Clinical manifestations

Presentation and course

Mevalonic aciduria shows considerable clinical heterogeneity, including an almost asymptomatic course (06). Stillbirths with skeletal malformations have been observed in affected families, possibly a result of the same genetic defect. Severely affected patients can present prenatally with hydrops fetalis (44) and at birth with congenital malformations and dysmorphic features such as microcephaly, dolichocephaly, wide irregular fontanelles, low-set and posteriorly rotated ears, down-slanted palpebral fissures, blue sclerae, and central cataracts (44). Signs of perinatal infection, together with chronic liver disease (52), interstitial lung disease (45), or neonatal-onset refractory colitis and recurrent rectal abscesses (13) may be mistaken for congenital infection, eg, cytomegalovirus infection. Cholestatic liver disease or neonatal-onset chronic hepatitis can progress to liver failure (08).

Cardinal manifestations include recurrent crises from infancy (high fever, vomiting, diarrhea, arthralgia, and mucocutaneous symptoms, such as aphthous stomatitis, pharyngitis, and skin rashes), failure to thrive, mild to severe psychomotor retardation, hypotonia, and (cardio-)myopathy. The latter can be slowly progressive and affects predominantly axial and proximal muscles. Patients may die of recurrent septicemia, macrophage activation syndrome, or multiorgan failure. Sometimes hematologic abnormalities predominate with normocytic hypoplastic anemia, leukocytosis, thrombocytopenia, and abnormal blood cell forms (23). These abnormalities may lead to the (mis)diagnoses of myelodysplastic syndromes or dyserythropoietic anemia (51; 02). Short stature, ataxia due to progressive cerebellar atrophy and ocular involvement with cataracts and retinal dystrophy become predominant findings after preschool age and can be major manifestations in later onset cases (26; 38; 46; 54; 50; 06).

In hyperimmunoglobulinemia D syndrome, recurrent febrile attacks are similar in frequency and severity to those in patients with mevalonic aciduria. The episodes last from 1 to 10 days with a median duration of 4 days and 12 to 30 episodes per year. Abdominal pain, arthralgia, headache, aphthae, and rashes dominate the clinical course (62; 02; 17; 07; 57; 65). Occasionally, patients present with oral and vaginal aphthous ulcers. The median age of first attack is 4 months (range, 0 to 240 months), with a median period of 8 to 10 years from onset of disease to diagnosis (65). Patients rarely remain asymptomatic throughout childhood and adolescence (57). The majority of patients have increased serum concentrations of IgD; however, 20% to 30% of patients with mevalonate kinase mutations and characteristic symptoms have normal serum IgD concentrations (12; 57). The frequency of attacks often decreases with the patient’s age and may subside in adolescence. However, 50% of adult patients still suffer from six or more attacks per year, life-threatening infections, and other autoimmune features, such as erosive polyarthritis, Sjögren syndrome, nummular keratopathy, and tumors. Renal amyloidosis has been observed as a long-term complication in about 4% (57). Gastrointestinal symptoms are very frequent during intercurrent crises but can also predominate and become continuous up to severe and early-onset colitis, requiring parental nutrition and inflammatory bowel disease-like intestinal inflammation, early onset ulcerative colitis, or proctitis (37; 57). Repeated aseptic peritonitis, jejunal obstruction, GI bleeding, ulcers, and intestinal perforation have been reported (43; 57). Most patients with hyperimmunoglobulinemia D syndrome display neither malformations nor neurologic abnormalities. However, a subgroup of adult patients develops neurologic signs or symptoms of various degrees, such as intellectual disability, ataxia, ocular symptoms, and epilepsy, reflecting a continuous spectrum between mevalonic aciduria and hyperimmunoglobulinemia D syndrome (59; 54; 02).

Most troublesome are frequent crises (26; 36; 02; 08; 50; 57; 65; 33; 06). These are characterized by high fever (frequently exceeding 40°C), vomiting, and diarrhea and are accompanied by abdominal pain, arthralgia, headache, subcutaneous edema, aphthous ulcers, and morbilliform rashes in some patients.

