RESUMO
Sphingolipids are ubiquitous lipids, present in the membranes of all cell types, the stratum corneum and the circulating lipoproteins. Autosomal recessive as well as dominant diseases due to disturbed sphingolipid biosynthesis have been identified, including defects in the synthesis of ceramides, sphingomyelins and glycosphingolipids. In many instances, these gene variants result in the loss of catalytic function of the mutated enzymes. Additional gene defects implicate the subcellular localization of the sphingolipid-synthesizing enzyme, the regulation of its activity, or even the function of a sphingolipid-transporter protein. The resulting metabolic alterations lead to two major, non-exclusive types of clinical manifestations: a neurological disease, more or less rapidly progressive, associated or not with intellectual disability, and an ichthyotic-type skin disorder. These phenotypes highlight the critical importance of sphingolipids in brain and skin development and homeostasis. The present article reviews the clinical symptoms, genetic and biochemical alterations, pathophysiological mechanisms and therapeutic options of this relatively novel group of metabolic diseases.
RESUMO
The mouse double minute 2 (MDM2) oncoprotein is recognized as a major negative regulator of the p53 tumor suppressor, but growing evidence indicates that its oncogenic activities extend beyond p53. Here, we show that MDM2 is recruited to chromatin independently of p53 to regulate a transcriptional program implicated in amino acid metabolism and redox homeostasis. Identification of MDM2 target genes at the whole-genome level highlights an important role for ATF3/4 transcription factors in tethering MDM2 to chromatin. MDM2 recruitment to chromatin is a tightly regulated process that occurs during oxidative stress and serine/glycine deprivation and is modulated by the pyruvate kinase M2 (PKM2) metabolic enzyme. Depletion of endogenous MDM2 in p53-deficient cells impairs serine/glycine metabolism, the NAD(+)/NADH ratio, and glutathione (GSH) recycling, impacting their redox state and tumorigenic potential. Collectively, our data illustrate a previously unsuspected function of chromatin-bound MDM2 in cancer cell metabolism.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Montagem e Desmontagem da Cromatina , Cromatina/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Serina/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proliferação de Células , Cromatina/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Glicina/metabolismo , Células HCT116 , Homeostase , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Nus , Mutação , Oxirredução , Estresse Oxidativo , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/genética , Interferência de RNA , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Fatores de Tempo , Transcrição Gênica , Transfecção , Carga Tumoral , Proteína Supressora de Tumor p53/genética , Proteínas de Ligação a Hormônio da TireoideRESUMO
We report the case of a boy who was diagnosed with mucopolysaccharidosis (MPS) VII at two weeks of age. He harbored three missense ß-glucuronidase (GUSB) variations in exon 3: two novel, c.422A>C and c.424C>T, inherited from his mother, and the rather common c.526C>T, inherited from his father. Expression of these variations in transfected HEK293T cells demonstrated that the double mutation c.422A>C;424C>T reduces ß-glucuronidase enzyme activity. Enzyme replacement therapy (ERT), using UX003 (vestronidase alfa), was started at four months of age, followed by a hematopoietic stem cell allograft transplantation (HSCT) at 13 months of age. ERT was well tolerated and attenuated visceromegaly and skin infiltration. After a severe skin and gut graft-versus-host disease, ERT was stopped six months after HSCT. The last follow-up examination (at the age of four years) revealed a normal psychomotor development, stabilized growth curve, no hepatosplenomegaly, and no other organ involvement. Intriguingly, enzyme activity had normalized in leukocytes but remained low in plasma. This case report illustrates: (i) The need for an early diagnosis of MPS, and (ii) the possible benefit of a very early enzymatic and/or cellular therapy in this rare form of lysosomal storage disease.
