Sodium nitrate alleviates functional muscle ischaemia in patients with Becker muscular dystrophy.

Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. BMD is caused by in-frame mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the sarcolemma. Among these is neuronal nitric oxide synthase mu (nNOSµ), which requires specific spectrin-like repeats (SR16/17) in dystrophin's rod domain and the adaptor protein α-syntrophin for sarcolemmal targeting. When healthy skeletal muscle is exercised, sarcolemmal nNOSµ-derived nitric oxide (NO) attenuates α-adrenergic vasoconstriction, thus optimizing perfusion. In the mdx mouse model of dystrophinopathy, this protective mechanism (functional sympatholysis) is defective, resulting in functional muscle ischaemia. Treatment with a NO-donating non-steroidal anti-inflammatory drug (NSAID) alleviates this ischaemia and improves the murine dystrophic phenotype. In the present study, we report that, in 13 men with BMD, sympatholysis is defective mainly in patients whose mutations disrupt sarcolemmal targeting of nNOSµ, with the vasoconstrictor response measured as a decrease in muscle oxygenation (near infrared spectroscopy) to reflex sympathetic activation. Then, in a single-arm, open-label trial in 11 BMD patients and a double-blind, placebo-controlled cross-over trial in six patients, we show that acute treatment with oral sodium nitrate, an inorganic NO donor without a NSIAD moiety, restores sympatholysis and improves post-exercise hyperaemia (Doppler ultrasound). By contrast, sodium nitrate improves neither sympatholysis, nor hyperaemia in healthy controls. Thus, a simple NO donor recapitulates the vasoregulatory actions of sarcolemmal nNOS in BMD patients, and constitutes a putative novel therapy for this disease.

The elbow flex-ex: a new sign to detect unilateral upper extremity non-organic paresis.

OBJECTIVE: To examine a new neurological sign that uses synergistic oppositional movements of the arms to evaluate for non-organic upper extremity weakness. METHODS: Patients with unilateral arm weakness were tested in a standing or sitting position with the elbows flexed at 30°. The examiner held both forearms near the wrists while asking the patient to flex or extend the normal arm at the elbow and simultaneously feeling for flexion or extension of the contralateral (paretic) arm. In patients with organic paresis, there was not a significant detectable force of contralateral opposition of the paretic limb. Patients with non-organic arm weakness had detectable strength of contralateral opposition in the paretic arm when the normal arm was tested. RESULTS: The test was first performed on 23 patients with no complaint of arm weakness. Then, 31 patients with unilateral arm weakness were tested (10 with non-organic weakness and 21 with organic weakness). The elbow flex-ex sign correctly identified the cause of weakness in all cases. CONCLUSIONS: The elbow flex-ex sign is useful in differentiating between functional and organic arm paresis.

Gastrointestinal and Urologic Sphincter Dysfunction in Stiff Person Syndrome.

OBJECTIVES: Stiff person syndrome is a neurologic disorder characterized by axial rigidity leading to progressive disability, with broad clinical spectrum. METHODS: We report 2 cases with unique clinical presentation. RESULTS: Two young men suffered progressive urinary retention requiring bladder catheterization, anorectal spasms and constipation, complicated subsequently with lower extremity trigger-induced spasms, and gait instability. Associated symptoms revealed brainstem involvement (vertigo, diplopia, and cranial neuropathies) and dysautonomia (abnormal sweating and orthostatic hypotension). Anal manometry demonstrated incomplete relaxation of the anal sphincter. The first case was associated with diabetes mellitus type I, did not respond to classical therapies, but was responsive to rituximab. The second case responded to intravenous immunoglobulin infusions. Paraneoplastic profiles were negative, and anti-GAD65 antibody titers remained elevated despite successful therapeutic responses. CONCLUSIONS: We want to raise awareness that stiff person syndrome can present with esophageal, anorectal, and urethral sphincter disturbance. Rituximab is a good therapeutic option in intractable cases.

Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy.

Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSµ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSµ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective-causing functional muscle ischemia-in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSµ is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSµ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3',5'-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSµ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.