These episodes appear to be noninfectious but can be triggered by minor intercurrent illnesses, vaccinations, or stress. Some patients develop uveitis, which worsens during crises, and others develop progressive myopathies. In childhood, episodes occur as often as 25 times per year, lasting 4 to 7 days on average. Laboratory investigations reveal elevated acute phase reactants (erythrocyte sedimentation rate, C-reactive protein, leukocytosis) and elevated immunoglobulins, including IgA, IgE, and, especially, IgD. The severity of the attacks does not correlate with the level of IgD in serum, and attacks may occur in small children before IgD concentrations become elevated. In the more severely affected patients, anemia, elevations of creatine kinase, and transaminases are present and may worsen during crises. Over years, the severity and the frequency of these attacks often decline and may eventually subside in adolescence, but they mostly persist for life (06). Very few patients never develop immunological crises and may present with mono- or oligosymptomatic late-onset nonsyndromic retinitis pigmentosa (53), sacroiliitis (11), inflammatory bowel disease, liver or cardiorespiratory disease, amyloid A amyloidosis, ataxia, or developmental delay only.

In an array of papers, heterozygous mutations in mevalonate kinase were identified as the cause of disseminated superficial actinic porokeratosis, an autosomal dominant skin disease localized to the skin and characterized by epidermal keratinization (66; 35).

Prognosis and complications

The prognosis for patients with mevalonic aciduria is severe but variable (26; 46; 50; 65; 06). A significant proportion of patients die within the first years of life. Beyond school age, the clinical course appears to be relatively stable with borderline intellectual disability, short stature, cerebellar ataxia, and muscular hypotonia in adolescence. Retinal dystrophy may become an important long-term manifestation of the disease. The dystrophic retinal process does not necessarily manifest itself as retinitis pigmentosa-like bone spicule pigmentations of the fundus. Cataracts and optic atrophy may be accompanying signs of retinal dystrophy. Therefore, the diagnostic evaluation and follow-up care should include ocular electrophysiology.

Hyperimmunoglobulinemia D syndrome has generally been considered to be a relatively benign condition. However, general health and social functioning were found to be significantly impaired, and long-term complications such as inflammatory bowel disease, erosive polyarthritis, Sjögren syndrome, and other chronic conditions are increasingly recognized (02; 57). Even with “only” inflammatory symptoms, general health perception and social functioning were found to be significantly impaired in patients. The functional impairments can have an adverse impact on quality of life, educational achievements, and employment status (62; 17). Furthermore, life expectancy may be reduced in some patients due to severe infections or the development of renal amyloidosis.

Biological basis

Etiology and pathogenesis

Mevalonic aciduria and hyperimmunoglobulinemia D syndrome are caused by a recessively inherited deficiency of mevalonate kinase (E.C. 2.7.1.36; ATP:(R)-mevalonate 5-phosphotransferase; McKusick 251170). The gene encoding mevalonate kinase (MVK) is located on chromosome 12q24 (20). Currently, more than 300 mutations have been reported on Infevers, an online database for autoinflammatory mutations. In mevalonic aciduria, mutations often cluster in the C-terminal region of the protein (24; 06). About 80% of patients with hyperimmunoglobulinemia D syndrome harbor the missense p.V337I mutation, a founder mutation in the Netherlands (02). This mutation primarily affects maturation (folding) of the protein, resulting in a temperature-sensitive expression of mevalonate kinase in vivo (30). In patients with hyperimmunoglobulinemia D syndrome, residual activity of mevalonate kinase of 5% to 15% may be demonstrable, whereas activity is absent in mevalonic aciduria patients (26).

Mevalonic acid is the product of the reaction catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a key regulatory site in the de novo synthesis of sterols and nonsterol isoprenes. In animals, the major product of mevalonate metabolism is cholesterol, some of which is converted to steroid hormones, bile acids, and vitamin D. Mevalonic acid is also converted into other products, including: (1) dolichols, which act as carriers in the assembly of carbohydrate chains of glycoproteins; (2) ubiquinones, which participate in electron transport and, consequently, mitochondrial function; (3) isopentenylated transfer RNAs, which are important for protein synthesis; and (4) geranylylated and farnesylated proteins (21). The latter are involved in intracellular signal transduction, growth control, and the cell cycle, including the proto-oncogene ras. Feedback inhibition from some of the mevalonate pathway substrates, specifically geranylgeranyl pyrophosphate and farnesyl pyrophosphate, proved nonsterol isoprenoids to have a key role in the regulation of mevalonate kinase. The impairment of geranylgeranylation and secondary disturbed geranylgeranylation of small guanosine triphosphatases (GTPases), which are linked to interleukin-1 activation, appear to be central for the inflammatory disease manifestations (61). In vivo loss of small GTPases, including RhoA or K-Ras, could be documented in affected patients, resulting in activation of the pyrin inflammasome and IL-1β secretion (41; 33). In addition, impaired isoprenylation results in impaired mitochondrial function as well as autophagy (60) and, consequently, increased IL-1 β secretion, activation of caspase-1 and caspase-3-related apoptosis, and, partly, caspase-1-associated pyroptosis, resulting in inflammasome activation and inflammatory reaction with fever.

