low back pain after tubular microdiskectomy of lumbar disk herniation.

OBJECTIVE: Tubular microdiskectomy (tMD) is one of the most commonly used for treating lumbar disk herniation. However, there still patients still complain of persistent postoperative residual low back pain (rLBP) postoperatively. This study attempts to develop a nomogram to predict the risk of rLBP after tMD. METHODS: The patients were divided into non-rLBP (LBP VAS score < 2) and rLBP (LBP VAS score ≥ 2) group. The correlation between rLBP and these factors were analyzed by multivariate logistic analysis. Then, a nomogram prediction model of rLBP was developed based on the risk factors screened by multivariate analysis. The samples in the model are randomly divided into training and validation sets in a 7:3 ratio. The Receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the diskrimination, calibration and clinical value of the model, respectively. RESULTS: A total of 14.3% (47/329) of patients have persistent rLBP. The multivariate analysis suggests that higher preoperative LBP visual analog scale (VAS) score, lower facet orientation (FO), grade 2-3 facet joint degeneration (FJD) and moderate-severe multifidus fat atrophy (MFA) are risk factors for postoperative rLBP. In the training and validation sets, the ROC curves, calibration curves, and DCAs suggested the good diskrimination, predictive accuracy between the predicted probability and actual probability, and clinical value of the model, respectively. CONCLUSION: This nomogram including preoperative LBP VAS score, FO, FJD and MFA can serve a promising prediction model, which will provide a reference for clinicians to predict the rLBP after tMD.

Risk factors for intracellular fatty accumulation in rotator cuff muscle: a histologic analysis.

BACKGROUND: Fatty accumulation in rotator cuff muscles has been associated with shoulder dysfunction, risk of repair failure, and poor postoperative outcomes. This study sought to assess risk factors associated with true fatty accumulation based on histologic analysis and determine whether preoperative function directly correlated with this fatty rotator cuff accumulation. METHODS: Supraspinatus muscle biopsy specimens obtained prospectively from patients undergoing arthroscopic rotator cuff repair were stained with LipidTOX to quantify lipid accumulation. Two-step cluster analysis with Goutallier classification was used to define the fatty and non-fatty rotator cuff groups. We further performed a receiver operating characteristic curve analysis to confirm the group cutoff values. RESULTS: In total, 51 patients (aged 60.1 ± 10.5 years) were included. There were 19 high-grade partial tears, 10 small tears, 7 medium tears, 10 large tears, and 5 massive tears. Both cluster and receiver operating characteristic curve analyses yielded a cutoff value of 30% LipidTOX/4',6-diamidino-2-phenylindole (DAPI) separating the fatty vs. non-fatty groups. In the univariate analysis, patients with fatty rotator cuffs were aged 63.2 years on average compared with 59.7 years in the non-fatty group (P = .038). Female patients made up 57.1% of the fatty cohort, which was statistically higher than the non-fatty group (P = .042). Massive and large tears were more likely to occur in the fatty group (P = .005). In the multivariate analysis, full tendon tears had the largest predictive status of falling into the fatty group (odds ratio, 15.4; P = .008), followed by female sex (odds ratio, 4.9; P = .036). Patients in the fatty group had significantly higher American Shoulder and Elbow Surgeons scores (P = .048) and lower visual analog scale scores (P = .002). DISCUSSION AND CONCLUSION: This prospective histologic assessment revealed that full-thickness rotator cuff tears and female sex were the largest risk factors for intracellular lipid accumulation. Although tear size correlated with fatty accumulation, the sex disparity is a noteworthy finding that warrants further research.

Using the anterior capsule of the hip joint to protect the tensor fascia lata muscle during direct anterior total hip arthroplasty: a randomized prospective trial.

