Mevalonate kinase deficiency and IBD: shared genetic background (original) (raw)
Related papers
Arthritis & rheumatology (Hoboken, N.J.), 2016
Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes. This study aimed to describe the genotype, phenotype and the response to treatment in an international cohort of MKD patients. All MKD cases were extracted from the Eurofever registry (EAHC Project No. 2007332), an international, multicenter registry that retrospectively collects data on children and adults suffering from autoinflammatory diseases. One hundred and fourteen MKD patients were included in this study. The median age of onset was 0.5 years. Patients had on average 12 episodes per year. Most patients had gastrointestinal symptoms (n=112), mucocutaneous involvement (n=99), lymphadenopathy (n=102) or musculoskeletal symptoms (n=89). Neurological complaints included headache (n=43), but also cerebellar syndrome (n=2) and mental retardation (n=4). AA-amyloidosis was noted in five patients, almost twice as many as expected from previous cohorts. Macrophage activatio...
Perinatal manifestation of mevalonate kinase deficiency and efficacy of anakinra
Pediatric Rheumatology, 2016
Background: Mevalonate kinase deficiency is a metabolic autoinflammatory syndrome caused by mutations in the MVK gene, mevalonate kinase, the key enzyme in the non-sterol isoprenoid biosynthesis pathway. Two phenotypes of mevalonate kinase deficiency are known based on the level of enzymatic deficiency, mevalonic aciduria and hyperimmunoglobulinemia D syndrome, but a wide spectrum of intermediate phenotypes has been reported. Currently one of the most effective treatments is biological therapy (with interleukin-1 antagonist anakinra or tumour necrosis factor-α inhibitor etanercept). Case presentation: The patient in this case has a phenotype contributing to a severe disease that caused the symptoms to manifest very early, in the prenatal period. Mevalonate kinase deficiency was suspected on the basis of clinical (hydrops fetalis, hepatosplenomegaly, hypotonia) and laboratory signs (anaemia, intense acute phase reaction, increased urinary excretion of mevalonic acid). Mutation analysis of the MVK gene confirmed the biochemical diagnosis. Treatment with the interleukin-1 antagonist anakinra was started (minimal dose of 1 mg/kg/day) and revealed its efficacy after three days. Conclusions: Our case highlights the need for a very detailed clinical and laboratory assessment in new-borns with any suggestion of autoinflammatory disorders. It is important that patients are diagnosed as early as possible to provide better multidisciplinary follow-up and therapy when needed.
Mevalonate kinase deficiency: Evidence for a phenotypic continuum
Neurology, 2004
Both mevalonic aciduria, characterized by psychomotor retardation, cerebellar ataxia, recurrent fever attacks, and death in early childhood, and hyper-immunoglobulin D (hyper-IgD) syndrome, with recurrent fever attacks without neurologic symptoms, are caused by a functional deficiency of mevalonate kinase. In a systematic review of known mevalonate kinase-deficient patients, the authors identified five adults with phenotypic overlap between these two syndromes, which argues for a continuous spectrum of disease. Mevalonate kinase deficiency should be considered in adult patients with fitting neurologic symptoms, with or without periodic fever attacks.
Diagnostics and Therapeutic Insights in a Severe Case of Mevalonate Kinase Deficiency
PEDIATRICS, 2007
Mevalonate kinase deficiency is a rare inborn disorder of isoprenoid and sterol biosynthesis characterized by a recurrent autoinflammatory syndrome and, in most severe cases, psychomotor delay. Clinical manifestations can be very complex and, in some cases, mimic a chronic inflammatory disease. Diagnosis is also complex and often requires immunologic, genetic, and biochemical investigations. There is no standardized therapy, but biological agents could help to control inflammatory complaints in some cases. A severe case of mevalonate kinase deficiency that was associated with nephritis and successfully treated with anakinra (interleukin 1 receptor antagonist) is reported here, and new insights into diagnosis and therapy of this complex disorder are discussed.
