Skeletal Muscle in Healthy Subjects versus Those with GNE-Related Myopathy: Evaluation with Shear-Wave US--A Pilot Study.

PURPOSE: To determine whether quantitative differences in shear-wave velocity (SWV) exist between normal skeletal muscle and those affected by GNE-related myopathy and to examine the effects of muscle anisotropy, depth, and axial preload on SWV in a healthy control group. MATERIALS AND METHODS: This study was approved by the institutional review board and compliant with HIPAA. Informed consent was obtained from all study volunteers. Eight patients (four women and four men aged 30-50 years) with genetically and biopsy-proved GNE-related myopathy and five healthy volunteers (three women and two men aged 27-33 years) underwent SWV imaging with use of a 9-MHz linear transducer. The gastrocnemius muscles were evaluated in the patients with GNE-related myopathy, and the gastrocnemius, vastus lateralis, and rectus femoris muscles were evaluated in the healthy cohort. The effect of muscle anisotropy, axial preload, and sample volume depth were examined in the healthy cohort. The effect of anisotropy at a fixed depth and preload were examined in the patients with GNE-related myopathy. RESULTS: Irrespective of the muscle, the mean SWV was significantly higher with the transverse orientation than with the longitudinal orientation (P < .001). In the healthy cohort, the mean SWV for superficial measurements was significantly lower than that for deep measurements (P < .02). The mean SWV with preload was significantly higher with compression (P < .001) for the rectus femoris only. The mean SWV was significantly lower in patients with GNE-related myopathy than in control subjects (P < .02). CONCLUSION: SWV parametric imaging may provide a useful quantitative adjunct in the assessment of disease activity in patients with GNE-related myopathy. There is diminished SWV and muscle anisotropy in GNE-related myopathy.

Fabry disease - underestimated in the differential diagnosis of multiple sclerosis?

OBJECTIVE: Fabry disease is a rare X-linked inherited lysosomal storage disorder affecting multiple organ systems. It includes central nervous system involvement via micro- and macroangiopathic cerebral changes. Due to its clinical symptoms and frequent MRI lesions, Fabry disease is commonly misdiagnosed as multiple sclerosis. We present an overview of cases from Fabry centres in Germany initially misdiagnosed with multiple sclerosis and report the clinical, MR-tomographical, and laboratory findings. METHODS: Eleven Fabry patients (one male, ten females) initially diagnosed with multiple sclerosis were identified from 187 patient records (5.9%) and analyzed for presenting symptoms, results of the initial diagnostic workup, and the clinical course of the disease. RESULTS: Four patients were identified as having a "possible" history of MS, and 7 patients as "definite" cases of multiple sclerosis (revised McDonald criteria). On average, Fabry disease was diagnosed 8.2 years (±9.8 years) after the MS diagnosis, and 12.8 years after onset of first symptoms (±10.3 years). All patients revealed white matter lesions on MRI. The lesion pattern and results of cerebrospinal fluid examination were inconsistent and non-specific. White matter lesion volumes ranged from 8.9 mL to 34.8 mL (mean 17.8 mL±11.4 mL). There was no association between extra-neurological manifestations or enzyme activity and lesion load. CONCLUSION: There are several anamnestic and clinical hints indicating when Fabry disease should be considered a relevant differential diagnosis of multiple sclerosis, e.g. female patients with asymmetric, confluent white matter lesions on MRI, normal spinal MR imaging, ectatic vertebrobasilar arteries, proteinuria, or lack of intrathecally derived immunoglobulin synthesis.

Juvenile-onset motor neuron disease caused by novel mutations in ß-hexosaminidase.

A 12 year-old female presented with a seven-year history of progressive muscle weakness, atrophy, tremor and fasciculations. Cognition was normal. Rectal biopsy revealed intracellular storage material and biochemical testing indicated low hexosaminidase activity consistent with juvenile-onset G(M2)-gangliosidosis. Genetic evaluation revealed compound heterozygosity with two novel mutations in the hexosaminidase ß-subunit (c.512-3 C>A and c.1613+15_1613+18dup). Protein analysis was consistent with biochemical findings and indicated only a small portion of ß-subunits were properly processed. These results provide additional insight into juvenile-onset G(M2)-gangliosidoses and further expand the number of ß-hexosaminidase mutations associated with motor neuron disease.

Long-term follow-up after gene therapy for canavan disease.

Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 10(11) vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.

Metronomic breathing shows altered parasympathetic baroreflex function in untreated Fabry patients and baroreflex improvement after enzyme replacement therapy.