BACKGROUND: The direct anterior approach for total hip arthroplasty (THA) has specific advantages, but injury to the tensor fasciae lata muscle (TFLM) remains a concern. This injury in part negates some of the advantages of the intermuscular approach, because injury of the muscle fibers of the TFLM can lead to less satisfactory clinical results. Thus, in this study, we propose an intraoperative method to protect the TFLM and demonstrate its feasibility. METHODS: Fifty-six patients undergoing THA by the direct anterior approach were divided randomly into two groups. In group A, the TFLM was protected by an autogenous tissue "pad" created from the anterior capsule of the joint which protect the TFLM from direct contact with the retractors. In group B, the operation was carried out with no protection of the TFLM except the attempt by the surgeons to consciously avoid injury of the TFLM. We evaluated magnitude of changes in the muscle cross-sectional area (MSCA) and fatty atrophy (FA) by magnetic resonance imaging. The differences in blood hemoglobin and serum levels of myoglobin, lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) were compared at different time, postoperatively. The Harris hip score, postoperative drainage volume and visual analogue scores (VAS) were compared between the two groups. RESULTS: LDH, CPK and myoglobin in group B were significantly higher than group A at 8, 24, and 48 h after the surgery. (p < 0.05) Compared to the group A, the decrease of hemoglobin in group B displayed significantly at 24 and 48 h after surgery. (P < 0.05) The significantly increased MSCA and FA of TFLM were demonstrated in group B. The PDV and VAS in group B were significantly higher than group A. (P < 0.05) The Harris score in group A was significantly higher than group B (P < 0.05) one month after surgery, but there was no significant difference six months later. CONCLUSIONS: Using the anterior capsule of the hip joint as an autogenous, protective capsular tissue pad to limit the trauma to the TFLM during a direct anterior approach to THA is an effective method to protect the TFLM and improve the clinical effect. TRIAL REGISTRATION: ChiCTR: ChiCTR1900025173. Retrospectively registered August 15, 2019.

Subscapularis structural integrity and function after arthroscopic Latarjet procedure at a minimum 2-year follow-up.

BACKGROUND: Subscapularis function after arthroscopic Bankart repair has been widely studied. However, data regarding subscapularis performance after arthroscopic Latarjet procedures are lacking. This study aimed to evaluate subscapularis clinical and radiologic performance after arthroscopic Latarjet procedures. METHODS: We included 40 patients who underwent arthroscopic Latarjet procedure with a minimum 2-year follow-up. Clinical evaluation included Western Ontario Shoulder Instability Index and Rowe scores, specific subscapularis isokinetic study, and lift-off tests. Contralateral measurements were used for comparison. Computed tomographic evaluation included graft consolidation, muscle dimensions, and degree of fatty atrophy, calculated as the mean muscle attenuation (MMA). RESULTS: There was a decrease of 8.3% of maximum internal rotation peak torque in the operated arm (P = .02). However, there was no significant difference in the agonist-antagonist ratio: 76.9% in the operated arm and 76% in the contralateral (P = .82). Lift-off strength test demonstrated a decrease in the first year but not at final follow-up (P = .38). There was a significant decrease in lift-off distance of 23% compared to the contralateral side (P < .001). Subscapularis MMA was diminished when compared to the infraspinatus/teres minor (P < .001) at the expense of its upper part (P = .03). Hyperlaxity and number of dislocation episodes were correlated to a lower MMA (P = .046 and P = .005). CONCLUSION: Arthroscopic Latarjet procedures provide satisfactory clinical results. There seems to be a diminished subscapularis MMA depending on its superior half. Hyperlaxity and number of previous dislocations were correlated to a lower MMA. Although there was a decrease in the maximum internal rotation peak torque, we did not find any difference in the agonist-antagonist ratio or in the final lift-off strength between sides.

The pathogenesis and management of cuff tear arthropathy.

Massive rotator cuff tears may lead to the development of cuff tear arthropathy (CTA). Although this pathology has been recognized for more than 150 years, treatment strategies have continued to evolve. During the last decade, there has been increased understanding of the molecular and cellular changes that govern rotator cuff tear outcomes and development of new treatment strategies to repair or reconstruct the rotator cuff. These have included an expansion of the use of arthroscopic double-row transosseous-equivalent repairs and the development of superior capsule reconstruction. However, the greatest change in the management of CTA has been the expansion of the use of reverse total shoulder arthroplasty, which has become the standard of care for patients who do not have a repair option and when nonoperative management has failed. This review article summarizes the current literature on the management of CTA, including nonoperative, repair, reconstruction, and replacement options, with a focus on literature in the last 5 years.

Outcome of lower trapezius transfer to reconstruct massive irreparable posterior-superior rotator cuff tear.

