Family with Ehlers-Danlos syndrome (combined classic and vascular type) with rare presentation of progressive myopathy and unusual association of severe facial and trigeminal motor weakness.

We report the clinical, radiological, biochemical, muscle histology, and electron microscopic features of two members of a family with combined Ehlers-Danlos syndrome (EDS) [classic and vascular type] and progressive myopathy as the primary manifestation. A 35-year old lady presented with severe gluteal and thigh muscle pain and easy fatigability for 5 years. She developed weakness and wasting of pelvic and pectoral girdles and thighs for 3 years and severe neck flexor and truncal weakness for 6 months. She had a history of recurrent jaw dislocation, easy bruising with hyperpigmentation, hyperextensibility of joints, translucent skin, and papyraceous scars. She had high myopia with astigmatism. She had wasting of temporalis, masseters, sternocleidomastoids and trapezius. There was moderate weakness of temporalis, masseters, and facial muscles. Muscle power was Medical Research Council (MRC) grade 4 at shoulders and arms, and grade 3+ at pelvis and thighs. Serum homocysteine level was normal, and creatine kinase (CK) was 275 IU. Two dimensional echocardiogram (2D Echo) showed myxomatous degeneration of mitral valves. Electromyography (EMG) was suggestive of a myopathic pattern. Muscle magnetic resonance imaging (MR) revealed severe fatty infiltration of paraspinal muscles, gluteus maximus and medius, quadriceps, hamstrings, and gastrocnemius. Electron microscopy showed an occasional distorted fibril with mild increase in oxytalan fibers and variation in thickness of blood vessel basement membrane. Her 15-year old daughter had exertion-induced myalgias, right hemifacial hypoplasia, myopia, hyperextensible joints, hyperelastic skin, and neck muscle weakness. However, her CK and 2D Echo were normal. This report presents the rare combination of classic and vascular type of EDS primarily presenting as muscle weakness and associated with facial and trigeminal motor weakness.

A comparative study of mPCR, MLPA, and muscle biopsy results in a cohort of children with Duchenne muscular dystrophy: a first study.

BACKGROUND: Multiplex ligation-dependant probe amplification (MLPA) is a highly sensitive and rapid alternative to multiplex polymerase chain reaction (PCR). Muscle biopsy should be reserved for mutation-negative cases. MATERIALS AND METHODS: An attempt was made to compare the sensitivity and pattern of mutations by mPCR and MLPA testing in a cohort with suspected Duchenne muscular dystrophy (DMD). Eighty-three children with DMD were enrolled for mPCR and MLPA testing. MLPA-negative cases underwent muscle immunohistochemistry (IHC) for dystrophin. RESULTS: Mean age of onset was 45.3 ± 25.2 months; and mean duration of illness was - 53.3 ± 30.8 months. About 11.9% patients had delayed mental milestones. Mean creatine kinase (CK) value was 12136.1 ± 8591.1 LU/L. mPCR detected deletions in 60/83 (72.3%). Proximal deletions were found in 8 (8.6%), distal deletions in 51 (54.8%), and, both proximal and distal deletions were found in 1. Majority of the deletions were <5 exons [34(36.6%)]; two showed large deletions of >10 exons (2.2%). Deletions in hot spot region occurred in 83.3%. MLPA in the same 83 samples detected deletions in an additional six cases and duplications in 6 (6.5%). Combined detection rate of deletion was 79.5%. Duplications were found in 7.2% of the whole sample. MLPA showed 14 (15.1%) proximal and 57 (61.3%) distal deletions, and proximal and distal deletion in 1. Large deletions (>10 exons) were seen in 6.5%, and single deletions were observed in 24 (36.4%). Most common multiple exon deletion was seen at 45-52 region in 7 samples (10.6%). Longest duplication extended from exon 60 to 66. In the 11 MLPA-negative cases, IHC confirmed dystrophinopathy in 36.36%, sarcoglycanopathy in 36.36%, and no deficiency in 27.27%. CONCLUSIONS: This is the first study from India and possibly in English literature, comparing the sensitivity and pattern of mutations by both mPCR and MLPA in the same cohort of DMD. It further validates that 36.4% of MLPA-negative cases were confirmed to have DMD by IHC. The clinical accuracy has been very high in our cohort. MLPA-negative samples should be subjected for next-generation sequencing before contemplating a biopsy.

In Vivo Evaluation of White Matter Abnormalities in Children with Duchenne Muscular Dystrophy Using DTI.

BACKGROUND AND PURPOSE: Duchenne muscular dystrophy is an X-linked disorder characterized by progressive muscle weakness and prominent nonmotor manifestations, such as a low intelligence quotient and neuropsychiatric disturbance. We investigated WM integrity in patients with Duchenne muscular dystrophy using DTI. MATERIALS AND METHODS: Fractional anisotropy and mean, axial, and radial diffusivity (DTI measures) were used to assess WM microstructural integrity along with neuropsychological evaluation in patients with Duchenne muscular dystrophy (n = 60) and controls (n = 40). Exon deletions in the DMD gene were confirmed using multiplex ligation-dependent probe amplification. Patients were classified into proximal (DMD Dp140+) and distal (DMD Dp140-) subgroups based on the location of the exon deletion and expression of short dystrophin Dp140 isoform. WM integrity was examined using whole-brain Tract-Based Spatial Statistics and atlas-based analysis of DTI data. The Pearson correlation was performed to investigate the possible relationship between neuropsychological scores and DTI metrics. RESULTS: The mean ages of Duchenne muscular dystrophy and control participants were 8.0 ± 1.2 years and 8.2 ± 1.4 years, respectively. The mean age at disease onset was 4.1 ± 1.8 years, and mean illness duration was 40.8 ± 25.2 months. Significant differences in neuropsychological scores were observed between the proximal and distal gene-deletion subgroups, with more severe impairment in the distal-deletion subgroup (P < .05). Localized fractional anisotropy changes were seen in the corpus callosum, parietal WM, and fornices in the patient subgroup with Dp140+, while widespread changes were noted in the Dp140- subgroup. The Dp140+ subgroup showed increased axial diffusivity in multiple WM regions relative to the Dp140- subgroup. No significant correlation was observed between clinical and neuropsychological scores and diffusion metrics. CONCLUSIONS: Widespread WM differences are evident in patients with Duchenne muscular dystrophy relative to healthy controls. Distal mutations in particular are associated with extensive WM abnormalities and poor neuropsychological profiles.