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This article confirms the existence of two variants of acute aortic pathology, the penetrating atherosclerotic ulcer (PAU) and the intramural hematoma (IMH), which are radiologically distinct from classic aortic dissection. Table 4 reviews the characteristics distinguishing PAU from classic aortic dissection and IMH. We took as a matter of definition that classic aortic dissection involves a flap which traverses the aortic lumen. We defined PAU and IMH as nonflap lesions, with PAU demonstrating a crater extending from the aortic lumen into the space surrounding the aortic lumen. This categorization can be summarized with the expression, "no flap, no dissection." With these definitions made, re-review of the imaging studies for the present report identified 36 such lesions out of 214 cases originally read as aortic dissection. Therefore, these variant lesions accounted for over 1 out of 8 acute aortic pathologies. Besides confirming the existence of the conditions, PAU and IMH, as distinct radiographic lesions, this series strongly suggests that these two conditions constitute distinct clinical entities as well. Table 4 summarizes the clinical patterns of these two entities as apparent from the present study, and contrasts them with classic aortic dissections. In particular, the following observations, some of which are consonant findings in smaller series, can be made regarding the typical patient profiles of PAU and IMH from the present study: The patients with PAU and IMH are distinctly older than those with type A aortic dissection (74.0 and 73.9 versus 56.5 years, P = 0.0001). Although not statistically significant, PAU and IMH patients tend to be older than patients with type B aortic dissections as well. For PAU and IMH, unlike aortic dissection, the concentration in the elderly is manifested in a very small standard deviation of the mean age (see Fig. 13); these two entities, PAU and IMH, are essentially diseases of the seventh, eighth, and ninth decades of life. Patients with PAU and IMH are almost invariably hypertensive (about 94% of cases). The pain of PAU and IMH mimics that of classic aortic dissection, with anterior symptoms in the ascending aortic lesions and intrascapular or back pain with descending aortic lesions. Unlike classic dissection, PAU and IMH do not produce branch vessel compromise or occlusion and do not result in ischemic manifestations in the extremities or visceral organs. PAU and IMH are more focal lesions than classic aortic dissection, which frequently propagates for much or the entire extent of the thoracoabdominal aorta. PAU is uniformly associated with severe aortic arteriosclerosis and calcification, whereas classic dissection often occurs in aortas with minimal arteriosclerosis and calcification. PAU and IMH tend to occur in even larger aortas than classic aortic dissection (6.2 and 5.5 versus 5.2 cm, P = 0.01). PAU and IMH are strongly associated with AAA, which is seen concomitantly in 42.1% of PAU patients and 29.4% of IMH patients. PAU and IMH are largely diseases of the descending aorta (90% for PAU and 71% for IMH). Although our pathology data is limited, we do feel that an inherent difference in the histologic intramural level of the hematoma may underlie the pathophysiologic process that determines which patient develops a typical dissection and which develops an intramural hematoma. In particular, we feel that the level of blood collection is more superficial, closer to the adventitia, in IMH than in typical aortic dissection. This may explain why the inner layer does not prolapse into the aorta on imaging studies or when the aorta is opened in the operating room. This more superficial location would also explain the high rupture rates as compared to classic aortic dissection (Fig. 14, Table 3). We did find PAU and IMH to behave much more malignantly than typical descending aortic dissection. As seen in Figure 6, the rupture rate is much higher than for aortic dissection. Docume
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PMID:Pathologic variants of thoracic aortic dissections. Penetrating atherosclerotic ulcers and intramural hematomas. 1058 37

Spastic paraplegia type 7 (SPG7) is an autosomal recessive form of hereditary spastic paraparesis (ARHSP) caused by mutations in paraplegin, a subunit of an ATP-dependent AAA-protease located within the inner mitochondrial membrane. We have identified a novel paraplegin mutation, c.1047insC, in a non-consanguineous Norwegian family with ARHSP. This is the first description of this disorder in the Norwegian population and, apart from mild ptosis in two siblings, the phenotype was essentially pure and late in onset.
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PMID:Hereditary spastic paraplegia caused by the novel mutation 1047insC in the SPG7 gene. 1856 70

Hereditary spastic paraplegias (HSP) are genetically and clinically heterogeneous neurodegenerative disorders. The purpose of this study was to assess the genotype and phenotype in a family with a complicated form of autosomal recessive hereditary spastic paraplegia (ARHSP). Neurological and neuropsychological evaluation, neurophysiologic studies, fiberoptic endoscopic evaluation of swallowing (FEES), neuroimaging analysis including diffusion tensor imaging (DTI), and mutation analysis of SPG4 and SPG7 gene were performed. The index case (mother) was affected by an adult-onset form of complicated ARHSP due to the homozygous splice site mutation c.1552+1 G>T in the SPG7 gene. This mutation leads to an abnormally spliced mRNA lacking exon 11. Additional clinical features were bilateral ptosis and subtle deficits in executive function. All three asymptomatic daughters carried the sequence variation c.1552+1 G>T in heterozygous state. DTI of the mother revealed disturbance of white matter (WM) integrity in the left frontal lobe, the left corticospinal tract and both sides of the brainstem. DTI of the daughters showed subtle WM alteration in the frontal corpus callosum. The novel mutation is the first splice site mutation found in the SPG7 gene. It removes part of the AAA domain of paraplegin protein, probably leading to a loss-of-function of the paraplegin-AFG3L2 complex in the mitochondrial inner membrane. The pattern of WM damage in the homozygote index case may be specific for SPG7-HSP. The detection of cerebral WM alterations in the corpus callosum of asymptomatic heterozygote carriers confirms this brain region as the most prominent and early location of fiber damage in ARHSP.
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PMID:A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects. 2010 56

We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C) in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7). Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28), a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2(Y616C) gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2(Y616C) complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other "mitochondrial" features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias.
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PMID:Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. 2202 84