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We report a novel 1 bp deletion (c.1834delC) in the MCT8 gene in a large Brazilian family with Allan‐Herndon‐Dudley syndrome (AHDS), an X linked condition characterised by severe mental retardation and neurological dysfunction. The c.1834delC segregates with the disease in this family and it was not present in 100 control chromosomes, further confirming its pathogenicity. This mutation causes a frameshift and the inclusion of 64 additional amino acids in the C‐terminal region of the protein. Pathogenic mutations in the MCT8 gene, which encodes a thyroid hormone transporter, results in elevated serum triiodothyronine (T3) levels, which were confirmed in four affected males of this family, while normal levels were found among obligate carriers. Through in vitro functional assays, we showed that this mutation decreases cellular T3 uptake and intracellular T3 metabolism. Therefore, the severe neurological defects present in the patients are due not only to deficiency of intracellular T3, but also to altered metabolism of T3 in central neurones. In addition, the severe muscle hypoplasia observed in most AHDS patients may be a consequence of high serum T3 levels.

Kyphomelic dysplasia has been described as a generalised skeletal dysplasia characterised by a disproportionate growth, bowing of long bones, mild facial dysmorphia, and normal intelligence, with radiologically flattened vertebrae, short ribs, and metaphyseal flaring. Twenty-one cases have been reported in the literature.1–14 However the diagnosis in several cases from the literature has been disputed. The case described by Maclean and co-workers10 was reported recently to have Schwartz-Jampel syndrome,15 and the family reported by Toledo et al 5 in fact had osteogenesis imperfecta. This led Spranger et al 15 to suggest that kyphomelic dysplasia does not exist. However, there is still a group of cases described as kyphomelic dysplasia, which do not fit the profile of these or other disorders that manifest as dwarfism and kyphomelia.16 The cases can be distinguished from campomelic dysplasia by the extraskeletal manifestations, mental retardation, ambiguous genitalia, severe tibial bowing, and hypoplastic scapulae in the latter,17 and from femoral hypoplasia-unusual facies syndrome by the hypoplasia of the femur.18 Several single case reports that show a related but still different phenotype have been described.19–21 Short-limbed dwarfism with normal intelligence does also occur in cartilage-hair hypoplasia (CHH; MIM 250250). Apart from dwarfism, major symptoms include fine, sparse hair, marked hypermobility of the smaller joints with short phalanges, and a variable immunodeficiency.22 Radiologically, the metaphyses are scalloped and sclerotic, especially around the knees, ankles, and anterior angulation of the entire sternum. The femur can be bowed, but usually only mildly so. There is no platyspondyly. CHH presenting in infancy can be difficult to diagnose.23,24 Mutations in the RMRP gene that codes for an RNA subunit of the mitochondrial RNA processing (MRP) RNAse complexes are the cause of CHH, with a common "Finnish" mutation +70A→G (A70G) in many …

Charcot-Marie-Tooth (CMT) disease is a motor and sensory neuropathy with clinical and genetic heterogeneity. Patients usually present in the first or second decade of life with distal muscle atrophy in the legs, areflexia, foot deformity (mainly pes cavus), and steppage gait. In most cases, hands are also involved as the disease progresses. CMT is the most frequent inherited neuropathy, with a prevalence in Spain of 28 in 100 000.1 Based on electrophysiological studies and histopathologic findings in nerve biopsies, CMT has been subcategorised into two main and distinct neuropathies: (i) demyelinating CMT (CMT1, MIM 118200) associated with reduction in a nerve conduction velocities (NCVs) in all nerves and segmental demyelination and remyelination (“onion bulbs”); and (ii) axonal CMT (CMT2, MIM 118220) associated with normal or almost normal NCVs and loss of myelinated axons. Other phenotypes are associated with motor and sensory nerve involvement: Dejerine-Sottas neuropathy (DSN, MIM 145900) is a severe demyelinating neuropathy with onset in infancy, delayed motor milestones, and NCVs less than 10 m/s; congenital hypomyelinating neuropathy (CHN, MIM 605253) is a dysmyelinating neuropathy characterised by infantile hypotonia, distal muscle weakness, and marked reduction of NCVs; hereditary neuropathy with liability to pressure palsies (HNPP, MIM 162500) is a milder sensory and motor neuropathy with periodic episodes of numbness, muscular weakness, and atrophy.2 Genetic heterogeneity is characteristic of the disease not just because of the large number of genes and loci associated with CMT (currently 21 genes),3–5 but also because the disease may segregate with different Mendelian patterns. The most frequent pattern of inheritance is autosomal dominant, but autosomal recessive and X linked segregation are also observed. The relationship of the type of CMT, demyelinating or axonal, with specific genes is not perfect. For instance, MPZ mutations are usually manifested clinically as an autosomal dominant …

Acute myocardial infarction (AMI) is a significant cause of mortality and morbidity. Substantial data support a plausible role for oxidised LDL (oxLDL) in the aetiology of this disease.1,2 The human OLR1 (or LOX 1) gene encodes the endothelium derived lectin-like oxidised low density lipoprotein (oxLDL) receptor, which is involved in the binding, internalisation, and proteolytic degradation of oxLDL, suggesting that it may play a significant role in atherogenesis.3 OLR1 is considered a good candidate for atherosclerosis and AMI since it is induced in vitro by inflammatory cytokines and in vivo by pro-atherogenic conditions like hypertension, hyperlipidaemia, and diabetes mellitus.4 Recently, upregulation of OLR1 has been shown in ischaemia reperfusion injury in the rat.5 OLR1 acts as a mediator of “endothelial dysfunction” favouring superoxide generation, inhibiting nitric oxide production, and enhancing endothelial adhesiveness for monocytes.6–8 It is noteworthy that the versatile activities of OLR1 also include the ability to bind not only oxLDL, but also aged red blood cells, apoptotic cells, and activated platelets.4 With this background, we sought to validate the hypothesis of OLR1 involvement in atherosclerosis and AMI by defining OLR1 genetic variation by an association study of intragenic SNPs. ### Study subjects The study included 150 individuals with AMI who were referred to the Centre of Atherosclerosis at the Medical School of the Tor Vergata University of Rome. All cases were clinically evaluated and all underwent coronary angiography and left ventriculography. The diagnosis of AMI was based on typical electrocardiographic changes and increased serum activities of at least two enzymes, such as creatine kinase, aspartate aminotransferase, and lactate dehydrogenase. The diagnosis was confirmed by the presence of wall motion abnormality on left ventriculography and attendant stenosis (>50%) in any of the major coronary arteries or in the left main coronary artery on coronary …