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Mevalonic aciduria(MEVA)

MedGen UID:
368373
Concept ID:
C1959626
Disease or Syndrome
Synonyms: MEVA; Mevalonicaciduria
SNOMED CT: Mevalonic aciduria (718558008); Complete mevalonate kinase deficiency (718558008)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): MVK (12q24.11)
 
Monarch Initiative: MONDO:0012481
OMIM®: 610377
Orphanet: ORPHA29

Definition

Mevalonic aciduria (MEVA), the first recognized defect in the biosynthesis of cholesterol and isoprenoids, is a consequence of a deficiency of mevalonate kinase (ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36). Mevalonic acid accumulates because of failure of conversion to 5-phosphomevalonic acid, which is catalyzed by mevalonate kinase. Mevalonic acid is synthesized from 3-hydroxy-3-methylglutaryl-CoA, a reaction catalyzed by HMG-CoA reductase (142910). Mevalonic aciduria is 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 to periodic fever syndrome (HIDS; 260920), which is also caused by mutation in the MVK gene (summary by Prietsch et al., 2003). [from OMIM]

Additional description

From MedlinePlus Genetics
People with MVA have signs and symptoms of the condition at all times, not just during episodes of fever. Affected children have developmental delay, problems with movement and balance (ataxia), recurrent seizures (epilepsy), progressive problems with vision, and failure to gain weight and grow at the expected rate (failure to thrive). Individuals with MVA typically have an unusually small, elongated head. In childhood or adolescence, affected individuals may develop eye problems such as inflammation of the eye (uveitis), a blue tint in the white part of the eye (blue sclera), an eye disorder called retinitis pigmentosa that causes vision loss, or clouding of the lens of the eye (cataracts). Affected adults may have short stature and may develop muscle weakness (myopathy) later in life. During fever episodes, people with MVA may have an enlarged liver and spleen (hepatosplenomegaly), lymphadenopathy, abdominal pain, diarrhea, and skin rashes. Children with MVA who are severely affected with multiple problems may live only into early childhood; mildly affected individuals may have a normal life expectancy.

During episodes of fever, people with HIDS typically have enlargement of the lymph nodes (lymphadenopathy), abdominal pain, joint pain, diarrhea, skin rashes, and headache. Occasionally they will have painful sores called aphthous ulcers around their mouth. In females, these may also occur around the vagina. Rarely, people with HIDS develop a buildup of protein deposits (amyloidosis) in the kidneys that can lead to kidney failure. Fever episodes in individuals with HIDS can be triggered by vaccinations, surgery, injury, or stress. Most people with HIDS have abnormally high levels of immune system proteins called immunoglobulin D (IgD) and immunoglobulin A (IgA) in the blood. It is unclear why some people with HIDS have high levels of IgD and IgA and some do not. Elevated levels of these immunoglobulins do not appear to cause any signs or symptoms. Individuals with HIDS do not have any signs and symptoms of the condition between fever episodes and typically have a normal life expectancy.

Mevalonate kinase deficiency has additional signs and symptoms, and the severity depends on the type of the condition. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria (MVA).

Mevalonate kinase deficiency is a condition characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. In childhood the fevers seem to be more frequent, occurring as often as 25 times a year, but as the individual gets older the episodes occur less often.  https://medlineplus.gov/genetics/condition/mevalonate-kinase-deficiency