BACKGROUND: Management of massive irreparable posterior-superior rotator cuff tear can be very challenging. This study reports the outcome of the lower trapezius transfer to reconstruct massive irreparable posterior-superior rotator cuff tear. METHODS: Included were 33 patients with an average age of 53 years (range, 31-66 years). All patients had symptomatic massive irreparable rotator cuff tear that failed conservative or prior surgical treatment and underwent reconstruction with lower trapezius transfer prolonged by Achilles tendon allograft. The tear was considered irreparable based on the magnetic resonance imaging finding of ≥2 full-thickness rotator cuff tears associated with shortening and retraction of the tendon to the level of the glenoid and a high grade of fatty infiltration of the muscles. This was confirmed at the time of the surgery. RESULTS: At an average follow-up of 47 months, 32 patients had significant improvement in pain, subjective shoulder value, and Disabilities of the Arm, Shoulder and Hand score and shoulder range of motion, including flexion, 120°; abduction, 90°; and external rotation 50°. One patient, with a body mass index of 36 kg/m(2), required débridement for an infection and then later underwent shoulder fusion. Patients with >60° of preoperative flexion had more significant gains in their range of motion. Shoulder external rotation improved in all patients regardless of the extent of the preoperative loss of motion. CONCLUSIONS: Transfer of the lower trapezius prolonged with Achilles tendon allograft to reconstruct massive irreparable posterior-superior rotator cuff tear may lead to good outcome in most patients, specifically for those who have preoperative flexion of >60°.

RORα-GABP-TFAM axis alleviates myosteatosis with fatty atrophy through reinforcement of mitochondrial capacity.

BACKGROUND: Fat infiltration in muscle, called 'myosteatosis', precedes muscle atrophy, which subsequently results in sarcopenia. Myosteatosis is frequently observed in patients with nonalcoholic fatty liver disease (NAFLD). We have previously reported that retinoic acid receptor-related orphan receptor-α (RORα) regulates mitochondrial dynamics and mitophagy in hepatocytes, resulting in an alleviation of NAFLD. In this study, we aimed to investigate the role of RORα in skeletal muscle and to understand molecular mechanisms by which RORα controls mitochondrial capacity, using an NAFLD-associated myosteatosis mouse model. METHODS: To establish a myosteatosis model, 7-week-old C57BL/6N mice were fed with high-fat diet (HFD). After 15 weeks of diet feeding, an adeno-associated virus vector encoding RORα (AAV-RORα) was injected to gastrocnemius (GA) muscles, or after 7 weeks of HFD feeding, JC1-40, an RORα agonistic ligand, was administered daily at a dose of 5 mg/kg/day by oral gavage for 5 weeks. Histological, biochemical and molecular analyses in various in vivo and in vitro experiments were performed. RESULTS: First, the number of oxidative MyHC2a fibres with intensive lipid infiltration increased by 3.8-fold in the red region of the GA of mice with myosteatosis (P < 0.001). RORα was expressed around MyHC2a fibres, and its level increased by 2.7-fold after HFD feeding (P < 0.01). Second, treatment of RORα ligands in C2C12 myoblasts, such as cholesterol sulfate and JC1-40, enhanced the number of oxidative fibres stained for MyHC1 and MyHC2a by two-fold to four-fold (P < 0.01), while it reduced the lipid levels in MyHC2a fibres by 20-50% (P < 0.001) in the presence of palmitic acids. Third, mitochondrial membrane potential (P < 0.01) and total area of mitochondria (P < 0.01) were enhanced by treatment of these ligands. Chromatin immunoprecipitation analysis showed that RORα bound the promoter of GA-binding protein α subunit gene that led to activation of mitochondrial transcription factor A (TFAM) in C2C12 myoblasts (P < 0.05). Finally, intramuscular transduction of AAV-RORα alleviated the HFD-induced myosteatosis with fatty atrophy; lipid contents in MyHC2a fibres decreased by 48% (P < 0.001), whereas the number of MyHC2b fibre increased by 22% (P < 0.001). Also, administration of JC1-40 improved the signs of myosteatosis in that it decreased the level of adipose differentiation-related protein (P < 0.01) but increased mitochondrial proteins such as cytochrome c oxidase 4 and TFAM in GA muscle (P < 0.01). CONCLUSIONS: RORα plays a versatile role in regulating the quantity of mitochondria and the oxidative capacity, ultimately leading to an improvement in myosteatosis symptoms.

Gluteal Muscle Fatty Atrophy: An Independent Risk Factor for Surgical Treatment in Elderly Patients Diagnosed with Type-III Fragility Fractures of the Pelvis.