Genetics on early onset inflammatory bowel disease: An update
Genes & Diseases, 2019
Inflammatory bowel disease (IBD) is more common in adults than in children. Onset of IBD before 17 years of age is referred as pediatric onset IBD and is further categorized as very early onset IBD (VEO-IBD) for children who are diagnosed before 6 years of age, infantile IBD who had the disease before 2 years of age and neonatal onset IBD for children less than 28 days of life. Children presenting with early onset disease may have a monogenic basis. Knowledge and awareness of the clinical manifestations facilitates early evaluation and diagnosis. Next generation sequencing is helpful in making the genetic diagnosis. Treatment of childhood IBD is difficult; targeted therapies and hematopoietic stem cell transplantation form the mainstay. In this review we aim to summarize the genetic defects associated with IBD phenotype. We describe genetic location and functions of various genetic defect associated with VEO-IBD with their key clinical manifestations. We also provide clinical clues to suspect these conditions and approaches to the diagnosis of these disorders and suitable treatment options.
Very-early-onset inflammatory bowel disease with a partial RIPK1/ BPHL deletion in an infant
The monogenic causes of very early-onset inflammatory bowel disease (VEO-IBD) have been defined by advanced genetic studies, which were usually related to primary immunodeficiencies. Receptor-interacting serine/threonine-protein kinase-1 RIPK-1 protein is an important signalling molecule in inflammation and cell death pathways. Its deficiency may lead to different clinical features, via immunodeficiency and/or inflammation. Here we discussed an infant with malnutrition, VEO-IBD, reccurrent infections and polyathritis, who had a partial deletion in RIPK1 gene, adjacent biphenyl hydrolase-like (BPHL) gene, and a homozygous p.Glu148Gln mutation in Mediterranean fever (MEFV) gene. The superimposing effect of immune dysregulation of these two defective genes may lead to severe clinical presentation of our patient.
BMC Pediatrics, 2019
Background: This case follows a 14-month-old female, who despite multiple presentations to several physicians, continued to have recurrent febrile episodes with gross motor delay. Her case revealed an often missed diagnosis of Mevalonate Kinase Deficiency, that now has an FDA approved treatment that both reduces recurrence and produces remission. Case presentation: A 14-month-old female with a history of gross motor delay, frequent Upper Respiratory Tract infections, and otitis media presented to an urgent care for inconsolability and refusal to bear weight on her right leg. She had recently been treated with amoxicillin for acute otitis media and had developed a diffuse maculopapular rash, without any associated respiratory or gastrointestinal distress that persisted beyond cessation of the antibiotics. The patient presented multiple times to an urgent care over the subsequent week for fussiness, fever, anorexia, lymphadenopathy, with labs concerning for worsening anemia and elevated inflammatory markers. Subsequently, the patient was admitted to the hospital for suspected osteomyelitis versus oncologic process. X-Ray imaging of the patient's lower extremities showed osseous abnormalities inconsistent with infection. A metabolic work-up showed elevated urine mevalonic acid, and follow-up genetic testing was positive for mutations in both copies of her mevalonate kinase gene. This led to the diagnosis of MKD. Conclusions: Often, episodic presentations require multiple perspectives to reveal the underlying cause. This case illustrates how apparent simple febrile episodes has the potential for more complexity upon further evaluation.
The Turkish journal of pediatrics
The hyperimmunoglobulinemia D syndrome (HIDS), so-called mevalonate kinase deficiency, is caused by recessive mutations in the gene encoding mevalonate kinase enzyme. HIDS is characterized by recurrent fever attacks of 3-7 days that begin in infancy and recur every 4-6 weeks. The febrile period is accompanied by lymphadenopathy, arthralgia, abdominal pain, diarrhea, aphthous ulcers, and varying degree of skin involvement. The course and severity of the disease may be quite different. There is no effective or proven therapy for HIDS. We report two cases with HIDS, which had separate clinical findings and treatment strategies.