Christophe Goubau

Homozygosity for aquaporin 7 G264V in three unrelated children with hyperglyceroluria and a mild platelet secretion defect

Purpose:Aquaporin 7 (AQP7) belongs to the aquaglyceroporin family, which transports glycerol and water. AQP7-deficient mice develop obesity, insulin resistance, and hyperglyceroluria. However, AQP7’s pathophysiologic role in humans is not yet known.Methods:Three children with psychomotor retardation and hyperglyceroluria were screened for AQP7 mutations. The children were from unrelated families. Urine and plasma glycerol levels were measured using a three-step enzymatic approach. Platelet morphology and function were studied using electron microscopy, aggregations, and adenosine triphosphate (ATP) secretion tests.Results:The index patients were homozygous for AQP7 G264V, which has previously been shown to inhibit transport of glycerol in Xenopus oocytes. We also detected a subclinical platelet secretion defect with reduced ATP secretion, and the absence of a secondary aggregation wave after epinephrine stimulation. Electron microscopy revealed round platelets with centrally located granules. Immunostaining showed AQP7 colocalization, with dense granules that seemed to be released after strong platelet activation. Healthy relatives of these patients, who were homozygous (not heterozygous) for G264V, also had hyperglyceroluria and platelet granule abnormalities.Conclusion:The discovery of an association between urine glycerol loss and a platelet secretion defect is a novel one, and our findings imply the involvement of AQPs in platelet secretion. Additional studies are needed to define whether AQP7 G264V is also a risk factor for mental disability.Genet Med 2013:15(1):55–63

The contribution of platelet studies to the understanding of disease mechanisms in complex and monogenetic neurological disorders.

Platelets, known for their role in primary haemostasis, prevent excessive bleeding after injury. The study of platelets has, therefore, traditionally focused on bleeding disorders. It has recently become evident, however, that platelet research can contribute to unravelling the disease mechanisms that underlie neuropathological disorders that have a subtle subclinical platelet phenotype. Platelets and neurosecretory cells have common gene expression profiles and share several biological features. This review provides a literature update on the use of platelets as easily accessible cells to study neurological disorders. We provide examples of the use of different platelet‐based tests to understand the underlying pathophysiological mechanisms for both complex and monogenetic neuropathological disorders. In addition to the well‐studied regulated granule secretion and serotonin metabolism, more recent studies have shown that defects in transcription factors, membrane transporters, G‐protein signal transduction, and cytoskeletal proteins can be investigated using platelets to gain information on their role in neuropathology.

Regulated granule trafficking in platelets and neurons: A common molecular machinery

Platelet function in primary hemostasis involves the secretion of granules upon activation, providing the localized delivery of effector proteins at sites of vascular injury. The sequential process of regulated secretion in platelets, from the biogenesis of the granules, through their transport and up to the exocytotic fusion process at the acceptor membrane, involves a complex molecular machinery conserved between some other specialized cells such as neurons. Mutations in genes encoding proteins involved in this process of granule trafficking have helped towards demystification of the underlying secretory mechanisms. Human diseases of trafficking encompass a broad symptomatology including a platelet-related bleeding diathesis and neuronal problems. In this review, we want to highlight the similarities in granule biology between platelets and neurons and further focus on some granule trafficking disorders that result in bleeding and neuropathology. This review provides evidence that platelet research can be expanded from traditional studies of isolated thrombopathies to the field of neuropathologies that include a platelet secretion defect.

Screening and evaluation tools of dysphagia in children with neuromuscular diseases: a systematic review

Dysphagia is frequent in paediatric patients with neuromuscular diseases (pNMD). Its detection is important for initiating early diagnosis and treatment as well as for minimizing related complications. The aim of this study was to review the literature on dysphagia screening and evaluation tools in pNMD.

Another cause of hyperglyceroluria: aquaporin 7 gene mutation.

T o the Editor: We read with interest the report of Barić et al (1) on glyceroluria and neonatal hemochromatosis. They state that glyceroluria has also been described in humans as a consequence of urine contamination, in fructose-1,6-diphosphatase deficiency and in glycerol kinase deficiency. Recently, we reported on another cause of hyperglyceroluria, namely a homozygous mutation in the aquaporin 7 gene (2). This disorder was detected in 7 children from 3 families, and in 1 of the mothers. Two of these children (from different families) were asymptomatic, as was the mother with this mutation. Two other children presented learning problems, and the remaining 3 showed delayed (psycho)motor development associated, in 1 or 2 patients, with epilepsy, hypotonia, autism, dolichocephaly, discrete facial dysmorphism, and small testes. One patient had mild proteinuria. Serum thyroid-stimulating hormone, measured in 4 children, was mildly increased or in the upper normal range. Serum thyroid hormone levels were normal except in 1 patient with a mildly decreased free thyroxin. All individuals with the mutation showed a mild platelet secretion defect with reduced ATP secretion. Because 3 of the 8 affected individuals were asymptomatic, it is uncertain whether the neurological and morphological features of the phenotype are part of this disorder. In our experience, this tubular hyperglyceroluria is not so rare because we discovered these 3 families in the course of 6 years.