Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria.

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (MKD/HIDS) are disorders of cholesterol biosynthesis caused by variants in the MVK gene and characterized by increased urinary excretion of mevalonic acid. So far, 30 MVA patients have been reported, suffering from recurrent febrile crises and neurologic impairment. Here, we present an in-depth analysis of the phenotypic spectrum of MVA and provide an in-silico pathogenicity model analysis of MVK missense variants. The phenotypic spectrum of 11 MVA patients (age range 0-51 years) registered in the Unified European Registry for Inherited Metabolic Disorders database was systematically analyzed using terms of the Human Phenotype Ontology. Biochemical, radiological as well as genetic characteristics were investigated. Six of eleven patients have reached adulthood and four have reached adolescence. One of the adolescent patients died at the age of 16 years and one patient died shortly after birth. Symptoms started within the first year of life, including episodic fever, developmental delay, ataxia, and ocular involvement. We also describe a case with absence of symptoms despite massive excretion of mevalonic acid. Pathogenic variants causing MVA cluster within highly conserved regions, which are involved in mevalonate and ATP binding. The phenotype of adult and adolescent MVA patients is more heterogeneous than previously assumed. Outcome varies from an asymptomatic course to early death. MVK variants cluster in functionally important and highly conserved protein domains and show high concordance regarding their expected pathogenicity.

A case report of mevalonate kinase deficiency in a 14-month-old female with fevers and lower extremity weakness.

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.

National survey of Japanese patients with mevalonate kinase deficiency reveals distinctive genetic and clinical characteristics.

OBJECTIVES: Mevalonate kinase deficiency (MKD), a rare autosomal recessive autoinflammatory syndrome, is caused by disease-causing variants of the mevalonate kinase (MVK) gene. A national survey was undertaken to investigate clinical and genetic features of MKD patients in Japan. METHODS: The survey identified ten patients with MKD. Clinical information and laboratory data were collected from medical records and by direct interviews with patients, their families, and their attending physicians. Genetic analysis and measurement of MVK activity and urinary excretion of mevalonic acid were performed. RESULTS: None of the 10 patients harbored MVK disease-causing variants that are common in European patients. However, overall symptoms were in line with previous European reports. Continuous fever was observed in half of the patients. Elevated transaminase was observed in four of the 10 patients, two of whom fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis. About half of the patients responded to temporary administration of glucocorticoids and NSAIDs; the others required biologics such as anti-IL-1 drugs. CONCLUSION: This is the first national survey of MKD patients in a non-European country. Although clinical symptoms were similar to those reported in Europe, the incidence of continuous fever and elevated transaminase was higher, probably due to differences in disease-causing variants.

A 6-year-old girl diagnosed with mevalonate kinase deficiency who had hydrops fetalis and neonatal-onset cholestasis.

We experienced a 6-year-old girl diagnosed with mevalonate kinase deficiency (MKD) who had cholestasis, anemia, and elevated inflammatory markers in neonatal period. She was admitted to our hospital because of fever and elevated inflammatory markers at 5 years 11months of age. Without using antibiotics, the fever and the inflammatory markers were spontaneously resolved. MKD was suspected from elevated serum IgD level and the recurrent febrile attacks. The genetic test revealed heterozygous mutation of p.Leu51Phe known as causative gene of MKD and p.Met 282Thr which is the novel mutation. In addition, urinary mevalonate levels increased both in afebrile and febrile periods, and mevalonate kinase activity level was very low. Prednisolone was administered on each attack, and her febrile attack has been controlled well since she was diagnosed with MKD. Fetal edema, cholestasis, anemia, elevation of inflammatory markers in her neonatal period are considered to be complications of MKD. Recurrent fever attacks compromise quality of life in patients with MKD. Children with unexplained cholestasis and anemia in neonatal period, or recurrent fever attacks with elevated inflammatory markers should be examined for MKD.

Mevalonate kinase deficiency associated with ataxia and retinitis pigmentosa in two brothers with MVK gene mutations.