In contrast to most inborn errors of metabolism, mevalonate kinase deficiency is a defect of a biosynthetic pathway. Symptoms are caused by a deficiency of end products and not by toxicity of the accumulating intermediate mevalonic acid. Intervention with lovastatin, an HMG-CoA reductase inhibitor, was attempted in two patients with mevalonic aciduria to ascertain if clinical manifestations might be the result of mevalonate toxicity (26). Doses of 0.3 to 0.6 mg/kg per day for more than 2 weeks resulted in severe critical clinical decompensation manifesting as elevated body temperature, acute myopathy, highly elevated creatine kinase, and worsened ataxia, diarrhea, and vomiting. After cessation of lovastatin therapy, clinical and biochemical changes slowly reversed. In 2019, Frey and colleagues confirmed in control blood mononuclear cells that inhibition of the mevalonate pathway with lovastatin resulted in increased response of IL-6, IL-12p40, and IFN-g mRNA following stimulation (16). This effect was abolished by adding mevalonate to the assay. Different from other autoinflammatory disorders, mevalonate kinase deficiency is a multicytokine disease with increased plasma levels of cytokines.

Despite lack of residual mevalonate kinase activity in cultured cells from affected patients, plasma levels of cholesterol are normal to near normal (partially related to more efficient uptake from the diet), as are the serum levels of lipoprotein, apolipoproteins, steroid hormones, and primary bile acids (26). In cultured skin fibroblasts from affected patients, the activities of HMG-CoA reductase and the levels of LDL receptors are significantly upregulated (29). HMG-CoA reductase and the LDL receptor are the key regulatory sites in the cholesterol pathway (21). Apparently, upregulated activities are compensatory responses in mevalonate kinase deficiency, ensuring (almost) sufficient production of mevalonic acid and thereby almost normal functioning of the pathway. Biallelic hypomorphic variants in HMG-CoA reductase could be identified in 15 individuals in six families, all from whole exome sequencing data of patients with limb-girdle muscular dystrophy (40; 64). In addition to elevated CK levels, plasma mevalonate was found to be reduced, when determined. In one severely affected patient, mevalonolactone was administered orally with 16 mg/kg bw up to three times a week. Impressive subjective as well as objective improvements occurred in all affected muscle groups, including the respiratory muscles, from 3 weeks of treatment. This resulted in significant lasting improvement in independence and daily activities. Bridging the pathophysiological link, the phenotype in some patients was reminiscent of statin-induced myopathy. Finally, in very rare instances, patients treated with statins can develop an autoimmune myopathy caused by antibodies against HMG-CoA reductase, resulting in limb-girdle muscular dystrophy (39).

Ubiquinone biosynthesis in cultured patient fibroblasts is decreased, consistent with decreased plasma levels of ubiquinone-10 in plasma from patients, whereas cholesterol biosynthesis in fibroblasts is normal (31; 29). These findings suggested that geranyl- and farnesyl-pyrophosphate, important intermediates at the branch-point between sterol and isoprenoid biosynthesis, are shuttled toward cholesterol synthesis at the expense of isoprene biosynthesis. Mitochondrial dysfunction due to reduced ubiquinone could be the link between neuroinflammation and neuronal degeneration.

The pathophysiological role of nonsterol isoprenes is further strengthened by the identification of biallelic variants in the GGPSI (MIM: 606982) gene as a “new” cause of congenital muscular dystrophy with sensorineural hearing loss (34). Elevation of IgD levels as well as elevated urinary LTE4 excretion appear to be secondary phenomena of the stimulation of the immune system (15). Oligosymptomatic disease courses, the fact that neurologic and inflammatory symptoms may occur at different ages, and that affected individuals with mevalonate kinase deficiency may have normal levels of IgD or no characteristic crises, suggest that a number of different pathogenetic mechanisms or constellations are responsible for the different clinical manifestations. Impaired prenylation of many proteins synthesized specifically in the retina was delineated as the cause of degeneration of photoreceptors, the retinal pigment epithelium, and the choroid in mevalonate kinase deficiency (49).

Epidemiology

Patients with mevalonic aciduria and hyperimmunoglobulinemia D syndrome and periodic fever syndrome have been identified in families of differing nationalities, although a high proportion of patients are from Northern Europe, including Germany, the Netherlands, and Czechoslovakia (26; 62; 02; 65; 06). Whether this is suggestive of a founder effect, a result of more accurate investigations for mevalonate kinase deficiency in European centers, or the result of a selective advantage of carriers for lower cholesterol levels in countries where the diet contains high amounts of saturated animal fats rich in cholesterol (63) is not known.

