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- Lysosome revisited – Connecting Rare and Common IllnessesPublication . Coutinho, Maria Francisca; Alves, SandraOur perception of the lysosome and its role in the cell has suffered a tremendous change since its discovery by Christian de Duve, 60 years ago. Traditionally depicted as cell's waste bin, this small organelle used to be regarded as just an end-point degradative compartment. Nevertheless, the early discovery of a group of rare life-threatening diseases which resulted from failures in that degradation process, the so-called Lysosomal Storage Disorders (LSDs), prompted the search for the underlying causes of such abnormalities and led to a greater understanding of lysosomal function and physiology. Nowadays, the lysosome is no longer viewed as a terminal organelle, but rather as the central regulator of cellular metabolic homeostasis, coordinating a very complex and interactive set of intracellular organelles that have a wide array of specialized functions: the endosomal-lysosomal system. During this same period, lysosomal dysfunction was also extensively documented in other diseases that afflict a much higher number of individuals than all LSDs together. The first clues on this association came from the recognition that Gaucher disease (GD) patients had a higher risk of developing multiple myeloma and/or PD. Numerous reports over the last decades have focused the comorbidity between this GD and either of those common conditions. But GD patients are far from being the only individuals afflicted by an LSD, who present a higher risk of developing a second disorder. There are several case reports of both patients and carriers of specific LSDs presenting with neuropathological findings suggestive of PD (-synuclein accumulation and inclusions, as well as loss of neurons in the substantia nigra), for example. Recently, that same 'risk association' was also documented for patient cohorts of Niemann-Pick type C, Mucopolysaccharidosis type III C and Fabry disease and the idea that a more general mechanism relating lysosomal dysfunction and the development of -synuclein aggregation disorders exists, is gaining supporters. Additional striking connections between common diseases and rare LSD are being unveiled nowadays. Mutations in one of the genes which is long-known to cause frontotemporal dementia (the most common cause of dementia in people under age 65) when mutated in one of its alleles, were recently shown to cause a novel LSD, neuronal ceroid lipofuscinosis 11, when affecting both its copies. In summary, we have come a long way since the first descriptions of LSDs were published and their underlying biochemical basis unveiled. Parallels across groups of traditionally unrelated neurological disorders have emerged, reshaping the way we think about the role of the lysosome and the whole system it controls. Pathophysiological boundaries have blurred between LSDs and other disorders including both early-onset neurogenetic conditions and late-onset neurodegenerative diseases. Ultimately, a better understanding of lysosomal dysfunction in all these conditions may provide valuable insights towards the development of therapeutic strategies for a multitude of presently untreatable disorders. So, let us wait for the next 60 years, and hope they will be as groundbreaking as the last ones.
- McArdle disease: mutational spectrum of Portuguese patientsPublication . Rocha, Hugo; Lopes, Altina; Soares, Gabriela; Negrão, Luis; Coelho, Teresa; Chorão, Rui; Lourenço, Teresa; Vilarinho, LauraMcArdle disease or Glycogen Storage Disease type V (GSD V; myophosphorylase deficiency; MIM 232600) its an inborn error of glycogen metabolism, caused by a deficiency in muscle specific isoform of glycogen phosphorylase. This metabolic myopathy is characterised by exercise intolerance, myalgia, cramps and episodic myoglobinuria, symptoms that usually appear during the second or third decade of life. The diagnosis was typically made in muscle biopsy by histological analysis (demonstration of subsarcolemmal glycogen deposits and negative histochemical stain for phosphorylase) and/or measurement of muscle phosphorylase activity. Although since 1984, when the gene of muscle isoform of phosphorylase (myophosphorylase) was cloned and assigned to chromosome 11 (11q13), molecular genetics analysis has been more and more used to confirm the clinical diagnosis. Until now, 146 pathogenic mutations have been described (according to HGMDTM) including nonsense, missense and framshift mutations. High genetic heterogeneity is a hallmark of McArdle disease with a very frequent common mutation among Caucasian populations – R49X (present in about 60% of the mutated alleles) – and several rare mutations, without a clear genotype/phenotype correlation. The authors will present molecular data from the characterisation of 53 Portuguese patients, from 42 families, with McArdle disease. Our results reveal the presence of the R49X mutation in 60 of the alleles (57%), in accordance to what has been described to other Caucasian populations, being identified a total of 15 different mutations were identified. These results allowed in many cases the diagnosis without the need of a muscle biopsy, but also provide valuable information for genetic counselling and to increase the knowledge about the molecular pathology of this disorder.
