Clara Barbot

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto

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Jorge Sequeiros

Universidade do Porto

Paula Coutinho

Hospital de São Sebastião

Inês Carrilho

Centro Hospitalar do Porto

Laura Vilarinho

National Institute of Health Dr. Ricardo Jorge

José Barros

Hospital de Santo António

Esmeralda Martins

Centro Hospitalar do Porto

Maria Luı́s Cardoso

University of Lisbon

Joana Damásio

Universidade do Porto

Pedro Mendonça

Instituto Portugues do Sangue e da Transplantacao, IP

Teresa Temudo

Hospital de Santo António

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134

Universidade do Porto

Hospital de Santo António

Inserm

Centro Hospitalar do Porto

Centre National de la Recherche Scientifique

University College London

Centro de Genética Clínica

University of Toronto

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto

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Brief Communication Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type

Chiara Aiello R. Cerone Esmeralda Martins Ubaldo Caruso Isabella Moroni

Methylmalonic aciduria (MMA) and homocystinuria, cblC type (MIM 277400) is the most frequent inborn error of vitamin B12. The recent identification of the disease gene, MMACHC, has permitted preliminary genotype–phenotype correlations. We studied 24 Italian and 17 Portuguese patients with cblC defect to illustrate the spectrum of mutations in a southern European population and discuss the impact that mutation identification has on routine diagnostic procedures. Since the metabolic defect raises the serum levels of homocysteine, we also tested if variants in MTHFR—playing a key role in homocysteine remethylation pathway—could act as genetic modifier in cblC defect. We found that the c.271dupA (accounting for 55% of the MMACH alleles in our cohort) followed by c.394C > T (16%) and c.331C > T (9%) were the most frequent mutations. In our study we also identified a novel mutation (c.544T > C). On the other hand, the MTHFR genotype did not appear to influence age at onset, the clinical phenotype and outcome of patients with cblC defect. This study shows that mutation screening for the most common MMACH mutations occurring in early-onset forms (c.271dupA and c.331C > T) seems to have a high diagnostic yield in a southern European population with cblC defect. Although the identification of the gene defect per se does not predict completely time and severity of disease appearance, our data corroborate the importance of a molecular testing to offer accurate prenatal diagnosis to couples at high risk of having affected children.

Homocystinuria

Methylmalonic aciduria

Hyperhomocysteinemia

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l-2-Hydroxyglutaric aciduria: clinical, biochemical and magnetic resonance imaging in six Portuguese pediatric patients

Brain and Development (1997)

Clara Barbot Isabel Fineza Luísa Diogo Maria Maria José Roberto Tude Melo

Macrocephaly

Dentate nucleus

Cerebral atrophy

Abnormality

Urinary urgency

10.1016/s0387-7604(97)00574-3

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Citations (83)

Ataxie avec apraxie oculomotrice de type 2 (AOA2) : étude clinique, biologique et corrélation génotype/phénotype d’une cohorte de 90 patients

Revue Neurologique (2010)

Mathieu Anheim B. Monga Marie‐Céline Fleury P Peterson Charles Clara Barbot

10.1016/s0035-3787(10)70006-0

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Hereditary Ataxia and Spastic Paraplegia in Portugal

JAMA Neurology (2013)

Paula Coutinho Luís Ruano José L. Loureiro Vítor Tedim Cruz José Barros

Importance: Epidemiological data on hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP) are scarce.Objective: To present the prevalence and distribution of HCA and HSP in Portugal.

Hereditary Spastic Paraplegia

Prevalence

Paraplegia

Cerebellar ataxia

10.1001/jamaneurol.2013.1707

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Citations (123)

Outcome of three cases of untreated maternal glutaric aciduria type I

European Journal of Pediatrics (2007)

Paula Garcia Esmeralda Martins Luísa Diogo Hugo Rocha Ana Marcão

Daughter

Glutaric acid

10.1007/s00431-007-0556-2

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Citations (34)

Pontocerebellar hypoplasia with microcephaly and dyskinesia: report of two cases

Developmental Medicine & Child Neurology (1997)

Clara Barbot Gisela Carneiro

We present two clinically diagnosed cases of pontocerebellar hypoplasia with microcephaly and dyskinesia (pontocerebellar hypoplasia type 2) from two different Portuguese families. Both children presented neurological involvement from birth, progressive microcephaly, exuberant chorea and dystonia, myoclonic jerks, pontocerebellar hypoplasia, and progressive cerebral cortical atrophy. One child had consanguineous parents.

