Objective. Mevalonic aciduria as a result of mevalonate kinase deficiency is an inborn error of cholesterol biosynthesis characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises, usually manifesting in early infancy, accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash. The febrile crises are similar to those observed in hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). Pathogenic mutations in the mevalonate kinase gene in both disorders have demonstrated a common genetic basis. Our aim was to describe the clinical picture of adolescent patients with mevalonate kinase deficiency and to expand the clinical and biochemical spectrum of mevalonate kinase deficiency, particularly with regard to HIDS.
Methods. We report the clinical history and biochemical findings of 3 patients with mevalonic aciduria.
Results. In 2 siblings with mevalonic aciduria, a 15-year-old girl and a 14-year-old boy, the phenotype shifted with age. Ataxia has become the predominant clinical manifestation, whereas the febrile attacks occur less frequently but as yet have not disappeared. Both of them show marked elevations of immunoglobulin D (IgD). Psychomotor development is retarded but not regressive. Short stature developed in both patients. Additional findings include the development of retinal dystrophy and cataracts in both of them. The third patient is a 6-year-old boy who presented at the age of 5 years with cerebellar ataxia and retinal dystrophy. He is different from all known patients with mevalonic aciduria because of the mild neurologic involvement and because he has never developed febrile crises. In addition, levels of IgD were repeatedly normal.
Conclusion. The clinical and biochemical spectrum of patients with mevalonic aciduria is heterogeneous. Manifestations of the disease seem to be age dependent, as evident from this first report of adolescent patients. In patients who survive infancy, short stature, ataxia caused by cerebellar atrophy, and ocular involvement with retinal dystrophy become predominant findings. Recurrent febrile crises seem to diminish with increasing age and may not even be an obligatory finding. Elevation of IgD is most likely a secondary phenomenon that seems to be linked to recurrent febrile crises.
- mevalonic aciduria
- mevalonate kinase deficiency
- hyperimmunoglobulinemia D and periodic fever syndrome
- cerebellar atrophy
- retinal dystrophy.
Mevalonic aciduria is an autosomal recessive inborn error of cholesterol biosynthesis caused by mevalonate kinase deficiency.1,2 This enzyme is located at the beginning of the cholesterol biosynthesis pathway compromising the biosynthesis of nonsterol isoprenes in addition to cholesterol. Patients with this enzyme defect show a wide range of symptoms, including dysmorphic features, cataracts, neurologic symptoms (hypotonia, developmental delay, ataxia associated with cerebellar atrophy), failure to thrive, recurrent febrile crises with enteropathy, hepatosplenomegaly, lymphadenopathy, arthralgia, edema, and morbilliform rashes. Laboratory investigations reveal elevated acute-phase reactants (erythrocyte sedimentation rate, C-reactive protein [CRP], leukocytosis), anemia, elevation of creatine kinase (CK) and transaminases, and, of diagnostic relevance, a large excretion of mevalonic acid in urine.1–9 At present, 16 patients have been reported.
Recently, increased excretion of mevalonic acid has also been described during acute crises of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS).10,11 The majority of patients with HIDS experience only recurrent febrile crises, without any neurologic abnormalities or dysmorphic features.12 Mutations in the mevalonate kinase gene were found to be 1 cause of HIDS. In HIDS, the reduction of mevalonate kinase enzymatic activity is not as profound as in mevalonic aciduria, and urinary mevalonic acid excretion is lower and variable. Therefore, HIDS has been considered to represent a mild allelic presentation of mevalonic aciduria.10,11
We report on the clinical history and laboratory findings of 3 patients with mevalonic aciduria caused by a virtually complete deficiency of mevalonate kinase. These patients expand the clinical spectrum of mevalonic aciduria in adolescence and provide new insight into the role of immunoglobulin D (IgD) in mevalonic aciduria.