- Molecular study is na importante tool in the confirmation of Inborn Errors of MetabolismPublication . Fonseca, Helena; Souza, Carolina; Vairo, Fillipo; Vilarinho, LauraThe urea cycle disorders (UCD) result from defects in the metabolism of waste nitrogen from the breakdown of protein and other nitrogen-containing molecules. Severe deficiency or total absence of activity of any of the first four enzymes (CPS1, OTC, ASS, ASL) in the urea cycle or the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor metabolites during the first few days of life. Infants with a severe urea cycle disorder are normal at birth but rapidly develop cerebral edema and the related signs of lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma. Deficiencies in each of the enzymes result in specific UCD. Citrullinemia and argininosuccinic aciduria are autosomal recessive disorder that lead to the accumulation of nitrogen as ammonia, ala¬nine, glutamate, and other intermediate metabolites. The diagnoses of these disorders are based on clinical suspicion and biochemical and molecular genetic testing. Plasma and urine quantitative amino acid analysis, determination of plasma concentrations of ammonia and measurement of urinary orotic acid can distinguish between the specific urea cycle defects. A definitive diagnosis of a urea cycle defect depends on either molecular genetic testing or measurement of enzyme activity. The authors present a symptomatic Brazilian case that came to our lab with a diagnosis the citrullinemia. The amino acid profile obtained by HPLC show an increase of citruline in plasma. To clarify this case the genes ASS1 and ASL that encodes the enzyme argininosuccinate synthetase and argininosuccinate lyase were studied by reported methods. The molecular study of ASL has allowed the identification of the homozygous mutation in this patient: the splicing mutation c.524+2T>G. The mutation is described in the literature. In this case the molecular study was essential to the correct establishment of the diagnosis.
- Adult-onset form in VLCAD deficiency: seven casesPublication . Sousa, Carmen; Marcão, Ana; Nogueira, Célia; Fonseca, Helena; Rocha, Hugo; Silva, Carla; Guimas, Arlindo; Evangelista, Teresinha; Maré, Rui; Vilarinho, LauraVery long chain acyl-Co-A dehydrogenase deficiency (VLCADD, MIM 201475) is an autosomal recessive disorder characterized by impaired mitochondrial β-oxidation of fatty acids with a chain length between 14 and 18 carbons. The prevalence of VLCAD deficiency in Portugal is 1/101,613. VLCADD has three forms of clinical presentation: severe early-onset; intermediate with childhood onset and adult-onset, of mild severity, characterized by exercise intolerance, myalgia and recurrent episodes of rhabdomyolysis. The development of electrospray ionization tandem mass spectrometry (MS/MS) has allowed beyond the screening of neonatal forms a marked improvement on diagnosis of the adult onset form. The authors report the acyl-carnitines profile that revealed accumulation of tetradecenoyl carnitine (C14:1) in seven individuals with clinical symptoms with the ages between 11 and 63. The eldest patient was diagnosed at the age of 63 years. These results were confirmed by molecular ACADVL gene analysis. When rhabdomyolysis is present in a patient, and after differential diagnosis, it is important to consider the possibility of a VLCAD deficiency. This late-onset form may be undetectable by acyl-carnitine profile in asymptomatic period, and only in crisis is informative. However, if VLCADD is considered the molecular analysis of ACADVL should be performed in all suspected cases.