PURPOSE: To report the clinical and molecular genetic findings in two brothers with retinitis pigmentosa (RP) and mevalonate kinase deficiency (MKD). METHODS: The brothers were examined clinically and with fundus autofluorescence, near-infrared autofluorescence, and spectral domain optical coherence tomography. Targeted resequencing was done with a custom designed gene panel containing 78 genes associated with RP. Mutations were confirmed by direct Sanger sequencing. RESULTS: Both brothers, aged 46 and 47 years, were found to carry compound heterozygous mutations in the MVK gene (c.59A>C, c.1000G>A) encoding mevalonate kinase. They presented with severe ataxia, pseudophakia due to early onset cataract, and progressed retinitis pigmentosa. In one brother with cystoid macular edema, treatment with dorzolamide was beneficial. Serum IgD levels were markedly increased in both brothers and mevalonic acid blood and urine levels were markedly increased in the one brother who could be examined. The disease severity differed between the brothers-one had more severe ataxia and less severe visual deficiency compared to the other. CONCLUSION: MKD can be associated with RP and early onset cataract. Most MKD patients developing RP carry the (p.Ala334Thr) mutation. Macular edema can be treated using local dorzolamide.

Putative modifier genes in mevalonate kinase deficiency.

Mevalonate kinase deficiency (MKD) is an autosomal recessive auto­inflammatory disease, caused by impairment of the mevalonate pathway. Although the molecular mechanism remains to be elucidated, there is clinical evidence suggesting that other regulatory genes may be involved in determining the phenotype. The identification of novel target genes may explain non­homogeneous genotype­phenotype correlations, and provide evidence in support of the hypothesis that novel regulatory genes predispose or amplify deregulation of the mevalonate pathway in this orphan disease. In the present study, DNA samples were obtained from five patients with MKD, which were then analyzed using whole exome sequencing. A missense variation in the PEX11γ gene was observed in homozygosis in P2, possibly correlating with visual blurring. The UNG rare gene variant was detected in homozygosis in P5, without correlating with a specific clinical phenotype. A number of other variants were found in the five analyzed DNA samples from the MKD patients, however no correlation with the phenotype was established. The results of the presents study suggested that further analysis, using next generation sequencing approaches, is required on a larger sample size of patients with MKD, who share the same MVK mutations and exhibit 'extreme' clinical phenotypes. As MVK mutations may be associated with MKD, the identification of specific modifier genes may assist in providing an earlier diagnosis.

Quantification of urinary mevalonic acid as a biomarker of HMG-CoA reductase activity by a novel translational LC-MS/MS method.

BACKGROUND: Mevalonic acid (MVA), as a product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, represents a potential multipurpose biomarker in health and disease. A translational urinary MVA quantification method was developed, validated and used to demonstrate the diurnal variation of urinary MVA excretion in rats and healthy children. METHODS: Urinary MVA was converted to mevalonolactone at pH 2, extracted with ethyl acetate and quantified by reversed-phase liquid chromatography-tandem mass spectrometry. RESULTS: The assay had a dynamic range of 0.0156-10 µg/ml with precision <15% CV, accuracy 85-115% and was transferred between laboratories. Urinary MVA excretion in rats and healthy children displayed a diurnal variation consistent with the known diurnal variation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. CONCLUSION: Urinary MVA can be quantified accurately over a wide dynamic range by a validated translational and transferable method with biomarker capability.

Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa.

OBJECTIVE: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disorder characterized by night blindness and peripheral vision loss, and in many cases leads to blindness. Despite extensive knowledge about genes involved in the pathogenesis of RP, the genetic cause remains elusive in many patients. In this study, we aimed to identify novel genes that are involved in the cause of RP. DESIGN: We present a case series with mutations in the mevalonate kinase (MVK) gene. PARTICIPANTS: A total of 769 patients with nonsyndromic RP and 174 Dutch control individuals participated in this study. METHODS: Exome sequencing analysis was performed in a proband of Dutch origin who was initially diagnosed with nonsyndromic autosomal recessive RP. Mutations in MVK were identified and subsequently tested for segregation within the patient's family and screened in a large cohort of patients with genetically unsolved RP. Patients with mutations underwent extensive clinical reexamination. MAIN OUTCOME MEASURES: Digital fundus photography, spectral-domain optical coherence tomography (OCT), and fundus autofluorescence analysis were performed in patients with MVK mutations. Mevalonate kinase (MK) enzyme activity was analyzed in cultured lymphoblastoid cells, and mevalonic acid levels were measured in urine samples. RESULTS: Exome variant filtering and prioritization led to the identification of compound heterozygous mutations in MVK (p.I268T and p.A334T) in the proband and her affected brother. Screening of our nonsyndromic RP patient cohort revealed an additional individual who was homozygous for the p.A334T alteration. Clinical reevaluation of all 3 patients showed a classic form of RP with variable extraocular symptoms, such as history of recurrent childhood febrile crises in 2 patients, mild ataxia in 1, and renal failure in 1. All 3 affected individuals showed a significantly decreased MK activity and highly elevated levels of urinary mevalonic acid. CONCLUSIONS: Although the MK activity in cells and mevalonic acid concentrations in urine are strongly aberrant and comparable to that in patients with systemic mevalonate kinase deficiency (MKD), only mild clinical symptoms related to this syndrome were observed in our patients. In the current article, we add another phenotype to the spectrum of diverging disorders associated with mutations in MVK.

