https://eprints.whiterose.ac.uk/81451/1/JAutoimmunFNl14.pdf

TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants – past, present and future

Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of~1: 50,000 and PA of~1:100’000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim to provide a trans-European consensus to guide practitioners, set standards of care and to help to raise awareness. To achieve these goals, the guidelines were developed using the SIGN methodology by having professionals on MMA/PA across twelve European countries and the U.S. gather all the existing evidence, score it according to the SIGN evidence level system and make a series of conclusive statements supported by an associated level of evidence. Although the degree of evidence rarely exceeds level C (evidence from non-analytical studies like case reports and series), the guideline should provide a firm and critical basis to guide practice on both acute and chronic presentations, and to address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Furthermore, these guidelines highlight gaps in knowledge that must be filled by future research. We consider that these guidelines will help to harmonize practice, set common standards and spread good practices, with a positive impact on the outcomes of MMA/PA patients.

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Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia

Derivatives of cobalamin (vitamin B(12)) are required for activity of two enzymes in humans. Adenosylcobalamin is required for activity of mitochondrial methylmalonylCoA mutase and methylcobalamin is required for activity of cytoplasmic methionine synthase. Deficiency in cobalamin, or inability to absorb cobalamin normally, can result in accumulation of methylmalonic acid and homocysteine in blood and urine. Methylmalonic acidemia can result in metabolic acidosis which in severe cases may be fatal. Hyperhomocysteinemia along with hypomethioninemia can result in hematologic (megaloblastic anemia, neutropenia, thrombocytopenia) and neurologic (subacute combined degeneration of the cord, dementia, psychosis) defects. Inborn errors affecting cobalamin absorption (inherited intrinsic factor deficiency, Imerslund–Gra¨ sbeck syndrome) and transport (transcobalamin deficiency) have been described. A series of inborn errors of intracellular cobalamin metabolism, designated cblA-cblG, have been differentiated by complementation analysis. These can give rise to isolated methylmalonic acidemia (cblA, cblB, cblD variant 2), isolated hyperhomocysteinemia (cblD variant 1, cblE, cblG) or combined methylmalonic acidemia and hyperhomocysteinemia (cblC, classic cblD, cblF). All these disorders are inherited as autosomal recessive traits. The genes underlying each of these disorders have been identified. Two other disorders, haptocorrin deficiency and transcobalamin receptor deficiency, have been described, but it is not clear that they have any consistent clinical phenotype.

Inborn errors of cobalamin absorption and metabolism

Several mutant genetic classes that cause isolated methylmalonic acidurias (MMAuria) are known based on biochemical, enzymatic and genetic complementation analysis. The mut(0) and mut(-) defects result from deficiency of MMCoA mutase apoenzyme which requires adenosyl-cobalamin (Ado-Cbl) as coenzyme. The cblA, cblB and the variant 2 form of cblD complementation groups are linked to processes unique to Ado-Cbl synthesis. The cblC, cblD and cblF complementation groups are associated with defective methyl-cobalamin synthesis as well. Mutations in the genes associated with most of these defects have been described. Recently a few patients have been described with mild MMAuria associated with mutations of the MMCoA epimerase gene or with neurological symptoms due to SUCL mutations. A comprehensive diagnostic approach involves investigations at the level of metabolites, genetic complementation analysis and enzymatic studies, and finally mutation analysis. MMA levels in urine range from 10-20 mmol/mol creatinine in mild disturbances of MMA metabolism to over 20000 mmol/mol creatinine in severe MMCoA mutase deficiency, but show considerable overlap and are of limited value for differential diagnosis. The underlying defect in isolated MMAuria can be characterized in cultured skin fibroblasts using several assays, e.g. conversion of propionate to succinate, specific activity of MMCoA, cobalamin adenosyltransferase assay, cellular uptake of CN-[(57)Co] cobalamin and its conversion to cobalamin coenzymes and complementation analysis. The reliable characterization of patients with isolated MMAuria pinpoints the correct gene for mutation analysis. Reliable classification of these patients is essential for ongoing and future prospective studies on treatment and outcome.

/pdf/causes-of-and-diagnostic-approach-to-methylmalonic-acidurias-209wxq3j5d.pdf

Causes of and diagnostic approach to methylmalonic acidurias.