- Two cases of late-onset Argininosuccinic aciduria with normal results at newborn screeningPublication . Marcão, Ana; Fonseca, Helena; Sousa, Carmen; Rocha, Hugo; Silva, Francisco; Vilarinho, LauraArgininosuccinic aciduria (ASA) is an autosomal recessive metabolic disorder caused by Argininosuccinate Lyase (ASL) deficiency, and it is the second most frequent urea cycle disorder, with an estimated frequency of 1:70 000. The human ASL gene is located on chromosome 7q11.21 and comprises 16 exons encoding a 464 amino acids long monomer. The enzyme is functional in a homotetrameric structure and is mainly expressed in the liver, although it can be found in several other tissues. The clinical presentation of ASA is very heterogeneous, ranging from asymptomatic to severe hyperammonemic neonatal-onset cases. Complex clinical phenotypes, with neurological deficits and hepatic complications adding to hyperammonemic episodes, are often observed. Biochemically, ASA is usually characterized by elevation of both citrulline and argininosuccinic acid in plasma and urine, but also at this level heterogeneity is observed, adding to a poor correlation found between residual enzymatic activity and the severity of the clinical phenotype. Newborn Screening (NBS) for ASA is widely established although some paradoxal results can be obtained due to the clinical and biochemical ASA heterogeneity: asymptomatic cases can be detected and, on the contrary, late-onset forms with important clinical manifestations observed since the first months of live can be missed due to normal biochemical results. ASA was included in the Portuguese NBS Program in 2005, based on elevated argininosuccinic acid blood levels. During these ten years of NBS two cases were identified and two other were missed. The missed cases were two brothers with a late-onset clinical form, which presented completely normal results at NBS. They are homozygous for R12Q mutation, which is a mutation reported to be associated with a mild clinical form of the disease and frequently found in late-onset ASA cases. Based on this finding it is important to keep in mind that a late-onset form of ASA should be considered for a child with clinical signs fitting this disease, even if NBS had a normal result.
- Excess mortality among the elderly in european countries, December 2014 to February 2015Publication . Mølbak, K.; Espenhain, L.; Nielsen, J.; Tersago, K.; Bossuyt, N.; Denissov, G.; Baburin, A.; Virtanen, M.; Fouillet, A.; Sideroglou, T.; Gkolfinopoulou, K.; Paldy, A.; Bobvos, J.; van Asten, L.; de Lange, M.; Nunes, Baltazar; Silva, Susana Pereira; Larrauri, A.; Gómez, I.L.; Tsoumanis, A.; Junker, C.; Green, H.; Pebody, R.; McMenamin, J.; Reynolds, A.; Mazick, A.Since December 2014 and up to February 2015, the weekly number of excess deaths from all-causes among individuals ≥ 65 years of age in 14 European countries have been significantly higher than in the four previous winter seasons. The rise in unspecified excess mortality coincides with increased proportion of influenza detection in the European influenza surveillance schemes with a main predominance of influenza A(H3N2) viruses seen throughout Europe in the current season, though cold snaps and other respiratory infections may also have had an effect.
- Genotype/phenotype correlation in Glycogen Storage Disease type IXPublication . Rocha, Hugo; Lopes, Altina; Rodrigues, Esmeralda; Silva, Ermelinda; Trindade, Eunice; Vaio, Francisco; Souza, Carolina; Leão, Elisa; Vilarinho, LauraGlycogen Storage Diseases type IX (GSD IX) are caused by a deficient activity of glycogen phosphorylase kinase and are due to mutations in PHKA1, PHKA2, PHKB or PHKG2. The first two genes are X-linked while the latter two follow an autosomal recessive inheritance. It is a common form of glycogenosis and collectively, defects in these genes are responsible for 25% of all cases of GSD, occurring with a frequency of 1 100,000 live births, with the majority of patients presenting mutation in the X-linked PHKA2 (75% of the cases). Infants with GSD IX present with hepatomegaly, growth retardation and elevated transaminases. Ketotic hypoglycemia and hypotonia may also be present. It most of situations it is a mild GSD, with a benign course, with patients becoming asymptomatic as they grow up. Nevertheless, patients with mutations in the subunit γ (PHKG2) have been associated to more severe phenotypes including increased risk of liver cirrhosis or hepatocelular carcinoma. Our laboratory performs the molecular characterisation of Glycogen Storage Diseases type IX for seven years now (since 2008) and a total of thirteen patients were molecularly diagnosed. From these nine (eight males and one female) present mutation in the X-linked PHKA2, while the remaining three had mutations in PHKG2. Those with mutations in PHKG2 present severe phenotypes, resembling other hepatic GSD’s like GSD I and GSD III, in contrast to those with mutations in PHKA2. Our results allowed not only an easier confirmation of the clinical diagnosis, but also contribute to establish better follow up protocols according to the genotype.
- Development of a U1 snRNA-adapted gene therapeutic strategy to correct 5’ splicing defects in lysosomal storage disordersPublication . Matos, Liliana; Alves, Sandra