Assuntos
Terapia de Reposição de Enzimas , Glucuronidase/genética , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose VII/genética , Mucopolissacaridose VII/terapia , Terapia Combinada , Glucuronidase/sangue , Glucuronidase/uso terapêutico , Glucuronidase/urina , Células HEK293 , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatomegalia/tratamento farmacológico , Humanos , Recém-Nascido , Leucócitos/enzimologia , Leucócitos/metabolismo , Masculino , Mucopolissacaridose VII/sangue , Mucopolissacaridose VII/diagnóstico , Mutação , Esplenomegalia/tratamento farmacológicoRESUMO
Maple syrup urine disease (MSUD), an inborn error of amino acids catabolism is characterized by accumulation of branched chain amino acids (BCAAs) leucine, isoleucine, valine and their corresponding alpha-ketoacids. Impact on the cognitive development has been reported historically, with developmental delays of varying degree. Currently, earlier diagnosis and improved management allow a better neurodevelopment, without requirement of special education. However, specific impairments can be observed, and so far, results of detailed neurocognitive assessments are not available. The aim of this study was to analyse neurocognitive profiles of French MSUD patients. This was a multicentre retrospective study on MSUD patients who underwent neurocognitive evaluation at primary school age. Twenty-one patients with classical neonatal onset MSUD were included. The patients' mean age at the time of evaluation was 8.7 years. The mean intellectual quotient (IQ) score was in the normal range (95.1 ± 12.6). In a subset of eight patients, a consistent developmental pattern of higher verbal than performance IQ was observed (mean of the difference 25.7 ± 8.7, p < 0.0001). No correlation could be established between this pattern and long-term metabolic balance (BCAA blood levels), or severity of acute metabolic imbalances, or leucine blood levels at diagnosis and time to toxin removal procedure. These data show that some MSUD patients may exhibit an abnormal neurocognitive profile with higher verbal than performance abilities. This might suggest an executive dysfunction disorder that would need to be further investigated by specialized testing. This pattern is important to detect in MSUD, as appropriate neuropsychological treatment strategies should be proposed.
Assuntos
Cognição/fisiologia , Doença da Urina de Xarope de Bordo/fisiopatologia , Aminoácidos de Cadeia Ramificada/sangue , Criança , Diagnóstico Precoce , Feminino , Humanos , Lactente , Recém-Nascido , Isoleucina/sangue , Leucina/sangue , Masculino , Doença da Urina de Xarope de Bordo/sangue , Estudos Retrospectivos , Instituições Acadêmicas , Valina/sangueRESUMO
Sphingolipids comprise a wide variety of molecules containing a sphingoid long-chain base that can be N-acylated. These lipids are particularly abundant in the central nervous system, being membrane components of neurons as well as non-neuronal cells. Direct evidence that these brain lipids play critical functions in brain physiology is illustrated by the dramatic consequences of genetic disturbances of their metabolism. Inherited defects of both synthesis and catabolism of sphingolipids are now identified in humans. These monogenic disorders are due to mutations in the genes encoding for the enzymes that catalyze either the formation or degradation of simple sphingolipids such as ceramides, or complex sphingolipids like glycolipids. They cause varying degrees of central nervous system dysfunction, quite similarly to the neurological disorders induced in mice by gene disruption of the corresponding enzymes. Herein, the enzyme deficiencies and metabolic alterations that underlie these diseases are reviewed. Their possible pathophysiological mechanisms and the functions played by sphingolipids one can deduce from these conditions are discussed. This article is part of a Special Issue entitled Brain Lipids.