Clinical features

From HPO
Arthralgia
MedGen UID:
13917
Concept ID:
C0003862
Sign or Symptom
Joint pain.
Elevated urine mevalonic acid level
MedGen UID:
1712812
Concept ID:
C5397655
Finding
An abnormally increased amount of mevanolate in the urine. Mevanolate is that hydroxy monocarboxylic acid anion that is the conjugate base of mevalonic acid.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Failure to thrive in infancy
MedGen UID:
358083
Concept ID:
C1867873
Finding
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
Simultaneous enlargement of the liver and spleen.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Fluctuating hepatomegaly
MedGen UID:
372149
Concept ID:
C1835881
Finding
Intermittently increased size of the liver.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Progressive cerebellar ataxia
MedGen UID:
140727
Concept ID:
C0393525
Disease or Syndrome
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Agenesis of cerebellar vermis
MedGen UID:
1768774
Concept ID:
C5437781
Congenital Abnormality
Congenital absence of the vermis of cerebellum.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Normocytic hypoplastic anemia
MedGen UID:
372147
Concept ID:
C1835875
Disease or Syndrome
A type of hypoplastic anemia in which the erythrocytes have a normal cell volume (the mean corpuscular volume is within normal limits).
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Dolichocephaly
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
Large fontanelles
MedGen UID:
105329
Concept ID:
C0456132
Finding
In newborns, the two frontal bones, two parietal bones, and one occipital bone are joined by fibrous sutures, which form a small posterior fontanelle, and a larger, diamond-shaped anterior fontanelle. These regions allow for the skull to pass the birth canal and for later growth. The fontanelles gradually ossify, whereby the posterior fontanelle usually closes by eight weeks and the anterior fontanelle by the 9th to 16th month of age. Large fontanelles are diagnosed if the fontanelles are larger than age-dependent norms.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Leukocytosis
MedGen UID:
9736
Concept ID:
C0023518
Disease or Syndrome
An abnormal increase in the number of leukocytes in the blood.
Morbilliform rash
MedGen UID:
115972
Concept ID:
C0234918
Finding
An exanthema consisting of widespread pink-to-red macules (flat spots of 2-10 mm in diameter) or papules (red bumps) that blanch with pressure. The macules and papules may cluster and merge to form sheets over several days.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Lymphadenopathy
MedGen UID:
96929
Concept ID:
C0497156
Disease or Syndrome
Enlargment (swelling) of a lymph node.
Increased circulating IgD level
MedGen UID:
372146
Concept ID:
C1835869
Finding
An abnormally increased level of immunoglobulin D in blood.
Fluctuating splenomegaly
MedGen UID:
322770
Concept ID:
C1835882
Finding
Intermittently increased size of the spleen.
Skin rash
MedGen UID:
1830322
Concept ID:
C5779628
Sign or Symptom
A red eruption of the skin.
Edema
MedGen UID:
4451
Concept ID:
C0013604
Pathologic Function
An abnormal accumulation of fluid beneath the skin, or in one or more cavities of the body.
Elevated erythrocyte sedimentation rate
MedGen UID:
57727
Concept ID:
C0151632
Finding
An increased erythrocyte sedimentation rate (ESR). The ESR is a test that measures the distance that erythrocytes have fallen after one hour in a vertical column of anticoagulated blood under the influence of gravity. The ESR is a nonspecific finding. An elevation may indicate inflammation or may be caused by any condition that elevates fibrinogen.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Elevated hepatic transaminase
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Elevated circulating C-reactive protein concentration
MedGen UID:
892906
Concept ID:
C4023452
Finding
An abnormal elevation of the C-reactive protein level in the blood circulation.
Increased circulating lactate dehydrogenase concentration
MedGen UID:
1377250
Concept ID:
C4477095
Finding
An elevated level of the enzyme lactate dehydrogenase in the blood circulation.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Underdeveloped nasal alae
MedGen UID:
322332
Concept ID:
C1834055
Congenital Abnormality
Thinned, deficient, or excessively arched ala nasi.
Triangular face
MedGen UID:
324383
Concept ID:
C1835884
Finding
Facial contour, as viewed from the front, triangular in shape, with breadth at the temples and tapering to a narrow chin.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Nuclear cataract
MedGen UID:
140274
Concept ID:
C0392557
Finding
A nuclear cataract is an opacity or clouding that develops in the lens nucleus. That is, a nuclear cataract is one that is located in the center of the lens. The nucleus tends to darken changing from clear to yellow and sometimes brown.
Blue sclerae
MedGen UID:
154236
Concept ID:
C0542514
Finding
An abnormal bluish coloration of the sclera.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disk (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.
Attenuation of retinal blood vessels
MedGen UID:
480605
Concept ID:
C3278975
Finding

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Mevalonic aciduria in Orphanet.

