Maple syrup urine disease
Jan. 08, 2023
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Mevalonic aciduria and hyperimmunoglobulinemia D syndrome represent the extremes of a complex and continuous disease spectrum caused by deficiency of mevalonate kinase, the first committed enzyme of cholesterol and nonsterol isoprene biosynthesis. The authors delineate the clinical entities of this multisystemic (inflammatory) disorder, the differential diagnosis, as well as therapeutic strategies. The diagnosis of mevalonic aciduria should be suspected in patients with mild dysmorphic features, progressive cerebellar ataxia, psychomotor retardation, failure to thrive, hepatosplenomegaly, liver failure, and, especially, recurrent febrile episodes. Uveitis, retinitis pigmentosa, cataracts, inflammatory bowel disease, and (cardio-) myopathy may develop in childhood and adolescence.
Mevalonic aciduria and hyperimmunoglobulinemia D syndrome are both characterized by recurrent, episodic, high-grade fever with lymphadenopathy, arthralgia, gastrointestinal problems, skin rashes, and oral or genital ulcers. Rarely, affected individuals with hyperimmunoglobulinemia D syndrome develop neonatal-onset chronic hepatitis or colitis, erosive polyarthritis or Sjögren syndrome, amyloidosis, renal angiomyolipoma, or neurologic symptoms only. Activation of the pyrin inflammasome and overproduction of the cytokine interleukin-1 beta (IL-β) are central to the pathophysiology, and in most patients, drugs targeting IL-β ameliorate or abort symptoms.
• Mevalonic aciduria, hyperimmunoglobulinemia D, and periodic fever syndrome are allelic diseases caused by monogenic defects of mevalonate kinase, resulting in a continuous spectrum of clinical symptoms. “Mevalonate kinase deficiency” is the common term for these conditions.
• Mevalonic aciduria is a severe multisystemic disease. Cardinal manifestations include dysmorphic features, mild to severe psychomotor retardation, failure to thrive, hypotonia, myopathy, hepatopathy, and severe recurrent inflammatory crises (musculoskeletal symptoms, fever, vomiting, and diarrhea).
• Hyperimmunoglobulinemia D syndrome is an early-onset periodic fever syndrome within a group of hereditary periodic fever syndromes. It is caused by increased plasma levels of cytokines, leading to an array of inflammatory symptoms and often long-term multisystem disease.
• Two criteria are pathognomonic for mevalonate kinase deficiency: onset of disease before 5 years of age or fever attacks combined with arthralgia lasting less than 14 days. If these criteria are not met, metabolic or molecular investigations for mevalonate kinase deficiency are mostly unwarranted.
• Individual patients can present with a monosymptomatic disease such as neonatal-onset chronic hepatitis, colitis or interstitial lung disease, ataxia, or retinitis pigmentosa.
• Disseminated superficial actinic porokeratosis could be linked to dominant mutations in mevalonate kinase.
Mevalonic aciduria, hyperimmunoglobulinemia D syndrome, and periodic fever syndrome are allelic recessive diseases with a continuous spectrum of clinical symptoms and severity caused by monogenic defects of mevalonate kinase, making “mevalonate kinase deficiency” the common and preferable term for these conditions. The defective enzyme is located proximally in the biosynthesis of cholesterol and nonsterol isoprenes. Although cholesterol metabolism has been the focus of intense research for decades and about 80% of cholesterol is derived by endogenous synthesis, mevalonic aciduria due to mevalonate kinase deficiency was only recognized in 1986 as the first inherited defect in cholesterol biosynthesis (27).
Mevalonic aciduria remains a rare disorder with slightly over 40 patients reported (03; 09; 19; 26; 37; 23; 24; 12; 56; 43; 45; 51; 48; 02; 08; 47; 41; 13; 42; 06).
Nearly 400 patients are known to suffer from hyperimmunoglobulinemia D syndrome, an autoinflammatory disorder, which was found to be allelic to mevalonic aciduria in 1999 (30; 59; 02; 53; 54). The relatively high prevalence in North European countries has been suggested to result from a selective advantage of carriers for lower cholesterol levels in countries where the diet contains high amounts of saturated animal fats rich in cholesterol (60).
Disseminated superficial actinic porokeratosis could be linked to dominant mutations in in mevalonate kinase (62; 34).
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