Mevalonate concentrations were determined with a stable isotope dilution assay and gas chromatography-mass spectroscopy. Mevalonate kinase activity was assayed as previously described in lymphocytes (patients 1 and 2) or cultured fibroblasts (patient 3).1 Mutation analysis was performed as previously described in cDNA10 and/or genomic DNA.13 Serum IgD concentrations were measured by means of nephelometry. Urinary leukotriene E4 was measured as previously described.14
Patient 1 is a 15-year-old girl. She is the first child of healthy, unrelated parents and was born at term after an uneventful pregnancy and delivery. After the third month of life, recurrent febrile crises started, associated with diarrhea and vomiting, hepatosplenomegaly, lymphadenopathy, exanthema, edema, and arthralgias. Lethargy and drowsiness during these episodes required nasogastric tube feeding each time. The crises were accompanied by marked elevations of erythrocyte sedimentation rate, CRP, leukocytes, transaminases, urinary leukotriene E4, and CK (up to 4300 U/L). Weight developed along the 10th percentile for the first years; length fell from the 25th to the 3rd percentile within the first year. After the age of 10 months, psychomotor retardation became obvious, along with muscular hypotonia and cerebellar ataxia. Diagnosis of mevalonic aciduria was made at the age of 2.2 years by urinary organic acid analysis by gas chromatography-mass spectroscopy, which revealed high urinary excretion of mevalonic acid (2000–29000 mmol/mol creatinine; controls <0.5 mmol/mol creatinine). Activity of mevalonate kinase in lymphocytes was severely impaired (2.4% of control mean). Molecular analysis revealed that the patient was homozygous for the mutation 1000G>A (A334T) in the mevalonate kinase gene.15 For a clinical synopsis until the age of 6 years and a detailed description of therapeutical interventions, see Hoffmann et al.2 Treatment consisted of antioxidative medication including vitamins C and E and ubiquinone as well as corticosteroids during acute crises. Ophthalmologic investigation at the age of 8 years revealed mild nuclear cataract. The fundi of both eyes showed a slightly pale yellowish optic nerve head, a narrowing of retinal vessels, a few bone spicule pigmentations, and countless minute defects of the retinal pigment epithelium dispersed throughout the periphery of the eye background so as to create the aspect of a “pepper and salt” fundus. These findings are indicative of retinal dystrophy, and vitamin E treatment was discontinued and replaced by vitamin A. Because of worsening of the acute febrile crises, vitamin E was reintroduced at 9 years of age. Over the following years, the febrile crises that initially had been as often as twice a month diminished and now occur every 4 to 6 months. Muscular hypotonia has induced kyphoscoliosis. Ataxia was progressive during early childhood and then stabilized. Since the age of 12 years, she is able to walk without help; her gait is broad and ataxic. Her speech is dysarthric, and her fine motor skills are impaired as a result of cerebellar ataxia. There is no major loss of vision as a result of retinal dystrophy. She has mild mental retardation, and her psychosocial development is satisfying. She attends a school for physically handicapped children with good results. Menstruation is regular since the age of 12 years. Short stature became obvious from the third year of life when her length dropped below the third percentile. After the age of 10 years, obesity developed. At the age of 15, her length is 8 cm below the third percentile, and her weight and head circumference are at the 90th percentile.
Patient 2, now 14 years old, is the brother of patient 1 and received his diagnosis at the age of 1.5 years, after the diagnosis had been made in his sister. Mevalonic acid in urine was similarly elevated between 1500 and 17 000 mmol/mol creatinine, and activity of mevalonate kinase in lymphocytes reduced to 2.1% of control mean. Like his sister, the patient was homozygous for the mutation 1000G>A (A334T) in the mevalonate kinase gene.15 He had completely normal physical and psychomotor development at the time of diagnosis, and magnetic resonance imaging (MRI) scans was normal. Soon after diagnosis, recurrent febrile crises started, similar to those in his sister. During 1 crisis at the age of 22 months, cardiomyopathy and a heart block developed, and respiratory insufficiency required artificial ventilation for 15 days. During the next years, he developed progressive ataxia, and MRI at the age of 4.5 years documented the development of severe cerebellar atrophy. For a clinical synopsis until the age of 5 years and a description of therapeutic interventions, see Hoffmann et al.2 Like in his sister, treatment was started with vitamin C, vitamin E, and ubiquinone as well as corticosteroids during acute crises. Ophthalmologic investigation at the age of 7 years revealed nuclear cataracts and fundus findings similar to those observed in his sister. Electroretinography revealed response amplitudes below the limit of detection in scotopic as well as in photopic conditions, together with the fundus findings indicative of retinal dystrophy. For this reason, vitamin E was replaced by vitamin A. The boy followed a more severe clinical course than his sister. Febrile crises have gradually diminished over the years but still occur every 6 weeks. He is able to walk with the help of a walking frame, but most of the time he is wheelchair bound. There is visual impairment as a result of retinal dystrophy with impaired dark adaptation. Together with his sister, he attends a school for physically handicapped children. During the first years of life, length developed along the 10th percentile, and weight developed along the 25th percentile. Short stature became obvious from the age of approximately 10 years. During the same time, obesity and severe kyphoscoliosis developed. At the age of 14, his length is 3 cm below the 3rd percentile, his weight is at the 75th percentile, and his head circumference 8 mm above the 90th percentile. Recently, IgD levels were determined outside febrile crises in both siblings and were found markedly elevated (200 and 284 U/mL, respectively, normal <100 U/mL).
