Longitudinal changes in clinical outcome measures in COL6-related dystrophies and LAMA2-related dystrophies.

OBJECTIVE: To identify the rate of change of clinical outcome measures in children with 2 types of congenital muscular dystrophy (CMD), COL6-related dystrophies (COL6-RDs) and LAMA2-related dystrophies (LAMA2-RDs). METHODS: Over the course of 4 years, 47 individuals (23 with COL6-RD and 24 with LAMA2-RD) 4 to 22 years of age were evaluated. Assessments included the Motor Function Measure 32 (MFM32), myometry (knee flexors and extensors, elbow flexors and extensors), goniometry (knee and elbow extension), pulmonary function tests, and quality-of-life measures. Separate linear mixed-effects models were fitted for each outcome measurement, with subject-specific random intercepts. RESULTS: Total MFM32 scores for COL6-RDs and LAMA2-RDs decreased at a rate of 4.01 and 2.60 points, respectively, each year (p < 0.01). All muscle groups except elbow flexors for individuals with COL6-RDs decreased in strength between 1.70% (p < 0.05) and 2.55% (p < 0.01). Range-of-motion measurements decreased by 3.21° (p < 0.05) at the left elbow each year in individuals with LAMA2-RDs and 2.35° (p < 0.01) in right knee extension each year in individuals with COL6-RDs. Pulmonary function demonstrated a yearly decline in sitting forced vital capacity percent predicted of 3.03% (p < 0.01) in individuals with COL6-RDs. There was no significant change in quality-of-life measures analyzed. CONCLUSION: Results of this study describe the rate of change of motor function as measured by the MFM32, muscle strength, range of motion, and pulmonary function in individuals with COL6-RDs and LAMA2-RDs.

Comparison of sitting and supine forced vital capacity in collagen VI-related dystrophy and laminin α2-related dystrophy.

BACKGROUND: Progressive, restrictive, respiratory insufficiency is the major cause of morbidity and mortality in Congenital Muscular Dystrophy (CMD). Nocturnal hypoventilation precedes daytime alveolar hypoventilation, and if untreated, may lead to respiratory failure and cor pulmonale. CMD consensus care guidelines recommend screening for respiratory insufficiency by conventional and dynamic (sitting to supine) pulmonary function testing (PFT) and evaluating for sleep disordered breathing if there is more than 20% relative reduction from sitting to supine FVC(L) (ΔFVC). OBJECTIVE: The objective of this retrospective study was to explore and characterize dynamic FVC measures in 51 individuals with two common subtypes of CMD, COL6-RD, and LAMA2-RD. METHODS: We compared sitting and supine FVC in patients with confirmed mutation(s) in either COL6 or LAMA2. We investigated influences of age, CMD subtype, gender, race, ambulatory status, and non-invasive positive pressure ventilation (NIPPV) status on FVC percent predicted (FVCpp) and ΔFVC. RESULTS: COL6-RD participants exhibited a significant difference between sitting and supine mean FVCpp (sitting 66.1, supine 55.1; P < 0.0001) and were 5.4 times more likely to have -ΔFVC >20% than those with LAMA2-RD when controlling for ambulant status. FVCpp sitting correlated inversely with age in individuals ≤18 years. CONCLUSION: FVCpp sitting decreases progressively in childhood in both CMD subtypes. However, our results point to a difference in diaphragmatic involvement, with COL6-RD individuals having more disproportionate diaphragmatic weakness than LAMA2-RD. A ΔFVC of greater than -20% should continue to be used to prompt evaluation of sleep-disordered breathing. Timely initiation of NIPPV may be indicated to treat nocturnal hypoventilation. Pediatr Pulmonol. 2017;52:524-532. © 2017 Wiley Periodicals, Inc.

Krabbe disease treated with hematopoietic stem cell transplantation: serial assessment of anisotropy measurements--initial experience.

PURPOSE: To prospectively compare diffusion-tensor magnetic resonance (MR) imaging anisotropy measurements of white matter (WM) regions in early and late treatment groups of Krabbe disease patients treated with stem cell transplantation. MATERIALS AND METHODS: The study was approved by the Institutional Review Board and was compliant with Health Insurance Portability and Accountability Act; informed consent was obtained from the families of all patients. Patients with early-onset Krabbe disease (four girls and three boys) underwent diffusion-tensor MR imaging before and after stem cell transplantation. Fractional anisotropy (FA) values from serial studies were compared in patients who underwent transplantation at less than 1 month (early group, two girls and one boy) and those who underwent transplantation at 5-8 months (late group, two girls and two boys). FA values were measured in the genu and splenium of the corpus callosum, the frontal WM, and the internal capsule; were compared with those of five age-matched children in the comparison group (normal MR images and no proved neurologic disease); and were expressed as a ratio. Images obtained after transplantation were evaluated at approximately 1 (n = 7), 2 (n = 6), 3 (n = 1), and 4 (n = 1) years. RESULTS: Before transplantation, mean FA ratios in the early group for all four WM regions ranged between 97% and 117%. At 1 year, mean FA ratios at all locations were either 92% or 93%. At 2 years after transplantation, mean FA ratios were between 83% and 92%. In one patient imaged at 3 years, the mean FA ratio was 97%; in another patient imaged at 4 years, the mean FA ratio was 77%. Before transplantation, mean FA ratios in the late group ranged between 55% and 74%. Mean FA ratios were between 37% and 50% at 1 year after transplantation and between 36% and 39% at 2 years. CONCLUSION: All patients had decreases in FA ratios over time. The early group had higher initial FA ratios and lower subsequent decreases, which may indicate amelioration of the dysmyelinating process.