Metabolism and energy requirements in pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder of coenzyme A homeostasis caused by defects in the mitochondrial pantothenate kinase 2. Patients with PKAN present with a progressive neurological decline and brain iron accumulation, but general energy balance and nutrition status among these patients has not been reported. To determine if defects in PANK2 change basic energy metabolism in humans, we measured body composition, resting energy expenditure, dietary intake, and blood metabolites among 16 subjects with PKAN. Subjects had a broad range of disease severity but, despite the essential role of coenzyme A in energy metabolism, the subjects had remarkably normal body composition, dietary intake and energy metabolism compared to population normal values. We did observe increased resting energy expenditure associated with disease severity, suggesting increased energy needs later in the disease process, and elevated urinary mevalonate levels.

No evidence for mevalonate shunting in moderately affected children with Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is caused by a genetic deficiency in 7-dehydrocholesterol (7-DHC) reductase (EC 1.3.1.21), the last enzyme of the cholesterol synthetic pathway. In SLOS, plasma cholesterol concentration is reduced and immediate precursor concentration (7-DHC) is elevated. Surprisingly, total sterol synthesis is reduced but HMG-CoA reductase activity, a rate-limiting enzyme in cholesterol synthesis is unaltered as judged by normal urinary excretion of mevalonic acid (MVA) (Pappu et al. J Lipid Res 43:1661-1669, 2002). These findings raise the possibility of increased diversion of MVA into the MVA shunt pathway away from sterol synthesis, by activation of the shunt pathway enzymes. To test this hypothesis, we measured the urinary excretion of 3-methylglutaconic acid (U-3MGC), a by-product of the shunt pathway, in 19 mildly to moderately severely affected SLOS subjects (ten males, nine females) receiving either a cholesterol-free or a high cholesterol diet, and in 20 age- and sex-matched controls. U-3MGC was similar in SLOS and controls, and was unaffected by dietary cholesterol intake. Further, no change in U-3MGC was observed in a subset of SLOS subjects (n = 9) receiving simvastatin. In contrast, U-MVA was reduced by cholesterol supplementation (~54%, p < 0.05) and by simvastatin (~50%, p < 0.04). There was no correlation between U-3MGC and either plasma sterol concentrations, urinary isoprenoids, or the subjects' clinical severity score. However U-3MGC was inversely correlated with age (p < 0.04) and body weight (p < 0.02), and higher in females than in males (~65%, p < 0.025). The data show that DHCR7 deficiency does not result in 3MGC accumulation in SLOS and suggest that the MVA shunt pathway is not activated in patients with the condition.

Clinical, genetic, and therapeutic diversity in 2 patients with severe mevalonate kinase deficiency.

Mevalonic aciduria (MA) represents the severest form of mevalonate kinase deficiency due to recessively inherited, loss-of-function MVK mutations. MA is an early-onset disorder characterized by a marked failure to thrive, diverse neurologic symptoms, dysmorphic features, and recurrent febrile episodes. However, significant clinical differences have been reported in the few cases published to date. Here we describe 2 unrelated Spanish patients with MA, emphasizing the clinical heterogeneity observed. One patient presented with the severe classic MA phenotype due to the homozygous p.Ile-268-Thr MVK genotype, with a poor response to conventional treatments. However, the anti-interleukin 1 agent anakinra in this patient resulted in improvement in many clinical and laboratory parameters. The second patient presented with an atypical milder phenotype because of an older age at disease onset, mild neurologic symptoms, absence of febrile episodes and dysmorphic features, and moderate-to-good response to conventional treatments. The novel p.Arg-241-Cys MVK mutation, associated with the already known p.Ser-135-Leu mutation, detected in this patient expands the genetic diversity of mevalonate kinase deficiency. This atypical presentation of MA suggests that it should be included in the differential diagnosis of unclassified patients with psychomotor retardation, failure to thrive or ataxia, even in the absence of febrile episodes.