BACKGROUND: Gluteal muscle fatty atrophy (gMFA) might impair pelvic stability and negatively influence remobilization in patients with fragility fractures of the pelvis (FFP). This study aimed to investigate the association between gMFA and surgical indication in patients with FFP. METHODS AND MATERIALS: A retrospective analysis of 429 patients (age ≥80) diagnosed with FFP was performed. gMFA of the gluteus maximus, medius, and minimus was evaluated using a standard scoring system based on computer tomography images. RESULTS: No significant difference was found in gMFA between genders or among FFP types. The severity of gMFA did not correlate with age. The severity of gMFA in the gluteus medius was significantly greater than in the gluteus maximus, whereas the most profound gMFA was found in the gluteus minimus. gMFA was significantly more severe in patients who underwent an operation than in conservatively treated patients with type-III FFP, and an independent correlation to surgical indication was found using logistic regression. CONCLUSION: Our findings imply that gMFA is an independent factor for surgical treatment in patients with type-III FFP. Besides focusing on the fracture pattern, the further evaluation of gMFA could be a feasible parameter for decision making toward either conservative or surgical treatment of type-III FFP.

Moderate to Severe Multifidus Fatty Atrophy is the Risk Factor for Recurrence After Microdiscectomy of Lumbar Disc Herniation.

OBJECTIVE: We attempted to investigate the potential risk factors of recurrent lumbar disc herniation (rLDH) after tubular microdiscectomy. METHODS: We retrospectively analyzed the data of patients who underwent tubular microdiscectomy. The clinical and radiological factors were compared between the patients with and without rLDH. RESULTS: This study included 350 patients with lumbar disc herniation (LDH) who underwent tubular microdiscectomy. The overall recurrence rate was 5.7% (20 of 350). The visual analogue scale (VAS) score and Oswestry Disability Index (ODI) at the final follow-up significantly improved compared with those preoperatively. There was no significant difference in the preoperative VAS score and ODI between the rLDH and non-rLDH groups, while the leg pain VAS score and ODI of the rLDH group were significantly higher than those of the non-rLDH group at final follow-up. This suggested that rLDH patients had a worse prognosis than non-rLDH patients even after reoperation. There were no significant differences in sex, age, body mass index, diabetes, current smoking and drinking, disc height index, sagittal range of motion, facet orientation, facet tropism, Pfirrmann grade, Modic changes, interdisc kyphosis, and large LDH between the 2 groups. Univariate logistic regression analysis revealed that rLDH was associated with hypertension, multilevel microdiscectomy, and moderate-severe multifidus fatty atrophy (MFA). A multivariate logistic regression analysis indicated that MFA was the sole and strongest risk factor for rLDH after tubular microdiscectomy. CONCLUSION: Moderate-severe MFA was a risk factor for rLDH after tubular microdiscectomy, which can serve as an important reference for surgeons in formulating surgical strategies and the assessment of prognosis.

Risk Factors of Low Back Pain Aggravation After Tubular Microdiscectomy of Lumbar Disc Herniation.

BACKGROUND: Although lumbar disc herniation (LDH) patients' sciatic symptoms such as leg pain can be improved by decompressive surgery, some patients report postoperative aggravated low back pain (LBP). However, the exact reason for this phenomenon remained unknown. METHODS: We retrospectively analyzed the prospectively collected LDH data of patients who underwent tubular microdiscectomy between December 2015 and December 2020. The patients were divided into aggravated and non-aggravated group according to whether the postoperative LBP visual analogue scale (VAS) score was higher than the preoperative score. We analyzed the relationship of the clinical and radiologic parameters with aggravated LBP. RESULTS: Postoperative aggravated LBP cases accounted for 14.1% (57 of 404) of this series. Of the 57 patients, 88% (50 of 57) had mild postoperative LBP aggravation (1-2), and 12% (7 of 57) had severe LBP aggravation (>2). The preoperative LBP VAS score of the aggravated group was significantly lower than that of the non-aggravated group (P < 0.001), while the LBP VAS score and Oswestry Disability Index at final follow-up was significantly higher in the aggravated group (P < 0.05). Additionally, the proportion of preoperative moderate-to-severe multifidus fatty atrophy (MFA) and lumbar facet joint degeneration (LFJD) was significantly higher in the aggravated group. A multiple stepwise logistic regression analysis indicated that the preoperative LBP VAS score (P < 0.001, odds ratio 0.266, 95% CI 0.161-0.439) and MFA (P < 0.001, odds ratio 4.491, 95% CI 2.092-9.640) were the risk factors for postoperative aggravated LBP. CONCLUSIONS: A preoperative lower LBP VAS score and moderate-to-severe MFA were associated with postoperative aggravated LBP. This will provide important guidance for patient's preoperative assessment and education.

