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Mevalonic aciduria(MEVA)

MedGen UID:
368373
Concept ID:
C1959626
Disease or Syndrome
Synonyms: MEVA; Mevalonate kinase deficiency; 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
Sources: HPO, OMIM
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)
 
OMIM®: 610377

Definition

Mevalonic aciduria, 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.\n\nDuring 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.\n\nMevalonate 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).\n\nMevalonate 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
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.
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
Simultaneous enlargement of the liver and spleen.
Lymphadenopathy
MedGen UID:
96929
Concept ID:
C0497156
Disease or Syndrome
Enlargment (swelling) of a lymph node.
Fluctuating splenomegaly
MedGen UID:
322770
Concept ID:
C1835882
Finding
Intermittently increased size of the spleen.
Attenuation of retinal blood vessels
MedGen UID:
480605
Concept ID:
C3278975
Finding
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 of loose or watery bowel movements.
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.
Fluctuating splenomegaly
MedGen UID:
322770
Concept ID:
C1835882
Finding
Intermittently increased size of the spleen.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
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
Psychomotor retardation
MedGen UID:
98405
Concept ID:
C0424230
Finding
Abnormally slow physical movement.
Joubert syndrome
MedGen UID:
98464
Concept ID:
C0431399
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
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.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Leukocytosis
MedGen UID:
9736
Concept ID:
C0023518
Disease or Syndrome
An abnormal increase in the number of leukocytes in the blood.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Increased circulating IgD level
MedGen UID:
372146
Concept ID:
C1835869
Finding
An abnormally increased level of immunoglobulin D in blood.
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).
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
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
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.
Skin rash
MedGen UID:
8732
Concept ID:
C0015230
Finding
A widespread, acute rash.
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
Simultaneous enlargement of the liver and spleen.
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.
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, CPK; EC 2.7.3.2) in the blood. CPK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Increased circulating IgD level
MedGen UID:
372146
Concept ID:
C1835869
Finding
An abnormally increased level of immunoglobulin D in blood.
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.
Elevated urine mevalonic acid
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.
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.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Large fontanelles
MedGen UID:
105329
Concept ID:
C0456132
Finding
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.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Skin rash
MedGen UID:
8732
Concept ID:
C0015230
Finding
A widespread, acute rash.
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.
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
Acquired Abnormality
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
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
Attenuation of retinal blood vessels
MedGen UID:
480605
Concept ID:
C3278975
Finding
Increased circulating IgD level
MedGen UID:
372146
Concept ID:
C1835869
Finding
An abnormally increased level of immunoglobulin D in blood.

Professional guidelines

PubMed

Shinar Y, Obici L, Aksentijevich I, Bennetts B, Austrup F, Ceccherini I, Costa JM, De Leener A, Gattorno M, Kania U, Kone-Paut I, Lezer S, Livneh A, Moix I, Nishikomori R, Ozen S, Phylactou L, Risom L, Rowczenio D, Sarkisian T, van Gijn ME, Witsch-Baumgartner M, Morris M, Hoffman HM, Touitou I; European Molecular Genetics Quality Network.
Ann Rheum Dis 2012 Oct;71(10):1599-605. Epub 2012 Jun 1 doi: 10.1136/annrheumdis-2011-201271. PMID: 22661645Free PMC Article

