Lysosomal targeting of the CLN7 membrane glycoprotein and transport via the plasma membrane require a dileucine motif.

CLN7 is a polytopic lysosomal membrane protein deficient in variant late infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder. In this study fluorescence protease protection assays and mutational analyses revealed the N- and C-terminal tails of CLN7 in the cytosol and two N-glycosylation sites at N371 and N376. Both partially and non-glycosylated CLN7 were correctly transported to lysosomes. To identify lysosomal targeting motifs, we generated CD4-chimera fused to the N- and C-terminal domains of CLN7. Lysosomal localization of the chimeric proteins requires a consensus acidic dileucine-based motif in the N-terminus and two tandem tyrosine-based signals in the C-terminus. Mutation of these sorting motifs resulted in cell surface redistribution of CD4 chimeras. However, the dileucine-based motif is of critical importance for lysosomal localization of the full-length CLN7 in different cell lines. Cell surface biotinylation revealed that at equilibrium 22% of total CLN7 is localized at the plasma membrane. Mutation of the dileucine motif or the co-expression of dominant-negative mutant dynamin K44A led to a further increase of CLN7 at the plasma membrane. Our data demonstrate that CLN7 contains several cytoplasmic lysosomal targeting signals of which the N-terminal dileucine-based motif is required for the predominant lysosomal targeting along the indirect pathway and clathrin-mediated endocytosis of CLN7.

Lumbar stenosis rates in symptomatic patients using weight-bearing and recumbent magnetic resonance imaging.

OBJECTIVE: The purpose of this study was to determine the rate of lumbar stenosis detected via magnetic resonance imaging (MRI) in patients with symptomatic foraminal stenosis, lateral recess stenosis, or central stenosis. METHODS: A retrospective review was performed on 1983 MRI scans from a 2-year period on 1486 symptomatic patients. Of these patients, 761 were scanned in the recumbent position using low-field (0.3 T, Airis II; Hitachi, Twinsburg, Ohio) MRI, and 725 were scanned in an upright sitting position using midfield (0.6 T) open Upright MRI (Fonar Corp, Melville, NY). In total, 986 serial scans (recumbent) and 997 serial scans (weight-bearing) were performed. RESULTS: Of scans performed in the recumbent position, stenoses were identified in 382 scans (38.8%), central stenosis in 119 scans (12%), lateral recess stenosis in 91 scans (9.2%), and foraminal stenosis in 327 scans (33.2%). Of scans performed in a weight-bearing position, stenoses were identified in 565 scans (56.7%), central stenosis in 136 scans (13.6%), lateral recess stenosis in 206 scans (20.7%), and foraminal stenosis in 524 scans (52.6%). CONCLUSIONS: The stenosis rates as indicated by MRI interpretation ranged between 38.5% (recumbent) and 56.7% (weight-bearing). These rates are higher than those reported in the medical literature for asymptomatic patients. Further study is needed to determine whether weight-bearing, compared with recumbent, MRI better informs the clinician in the diagnosis of spinal stenosis.

Lumbar disk protrusion rates of symptomatic patients using magnetic resonance imaging.

OBJECTIVE: The purpose of this study was to determine the rate of disk protrusions detected via magnetic resonance imaging (MRI) in patients symptomatic for spine pain, radiculopathy, or other spine-related pain. METHODS: A retrospective review of 1983 MRI scans was performed over a 2-year period on 1486 patients, each of whom was symptomatic for spine pain, radiculopathy, or other noncancer, spine-related pain. Of these patients, 761 were scanned in the recumbent position using low-field (0.3 T, Airis II, Hitachi, Twinsburg, Ohio) MRI, and 725 were scanned in an upright, sitting position using mid-field (0.6 T) open Upright MRI (Fonar, Melville, NY). In total, 986 serial scans were performed on patients in the recumbent position and 997 serial scans on patients in the weight-bearing position. RESULTS: One or more disk protrusions were identified in 73.3% of scans performed in the sitting position and in 50.1% of scans performed in the recumbent position. Most disk protrusions occurred at L5-S1 (52.3% and 29.8%), L4-L5 (42.6% and 26.7%), and L3-L4 (26.7% and 13.1%) in upright and recumbent positions, respectively. CONCLUSIONS: The disk protrusion rate in this group of patients ranged between 50.1% (recumbent) and 73.3% (weight-bearing). These rates are higher than rates reported in the medical literature for asymptomatic patients, a finding that supports the decision to further evaluate patients with persistent spine-related pain.

Vestibular dysfunction in patients with chronic pain or underlying neurologic disorders.