Assuntos
Glicosídeo Hidrolases/deficiência , Transtornos do Metabolismo dos Lipídeos/metabolismo , Metabolismo dos Lipídeos/genética , Doenças do Sistema Nervoso/metabolismo , Esfingolipídeos/metabolismo , Animais , Expressão Gênica , Glicosídeo Hidrolases/genética , Humanos , Transtornos do Metabolismo dos Lipídeos/genética , Transtornos do Metabolismo dos Lipídeos/patologia , Camundongos , Mutação , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Ratos , Esfingolipídeos/químicaRESUMO
Obstructive nephropathy is a frequently encountered situation in newborns. In previous studies, the urinary peptidome has been analyzed for the identification of clinically useful biomarkers of obstructive nephropathy. However, the urinary proteome has not been explored yet and should allow additional insight into the pathophysiology of the disease. We have analyzed the urinary proteome of newborns (n = 5/group) with obstructive nephropathy using label free quantitative nanoLC-MS/MS allowing the identification and quantification of 970 urinary proteins. We next focused on proteins exclusively regulated in severe obstructive nephropathy and identified Arginase 1 as a potential candidate molecule involved in the development of obstructive nephropathy, located at the crossroad of pro- and antifibrotic pathways. The reduced urinary abundance of Arginase 1 in obstructive nephropathy was verified in independent clinical samples using both Western blot and MRM analysis. These data were confirmed in situ in kidneys obtained from a mouse obstructive nephropathy model. In addition, we also observed increased expression of Arginase 2 and increased total arginase activity in obstructed mouse kidneys. mRNA expression analysis of the related arginase pathways indicated that the pro-fibrotic arginase-related pathway is activated during obstructive nephropathy. Taken together we have identified a new actor in the development of obstructive nephropathy in newborns using quantitative urinary proteomics and shown its involvement in an in vivo model of disease. The present study demonstrates the relevance of such a quantitative urinary proteomics approach with clinical samples for a better understanding of the pathophysiology and for the discovery of potential therapeutic targets.
Assuntos
Arginase/urina , Hidronefrose/urina , Rim/metabolismo , Proteoma/metabolismo , Insuficiência Renal/urina , Animais , Arginase/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Hidronefrose/congênito , Hidronefrose/patologia , Lactente , Recém-Nascido , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteoma/genética , Proteômica/métodos , Insuficiência Renal/congênito , Insuficiência Renal/patologia , Transdução de SinaisRESUMO
Monogenic defects of sphingolipid biosynthesis have been recently identified in human patients. These enzyme deficiencies affect the synthesis of sphingolipid precursors, ceramides or complex glycosphingolipids. They are transmitted as autosomal recessive or dominant traits, and their resulting phenotypes often replicate the abnormalities seen in murine models deficient for the corresponding enzymes. In quite good agreement with the known critical roles of sphingolipids in cells from the nervous system and the epidermis, these genetic defects clinically manifest as neurological disorders, including paraplegia, epilepsy or peripheral neuropathies, or present with ichthyosis. The present review summarizes the genetic alterations, biochemical changes and clinical symptoms of this new group of inherited metabolic disorders. Hypotheses regarding the molecular pathophysiology and potential treatments of these diseases are also discussed.
Assuntos
Glicoesfingolipídeos/biossíntese , Erros Inatos do Metabolismo Lipídico/genética , Esfingolipídeos/biossíntese , Animais , Ataxia/genética , Modelos Animais de Doenças , Epilepsia/genética , Humanos , Camundongos , Mutação , Paraplegia/genética , Doenças do Sistema Nervoso Periférico/genética , Fenótipo , Retinite/genéticaRESUMO
SCOPE: Non-alcoholic fatty liver disease (NAFLD) is a sexually dimorphic disease influenced by dietary factors. Here, the metabolic and hepatic effects of dietary amino acid (AA) source is assessed in Western diet (WD)-induced NAFLD in male and female mice. METHODS AND RESULTS: The AA source is either casein or a free AA mixture mimicking the composition of casein. As expected, males fed a casein-based WD display glucose intolerance, fasting hyperglycemia, and insulin-resistance and develop NAFLD associated with changes in hepatic gene expression and microbiota dysbiosis. In contrast, males fed the AA-based WD show no steatosis, a similar gene expression profile as males fed a control diet, and a distinct microbiota composition compared to males fed a casein-based WD. Females are protected against WD-induced liver damage, hepatic gene expression, and gut microbiota changes regardless of the AA source. CONCLUSIONS: Free dietary AA intake prevents the unhealthy metabolic outcomes of a WD preferentially in male mice.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Masculino , Feminino , Animais , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Caseínas/farmacologia , Fígado/metabolismo , Dieta Ocidental/efeitos adversos , Aminoácidos/metabolismo , Camundongos Endogâmicos C57BL , Dieta HiperlipídicaRESUMO
A better understanding of the functions sphingolipids play in living organisms can be achieved by analyzing the biochemical and physiological changes that result from genetic alterations of sphingolipid metabolism. This review summarizes the current knowledge gained from studies both on human patients and mutant animals (mice, cats, dogs, and cattle) with genetic disorders of sphingolipid metabolism. Genetic alterations affecting the biosynthesis, transport, or degradation of simple sphingolipids are discussed.