Recent clinical studies

Etiology

Haas D, Niklowitz P, Hörster F, Baumgartner ER, Prasad C, Rodenburg RJ, Hoffmann GF, Menke T, Okun JG
J Inherit Metab Dis 2009 Aug;32(4):570-5. Epub 2009 Jun 7 doi: 10.1007/s10545-009-1150-8. PMID: 19504350
Celec P, Behuliak M
Med Hypotheses 2008;70(5):938-40. Epub 2007 Nov 26 doi: 10.1016/j.mehy.2007.08.030. PMID: 18037572
Neven B, Valayannopoulos V, Quartier P, Blanche S, Prieur AM, Debré M, Rolland MO, Rabier D, Cuisset L, Cavazzana-Calvo M, de Lonlay P, Fischer A
N Engl J Med 2007 Jun 28;356(26):2700-3. doi: 10.1056/NEJMoa070715. PMID: 17596604
Bretón Martínez JR, Cánovas Martínez A, Casaña Pérez S, Escribá Alepuz J, Giménez Vázquez F
J Inherit Metab Dis 2007 Oct;30(5):829. Epub 2007 Jun 21 doi: 10.1007/s10545-007-0618-7. PMID: 17578678
Haas D, Hoffmann GF
Orphanet J Rare Dis 2006 Apr 26;1:13. doi: 10.1186/1750-1172-1-13. PMID: 16722536Free PMC Article

Diagnosis

Szymanski AM, Dávila Saldaña B, Ferreira CR, Loechelt B, Jung L
Pediatr Transplant 2020 Feb;24(1):e13604. Epub 2019 Oct 25 doi: 10.1111/petr.13604. PMID: 31651069
Prasad C, Salvadori MI, Rupar CA
Mol Genet Metab 2012 Dec;107(4):756-9. Epub 2012 Oct 24 doi: 10.1016/j.ymgme.2012.10.019. PMID: 23146290
Brucknerova I, Behulova D, Sebova C, Bzduch V, Mach M, Dubovicky M, Ujhazy E
Neuro Endocrinol Lett 2009;30 Suppl 1:29-31. PMID: 20027140
Bretón Martínez JR, Cánovas Martínez A, Casaña Pérez S, Escribá Alepuz J, Giménez Vázquez F
J Inherit Metab Dis 2007 Oct;30(5):829. Epub 2007 Jun 21 doi: 10.1007/s10545-007-0618-7. PMID: 17578678
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

Pietrasanta C, Minoia F, Torreggiani S, Ronchi A, Gattorno M, Volpi S, Ceccherini I, Mosca F, Filocamo G, Pugni L
Clin Immunol 2019 Aug;205:25-28. Epub 2019 May 13 doi: 10.1016/j.clim.2019.05.002. PMID: 31096039
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

Prasad C, Salvadori MI, Rupar CA
Mol Genet Metab 2012 Dec;107(4):756-9. Epub 2012 Oct 24 doi: 10.1016/j.ymgme.2012.10.019. PMID: 23146290
Raupp P, Varady E, Duran M, Wanders RJ, Waterham HR, Houten SM
Arch Dis Child Fetal Neonatal Ed 2004 Jan;89(1):F90-1. PMID: 14711867Free PMC Article
Nimubona L, Laloum D, Rolland MO, Read MH, Guillois B, Duhamel JF
Acta Paediatr 2002;91(6):714-6. doi: 10.1080/080352502760069179. PMID: 12162608
Houten SM, Romeijn GJ, Koster J, Gray RG, Darbyshire P, Smit GP, de Klerk JB, Duran M, Gibson KM, Wanders RJ, Waterham HR
Hum Mol Genet 1999 Aug;8(8):1523-8. doi: 10.1093/hmg/8.8.1523. PMID: 10401001
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

Clinical prediction guides

Browne C, Timson DJ
Ann Hum Genet 2015 Nov;79(6):451-9. Epub 2015 Sep 29 doi: 10.1111/ahg.12126. PMID: 26420133
Brucknerova I, Behulova D, Sebova C, Bzduch V, Mach M, Dubovicky M, Ujhazy E
Neuro Endocrinol Lett 2009;30 Suppl 1:29-31. PMID: 20027140
Neven B, Valayannopoulos V, Quartier P, Blanche S, Prieur AM, Debré M, Rolland MO, Rabier D, Cuisset L, Cavazzana-Calvo M, de Lonlay P, Fischer A
N Engl J Med 2007 Jun 28;356(26):2700-3. doi: 10.1056/NEJMoa070715. PMID: 17596604
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

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