A recurrent single-amino acid deletion (p.Glu500del) in the head domain of ß-cardiac myosin in two unrelated boys presenting with polyhydramnios, congenital axial stiffness and skeletal myopathy.

BACKGROUND: Alterations in the MYH7 gene can cause cardiac and skeletal myopathies. MYH7-related skeletal myopathies are extremely rare, and the vast majority of causal variants in the MYH7 gene are predicted to alter the rod domain of the of ß-cardiac myosin molecule, resulting in distal muscle weakness as the predominant manifestation. Here we describe two unrelated patients harboring an in-frame deletion in the MYH7 gene that is predicted to result in deletion of a single amino acid (p.Glu500del) in the head domain of ß-cardiac myosin. Both patients display an unusual skeletal myopathy phenotype with congenital axial stiffness and muscular hypertonus, but no cardiac involvement. RESULTS: Clinical data, MRI results and histopathological data were collected retrospectively in two unrelated boys (9 and 3.5 years old). Exome sequencing uncovered the same 3-bp in-frame deletion in exon 15 (c.1498_1500delGAG) of the MYH7 gene of both patients, a mutation which deletes a highly conserved glutamate residue (p.Glu500del) in the relay loop of the head domain of the ß-cardiac myosin heavy chain. The mutation occurred de novo in one patient, whereas mosaicism was detected in blood of the father of the second patient. Both boys presented with an unusual phenotype of prenatal polyhydramnios, congenital axial stiffness and muscular hypertonus. In one patient the phenotype evolved into an axial/proximal skeletal myopathy without distal involvement or cardiomyopathy, whereas the other patient exhibited predominantly stiffness and respiratory involvement. We review and compare all patients described in the literature who possess a variant predicted to alter the p.Glu500 residue in the ß-cardiac myosin head domain, and we provide in-silico analyses of potential effects on polypeptide function. CONCLUSION: The data presented here expand the phenotypic spectrum of mutations in the MYH7 gene and have implications for future diagnostics and therapeutic approaches.

Concurrent TNFRSF1A R92Q and pyrin E230K mutations in a child with multiple sclerosis.

We report a 16-year-old female patient with a severe course of multiple sclerosis and concomitant symptoms suggestive of a hereditary autoinflammatory disease. Genetic analyses revealed that she inherited a TNFRSF1A R92Q mutation from her mother and a pyrin E230K mutation from her father. To our knowledge, this is the first report of a patient with severe childhood multiple sclerosis and mutations in two genes which predispose to hereditary autoinflammatory disorders. We speculate that these mutations contribute to early multiple sclerosis manifestation and enhance the inflammatory damage inflicted by the autoimmune response.

Fish oil supplementation improves visual evoked potentials in children with phenylketonuria.

Visual evoked potentials (VEP) were measured in 36 patients with early-treated phenylketonuria (PKU; aged 1 to 11 years) and good metabolic control before and after supplementation with omega-3 long-chain polyunsaturated fatty acids (LC-PUFA) from fish oil. Patients with PKU had significantly longer P100 latencies than 22 age-matched control subjects. After 3 months of LC-PUFA supplementation, VEP latencies improved significantly in PKU patients but did not change in 12 untreated healthy children. The authors conclude that omega-3 LC-PUFA are essential substrates for nervous system function even beyond infancy.

Deficiency in complex IV (cytochrome c oxidase) of the respiratory chain, presenting as a leukodystrophy in two siblings with Leigh syndrome.

Two siblings with Leigh syndrome presenting at the age of 6 months with clinical and radiological features suggestive of a leukodystrophy are reported. A deficiency in complex IV of the respiratory chain (cytochrome c oxidase) was demonstrated in muscle mitochondria of both patients. To our knowledge, this is the first familial case of Leigh syndrome due to cytochrome c oxidase deficiency, presenting clinically and radiologically with signs of a leukodystrophic process. We suggest that respiratory chain enzyme defects should be considered in the differential diagnosis of cases suggestive of a leukodystrophy.

Return to participation - significant improvement after bilateral pallidal stimulation in rapidly progressive DYT-1 dystonia.

We report the case of an 8-year-old girl who developed progressive generalized dystonia, rendering her unable to walk and sit within months despite medical therapy with dopamine and anti-cholinergic agents. She was found to have a 9q34.1 GAG-deletion, which is known to cause DYT1-dystonia. DYT-1 dystonia is an autosomal dominant condition with incomplete penetrance that usually starts in childhood. It is known to be refractory to pharmacotherapy. Reports on deep brain stimulation in this condition reveal marked benefits of the treatment in the pediatric and adult populations. The patient underwent bilateral stimulation of the internal globus pallidus 18 months after symptom onset. Postoperatively, her clinical status improved significantly as measured by the Burke-Fahn-Marsden dystonia rating scale and the resolution of a unilateral hip dislocation. Normal participation was regained.

Serum levels of matrix metalloproteinases-2 and -9 and their tissue inhibitors in inflammatory neuromuscular disorders.

We monitored serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) before and during intravenously applied immunoglobulin (IVIG) therapy in 33 patients with chronic immune-mediated neuropathies and myopathies and 15 controls. Baseline MMP-2 and TIMP-2 serum levels were lower and MMP-9 and TIMP-1 serum levels higher in all patients compared to age-matched controls. Eight days after IVIG treatment, MMP-2, TIMP-2, and TIMP-1 serum levels increased, while MMP-9 serum levels decreased, indicating tissue repair. After 60 days, MMP-9 levels increased, MMP-2 approached normal levels, while TIMP-1 and TIMP-2 serum levels were below day 8 levels, indicating relapsing tissue damage. Comparing the MMP/TIMP results with the clinical courses, IVIG treatment tended to change MMP/TIMP levels in a way that paralleled clinical improvement and relapse. In sum, during a distinct time period, IVIG therapy seems to be able to modulate MMP-mediated tissue repair.

Myogenic changes of the levator ani muscle in premenopausal women: the impact of vaginal delivery and age.

The aim of this study was to evaluate the impact of parity and age on histomorphology of the pelvic floor muscles in female cadavers of reproductive age and to find out whether there is evidence of myogenic or neurogenic muscle injury. In a cross-sectional study 45 premenopausal unfixed and fresh female cadavers were studied. Four groups were defined: nulliparous and parous women under the age of 40 and over 40 years of age. The pelvic floor was biopsied at six standardized locations. For evaluation of the quantitative parameters and fiber type identification, actomyosin ATPase at pH 9.4 was used. For histomorphological evaluation, sections were stained with hematoxylin/eosin, van Gieson, and Gomori trichrome. The circumference of type I fibers is significantly larger in nulliparous women younger than 40 years compared to nulliparae older than 40 years. Comparing these groups, the form factor of type II fibers also increases significantly, presenting a more circular cell form. Compared to nulliparae, vaginal delivery led to a significant difference regarding the presence of centrally located nuclei, fibrosis, and variation in fiber diameter. In nulliparous women, these significant changes were also found with increasing age. In women with a history of vaginal delivery, no further increase in these characteristics could be detected with increasing age. Comparing the three different biopsy sites, all three changes were more pronounced in the ventral part. There was no evidence of grouped fiber atrophy, small angulated fibers, or type grouping in any of the biopsy specimens. Aging and vaginal childbirth lead to histomorphological changes of the pelvic floor muscle that are consistent with changes of myogenic origin. Evidence of neurogenic damage could not be demonstrated.