OBJECTIVE: In untreated Fabry patients without overt autonomic dysfunction and normal baroreflex sensitivity (BRS) at rest, BRS is impaired during orthostatic, sympathetic challenge but normalizes after enzyme-replacement therapy (ERT) (Hilz et al., J Hypertens 2010; 28:1438-1448). This study evaluated BRS during parasympathetic challenge with six cycles per minute metronomic deep breathing (MDB) in Fabry patients before and after ERT. METHODS: In 22 Fabry patients (28 ±â€Š8 years), we monitored RR-intervals (RRIs), SBP, and respiratory frequency during spontaneous breathing (spont_breath) and MDB, before and after 18 (11 patients) or 23 months (11 patients) of biweekly ERT (1.0 mg/kg agalsidase beta). We determined spectral powers of mainly sympathetic low-frequency (0.04-0.15 Hz) RRI fluctuations, parasympathetic high-frequency (0.15-0.5 Hz) RRI fluctuations, sympathetically mediated low-frequency powers of SBP and high-frequency powers of SBP. We calculated BRS (ms/mmHg) during spont_breath and MDB as low-frequency-high-frequency alpha index (coherence >0.5). We compared parameters during spont_breath and MDB within and between patients before and after ERT and 15 age-matched (27 ±â€Š5 years) healthy men (RANOVA and posthoc analysis; significance: P < 0.05). RESULTS: During spont_breath and MDB, parameters were similar between groups. Within the three groups, RRIs were lower, whereas RRI low-frequency powers and SBP low-frequency powers were higher during MDB than during spont_breath. BRS was similar during MBD and spont_breath in untreated patients (P > 0.05), but increased significantly with MDB in patients after ERT (P = 0.048) and in controls (P = 0.035). CONCLUSION: In untreated Fabry patients, MDB uncovers impaired BRS. After 18 or 23 months of ERT, MDB-induced BRS increase is similar in Fabry patients and controls, demonstrating that ERT not only restores sympathetic but also parasympathetic baroreflex activation.

Enzyme replacement therapy improves cardiovascular responses to orthostatic challenge in Fabry patients.

OBJECTIVE: Fabry patients have autonomic dysfunction but usually do not present clinically overt signs of orthostatic dysregulation. This study evaluated orthostatic regulation and baroreflex sensitivity (BRS) in untreated Fabry patients and possible baroreflex improvement with enzyme replacement therapy (ERT). METHODS: In 22 Fabry patients (aged 28W8 years), we assessed electrocardiographic RR intervals (RRIs), SBP, DBP and respiratory frequency, in supine and standing position, before and after 18 (11 patients) or 23 months (11 patients) of biweekly alpha-galactosidase A infusions (1.0 mg/kg agalsidase beta). We determined spectral powers of mainly sympathetically mediated low-frequency (0.04-0.15 Hz) and parasympathetically mediated high-frequency (0.15-0.5 Hz) RRI fluctuations, and sympathetic low-frequency powers of blood pressure fluctuations. We normalized RRI powers by relating low-frequency and high-frequency powers to total powers (low-frequency + high-frequency powers), assessed the RRI low-frequency/high-frequency ratio reflecting sympathicovagal balance. As a measure of BRS, we used the alpha-index, obtained as square root of the ratio between powers of simultaneous spectral analyses of spontaneous low-frequency variabilities in RRIs and SBP (coherence>0.5). We compared parameters in supine and standing position of untreated and treated patients with those of 15 healthy age-matched (27+/-5 years) men (repeated-measure analysis of variance, significance at P<0.05). RESULTS: Supine biosignals were similar in all groups. Upon standing, RRIs were lower in controls and patients after ERT than in patients before ERT (P<0.05); normalized RRI high-frequency powers as well as BRS decreased, whereas DBP, low-frequency/high-frequency ratios and sympathetic low-frequency powers of SBP increased in controls and treated patients only (P<0.05). CONCLUSION: Reduced increase in heart rate, blood pressure and sympathetic activation, and limited cardiovagal withdrawal and BRS adjustment seen in untreated Fabry patients upon standing normalized after 18 and 23 months of ERT demonstrating improved baroreflex function, which, in turn, is an established parameter of improved disease prognosis.

Newborn screening for Krabbe disease: the New York State model.

Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders.

Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease.

In Fabry disease, there is glycosphingolipid storage in vascular endothelial and smooth muscle cells and neurons of the autonomic nervous system. Vascular or autonomic dysfunction is likely to compromise cerebral blood flow velocities and cerebral autoregulation. This study was performed to evaluate cerebral blood flow velocities and cerebral autoregulation in Fabry patients. In 22 Fabry patients and 24 controls, we monitored resting respiratory frequency, electrocardiographic RR-intervals, blood pressure, and cerebral blood flow velocities (CBFV) in the middle cerebral artery using transcranial Doppler sonography. We assessed the Resistance Index, Pulsatility Index, Cerebrovascular Resistance, and spectral powers of oscillations in RR-intervals, mean blood pressure and mean CBFV in the high (0.15-0.5 Hz) and sympathetically mediated low frequency (0.04-0.15 Hz) ranges using autoregressive analysis. Cerebral autoregulation was determined from the transfer function gain between the low frequency oscillations in mean blood pressure and mean CBFV. Mean CBFV (P < 0.05) and the powers of mean blood pressure (P < 0.01) and mean CBFV oscillations (P < 0.05) in the low frequency range were lower,while RR-intervals, Resistance Index (P < 0.01), Pulsatility Index, Cerebrovascular Resistance (P < 0.05), and the transfer function gain between low frequency oscillations in mean blood pressure and mean CBFV (P < 0.01) were higher in patients than in controls. Mean blood pressure, respiratory frequency and spectral powers of RR-intervals did not differ between the two groups (P > 0.05). The decrease of CBFV might result from downstream stenoses of resistance vessels and dilatation of the insonated segment of the middle cerebral artery due to reduced sympathetic tone and vessel wall pathology with decreased elasticity. The augmented gain between blood pressure and CBFV oscillations indicates inability to dampen blood pressure fluctuations by cerebral autoregulation. Both, reduced CBFV and impaired cerebral autoregulation, are likely to be involved in the increased risk of stroke in patients with Fabry disease.