Professional guidelines

PubMed

Sánchez-Manubens J, Iglesias E, Anton J
Expert Rev Clin Immunol 2019 Mar;15(3):215-220. Epub 2019 Jan 26 doi: 10.1080/1744666X.2019.1571410. PMID: 30652926
Esposito S, Ascolese B, Senatore L, Bosis S, Verrecchia E, Cantarini L, Rigante D
Int J Immunopathol Pharmacol 2014 Oct-Dec;27(4):491-8. doi: 10.1177/039463201402700404. PMID: 25572728
Mandey SH, Schneiders MS, Koster J, Waterham HR
Hum Mutat 2006 Aug;27(8):796-802. doi: 10.1002/humu.20361. PMID: 16835861

Recent clinical studies

Etiology

Brennenstuhl H, Nashawi M, Schröter J, Baronio F, Beedgen L, Gleich F, Jeltsch K, von Landenberg C, Martini S, Simon A, Thiel C, Tsiakas K, Opladen T, Kölker S, Hoffmann GF, Haas D; Unified Registry for Inherited Metabolic Disorders (U-IMD) Consortium and the European Registry for Hereditary Metabolic Disorders (MetabERN)
J Inherit Metab Dis 2021 Sep;44(5):1272-1287. Epub 2021 Jun 28 doi: 10.1002/jimd.12412. PMID: 34145613
Tricarico PM, Marcuzzi A, Piscianz E, Monasta L, Crovella S, Kleiner G
Int J Mol Sci 2013 Nov 26;14(12):23274-88. doi: 10.3390/ijms141223274. PMID: 24287904Free PMC Article
Kanungo S, Soares N, He M, Steiner RD
Dev Disabil Res Rev 2013;17(3):197-210. doi: 10.1002/ddrr.1114. PMID: 23798009
Stoffels M, Simon A
Curr Opin Rheumatol 2011 Sep;23(5):419-23. doi: 10.1097/BOR.0b013e328349c3b1. PMID: 21760510
Kelley RI, Herman GE
Annu Rev Genomics Hum Genet 2001;2:299-341. doi: 10.1146/annurev.genom.2.1.299. PMID: 11701653

Diagnosis

Elhani I, Hentgen V, Grateau G, Georgin-Lavialle S
Mol Genet Metab 2022 Jun;136(2):85-93. Epub 2022 Apr 30 doi: 10.1016/j.ymgme.2022.04.006. PMID: 35525811
Politiek FA, Waterham HR
Front Immunol 2021;12:724991. Epub 2021 Sep 3 doi: 10.3389/fimmu.2021.724991. PMID: 34539662Free PMC Article
Zhang S
Pediatr Rheumatol Online J 2016 May 4;14(1):30. doi: 10.1186/s12969-016-0091-7. PMID: 27142780Free PMC Article
Jira P
Handb Clin Neurol 2013;113:1845-50. doi: 10.1016/B978-0-444-59565-2.00054-X. PMID: 23622407
Haas D, Hoffmann GF
Orphanet J Rare Dis 2006 Apr 26;1:13. doi: 10.1186/1750-1172-1-13. PMID: 16722536Free PMC Article

