The LMNA gene mutations account for 33% of the DCMs with AVB, all familial autosomal dominant. Increased sCPK in patients with DCM without AVB is not a useful predictor of LMNA mutation.

Mitochondrial (mt)DNA defects , both deletions and tRNA point mutations , have been associated with cardiomyopathies. The aim of the study was to determine the prevalence of pathological mtDNA mutations and to assess associated defects of mitochondrial enzyme activity in dilated cardiomyopathy (DCM) patients with ultrastructural abnormalities of cardiac mitochondria. In a large cohort of 601 DCM patients we performed conventional light and electron microscopy on endomyocardial biopsy samples. Cases with giant organelles , angulated , tubular , and concentric cristae , and crystalloid or osmiophilic inclusion bodies were selected for mtDNA analysis. Mutation screening techniques , automated DNA sequencing, restriction enzyme digestion , and densitometric assays were performed to identify mtDNA mutations, assess heteroplasmy , and quantify the amount of mutant in myocardial and blood DNA. Of 601 patients (16 to 63 years; mean , 43.5 ؎ 12.7 years) , 85 had ultrastructural evidence of giant organelles , with abnormal cristae and inclusion bodies; 19 of 85 (22.35%) had heteroplasmic mtDNA mutations (9 tRNA, 5 rRNA , and 4 missense , one in two patients) that were not found in 111 normal controls and in 32 DCM patients without the above ultrastructural mitochondrial abnormalities. In all cases , the amount of mutant was higher in heart than in blood. In hearts of patients that later underwent transplantation , cytochrome c oxidase (Cox) activity was significantly lower in cases with mutations than in those without or controls (P ‫؍‬ 0.0008). NADH dehydrogenase activity was only slightly reduced in cases with mutations (P ‫؍‬ 0.0388) , whereas succinic dehydrogenase activity did not significantly differ between DCM patients with mtDNA mutations and those without or controls. The present study represents the first attempt to detect a morphological, easily identifiable marker to guide mtDNA mutation screening. Pathological mtDNA mutations are associated with ultrastructurally abnormal mitochondria, and reduced Cox activity in a small subgroup of non-otherwise-defined, idiopathic DCMs, in which mtDNA defects may constitute the basis for, or contribute to, the development of congestive heart failure. (Am J Pathol 1998, 153:1501-1510)

Primary (AL) amyloidosis is a plasma cell dyscrasia characterized by extracellular deposition of monoclonal light-chain variable region (V) fragments in the form of amyloid fibrils. Light-chain amyloid is rare, and it is not fully understood why it occurs in only a fraction of patients with a circulating monoclonal component and why it typically associates with isotype and VI family light-chain proteins. To provide insights into these issues, we obtained complete nucleotide sequences of monoclonal V regions from 55 consecutive unselected cases of primary amyloidosis and the results were compared with the light-chain expression profile of polyclonal marrow plasma cells from 3 healthy donors (a total of 264 sequences). We demonstrated that: (1) the III family is the most frequently used both in amyloidosis (47%) and in polyclonality (43%); (2) both conditions are characterized by gene restriction; (3) a very skewed repertoire is a feature of amyloidosis, because just 2 germline genes belonging to the III and VI families, namely 3r (22% of cases, III) and 6a (20%, VI), contributed equally to encode 42% of amyloid V regions; (4) these same 2 gene segments have a strong association with amyloidosis if their prevalences are compared with those in polyclonal conditions (3r, 8.3%, P ‫؍‬ .024; 6a, 2.3%, P ‫؍‬ .0008, 2 test); (5) the J 2/3 segment, encoding the fourth framework region, appears to be slightly overrepresented in AL (83% versus 67%, P ‫؍‬ .03), and this might be related to preferential J 2/3 rearrangement in amyloid (11 of 12 cases) versus polyclonal 3r light chains (13 of 22 cases). These findings demonstrate that V -J expression is more restricted in plasma cells from amyloidosis than from polyclonal bone marrow and identify 3r as a new disease-associated gene segment. Overusage of just 2 gene segments, 3r and 6a, can thus account for the light-chain overrepresentation typical of this disorder. (Blood. 2002;100: 948-953)