Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias.

Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.

The Emerging Role of Combined Brain/Heart Magnetic Resonance Imaging for the Evaluation of Brain/Heart Interaction in Heart Failure.

Heart failure (HF) patients frequently develop brain deficits that lead to cognitive dysfunction (CD), which may ultimately also affect survival. There is an important interaction between brain and heart that becomes crucial for survival in patients with HF. Our aim was to review the brain/heart interactions in HF and discuss the emerging role of combined brain/heart magnetic resonance imaging (MRI) evaluation. A scoping review of published literature was conducted in the PubMed EMBASE (OVID), Web of Science, Scopus and PsycInfo databases. Keywords for searches included heart failure, brain lesion, brain, cognitive, cognitive dysfunction, magnetic resonance imaging cardiovascular magnetic resonance imaging electroencephalogram, positron emission tomography and echocardiography. CD testing, the most commonly used diagnostic approach, can identify neither subclinical cases nor the pathophysiologic background of CD. A combined brain/heart MRI has the capability of diagnosing brain/heart lesions at an early stage and potentially facilitates treatment. Additionally, valuable information about edema, fibrosis and cardiac remodeling, provided with the use of cardiovascular magnetic resonance, can improve HF risk stratification and treatment modification. However, availability, familiarity with this modality and cost should be taken under consideration before final conclusions can be drawn. Abnormal CD testing in HF patients is a strong motivating factor for applying a combined brain/heart MRI to identify early brain/heart lesions and modify risk stratification accordingly.

Friedreich's Ataxia: Case series and the Additive Value of Cardiovascular Magnetic Resonance.

BackgroundFriedreich's ataxia (FA) is an autosomal-recessive neurodegenerative disease characterised by neurologic, cardiac and endocrine abnormalities. Currently, Friedreich cardiomyopathy (FA-CM) staging is based on early ECG findings, high sensitivity troponin (hsTNT) ≥14 ng/ml and echocardiographic left ventricular (LV) morphologic and functional evaluation. However, further parameters, accessible only by cardiovascular magnetic resonance (CMR), such as myocardial oedema, perfusion defects, replacement and/or diffuse myocardial fibrosis, may have a place in the staging of FA-CA. Our aim was to elucidate the additive value of CMR in FA-CM.MethodsThree FA cases were assessed using ECG, 24 h Holter recording, hsTNT, routine ECHO including wall dimension, valvular and ventricular function evaluation and CMR using 1.5T Ingenia system. Ventricular volumes-function, wall dimensions and fibrosis imaging using late gadolinium enhancement (LGE) was performed.ResultsAll FA patients had non-specific ECG changes, almost normal 24 h Holter recording, mild hypertrophy with normal function assessed by echocardiography and increased hsTNT. However, the CMR evaluation revealed the presence of LGE >5% of LV mass, indicative of severe fibrosis. Therefore, the FA patients were re-categorized as having severe FA-CA, although their LVEF remained normal.ConclusionThe combination of classical diagnostic indices and CMR may reveal early asymptomatic FA-CM and motivate the early initiation of cardiac treatment. Furthermore, these indices can be also used to validate specific treatment targets in FA, potentially useful in the prevention of FA-CM.

A dynamic trinucleotide repeat (TNR) expansion in the DMD gene.

Dystrophinopathies are allelic X-linked myopathies caused by large deletions/duplications or small lesions along the DMD gene. An unexpected dynamic trinucleotide (GAA) expansion, ranging from ∼59 to 82 pure GAA repeats, within the DMD intron 62, was revealed to segregate through three family generations. From the pedigree, two female patients were referred for DMD investigation due to chronic myopathy and a muscle biopsy compatible with dystrophinopathy. As the size of the GAA repeat is limited to 11-33 within the general population our findings may provide a novel insight towards a Trinucleotide Repeat Expansion. Whether this TNR has an impact on the reported phenotype remains to be resolved.