Microcephaly

10.1111/j.1469-8749.1997.tb07485.x

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Citations (10)

The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin

Nature Genetics (2001)

Maria-Céu Moreira Clara Barbot Nobutada Tachi Naoki Kozuka Eiji Uchida

10.1038/ng1001-189

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Citations (430)

Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin

Human Mutation (2005)

Laura Vilarinho Maria Luı́s Cardoso Paulo Gaspar Clara Barbot Luı́sa Azevedo

We studied 21 patients, from 18 families, with L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic disorder with a homogeneous presentation: progressive neurodegeneration with extrapyramidal and cerebellar signs, seizures, and subcortical leukoencephalopathy. Increased levels of L-2-hydroxyglutaric acid in body fluids proved the diagnosis of L-2-HGA in all 21 patients. We analyzed the L-2-HGA gene (L2HGDH), recently found to be mutated in consanguineous families with L-2-HGA, and identified seven novel mutations in 15 families. Three mutations appeared to be particularly prevalent in this Portuguese panel: a frameshift mutation (c.529delC) was detected in 12 out of 30 mutant alleles (40%), a nonsense mutation (c.208C>T; p.Arg70X) in 7/30 alleles (23%), and a missense mutation (c.293A>G; p.His98Arg) in four out of 30 mutant alleles (13%), suggesting that common origin may exist. Furthermore, two novel missense (c.169G>A; p.Gly57Arg, c.1301A>C; p.His434Pro) and two splice error (c.257-2A>G, c.907-2A>G) mutations were found. All the mutations presumably lead to loss-of-function with no relationship between clinical signs, progression of the disease, levels of L-2-HGA and site of the mutation. In the three remaining families, no pathogenic mutations in the L-2-HGA were found, which suggests either alterations in regulatory regions of the gene or of its intervening sequences, compound heterozygosity for large genomic deletion and, or further genetic heterogeneity.

10.1002/humu.9373

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Citations (38)

LIVER TRANSPLANTATION IN ARGININAEMIA

Journal of Pediatric Gastroenterology and Nutrition (2005)

E Santos Silva Esmeralda Martins M. Ribeiro Rodero Cardoso Clara Barbot Laura Vilarinho

10.1002/j.1536-4801.2005.tb01248.x

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Novel MAG Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype

Journal of Clinical Medicine (2020)

Mariana Santos Joana Damásio Célia Kun‐Rodrigues Clara Barbot Jorge Sequeiros

Homozygous variants in MAG, encoding myelin-associated glycoprotein (MAG), have been associated with complicated forms of hereditary spastic paraplegia (HSP). MAG is a glycoprotein member of the immunoglobulin superfamily, expressed by myelination cells. In this study, we identified a novel homozygous missense variant in MAG (c.124T>C; p.Cys42Arg) in a Portuguese family with early-onset autosomal recessive cerebellar ataxia with neuropathy and oculomotor apraxia. We used homozygosity mapping and exome sequencing to identify the MAG variant, and cellular studies to confirm its detrimental effect. Our results showed that this variant reduces protein stability and impairs the post-translational processing (N-linked glycosylation) and subcellular localization of MAG, thereby associating a loss of protein function with the phenotype. Therefore, MAG variants should be considered in the diagnosis of hereditary cerebellar ataxia with oculomotor apraxia, in addition to spastic paraplegia.

Hereditary Spastic Paraplegia

Cerebellar ataxia

Disease gene identification

Apraxia

10.3390/jcm9041212

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Citations (4)