Prevention

Only the mating of heterozygotes for mevalonate kinase deficiency can result in an affected child, with each pregnancy having a 1 in 4 chance of producing an affected fetus. Genetic counseling for a family with a previously documented child is recommended. Mevalonic acid may be measured accurately in amniotic fluid by use of an isotope dilution gas chromatography/mass spectrometry assay method employing deuterium-labeled mevalonic acid as internal standard (28). Mevalonate kinase activity can be measured in cultured amniocytes and biopsied chorionic villus tissue (27; 25), and molecular diagnosis can be performed in informative families.

Genetics are different in disseminated superficial actinic porokeratosis; both dominant germline and somatic variants have been described in the mevalonate kinase gene.

Differential diagnosis

Although patients with mevalonate kinase deficiency have a recognizable phenotype of serious clinical manifestations, many will remain undiagnosed for years, on average 8 to 10 years (26; 02; 06). This is even more the case in patients displaying mono- or oligosymptomatic manifestations such as neonatal-onset hepatitis or colitis, ataxia, or retinitis pigmentosa. In a survey of hyperimmunoglobulinemia D syndrome, the median period from onset of disease to diagnosis was 9.9 years (62). Metabolic acidosis, lactic acidemia, and hyperammonemia, the usual concomitants of organic acid disorders, are conspicuously absent.

In more severely affected patients with mevalonic aciduria, the constellation of early-onset failure to thrive, congenital malformations, developmental retardation, hepatosplenomegaly, lymphadenopathy, and anemia might suggest chromosomal aberrations or congenital infections. Sometimes hematological abnormalities predominate with normocytic hypoplastic anemia, leukocytosis, thrombocytopenia, and abnormal blood cell forms (23), leading to misdiagnoses of myelodysplastic syndromes or dyserythropoietic anemia (51). Moderately affected patients may be classified among those with psychomotor retardation, myopathy, specifically limb-girdle muscular dystrophy, and ataxia. Recurrent crises with fever, diarrhea, arthralgia, and mucocutaneous manifestations might suggest infectious or autoimmune disease (26). The development of uveitis in some patients parallels that seen in juvenile rheumatoid arthritis (46).

If developmental delay and neurologic symptoms are not prominent, the differential diagnosis is likely to focus within the group of systemic autoinflammatory disorders. This group consists of other inherited syndromes: familial Mediterranean fever; TNF receptor-associated periodic syndrome; cryopyrin-associated periodic syndrome; familial cold autoinflammatory syndrome/Muckle-Wells syndrome/chronic infantile neurologic cutaneous and articular syndrome; periodic fever and aphthous ulcers, pharyngitis, and adenitis (PFAPA syndrome); pyogenic arthritis pyoderma acne syndrome (PAPA syndrome); NLRP12-associated periodic syndrome and DIRA (interleukin-1 receptor antagonist deficiency) syndrome.

Diagnostic workup

The major diagnostic criterion for mevalonic aciduria is persistently, grossly elevated mevalonic acid in urine, plasma, and CSF (28; 26). Hyperimmunoglobulinemia D syndrome is often suggested by the demonstration of elevated IgD, elevated lgA in 80% of patients, and can be confirmed by elevated mevalonic acid in urine. However, IgD is often normal in children younger than 3 years of age and in 20% to 30% of older individuals (30; 57). Patients with mevalonic aciduria excrete about 500 to 56,200 mmol mevalonic acid/mol creatinine in urine compared to 0.09 to 0.43 mmol/mol creatinine in controls (26). In milder affected patients and especially in hyperimmunoglobulinemia D syndrome, significant elevations may only be found during febrile crises with only slight elevations between attacks, or they may even remain normal (57). The sensitivity of organic acid analysis is inadequate to recognize these slight elevations because of multiple secondary product formation during gas chromatography and mass spectrometry analysis (28). Accurate quantification of mevalonic acid is achieved only by using an isotope dilution gas chromatography/mass spectrometry assay method, employing deuterium-labeled mevalonic acid as internal standard (28). Therefore, a specific suspicion should be followed by a sensitive measurement of mevalonic acid by stable isotope dilution analysis. Sensitivity is 92% and specificity 90% (32). The diagnosis should be confirmed by mutation analysis or assay of mevalonate kinase in white blood cells or cultured fibroblasts (25), but again, one patient with proven pathogenic mutations and elevated mevalonate acid excretion has been identified, whose enzyme activity was reportedly entirely normal (61). Carrier detection is also possible by enzymatic essay, although the results are sometimes equivocal, or by DNA analysis, if mutations have been found in the index patient (24).