Cobalamin deficiency in the newborn usually results from cobalamin deficiency in the mother. Megaloblastic anaemia, pancytopenia and failure to thrive can be present, accompanied by neurological deficits if the diagnosis is delayed. Most cases of spina bifida and other neural tube defects result from maternal folate and/or cobalamin insufficiency in the periconceptual period. Polymorphisms in a number of genes involved in folate and cobalamin metabolism exacerbate the risk. Inborn errors of cobalamin metabolism affect its absorption, (intrinsic factor deficiency, Imerslund-Grasbeck syndrome) and transport (transcobalamin deficiency) as well as its intracellular metabolism affecting adenosylcobalamin synthesis (cblA and cblB), methionine synthase function (cblE and cblG) or both (cblC, cblD and cblF). Inborn errors of folate metabolism include congenital folate malabsorption, severe methylenetetrahydrofolate reductase deficiency and formiminotransferase deficiency. The identification of disease-causing mutations in specific genes has improved our ability to diagnose many of these conditions, both before and after birth.

Acquired and inherited disorders of cobalamin and folate in children

Cobalamin nonresponsive methylmalonic acidemia (MMA, mut complementation class) results from mutations in the nuclear gene MUT, which codes for the mitochondrial enzyme methylmalonyl CoA mutase (MCM). To better elucidate the spectrum of mutations that cause MMA, the MUT gene was sequenced in 160 patients with mut MMA. Sequence analysis identified mutations in 96% of disease alleles. Mutations were found in all coding exons, but predominantly in exons 2, 3, 6, and 11. A total of 116 different mutations, 68 of which were novel, were identified. Of the 116 different mutations, 53% were missense mutations, 22% were deletions, duplications or insertions, 16% were nonsense mutations, and 9% were splice-site mutations. Sixty-one of the mutations have only been identified in one family. A novel mutation in exon 2, c.322C>T (p.R108C), was identified in 16 of 27 Hispanic patients. SNP genotyping data demonstrated that Hispanic patients with this mutation share a common haplotype. Three other mutations were seen exclusively in Hispanic patients: c.280G>A (p.G94R), c.1022dupA, and c.970G>A (p.A324T). Seven mutations were seen almost exclusively in black patients, including the previously reported c.2150G>T (p.G717V) mutation, which was identified in 12 of 29 black patients. Two mutations were seen only in Asian patients. Some frequently identified mutations were not population-specific and were identified in patients of various ethnic backgrounds. Some of these mutations were found in mutation clusters in exons 2, 3, 6, and 11, suggesting a recurrent mutation.

Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype

Two cases of fulminant pulmonary legionellosis, complicated by prolonged intensive care unit stays and acute respiratory distress syndrome, and who were recently treated with infliximab for Crohn’s disease, are described. A review of the literature revealed three additional cases in patients with inflammatory bowel disease, and a total of 22 cases of Legionella pneumophila pneumonia in the context of treatment with antitumour necrosis (TNF)-alpha medications. The median age of the patients was 49 years, and men and women were affected equally. The case fatality rate was 14% (three of 22). Early recognition and treatment of this anti-TNF-alpha-related complication would likely result in reduced mortality and morbidity. Physicians prescribing anti-TNF-alpha drugs should be aware of this association.

/pdf/fulminant-legionellosis-in-two-patients-treated-with-560plcrp7o.pdf

Fulminant Legionellosis in Two Patients Treated with Infliximab for Crohn’s Disease: Case Series and Literature Review

Toxoplasma gondii has been well-documented to cause central nervous system infections in immunodeficient patients. The present study describes a case of central nervous system toxoplasmosis in a patient with common variable immunodeficiency and newly diagnosed large granular lymphocytic leukemia, with a review of the literature for this association.

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Case report and review of the literature: Toxoplasma gondii encephalitis in a 40-year-old woman with common variable immunodeficiency and a new diagnosis of large granular lymphocytic leukemia

Adam Hofmann

Papers

Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype

Fulminant Legionellosis in Two Patients Treated with Infliximab for Crohn’s Disease: Case Series and Literature Review

Case report and review of the literature: Toxoplasma gondii encephalitis in a 40-year-old woman with common variable immunodeficiency and a new diagnosis of large granular lymphocytic leukemia