Danon disease in a Sardinian family: different aspects of the same mutation-a case report

Background Danon disease (DD) is a rare X-linked disorder due to mutations in the lysosome-associated membrane protein 2 gene. It is characterized by a clinical triad of hypertrophic cardiomyopathy, skeletal myopathy, and a variable degree of intellectual disability. Case summary In this case series, we describe a mother and her son affected by DD, highlighting consistent clinical severity despite the expected variability related to gender. The mother (Case 1) presented isolated cardiac involvement, with an arrhythmogenic phenotype that evolved into severe heart failure requiring heart transplantation (HT). Danon disease was diagnosed 1 year after this event. Her son (Case 2) showed an earlier age onset of symptoms with complete atrioventricular block and fast progression of cardiac disease. Diagnosis was established 2 years after clinical presentation. He is currently listed for HT. Discussion In both of our patients, diagnostic delay was extremely long and could have been avoided by emphasizing the relevant clinical red flags. Patients affected by DD may present clinical heterogeneity in terms of natural history, age of onset, and cardiac and extracardiac involvement, even in the same family. Early diagnosis that phenotypic sex differences may impact is a crucial factor in managing patients with DD. Considering the rapid progression of cardiac disease and the poor prognosis, early diagnosis is important and close surveillance should be mandatory during follow-up

A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron.

Background Hepcidin plays a key role in body iron metabolism by preventing the release of iron from macrophages and intestinal cells. Defective hepcidin synthesis causes iron loading, while overproduction results in defective reticuloendothelial iron release and iron absorption. Design and Methods We studied a Sardinian family in which microcytic anemia due to defective iron absorption and utilization is inherited as a recessive character. Five members showed iron deficiency anemia that was not responsive to oral iron and only partially responsive to parenteral iron administration. To investigate the involvement of known genes implicated in iron metabolism we carried out linkage analysis with microsatellite markers mapping close to these genes. Afterwards, a genome-wide search was performed. Results No linkage was found between the phenotype of the patients and several known human genes involved in iron metabolism ( DMT1, TF, TFRC, ZIRTL, HAMP, HJV ). Genome-wide scanning by microsatellites and single nucleotide polymorphisms showed a multipoint LOD score of 5.6 on chromosome 22q12.3–13.1, where the matriptase-2 (also known as transmembrane protease, serine 6 or TMPRSS6 ) gene is located. Its murine counterpart ( Tmprss6 ) has recently been found to be an essential component of a pathway that detects iron deficiency and suppresses hepcidin production. Sequencing analysis of TMPRSS6 revealed a homozygous causal mutation, predicting a splicing error and a truncated TMPRSS6 protein in affected members. Homozygous subjects had inappropriately elevated levels of serum and urinary hepcidin. Conclusions The findings of this study suggest that the observed TMPRSS6 mutation leads to overproduction of hepcidin and, in turn, to defective iron absorption and utilization. More generally, they confirm in humans the inhibitory effect of matriptase-2 on hepcidin synthesis already demonstrated in mice

Responsiveness to oral iron and ascorbic acid in a patient with IRIDA

Mutations in TMPRSS6 gene cause iron-refractory iron deficiency anemia, a rare autosomal recessive disorder characterized by hypochromic microcytic anemia not responsive to oral iron therapy and partially responsive to parenteral iron administration. Here we report a female infant homozygous for a loss of function mutation in TMPRSS6 gene, who responded to oral iron therapy when supplemented with ascorbic acid

Cerebral cavernous malformations and unilateral moyamoya in a patient with a new mutation in the KRIT-1 /CCM1 gene.

Cerebral cavernous malformations (CCMs) are vascular anomalies with dilated, thin-walled capillaries. The disease can occur in sporadic or autosomal dominant-inherited forms (familiar forms), with incomplete penetrance and multiple lesions [1]. Moyamoya disease (MMD) is a dynamic cerebrovascular disease [2] where the outgrowth of small collateral vessels produces the radiological image of a hazy ‘puff of smoke', giving its name to the disease. According to the diagnostic criteria, MMD is characterized by stenosis or occlusion of the terminal portion of the Internal Carotid Artery (ICA) and/or the proximal portions of the anterior or the middle cerebral arteries (ACAs, MCAs), with irregular vascular networks near the stenosis. The disease is defined ‘probable' or ‘unilateral' MMD when findings are unilateral and ‘definite' MMD, when findings are bilateral [3]. Unilateral MMD occurs in almost 10-15% of all MMD: in children it usually extends bilaterally within 1-2 years, otherwise the disease tends to remain unilateral in adults [4]. We report here a case of cerebral cavernous angiomatosis associated with unilateral MMD in a patient with a first-ever described mutation in the KRIT1/CCM1 gene