Management

Despite the rarity of the disorder, therapeutic regimens for mevalonic aciduria have been at least partially studied (33). Dietary supplementation of cholesterol may reduce frequency and severity of febrile attacks in some mildly affected patients but has compromised more severely affected patients (26). Long-term administration of ubiquinone-50 together with vitamin C and E appears to further stabilize the clinical course and improve somatic and psychomotor development. The rationale is to correct ubiquinone-50 deficiency and to increase free radical scavengers (46). Intervention with paracetamol/NSAIDs plus corticosteroids (prednisone 2 mg /kg per day) is beneficial in about a third of patients during clinical crises, often with resolution of the crises within 24 hours. Treatment with the IL-1 receptor antagonist canakinumab for IL-1 blockade shows the best effects (17; 37; 33) and has been approved by the European Medicines Agency and U.S. Food and Drug Administration for the treatment of mevalonate kinase deficiency. In addition, an on-demand use of anakinra can significantly shorten relapses (04). In individual patients with unsatisfactory response, tocilizumab, a humanized monoclonal antibody targeting the IL-6 receptor, has been successful (47). In 2007, Neven and colleagues reported a positive response to allogenic stem cell transplantation in a boy with mevalonic aciduria and severe, life-threatening inflammatory attacks that could not be controlled (42). This report has been supported by similar successes in a few patients (08; 18) and even by haploidentical alpha/beta T-cell and B-cell depleted stem cell transplantation, with a low risk of acute and chronic graft-versus-host disease or infective complications (14). In one girl, improvement of cerebral myelination was demonstrated on MRI after allogenic stem cell transplantation. This patient also showed resolution of spastic diplegia following additional liver transplantation. Stem cell transplantation offers an important therapeutic option for severe mevalonic aciduria, including its neurologic features. However, there is a risk of relapse; therefore, this procedure is not a fully curative option (55).

Treatment of hyperimmunoglobulinemia D syndrome is also difficult and often supportive. Various standard antiinflammatory drugs including colchicine, NSAIDs, steroids, and thalidomide have failed to suppress the attacks. About a quarter of patients respond favorably to nonsteroidal anti-inflammatory drugs (NSAIDs) or high-dose prednisone (17; 33). Anti-TNF treatment showed a positive response in a few patients (10; 58). IL-1 blockade by the receptor antagonists anakinra or canakinumab have emerged as the treatment of choice, with more patients responding to anakinra (90%) than to etanercept (65%). Anakinra is rapidly eliminated with a serum half-time of 4 to 6 hours, whereas the half-time of canakinumab is 22 to 25 days, meaning that it only needs to be administered once every 6 to 8 weeks (05; 62; 17; 58; 22) with better results (01). Side effects of anakinra have included pain at the injection site (04) and neutropenia, and higher doses may be associated with infectious complications such as bacterial pneumonia (17) and herpes zoster infection (07). Patient initiated on-demand treatment starting at the prodromal stage of the attack with the IL-1 receptor antagonist anakinra was shown to decrease the duration and severity of fever attacks in most patients (04; 17) and is an alternative to continuous therapy. Again, the therapeutic effect is possibly better with canakinumab (17; 58; 22). Only canakinumab has been approved by the European Medicines Agency and U.S. Food and Drug Administration for the treatment of mevalonate kinase deficiency. Unfortunately, the costs of canakinumab are about 7 to 10 times those of anakinra.

Long-term follow-up should include regular general physical examination, monitoring growth and development of children, ophthalmological examination for retinitis pigmentosa and cataracts, neurologic examination, blood count, and measurement of inflammatory parameters, such as C-reactive protein and serum amyloid A, and muscle and liver enzymes. Urine analysis should be performed for renal complications such as glomerulonephritis and renal angiomyolipoma.

Special considerations

Pregnancy

Prenatal diagnosis of mevalonic aciduria is possible via molecular investigations in informative families. In at-risk families, mevalonic acid can be measured accurately in amniotic fluid by an isotope-dilution gas chromatography and mass spectrometry method. Determination of mevalonate kinase activity in cultured amniocytes and biopsied chorionic villus is also possible (27; 28; 25; 38). In affected pregnancies, elevated levels of mevalonic acid have been detected in maternal urine (27; 28; 38). Significant elevations of mevalonic acid were detected in autopsied tissues from an affected fetus, including lymph nodes, adrenals, ovaries, spleen, liver, and brain (28).

Hyperimmunoglobulinemia D syndrome is usually not considered appropriate for prenatal diagnosis.