Assuntos
Esfingolipídeos/metabolismo , Aldeído Liases/fisiologia , Animais , Transporte Biológico , Proteínas de Transporte/genética , Ceramidases/genética , Ceramidases/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Glicoproteínas de Membrana/genética , Proteína C1 de Niemann-Pick , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Proteínas Serina-Treonina Quinases/genética , Serina C-Palmitoiltransferase/genética , Serina C-Palmitoiltransferase/fisiologiaRESUMO
Sphingolipids play a key structural role in cellular membranes and/or act as signaling molecules. Inherited defects of their catabolism lead to lysosomal storage diseases called sphingolipidoses. Although progress has been made toward a better understanding of their pathophysiology, several issues still remain unsolved. In particular, whether lysosphingolipids, the deacylated form of sphingolipids, both of which accumulate in these diseases, are simple biomarkers or play an instrumental role is unclear. In the meanwhile, evidence has been provided for a high risk of developing malignancies in patients affected with Gaucher disease, the most common sphingolipidosis. This article aims at analyzing the potential involvement of lysosphingolipids in cancer. Knowledge about lysosphingolipids in the context of lysosomal storage diseases is summarized. Available data on the nature and prevalence of cancers in patients affected with sphingolipidoses are also reviewed. Then, studies investigating the biological effects of lysosphingolipids toward pro or antitumor pathways are discussed. Finally, original findings exploring the role of glucosylsphingosine in the development of melanoma are presented. While this lysosphingolipid may behave like a protumorigenic agent, further investigations in appropriate models are needed to elucidate the role of these peculiar lipids, not only in sphingolipidoses but also in malignant diseases in general.
RESUMO
Danon disease is an X-linked lysosomal disorder, characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation. We report a family with a novel mutation, in which the mother and her three sons were affected with various clinical presentations. A massive hypertrophy of the left ventricle was the predominant feature in the three male patients, with different degrees of severity of cardiac symptoms, from isolated palpitations to cardiac failure and sudden death. Muscle pain and weakness were also variable, but constantly associated with increased plasma CK levels. Finally, the male patients had variable degree of a mental retardation. The mother had an attenuated phenotype, limited to a mild hypertrophic cardiomyopathy with premature ventricular contractions diagnosed during her 40's. Microscopy examination of skeletal muscle biopsy, performed in the youngest patient, demonstrated atrophic myofibers with intracytoplasmic vacuoles suggesting lysosomal glycogen storage disease. Immunohistochemistry analyses in muscle specimen showed no detectable Lysosomal-Associated Membrane Protein-2 (LAMP-2), in keeping with the diagnosis of Danon disease. However, a very low expression of a shortened LAMP-2 protein could be evidenced by Western-blot in the patient's fibroblasts. Molecular investigations identified a novel splicing mutation (IVS6 + 1delG) in the LAMP-2 gene. This case report highlights the intrafamilial variability of Danon disease phenotype. In this case, morphological examination of muscle biopsy, showing lysosomal storage myopathy, and immunohistochemistry analyses can provide key elements for orienting etiologic investigations.