Peritumoral brain regions in gliomas and meningiomas: investigation with isotropic diffusion-weighted MR imaging and diffusion-tensor MR imaging.

PURPOSE: To retrospectively measure the diffusion-weighted (DW) imaging characteristics of peritumoral hyperintense white matter (WM) and peritumoral normal-appearing WM, as seen on T2-weighted magnetic resonance (MR) images of infiltrative high-grade gliomas and meningiomas. MATERIALS AND METHODS: Seventeen patients with biopsy-proved glioma and nine patients with imaging findings consistent with meningioma and an adjacent hyperintense region on T2-weighted MR images were examined with DW and diffusion-tensor MR imaging. Apparent diffusion coefficients (ADCs) were measured on maps generated from isotropic DW images of enhancing tumor, hyperintense regions adjacent to enhancing tumor, normal-appearing WM adjacent to hyperintense regions, and analogous locations in the contralateral WM corresponding to these areas. Fractional anisotropy (FA) was measured in similar locations on maps generated from diffusion-tensor imaging data. Changes in ADC and FA in each type of tissue were compared across tumor types by using a two-sample t test. P <.05 indicated statistical significance. RESULTS: Mean ADCs in peritumoral hyperintense regions were 1.309 x 10(-3) mm2/sec (mean percentage of 181% of normal WM) for gliomas and 1.427 x 10(-3) mm2/sec (192% of normal value) for meningiomas (no significant difference). Mean ADCs in peritumoral normal-appearing WM were 0.723 x 10(-3) mm2/sec (106% of normal value) for gliomas and 0.743 x 10(-3) mm2/sec (102% of normal value) for meningiomas (no significant difference). Mean FA values in peritumoral hyperintense regions were 0.178 (43% of normal WM value) for gliomas and 0.224 (65% of normal value) for meningiomas (P =.05). Mean FA values for peritumoral normal-appearing WM were 0.375 (83% of normal value) for gliomas and 0.404 (100% of normal value) for meningiomas (P =.01). CONCLUSION: The difference in FA decreases in peritumoral normal-appearing WM between gliomas and meningiomas was significant, and the difference in FA decreases in peritumoral hyperintense regions between these tumors approached but did not reach significance. These findings may indicate a role for diffusion MR imaging in the detection of tumoral infiltration that is not visible on conventional MR images.

Evaluation of normal age-related changes in anisotropy during infancy and childhood as shown by diffusion tensor imaging.

OBJECTIVE: The first purpose of this study was to compare the degree of anisotropy in compact white matter and noncompact white matter in each of three pediatric age groups using diffusion tensor imaging. We hypothesized that anisotropy would be higher in compact white matter than in noncompact white matter in each age group. The second purpose of our study was to compare the increase in anisotropy over time in compact versus noncompact white matter during early childhood. We hypothesized that increases in anisotropy would be higher in noncompact white matter. MATERIALS AND METHODS: We retrospectively analyzed anisotropy maps derived from diffusion tensor imaging studies performed in 66 pediatric patients (age range, 4 days-71 months; mean age, 18.6 months) who underwent clinical MR imaging and were found to have no abnormalities on conventional MR images. Anisotropy was measured in three compact white matter structures (corpus callosum, internal capsule, cerebral peduncle) and two regions of noncompact white matter (corona radiata and peripheral white matter). Patients were assigned to one of the three following groups on the basis of age: group 1, younger than 12 months (n = 40); group 2, 12-35 months (n = 11); and group 3, 36-71 months (n = 15). First, we compared anisotropy values of noncompact white matter with those of compact white matter for each age group. Second, we compared the increase over time in anisotropy of noncompact white matter regions with that seen in compact white matter structures. RESULTS: Among all three age groups, anisotropy measurements in compact white matter structures were higher than those in noncompact white matter (p < 0.01). The mean anisotropy values in noncompact white matter for groups 1, 2, and 3, respectively, were 0.349, 0.480, and 0.531. The mean anisotropy values in compact white matter for groups 1, 2, and 3, respectively, were 0.494, 0.646, and 0.697. When age groups were compared, a statistically significant increase in anisotropy was seen in both compact white matter and noncompact white matter (p < 0.01). However, the increase in anisotropy was significantly greater in non-compact white matter regions than in compact white matter structures when comparing group 1 with group 3 (p < 0.01) as well as group 1 with group 2 (p < 0.01). CONCLUSION: Although anisotropy measurements were higher in compact than non-compact white matter in all three age groups, the increase in anisotropy was greater in non-compact white matter across each of the three groups. These data suggest that although myelination is initially greater in compact white matter, the change in myelination may be greater in noncompact white matter during the first few years after infancy.