A new phenotype of muscle glycogen synthase deficiency (GSD0B) characterized by an adult onset myopathy without cardiomyopathy.

Muscle Glycogenosis type 0 (GSD0B) is an extremely rare disorder first recognized in 2007 in three siblings with childhood onset and severe cardiomyopathy. Since then, a few cases with severe cardiac involvement and premature death have been reported. We describe two unrelated cases presenting with an adult-onset myopathy with no heart involvement. Clinical features were quite similar in both patients, mainly characterized by early fatigability, myalgia and muscle weakness. Muscle biopsy revealed marked glycogen depletion in nearly all myofibers. Biochemical assay demonstrated a marked reduction of Glycogen Synthase (GS) activity. Sequence analysis of GYS1 revealed two new variants: a homozygous G to C substitution in the splice donor consensus site (c.678+1G>C) in patient1 and a homozygous missense variant c.630G>C in exon 3 (p. Asp145His) in patient 2. This study describes a new phenotype of muscle GSD0B presenting with adult onset, proximal myopathy, no cardiac abnormalities and a quite benign disease course. This report highlights the importance of a systematic diagnostic approach that includes muscle morphology and enzymatic assay to facilitate the identification of adult patients with GSD0B.

Intracranial aneurysm management in patients with late-onset Pompe disease (LOPD).

Pompe disease is a rare hereditary metabolic disorder caused by α-glucosidase (GAA) deficiency. The late-onset form of the disease (LOPD) is considered a multisystemic disorder which could involve vascular system with cerebrovascular abnormalities such as intracranial aneurysms or dolichoectasia. Intracranial aneurysm rupture may represent a life-threatening emergency. A possible treatment of unruptured intracranial aneurysms (UIAs) should consider both aneurysm-related (aneurysmal size, shape, localization, numbers and hemodynamic factors) and patient-related risk factors (patient's age and sex, hypertension, smoke exposure). Moreover, UIAs management of LOPD patients needs also to take into account the altered blood vessels integrity and elasticity, whose consistency is likely weakened by the deficient GAA activity as a further potential risk factor. We herein present our approach for of UIAs management in three patients with LOPD. Among them, only one patient with a left saccular UIA of the anterior communicating artery, after careful consideration of risk factors, underwent the endovascular treatment. The other two patients were scheduled for a 1-year follow-up, according to radiological, clinical, and risk evaluation features. Finally, we would like to suggest some general recommendations for UIAs management. In particular, if no risk factors are identified, a cautious yearly follow-up is suggested; otherwise, if risk factors are present, endovascular treatment should be considered.

Hippo signaling pathway is altered in Duchenne muscular dystrophy.

Hippo signaling pathway is considered a key regulator of tissue homeostasis, cell proliferation, apoptosis and it is involved in cancer development. In skeletal muscle, YAP, a downstream target of the Hippo pathway, is an important player in myoblast proliferation, atrophy/hypertrophy regulation, and in mechano-trasduction, transferring mechanical signals into transcriptional responses. We studied components of Hippo pathway in muscle specimens from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy type 2A and type 2B and healthy subjects. Only DMD muscles had decreased YAP1 protein expression, increased LATS1/2 kinase activity, low Survivin mRNA expression and high miR-21 expression. In light of our novel results, a schematic model is postulated: low levels of YOD1 caused by increased inhibition by miR-21 lead to an increase of LATS1/2 activity which in turn augments phosphorylation of YAP. Reduced amount of active YAP, which is also a target of increased miR-21, causes decreased nuclear expression of YAP-mediated target genes. Since it is known that YAP has beneficial roles in promoting tissue repair and regeneration after injury so that its activation may be therapeutically useful, our results suggest that some components of Hippo pathway could become novel therapeutic targets for DMD treatment.

Intracranial arterial abnormalities in patients with late onset Pompe disease (LOPD).

BACKGROUND AND OBJECTIVES: Pompe disease is a rare metabolic disorder due to lysosomal alpha-glucosidase (GAA) deficiency. It is considered as a multi-systemic disease since, although glycogen accumulation is largely prominent in heart, skeletal and respiratory muscles, other organs can also be affected. As regards the vascular system, few reports have documented cerebrovascular malformations in Pompe patients. The aim of this study was to define the presence and type of intracranial arterial abnormalities in a cohort of late onset Pompe disease (LOPD) patients. METHODS: We have studied 21 LOPD patients with cerebral CT angiography (CTA), using maximum intensity projection and volume rendering technique for 3D-image reconstruction. RESULTS: We found intracranial arterial abnormalities in 13/21 patients (62 %), of whom: 2/21 patients (9.5 %) showed an unruptured intracranial aneurysm (respectively 2 and 4 mm), 10/21 (47 %) had a vertebrobasilar dolichoectasia (VBD) and 1/21 a basilar artery fenestration. Signs of lacunar encephalopathy (insular, capsular and frontal subcortical lesions) were detected in 13/21 patients (62 %) and this correlated with the presence of respiratory impairment (p = 0.017). CONCLUSIONS: These findings differ from what has been previously observed in healthy, aged-matched populations and confirm that cerebral arteries abnormalities, mainly involving the posterior circle, are not so rare in LOPD patients and are often accompanied by a lacunar encephalopathy that might represent a hypoxic-ischemic origin. A CTA or an MRA is recommended, in LOPD patients, for early detection of cerebrovascular malformations as they could lead to life-threatening events such as sub-arachnoid haemorrhage or brainstem compression.