Assuntos
Doença de Depósito de Glicogênio Tipo IIb/diagnóstico , Doença de Depósito de Glicogênio Tipo IIb/genética , Proteínas de Membrana Lisossomal/genética , Mutação , Adolescente , Adulto , Biópsia , Criança , Feminino , Variação Genética , Humanos , Imuno-Histoquímica/métodos , Deficiência Intelectual/genética , Proteína 2 de Membrana Associada ao Lisossomo , Lisossomos/patologia , Masculino , Músculo Esquelético/metabolismo , FenótipoRESUMO
Induction of apoptosis by TNF has recently been shown to implicate proteases from lysosomal origin, the cathepsins. Here, we investigated the role in apoptosis of palmitoyl protein thioesterase 1 (PPT1), another lysosomal enzyme that depalmitoylates proteins. We show that transformed fibroblasts derived from patients with the infantile form of neuronal ceroid lipofuscinosis (INCL), a neurodegenerative disease due to deficient activity of PPT1, are partially resistant to TNF-induced cell death (57-75% cell viability vs. 15-30% for control fibroblasts). TNF-initiated proteolytic cleavage of caspase-8, Bid and caspase-3, as well as cytochrome c release was strongly attenuated in INCL fibroblasts as compared to control cells. Noteworthy, activation of p42/p44 mitogen-activated protein kinase and of transcription factor NF-kappaB by TNF, and induction of cell death by staurosporine or chemotherapeutic drugs in INCL cells were unaffected by PPT1 deficiency. Resistance to TNF-induced apoptosis was also observed in embryonic fibroblasts derived from Ppt1/Cln1-deficient mice but not from mice with a targeted deletion of Cln3 or Cln5. Finally, reconstitution of PPT1 activity in mutant cells was accompanied by resensitization to TNF-induced caspase activation and toxicity. These observations emphasize for the first time the role of PPT1 and, likely, protein depalmitoylation in the regulation of TNF-induced apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Glicoproteínas de Membrana/fisiologia , Proteínas de Membrana/metabolismo , Chaperonas Moleculares/fisiologia , Tioléster Hidrolases/fisiologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Western Blotting , Transformação Celular Neoplásica , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Citometria de Fluxo , Humanos , Proteínas de Membrana Lisossomal , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Lipofuscinoses Ceroides Neuronais/enzimologia , Lipofuscinoses Ceroides Neuronais/patologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Pele/citologia , Pele/efeitos dos fármacos , Pele/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismoRESUMO
The roles of ceramide and its catabolites, i.e., sphingosine and sphingosine 1-phosphate, in the development of malignancies and the response to anticancer regimens have been extensively described. Moreover, an abundant literature points to the effects of glucosylceramide synthase, the mammalian enzyme that converts ceramide to ß-glucosylceramide, in protecting tumor cells from chemotherapy. Much less is known about the contribution of ß-glucosylceramide and its breakdown products in cancer progression. In this chapter, we first review published and personal clinical observations that report on the increased risk of developing cancers in patients affected with Gaucher disease, an inborn disorder characterized by defective lysosomal degradation of ß-glucosylceramide. The previously described mechanistic links between lysosomal ß-glucosylceramidase, ß-glucosylceramide and/or ß-glucosylphingosine, and various hallmarks of cancer are reviewed. We further show that melanoma tumor growth is facilitated in a Gaucher disease mouse model. Finally, the potential roles of the ß-glucosylceramidase protein and its lipidic substrates and/or downstream products are discussed.
RESUMO
Much is known about the pathways that control the biosynthesis, transport and degradation of sphingolipids. During the last two decades, considerable progress has been made regarding the roles this complex group of lipids play in maintaining membrane integrity and modulating responses to numerous signals. Further novel insights have been provided by the analysis of newly discovered genetic diseases in humans as well as in animal models harboring mutations in the genes whose products control sphingolipid metabolism and action. Through the description of the phenotypic consequences of genetic defects resulting in the loss of activity of the many proteins that synthesize, transport, bind, or degrade sphingolipids, this review summarizes the (patho)physiological functions of these lipids.