[Hyperimmunoglobulinemia D and periodic fever syndrome].

Hyperimmunogloblinemia D and periodic fever syndrome (HIDS) is inherited autoinflammatory syndrome caused by deficiency of the mevalonate kinase (MK), which is involved in metabolism of cholesterol. The disease is characterized as periodic fever from early infancy accompanied by elevated serum C-reactive protein. Since clinical symptoms such as abdominal symptom, skin rash, and arthritis are common to other autoinflammatory disease, the diagnosis of HIDS during clinical work is difficult for the physicians without suspicion of HIDS for infants suffering from fever of unknown origin. Moreover, serum IgD levels are not high during infancy conflicting to the name of the disease, which is often misunderstood in the clinicians. Thus, the diagnosis of HIDS in Japan is bothering, depending on the lack of correct recognition of the disease and on the lack of commercially available examination for the disease. It is important for clinicians, especially pediatricians to update current knowledge about HIDS and to learn the appropriate way to the definitive diagnosis of HIDS, because HIDS patients exist also in Japan and the specific therapies for HIDS would be developed in the near future.

Effects of soy protein on lipoprotein lipids and fecal bile acid excretion in men and women with moderate hypercholesterolemia.

BACKGROUND: Soy protein (SP) and low-fat dairy product consumption have been suggested to have hypocholesterolemic effects, although the responsible mechanisms are poorly understood. OBJECTIVE: This randomized, controlled, parallel arm trial evaluated the effects of an insoluble fraction of SP and total milk proteins (TMPs) with high calcium content on the fasting lipid profile. It also assessed the potential contributions of increased excretion of bile acids and neutral sterols to their lipid-altering effects. METHODS: Subjects with hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C] 100-199 mg/dL) followed the Therapeutic Lifestyle Changes diet for 4 weeks, followed by a 2-week lead-in with 3.75 g/d colesevelam HCl. Individuals with LDL-C lowering of ≥5.0% with colesevelam HCl were randomly assigned to one of two groups after a 3-week washout: 1) 25 g/d of an insoluble fraction of partially hydrolyzed SP or 2) 25 g/d TMP. RESULTS: Both SP and TMP reduced atherogenic lipoproteins, as indicated by changes in total cholesterol (-7.4% and -3.6%), LDL-C (-10.9% and -5.9%), nonhigh-density lipoprotein cholesterol (-10.8% and -3.9%), and apolipoprotein B (-9.7% and -2.4%), respectively (P < .05 for between group differences except LDL-C, P = .085). No significant increases were observed in either group for fecal bile acids or neutral sterols. CONCLUSION: These results confirm that SP consumption exerts a hypocholesterolemic effect and indicate that TMP elicits a less pronounced response. However, these findings do not support the hypothesis that increased bile acid excretion is an important contributor to the hypocholesterolemic effects of either protein source.

Elevated immunoglobulin D levels in children with PFAPA syndrome.

BACKGROUND: The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome appears to be more common than generally appreciated and should be differentiated from hereditary periodic fever syndromes, particularly from mevalonate kinase deficiency (MKD). PATIENTS AND METHODS: 14 unrelated patients (7 males, 7 females) met clinical criteria for both the PFAPA syndrome and MKD. Immunoglobulin D (IgD) levels, mevalonic aciduria and mevalonate kinase (MVK) genotype was determined in all patients. RESULTS: Children experienced their first febrile episode at the age of 24.5±5.9 months (mean±SD), the clinical diagnosis of PFAPA syndrome was established with delay at 42.7±11.7 months. The duration of febrile episodes was 3.4±0.2 days, the asymptomatic interval between them lasted 5.4±0.9 weeks. Accompanying symptoms included pharyngitis (92.8%), cervical lymphadenitis (85.7%), aphthous stomatitis (21.4%), arthralgia (14.3%) and skin erythema (35.7%). Neither mevalonic aciduria nor MVK gene mutations were found in any of the subjects, however, unexpectedly, increased plasma IgD (322.2±29.2 U/l) levels were detected in all patients. CONCLUSION: Raised IgD levels may represent a non-specific epiphenomenon, which frequently accompanies PFAPA syndrome as well as MKD. Because of the overlapping clinical and laboratory features, genetic testing of the MVK gene is indicated to differentiate these two conditions, if clinical criteria for both are fulfilled.