Therapy

Sánchez-Manubens J, Iglesias E, Anton J
Expert Rev Clin Immunol 2019 Mar;15(3):215-220. Epub 2019 Jan 26 doi: 10.1080/1744666X.2019.1571410. PMID: 30652926
Peciuliene S, Burnyte B, Gudaitiene R, Rusoniene S, Drazdiene N, Liubsys A, Utkus A
Pediatr Rheumatol Online J 2016 Mar 25;14(1):19. doi: 10.1186/s12969-016-0081-9. PMID: 27012807Free PMC Article
Hargreaves IP
Mitochondrion 2007 Jun;7 Suppl:S175-80. Epub 2007 Mar 16 doi: 10.1016/j.mito.2007.02.009. PMID: 17442628
Haas D, Hoffmann GF
Orphanet J Rare Dis 2006 Apr 26;1:13. doi: 10.1186/1750-1172-1-13. PMID: 16722536Free PMC Article
Hoffmann GF, Charpentier C, Mayatepek E, Mancini J, Leichsenring M, Gibson KM, Divry P, Hrebicek M, Lehnert W, Sartor K
Pediatrics 1993 May;91(5):915-21. PMID: 8386351

Prognosis

Brennenstuhl H, Nashawi M, Schröter J, Baronio F, Beedgen L, Gleich F, Jeltsch K, von Landenberg C, Martini S, Simon A, Thiel C, Tsiakas K, Opladen T, Kölker S, Hoffmann GF, Haas D; Unified Registry for Inherited Metabolic Disorders (U-IMD) Consortium and the European Registry for Hereditary Metabolic Disorders (MetabERN)
J Inherit Metab Dis 2021 Sep;44(5):1272-1287. Epub 2021 Jun 28 doi: 10.1002/jimd.12412. PMID: 34145613
Zhang S
Pediatr Rheumatol Online J 2016 May 4;14(1):30. doi: 10.1186/s12969-016-0091-7. PMID: 27142780Free PMC Article
Peciuliene S, Burnyte B, Gudaitiene R, Rusoniene S, Drazdiene N, Liubsys A, Utkus A
Pediatr Rheumatol Online J 2016 Mar 25;14(1):19. doi: 10.1186/s12969-016-0081-9. PMID: 27012807Free PMC Article
Kanungo S, Soares N, He M, Steiner RD
Dev Disabil Res Rev 2013;17(3):197-210. doi: 10.1002/ddrr.1114. PMID: 23798009
Hoffmann GF, Gibson KM, Trefz FK, Nyhan WL, Bremer HJ, Rating D
Eur J Pediatr 1994;153(7 Suppl 1):S94-100. doi: 10.1007/BF02138786. PMID: 7957396

Clinical prediction guides

Dvaladze A, Tavares E, Di Scipio M, Nimmo G, Grudzinska-Pechhacker MK, Paton T, Tumber A, Li S, Eileen C, Ertl-Wagner B, Mamak E, Hoffmann G, Marshall CR, Haas D, Mayatepek E, Schulze A, Heon E, Vincent A
Clin Genet 2022 Dec;102(6):524-529. Epub 2022 Aug 14 doi: 10.1111/cge.14207. PMID: 35916082
Sánchez-Manubens J, Iglesias E, Anton J
Expert Rev Clin Immunol 2019 Mar;15(3):215-220. Epub 2019 Jan 26 doi: 10.1080/1744666X.2019.1571410. PMID: 30652926
Stoffels M, Simon A
Curr Opin Rheumatol 2011 Sep;23(5):419-23. doi: 10.1097/BOR.0b013e328349c3b1. PMID: 21760510
Hoffmann GF, Charpentier C, Mayatepek E, Mancini J, Leichsenring M, Gibson KM, Divry P, Hrebicek M, Lehnert W, Sartor K
Pediatrics 1993 May;91(5):915-21. PMID: 8386351
Schafer BL, Bishop RW, Kratunis VJ, Kalinowski SS, Mosley ST, Gibson KM, Tanaka RD
J Biol Chem 1992 Jul 5;267(19):13229-38. PMID: 1377680

Recent systematic reviews

Elhani I, Hentgen V, Grateau G, Georgin-Lavialle S
Mol Genet Metab 2022 Jun;136(2):85-93. Epub 2022 Apr 30 doi: 10.1016/j.ymgme.2022.04.006. PMID: 35525811

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