Integrin α7 Mutations Are Associated With Adult-Onset Cardiac Dysfunction in Humans and Mice.

Background Integrin α7ß1 is a major laminin receptor in skeletal and cardiac muscle. In skeletal muscle, integrin α7ß1 plays an important role during muscle development and has been described as an important modifier of skeletal muscle diseases. The integrin α7ß1 is also highly expressed in the heart, but its precise role in cardiac function is unknown. Mutations in the integrin α7 gene (ITGA7) have been reported in children with congenital myopathy. Methods and Results In this study, we described skeletal and cardiac muscle pathology in Itga7-/- mice and 5 patients from 2 unrelated families with ITGA7 mutations. Proband in family 1 presented a homozygous c.806_818del [p.S269fs] variant, and proband in family 2 was identified with 2 intron variants in the ITGA7 gene. The complete absence of the integrin α7 protein in muscle supports the ITGA7 mutations are pathogenic. We performed electrocardiography, echocardiography, or cardiac magnetic resonance imaging, and histological biopsy analyses in patients with ITGA7 deficiency and Itga7-/- mice. The patients exhibited cardiac dysrhythmia and dysfunction from the third decade of life and late-onset respiratory insufficiency, but with relatively mild limb muscle involvement. Mice demonstrated corresponding abnormalities in cardiac conduction and contraction as well as diaphragm muscle fibrosis. Conclusions Our data suggest that loss of integrin α7 causes a novel form of adult-onset cardiac dysfunction indicating a critical role for the integrin α7ß1 in normal cardiac function and highlights the need for long-term cardiac monitoring in patients with ITGA7-related congenital myopathy.

Drug-associated progressive multifocal leukoencephalopathy: a clinical, radiological, and cerebrospinal fluid analysis of 326 cases.

The implementation of a variety of immunosuppressive therapies has made drug-associated progressive multifocal leukoencephalopathy (PML) an increasingly prevalent clinical entity. The purpose of this study was to investigate its diagnostic characteristics and to determine whether differences herein exist between the multiple sclerosis (MS), neoplasm, post-transplantation, and autoimmune disease subgroups. Reports of possible, probable, and definite PML according to the current diagnostic criteria were obtained by a systematic search of PubMed and the Dutch pharmacovigilance database. Demographic, epidemiologic, clinical, radiological, cerebrospinal fluid (CSF), and histopathological features were extracted from each report and differences were compared between the disease categories. In the 326 identified reports, PML onset occurred on average 29.5 months after drug introduction, varying from 14.2 to 37.8 months in the neoplasm and MS subgroups, respectively. The most common overall symptoms were motor weakness (48.6 %), cognitive deficits (43.2 %), dysarthria (26.3 %), and ataxia (24.1 %). The former two also constituted the most prevalent manifestations in each subgroup. Lesions were more often localized supratentorially (87.7 %) than infratentorially (27.4 %), especially in the frontal (64.1 %) and parietal lobes (46.6 %), and revealed enhancement in 27.6 % of cases, particularly in the MS (42.9 %) subgroup. Positive JC virus results in the first CSF sample were obtained in 63.5 %, while conversion after one or more negative outcomes occurred in 13.7 % of cases. 52.2 % of patients died, ranging from 12.0 to 83.3 % in the MS and neoplasm subgroups, respectively. In conclusion, despite the heterogeneous nature of the underlying diseases, motor weakness and cognitive changes were the two most common manifestations of drug-associated PML in all subgroups. The frontal and parietal lobes invariably constituted the predilection sites of drug-related PML lesions.

The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene.

BACKGROUND: The clinical syndrome of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) was first described 20 years ago, but it was only recently that whole exome sequencing unveiled the causative mutation in the ATP1A3 gene. We present four patients from the seventh and eighth family identified worldwide, provide a critical review of all patients published thus far, and speculate about the pathophysiologic processes underlying the acute neurological manifestations. CLINICAL OBSERVATIONS: The individuals presented here experienced one to three paroxysmal, short-lasting episodes in childhood with cerebellar symptoms and signs, hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness. An underlying c.2452G>A mutation in the ATP1A3 gene was found in all four individuals. Besides the persisting CAPOS features, other possibly related sequelae included dystonia, myoclonus, and emotional and behavioral changes. After initiation of acetazolamide in two patients, no further episodes occurred. CONCLUSION: Targeted sequencing of the ATP1A3 gene is recommended in children exhibiting paroxysmal, fever-induced ataxia and in adults with a more or less stationary or slowly progressive cerebellar syndrome since childhood accompanied by mixed combinations of areflexia, pes cavus, profound visual impairment, and/or sensorineural hearing loss. Similar to some other types of episodic ataxia, acetazolamide may be considered in patients with CAPOS syndrome to prevent or attenuate bouts of ataxia, but this requires further study.

[Non-transferrin-bound iron: a promising biomarker in iron overload disorders]. / 'Non-transferrin-bound iron': een veelbelovende biomarker bij ijzerstapelingsziekten.

Iron overload disorders are common and, if left untreated, severe systemic diseases that can have both genetic and acquired causes. Hereditary haemochromatosis, ß-thalassaemia, myelodysplastic syndromes and sickle cell disease are among the most important examples. Iron that is not bound to transferrin, haem or ferritin (non-transferrin-bound iron, NTBI) seems to play a key role in the pathophysiology of these disorders. NTBI is a heterogeneous group of potentially toxic iron complexes in plasma which are generated almost exclusively under pathological conditions. Cellular uptake of NTBI contributes to its toxicity and is mediated by several organ-specific transporters and receptors. NTBI-induced toxicity is the result of oxidative damage to various macromolecules by reactive oxygen species (ROS). In the near future, we hypothesize that NTBI will have important implications for both diagnosis and treatment of iron overload disorders. However, before NTBI can be applied to patient care, the currently available assays need further clinical and analytical validation.