Mevalonate kinase deficiency

Georg F Hoffmann MD (Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.)
Dorothea Haas MD (Dr. Haas of University Children's Hospital in Heidelberg, Germany, has no relevant financial relationships to disclose.)
Jennifer Friedman MD, editor. (

Dr. Friedman of the University of California San Diego has no relevant financial relationships to disclose.

Originally released November 28, 1994; last updated September 6, 2020; expires September 6, 2023


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 myopathy may develop in childhood and adolescence. Mevalonic aciduria and hyperimmunoglobulinemia D syndrome are both characterized by recurrent fever episodes 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. Overproduction of the cytokine interleukin-1 beta (IL-β) is central to the pathophysiology, and in most patients, drugs targeting IL-β ameliorate or abort symptoms.

Key points


• 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 paradigmatic 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.


• Clinical stabilization and cessation of attacks can be achieved with non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids in about 30% of patients. IL-1 blockade targets the central pathophysiological cascade and ameliorates or aborts symptoms in about 80% to 90% of patients.

Historical note and terminology

Mevalonic aciduria, hyperimmunoglobulinemia D syndrome, and periodic fever syndrome are allelic diseases with a continuous spectrum of clinical symptoms 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 (Hoffmann et al 1986).

Mevalonic aciduria remains a rare disorder with slightly over 40 patients reported in the literature (Berger et al 1985; de Klerk et al 1988; Gibson et al 1997a; Hoffmann et al 1993; Mancini et al 1993; Hinson et al 1998; Hinson et al 1999; Di Rocco et al 2001; Tsimaratos et al 2001; Prietsch et al 2003; Raupp et al 2004; Simon et al 2004; Samkari et al 2010; Bader-Meunier et al 2011; Chaudhury et al 2012; Ruiz Gomez et al 2012; Peciuliene et al 2016; Dunn et al 2018; Pietrasanta et al 2019).

More than 400 patients are known to suffer from hyperimmunoglobulinemia D syndrome, an autoinflammatory disorder, which was found to be allelic to mevalonic aciduria in 1999 (Houten et al 1999; van der Hilst et al 2008; Bader-Meunier et al 2011; Tahara et al 2011; ter Haar et al 2016). 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 (Vuch et al 2013).

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