Allogeneic bone marrow transplantation in mevalonic aciduria.

Mevalonic aciduria is a rare, inborn error of isoprene biosynthesis characterized by severe, periodic attacks of fever and inflammation, developmental delay, ataxia, and dysmorphic features. This autosomal recessive disease is caused by a mutation in the mevalonate kinase gene that severely reduces mevalonate kinase activity. A 3-year-old boy with mevalonic aciduria whose condition had failed to improve with antiinflammatory treatment underwent allogeneic bone marrow transplantation from an HLA-identical sister who was a heterozygous carrier of the mutant gene. We observed sustained remission of febrile attacks and inflammation during a 15-month follow-up period.

Mevalonic aciduria: report of two cases.

Mevalonic aciduria is a rare disease that is a consequence of a deficiency of mevalonate kinase, an inborn error in the biosynthesis of cholesterol. Approximately 30 cases have been reported. We present our data on two siblings with mevalonic aciduria as a contribution to the recognition of this subject. Both were born after uneventful pregnancies. Their parents were healthy and not consanguineous. They had normal somatic and psychomotor development until they were around 2 years old. After the second year of life they developed mental retardation, ataxia and hypotonia. MRI showed cerebellar atrophy of both hemispheres and vermis. One sibling, from the age of 10 years onwards, suffered from complex partial seizures that were controlled with levetiracetam and lamotrigine. At 11 and 12 years of age, respectively, they were able to walk without help, but their gait was broad and ataxic. Their speech was dysarthric, fine motor skills were impaired as result of cerebellar ataxia, and they had moderate mental retardation. Diagnosis of mevalonic aciduria was made at this age through urinary organic acid analysis by gas chromatography-mass spectroscopy, which revealed high urinary excretion of mevalonic acid. They are currently 18 and 17 years old, respectively, show mental retardation and are able to walk but with difficulty. In our patients, ataxia due to cerebellar atrophy and mental retardation have been the predominant clinical manifestations. In mildly affected patients who survive infancy, these seem to be the predominant findings.

Time-of-intake (morning versus evening) of extended-release fluvastatin in hyperlipemic patients is without influence on the pharmacodynamics (mevalonic acid excretion) and pharmacokinetics.

OBJECTIVE: Statins inhibit the rate-limiting step in cholesterol biosynthesis, the conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate by HMG-CoA reductase. Statins are usually taken in the evening as the HMG-CoA reductase activity is high during the night. This recommendation might not apply if statins are given as extended-release (ER) formulations. The present study investigated the influence of time of intake of fluvastatin 80 mg ER on cholesterol biosynthesis. Main objectives were to measure the change in 24-hour urinary mevalonic acid excretion, to determine plasma concentrations of mevalonic acid and fluvastatin and to monitor triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol. METHODS: This was a randomized, 2-period crossover study in 26 hypercholesterolemic patients who received a single daily dose of fluvastatin both in the morning and in the evening. RESULTS: At baseline, the amount of mevalonic acid was 204.9 +/- 68.1 microg/g creatinine. After a single dose of fluvastatin mean urine values of mevalonate were significantly reduced to 129.8 +/- 66.2 micro/g (evening) and to 118.7 +/-34.3 microg/g (morning; n.s. between groups), thus representing a reduction of about 39%. Compared to baseline, plasma mevalonate concentrations were decreased by fluvastatin resulting in similar 24-hour profiles after the morning and the evening dosage. The pharmacokinetics of fluvastatin were similar in both periods of the study, with higher plasma concentrations for several hours following the evening dosage. CONCLUSION: This study demonstrates that fluvastatin ER is equally effective in inhibiting cholesterol biosynthesis when given once daily in the morning and once daily in the evening.