In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions.

Mutations in coiled-coil-helix-coiled-coil-helix-domain containing 10 (CHCHD10), a mitochondrial twin CX9C protein whose function is still unknown, cause myopathy, motor neuron disease, frontotemporal dementia, and Parkinson's disease. Here, we investigate CHCHD10 topology and its protein interactome, as well as the effects of CHCHD10 depletion or expression of disease-associated mutations in wild-type cells. We find that CHCHD10 associates with membranes in the mitochondrial intermembrane space, where it interacts with a closely related protein, CHCHD2. Furthermore, both CHCHD10 and CHCHD2 interact with p32/GC1QR, a protein with various intra and extra-mitochondrial functions. CHCHD10 and CHCHD2 have short half-lives, suggesting regulatory rather than structural functions. Cell lines with CHCHD10 knockdown do not display bioenergetic defects, but, unexpectedly, accumulate excessive intramitochondrial iron. In mice, CHCHD10 is expressed in many tissues, most abundantly in heart, skeletal muscle, liver, and in specific CNS regions, notably the dopaminergic neurons of the substantia nigra and spinal cord neurons, which is consistent with the pathology associated with CHCHD10 mutations. Homozygote CHCHD10 knockout mice are viable, have no gross phenotypes, no bioenergetic defects or ultrastructural mitochondrial abnormalities in brain, heart or skeletal muscle, indicating that functional redundancy or compensatory mechanisms for CHCHD10 loss occur in vivo. Instead, cells expressing S59L or R15L mutant versions of CHCHD10, but not WT, have impaired mitochondrial energy metabolism. Taken together, the evidence obtained from our in vitro and in vivo studies suggest that CHCHD10 mutants cause disease through a gain of toxic function mechanism, rather than a loss of function.

Treatment of vascular lesions with balloon catheters.

During a 4 year period, 48 patients were treated with balloon catheters. There were 39 fistulas and nine aneurysms. Detachable balloons with a modified Debrun technique were used in 37 patients. Different kinds of technical problems were encountered. The arterial axis remained patent in 29 of the 37 fistulas; in the two mixed internal and external carotid-cavernous sinus fistulas, combined embolization with dura, isobutyl cyanoacrylate, and detachable balloon was used. In six of the nine aneurysms the arterial axis was occluded with a detachable balloon. In three of 48 patients, severe neurologic complications resulted in death.

Myelopathy and radiculopathy due to cervical spondylosis: myelographic-CT correlations.

Forty patients with symptoms and signs of radicular disease or spinal cord involvement secondary to cervical spondylosis were studied with myelography (using nonionic water-soluble contrast medium) followed by computed tomographic (CT) myelography. In 17 patients CT was also performed before myelography. CT myelography adds useful information to the myelographic findings. Cord compression is better evaluated and osteophytes can be differentiated from disk herniation. Plain CT can demonstrate a herniated disk but with less accuracy than CT myelography. Cord and root compression are not seen directly on plain CT; for this reason myelography should be the first procedure in patients with myelopathy or myeloradiculopathy, which may be followed by CT myelography.

MRI and cognitive patterns in relapsing-remitting multiple sclerosis.

We studied the relationships between magnetic resonance imaging (MRI) and the Luria-Nebraska Neuropsychological Battery (LNNB) in 64 patients with relapsing-remitting multiple sclerosis (MS). MRI films were scored according to arbitrary descriptive criteria designed to emphasize patterns of alterations. Five groups were created: group 1 and 2 had typical discrete white matter lesions, group 3 had confluent lesions, group 4 had large discrete lesions and group 5 had only few small lesions. In addition, groups 2 and 3 had evidence of parenchymal atrophy. Groups 2 and 3 were the most impaired on the LNNB, but none of these patients was actually demented. Groups 1 and 5 were globally intact in spite of very different mean age and MRI pattern. Group 4 was composed of younger subjects with a shorter disease duration; they showed mild loss of attentive and abstracting abilities. We suggest that since their MRI was showing greater signs of local biological activity their mental deficits may be a transitory condition capable of two distinct outcomes: a favorable one as in groups 1 and 5, and a slowly progressive one associated with loss of brain tissue as in groups 2 and 3.

Influence of age on carotid atheroma in patients with reversible ischemic attacks.

To evaluate the influence of age on carotid atheroma we reviewed the angiographic findings in 120 patients with reversible ischemic attacks. The prevalence and severity of atherosclerotic lesions increased significantly with age, and this difference persisted after adjusting for hypertension. These results may at least partly explain the poor long term prognosis for elderly subjects with reversible ischemic attacks, and underscore the importance of taking age into account when relating clinical and angiographic findings in patients with cerebrovascular ischemia.

Treatment of external carotid arteriovenous fistula with detachable balloon.

A simple fistula between the external carotid artery and the internal jugular vein was treated for the first time using Debrun's technique with a detachable balloon catheter. The nature of the fistulous connection makes the release of the balloon inflated with silicone completely harmless. The occlusion of the fistula, while maintaining the patency of the remaining branches of the external carotid artery, proves this technique to be the most appropriate for the treatment of arteriovenous fistulae in the neck.

The complementary role of angiography and CT in the diagnosis of cerebral sinovenous occlusion.

Three patients with angiographic and CT findings of cerebral sinovenous occlusion are described. Filling defects within the venous pathways are well demonstrated by angiography. Some of the most characteristic CR signs are here described. Full evaluation, including the clinical history, angiography and computed tomography is essential.

Neuroradiological treatment of carotid and vertebral fistulas and intracavernous aneurysms. Technical problems and results.

Thirty-three patients have been treated with balloon catheters since 1978. Debrun's detachable balloons were used in 31 and a Fogarty catheter in the other two. Problems were encountered from the introduction of the catheter to the detachment of the balloon. We have treated 21 fistulas between the internal carotid and cavernous sinus, 3 fistulas between the external carotid and jugular vein, 2 mixed fistulas between internal and external carotid and cavernous sinus, 2 vertebral fistulas and 5 intracavernous aneurysms. Delayed angiographic control has shown that the arterial axis remained patent in a high percentage of cases and that the formation of an asymptomatic pseudo-aneurysmal sac within the cavernous sinus is the rule. Long-term clinical follow-up has confirmed the angiographic results. In two patients neurological complications led to the patients' death.