Patient 3 is a 6-year-old boy and the second child of healthy, unrelated parents. He was born after an uneventful pregnancy at 40 weeks of gestation. Birth weight was 3400 g, length was 49 cm, head circumference was 35 cm, Apgar scores were 9/10/10. After weaning at the age of 8 months, there was a short period of poor weight gain. His psychomotor development was normal during the first year of life. He was able to walk at 16 months of age. Retarded speech development became obvious after the age of 2 years. Episodes with fever, related to otopharyngeal or gastrointestinal infections, occurred approximately twice a year during the first 6 years of life (a frequency normal in this age group). During these infections, there was no unusual severe general malaise or long recovery. At the age of 3.25 years, adenectomy was performed. Because of mild retardation in psychomotor development and a general “clumsiness,” a metabolic screening was performed at the age of 5.5 years. Urinary organic acid analysis revealed high urinary excretion of mevalonic acid (553–862 mmol/mol creatinine). Diagnosis was confirmed by a very low mevalonate kinase activity in cultured skin fibroblasts (0.4% of control mean). Molecular analysis revealed that the patient was heterozygous for 2 mutations in the mevalonate kinase gene: 72insT and 1000G>A (A334T). The first mutation has not been previously observed; the second is the same as in patients 1 and 2. MRI revealed severe cerebellar atrophy (Fig 1), explaining the clinical finding of moderate cerebellar ataxia as the predominant symptom. Ophthalmologic investigation showed retinal dystrophy with impairment of visual function (field constriction and lack of dark adaptation) mainly confined to the retinal periphery, largely corresponding to retinitis pigmentosa and proved by electrophysiologic ocular assessment. Fundus findings comprised thinned retinal vessels, uneven retinal surface reflections, and optic atrophy of moderate extent, but no retinitis pigmentosa-like bone spicule pigmentation of the retina. No cataract formation and no cellular infiltration of the vitreous was found. All clinical and laboratory parameters reported to be disturbed in patients with mevalonic aciduria were checked. The boy showed no signs of dysmorphology, lymphadenopathy, hepatosplenomegaly, enteropathy, arthralgias, or skin rashes (apart from a hemangioma on the right cheek). His weight and length were at the 10th percentile. Blood tests for erythrocyte sedimentation rate, CRP, leukocytes, and transaminases were unremarkable. Analyses of IgD were repeatedly within normal limits (22 and 23 U/mL, normal <100 U/mL). CK was initially found to be elevated (168 U/L), but later was normal (63 U/L). Urinary leukotriene E4 as well as total, reduced, and oxidized forms of coenzyme Q10 in plasma were found to be within normal ranges. Treatment with vitamins C and E and ubiquinone was started promptly after diagnosis.
Clinical Findings and Outcome
Up to now, together with our newly reported patient 3, a total of 17 patients with mevalonic aciduria have been reported in the literature.1–9 The clinical picture in patients with mevalonic aciduria shows considerable variation. Severe forms may be lethal in early infancy or even lead to intrauterine death.2,4 Little is known about the long-term outcome in mildly affected patients who survive early infancy. No adolescent patient has previously been reported.