CONTEXT: Individuals with vestibular dysfunction are at increased risk for falling. In addition, vestibular dysfunction is associated with chronic pain, which could present a serious public health concern as approximately 43% of US adults have chronic pain. OBJECTIVE: To assess the incidence of vestibular dysfunction in patients receiving medication for chronic, noncancer pain or other underlying neurologic disorders and to determine associated follow-up therapeutic and diagnostic recommendations. METHODS: The authors conducted a retrospective medical record review of consecutive patients who were treated in their private neuroscience practice with medications for chronic pain or underlying neurologic disorders in 2011. All patients underwent a series of tests using videonystagmography for the assessment of vestibular function. Test results and recommendations for therapy and additional testing were obtained. RESULTS: Medical records of 124 patients (78 women, 46 men) were reviewed. Vestibular deficits were detected in 83 patients (66.9%). Patient ages ranged from 29 through 72 years, with a mean age of 50.7 years for women and 52.5 years for men. Physician-recommended therapy and follow-up testing were as follows: 32 patients (38.6%), neurologic examination and possible magnetic resonance (MR) imaging or computed tomography (CT) of the brain; 26 patients (31.3%), vestibular rehabilitation therapy only; 22 patients (26.5%), vestibular and related balance-function rehabilitation therapy, further neurologic examination, and possible MR imaging or CT; 2 patients (2.4%), balance-function rehabilitation therapy and specialized internal auditory canal high-magnification MR imaging or CT to assess for acoustic neuroma; and 1 patient (1.2%), specialized internal auditory canal high-magnification MR imaging or CT to evaluate for possible intracanalicular acoustic neuroma. CONCLUSION: Patients being treated with medications for chronic, noncancer pain or other underlying neurologic disorders may have a higher-than-average incidence of vestibular dysfunction. Baseline assessment and monitoring of the vestibular apparatus may be indicated for these patients.

Scoliosis rates in symptomatic patients as demonstrated with weight-bearing or supine MR imaging.

CONTEXT: In the United States an estimated 6 million persons are affected by scoliosis, which is characterized by a 3-dimensional deformity of the spine that involves a curvature in the sagittal, frontal, and transverse planes. OBJECTIVE: To determine the rates of scoliosis in patients with spine-related pain unassociated with cancer, as demonstrated by magnetic resonance (MR) images obtained with patients in either a weight-bearing or a supine position. METHODS: The authors conducted a retrospective review of MR images obtained during a 2-year period in patients referred because of symptoms of radiculopathy or other spine-related pain unassociated with cancer and unresolved after conservative treatment. Images were obtained either with the patient supine or with the patient in a weight-bearing, seated position, and all images were reviewed by a neuroimaging physician. Scoliosis was assessed according to the Cobb angle method. RESULTS: A total of 1982 MR images from 1486 patients were reviewed. Of those, 986 images in 761 patients were obtained with a low-field-strength (0.3-T) MR imager with the patient supine, and 996 images in 725 patients were obtained with a mid-field-strength (0.6-T) MR imager with the patient in a weight-bearing, seated position. Scoliosis (dextroscoliosis, levoscoliosis, or both) was identified in 958 MR images (48.3%), of which 779 (78.2%) were obtained with patients in a weight-bearing position and 179 (18.2%) were obtained with patients in a supine position. CONCLUSION: The scoliosis rate was lower in the supine MR imaging group than in the weight-bearing MR imaging group. Scoliosis rates may be affected by the position in which the patient is examined, with the possibility that the weight-bearing position differentially exposes scoliosis, compared with the supine position.

Lumbar magnetic resonance imaging hypolordosis in symptomatic patients: association with paraspinal muscle spasms.

OBJECTIVE: This study examined a set of patients who were symptomatic for low back pain and who had significant lumbar hypolordosis as assessed by visual evaluation of magnetic resonance images to investigate the frequency of comorbid paraspinal muscle spasms as determined via history or physical examination. METHODS: A retrospective chart review was performed on 50 patients who had significant hypolordosis on magnetic resonance imaging (MRI) (Cobb angle <20 degrees ) to determine whether they were positive for paraspinal muscle spasms by either history or physical examination. RESULTS: Of the 50 patients with significant hypolordosis on MRI, 66% (33) had a history of paraspinal muscle spasms, 76% (38) had a positive physical examination for palpation of paraspinal muscle spasms, and 48% (24) were positive for both history and physical examination. CONCLUSIONS: This retrospective study suggests that most symptomatic patients with significant hypolordosis on lumbar MRI have a positive history or physical examination for paraspinal muscle spasm. Thus, MRI finding of significant hypolordosis (Cobb angle <20 degrees ) could potentially be a valuable tool in addition to medical history and physical examination in aiding clinicians in diagnosing paraspinal muscle spasms in symptomatic patients and in helping them to formulate appropriate and effective treatments.