Association of Preoperative Gluteal Muscle Fatty Infiltration With Patient Outcomes in Women After Hip Abductor Tendon Repair Augmented With LARS.

BACKGROUND: Hip abductor tendon repair has demonstrated encouraging outcomes. The influence of fatty infiltration (FI) on outcome has not been explored. PURPOSE: To investigate the association between preoperative hip abductor FI and clinical outcome after hip abductor tendon repair. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 84 women underwent hip abductor tendon repair. The mean age was 64.6 years (range, 43-84 years); body mass index, 27.7 (range, 20.0-40.2); and duration of symptoms, 3.4 years (range, 6 months-20 years). The 6-minute walk test, isometric hip abduction strength assessment, and patient-reported outcome measures, including the Harris Hip Score and Oxford Hip Score, were completed presurgery and 2 years after surgery. Patient satisfaction and perceived improvement were assessed 2 years after surgery. All patients underwent preoperative magnetic resonance imaging on the affected hip, and the Goutallier system was used to grade the degree of FI in the anterior, middle, and posterior thirds of the gluteus medius and minimus on a 0-4 ordinal scale. A single FI score for the gluteus medius and minimus was calculated, as was a combined FI score. RESULTS: All clinical scores significantly improved over time (P < .001). Preoperatively, FI was more severe in the gluteus minimus, with the most severe FI (grades 2-4) demonstrated in the middle (n = 56, 66.7%) and anterior (n = 17, 20.2%) portions of the gluteus minimus and the middle (n = 27, 32.1%) and anterior (n = 12, 14.3%) portions of the gluteus medius. Older age was associated with greater FI (combined FI score: r = 0.529, P < .001), although duration of symptoms (r = 0.035, P = .753) and body mass index (r = 0.089, P = .464) were not. Greater FI was associated with less improvement in hip strength of the unaffected leg (coefficient, -1.6, 95% CI: -2.8 to -0.4), although no other significant associations were observed between FI and pre- or postoperative clinical scores. CONCLUSION: Preoperative FI was not associated with pertinent parameters of patient outcome after hip abductor tendon repair, including pain, symptoms, functional capacity, perceived improvement, and satisfaction. Based on these outcomes, surgical repair may be considered in the presence of more severe FI.

Assessment of hip abductors by MRI after total hip arthroplasty and effect of fatty atrophy on functional outcome.

OBJECTIVES: The aim of this study was to evaluate how fatty atrophy (FA) of the hip abductors in operated and non-operated hips affected the functional outcome following arthroplasty. METHODS: Forty-four hips of 22 patients (8 males and 14 females; mean age: 60 ±â€¯14.4 (range: 24-84)) who matched the inclusion criteria and willing to participate in the study were retrospectively evaluated. The mean follow-up was 13.8 ±â€¯2.3 (range: 10-18) months Magnetic resonance imaging (MRI) and Harris Hip Score (HHS) were used to evaluate muscle degeneration and functional outcome after unilateral THA through a posterolateral approach. The FA grade was evaluated using Goutallier grading system. Non-operated hips of subjects were used as the control. Age, duration after the operation, gluteal muscle FA, and the relationships with HHS were evaluated. RESULTS: FA was more evident in the operated hip (p < 0.05), and was more in the gluteus minimus than in the gluteus medius in both hips (p < 0.05). Patients' age was not correlated with gluteal muscle FA in the operated hip (p > 0.05), whereas there was a positive correlation with the contra-lateral hip (p < 0.05). Duration after surgery did not affect gluteal muscle FA in the operated hip. Older age and FA of either the operated or healthy hip resulted in poorer HHS (p < 0.05). HHS had the strongest correlations with patient age (p < 0.001) and FA (p = 0.026) of the gluteus minimus of contralateral hip. CONCLUSION: Following THA, there was marked FA in the operated hip compared to that in the contralateral hip. In these cases, degree of FA in the replaced hip did not correlate with patients' age. Fatty atrophy of the gluteus minimus precedes that of gluteus medius. FA of the contralateral gluteus minimus and patient age are strongly correlated with lower HHS. LEVEL OF EVIDENCE: Level IV, diagnostic study. LEVEL OF EVIDENCE: Level IV, diagnostic study.

Arthroscopic single-row repair of massive potentially irreparable postero-superior cuff tear.