Recurrent febrile crises, which are typical in late infancy and childhood,2 diminish with increasing age. Moreover, patient 3 demonstrates that febrile crises are not an obligatory finding in mevalonic aciduria. Recently, a 4-year-old boy with mevalonic aciduria was reported with febrile crises as the only symptom8; the observation period, however, might not have been long enough. In all other patients reported so far, mental retardation and ataxia as a result of cerebellar atrophy became constant findings after infancy. In addition, stunted growth seems to develop in childhood. Our patients demonstrate that retinal dystrophy may become another important finding in the course of this disease. The dystrophic retinal process does not necessarily have to disclose itself by retinitis pigmentosa-like bone spicule pigmentations of the fundus, and therefore the diagnostic work-up in mevalonic aciduria should comprise ocular electrophysiology. Cataract as well as optic atrophy may be accompanying symptoms of retinal dystrophy. Cerebellum and retina seem to be very susceptible to oxidative stress and/or toxicity of mevalonic acid. Their level of involvement may ultimately determine the long-term prognosis. Unfortunately, a successful long-term treatment preventing the neurologic and ophthalmological sequelae has not yet been developed.
Mevalonic Aciduria, IgD, and HIDS
The pathogenesis of the acute febrile crises in mevalonic aciduria still remains unclear. The recently found common genetic basis of mevalonic aciduria and HIDS might give insights into the pathogenetic background.10,11 It suggests a role of mevalonate kinase and cholesterol as well as nonsterol isoprenoid biosynthesis with respect to the acute-phase response and fever.16
In patients with mevalonic aciduria, IgD levels may vary depending on the clinical picture. In general, patients with mevalonic aciduria show the full clinical spectrum (neurologic symptoms + recurrent crises). IgD levels have been reported in 6 patients with the full clinical picture of mevalonic aciduria; they have been found elevated in all of them (100%)9 (patients 1 and 2, this report). In addition, they were found to be higher during crises than during intervals of well-being.9 The same is true for acute-phase reactants such as erythrocyte sedimentation rate, CRP, and leukocytosis. In contrast, our third patient showed only neurologic symptoms and no recurrent crises. IgD was repeatedly normal, suggesting that the elevation of IgD is a secondary phenomenon, associated with the recurrent febrile crises. Described recently was a patient with mevalonic aciduria who presented only with recurrent febrile crises but no neurologic symptoms (ie, the classical clinical picture of a so-called HIDS); IgD, however, was reported to be normal in this patient.8
The term HIDS is only descriptive and therefore should be replaced by the underlying molecular or enzymatic diagnoses. It seems to encompass a group of inflammatory diseases in which elevation of IgD levels as well as urinary leukotriene E4 excretion are secondary phenomena of the stimulation of the immune system.17 Periodic fever and elevated IgD can result from other, still unknown, causes.18 However, in association with mevalonic aciduria, it should be considered as 1 important part of the variable spectrum of mevalonate kinase deficiency. That neurologic and/or inflammatory symptoms may be predominant at different ages and that 1 may even be completely absent in an individual patient suggests that at least 2 different pathogenetic mechanisms are responsible for the clinical manifestations of mevalonate kinase deficiency.
- ↵Hoffmann GF, Charpentier C, Mayatepek E, et al. Clinical and biochemical phenotype in 11 patients with mevalonic aciduria. Pediatrics.1993;91 :915– 921
- ↵De Klerk JB, Duran M, Dorland L, Brouwers HA, Bruinvis L, Ketting D. A patient with mevalonic aciduria presenting with hepatosplenomegaly, congenital anaemia, thrombocytopenia and leukocytosis. J Inherit Metab Dis.1988;11(suppl 2) :233– 236
- ↵Hinson DD, Chambliss KL, Hoffmann GF, Krisans S, Keller RK, Gibson KM. Identification of an active site alanine in mevalonate kinase through characterization of a novel mutation in mevalonate kinase deficiency. J Biol Chem.1997;272 :26756– 26760
- ↵Houten SM, Wanders RJ, Waterham HR. Biochemical and genetic aspects of mevalonate kinase and its deficiency. Biochim Biophys Acta.2000;1529(1–3) :19– 32
- ↵Frenkel J, Willemsen MA, Weemaes CM, Dorland L, Mayatepek E. Increased urinary leukotriene E(4) during febrile attacks in the hyperimmunoglobulinaemia D and periodic fever syndrome. Arch Dis Child.2001;85 :158– 159
- ↵Frenkel J, Houten SM, Waterham HR, et al. Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D. Rheumatology (Oxford).2001;40 :579– 584
- Copyright © 2003 by the American Academy of Pediatrics