Assuntos
Erros Inatos do Metabolismo Lipídico/metabolismo , Esfingolipídeos/metabolismo , Animais , Galactosilceramidas/fisiologia , Gangliosídeos/fisiologia , Glucosilceramidas/fisiologia , Humanos , Lactosilceramidas/fisiologia , Lisofosfolipídeos/metabolismo , Camundongos , Transporte Proteico , Receptores de Lisoesfingolipídeo/deficiência , Esfingomielina Fosfodiesterase/deficiência , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Sulfoglicoesfingolipídeos/metabolismoRESUMO
BACKGROUND: beta-Mannosidosis (OMIM 248510) is a rare inborn lysosomal storage disorder caused by the deficient activity of beta-mannosidase, an enzyme encoded by a single gene (MANBA) located on chromosome 4q22-25. To date, only 20 cases of this autosomal recessive disorder have been described and 14 different MANBA mutations were incriminated in the disease. These are all null mutations or missense mutations that abolish beta-mannosidase activity. In this study, we characterized the molecular defect of a new case of beta-mannosidosis, presenting with a severe neurological disorder. METHODS: Genomic DNA was isolated from peripheral blood leukocytes of the patient to allow MANBA sequencing. The identified mutation was engineered by site-directed mutagenesis and the mutant protein was expressed through transient transfection in HEK293T cells. The beta-mannosidase expression and activity were respectively assessed by Western blot and fluorometric assay in both leukocytes and HEK293T cells. RESULTS: A missense disease-associated mutation, c.1922G>A (p.Arg641His), was identified for which the patient was homozygous. In contrast to previously described missense mutations, this substitution does not totally abrogate the enzyme activity but led to a residual activity of about 7% in the patient's leukocytes, 11% in lymphoblasts and 14% in plasma. Expression studies in transfected cells also resulted in 7% residual activity. CONCLUSION: Correlations between MANBA mutations, residual activity of beta-mannosidase and the severity of the ensuing neurological disorder are discussed. Whether the c.1922G>A mutation is responsible for a yet undescribed pseudodeficiency of beta-mannosidase is also discussed.
Assuntos
Mutação de Sentido Incorreto , beta-Manosidase/genética , beta-Manosidose/genética , Western Blotting , Linhagem Celular , Criança , Análise Mutacional de DNA , Demência Vascular/complicações , Demência Vascular/genética , Feminino , Expressão Gênica , Humanos , Masculino , Mutagênese Sítio-Dirigida , Linhagem , Transfecção , beta-Manosidase/deficiência , beta-Manosidose/complicaçõesRESUMO
Ceramides are membrane lipids implicated in the regulation of numerous biological functions. Recent evidence suggests that specific subsets of molecular species of ceramide may play distinct physiological roles. The importance of this family of molecules in vertebrates is witnessed by the deleterious consequences of genetic alterations in ceramide metabolism. This brief review summarizes the clinical presentation of human disorders due to the deficiency of enzymes involved either in the biosynthesis or the degradation of ceramides. Information on the possible underlying pathophysiological mechanisms is also provided, based on knowledge gathered from animal models of these inherited rare conditions. When appropriate, tools for chemical and molecular diagnosis of these disorders and therapeutic options are also presented.
Assuntos
Ceramidas/metabolismo , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Animais , Ceramidas/biossíntese , HumanosRESUMO
We describe the case of a young woman, from a consanguineous family, affected by adult Refsum disease (ARD, OMIM#266500). ARD is a rare peroxisomal autosomal recessive disease due to deficient alpha-oxidation of phytanic acid (PA), a branched-chain fatty acid. The accumulation of PA in organs is thought to be responsible for disease symptoms. The patient presented only bilateral shortening of metatarsals and has been treated with a low-PA diet. She is homoallelic for the c.135-2A > G mutation of PHYH, and she married her first cousin carrying the same mutation. She was pregnant seven times and had two homozygous girls. Due to a potential exacerbation of the disease during the third trimester of pregnancy, her weight and plasma PA levels were monitored. No specific events were noticed for the mother during the pregnancies and postpartum periods. This case also raised the question of potential exposure to PA (and its subsequent toxicity) of a homozygous fetus in a homozygous mother. Despite modestly elevated plasma concentrations of PA at birth (<30 µmol/L), the two affected girls did not present any specific sign of ARD and have so far developed normally. As only a few determinations of plasma PA levels in the mother could be performed during pregnancies, showing mild elevations (<350 µmol/L), it remains difficult to conclude as to a possible transplacental crossing of PA.