PURPOSE: We retrospectively evaluated the results of complete repair of massive potentially irreparable postero-superior tears in a consecutive cohort of patients. With the increasing and widespread use of superior capsular reconstruction, a complete repair of the superior cuff, also if not functional, may be a valuable option for irreparable cuff lesions. METHODS: A consecutive case series of massive potentially irreparable postero-superior cuff tears that underwent complete repair was included in the study. Irreparability of cuff tear was defined when on preoperative MRI images, a positive tangent sign, a Goutallier 3-4 stage of fatty infiltration, and an absent acromion-humeral distance were present. A single-row complete repair was performed using triple-loaded titanium suture anchors. Operative time was recorded, as well as intra- and postoperative complications. Patients were followed for 12 months post-op; they were clinically evaluated with the use of constant score (CS) and subjective shoulder value (SSV) at 3, 6, and 12 months; a 12-month postoperative ultrasound evaluation was obtained. RESULTS: Thirty-two patients satisfying the inclusion criteria were enrolled. The mean age was 52 years (range 41-58). The repair was completed with a mean use of 2.4 triple-loaded suture anchors (range 2-4); the mean operative time was 70 min (range 45-90). The mean preoperative CS was 55 (range 45-75, SD 17), while the SSV was 40 (range 30-70, SD 22). At the final follow-up, the mean CS and SSV were 72 (range 62-85, SD 8) and 80 (range 60-90, SD 10) (p < 0.001 with respect to the preoperative scores), respectively. At the final follow-up, sonography showed a complete healing of the cuff in 20 cases (62.5%). No intra-operative complications occurred; at the final follow-up, five patients (15, 6%) were not satisfied of the results and asked for revision surgery. CONCLUSIONS: The complete repair of massive potentially irreparable rotator cuff tear in patients younger than 60 years old yielded good results at a short-term follow-up, with a sonographic re-tear rate of about 20%. Even if it is logical to consider a tendon with severe fatty degeneration as non-functional, the superior soft tissue reconstruction we achieved may have at least the same results of a superior capsular reconstruction, with obvious lower costs. LEVEL OF EVIDENCE: Level 4, case series with no comparison group.

Massive Rotator Cuff Tear: When to Consider Reverse Shoulder Arthroplasty.

PURPOSE OF REVIEW: The purpose of this review is to discuss the indications for reverse shoulder arthroplasty (RSA) in the treatment of massive rotator cuff tear (MCT), review the reported outcomes in the literature, and outline our approach and surgical technique for treating these patients. RECENT FINDINGS: While RSA remains a successful and well-accepted treatment for cuff tear arthropathy (CTA), management of MCT in the absence of arthritis is controversial. In this particular setting, patients best suited for RSA are elderly, lower-demand individuals with chronic, irreparable MCT, and pseudoparalysis. Age < 60, better pre-operative function and upper extremity neurologic dysfunction are potential risk factors for poor outcome with RSA in this population. Long-term follow-up studies of RSA for CTA and MCT show good functional outcomes and implant survival > 90% at 10 years. Treatment of MCT must be individualized for each patient. When patient selection is optimized, RSA is a reliable means of relieving pain and improving function with excellent success. Further investigation is necessary to better define its indications and assess the role of alternative, joint-salvaging procedures.

NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype.

The purpose of this study was to describe a pedigree with NEFL N98S mutation associated with a dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) and heterogeneous early-onset phenotype. The pedigree comprised two patients, the proband and her son, aged 38 and 5 years. The proband, evaluated at age 31, showed delayed motor milestones that, as of the second decade, evolved into severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound. By then, a working diagnosis of sporadic early onset cerebellar ataxia with peripheral neuropathy was established. Screening of mutations associated with SCA and autosomal recessive cerebellar ataxias was negative. Her son showed a mild phenotype characterized by delayed motor milestones, and lower-limb hypotonia and areflexia. Electrophysiology in both patients showed nerve conduction slowing in the intermediate range, both in proximal and distal nerve segments, but where compound muscle action potentials exhibited severe attenuation there was conduction slowing down to the demyelinating range. In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy; furthermore, on water sensitive MRI sequences there was edema of calf muscles. We conclude that the NEFL N98S mutation is associated with a DI-CMT phenotype characterized by early-onset sensorimotor neuropathy delaying motor milestones, which may evolve into a severe and complex clinical picture including cerebellar ataxia.