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Fumarase deficiency(FMRD)

MedGen UID:
87458
Concept ID:
C0342770
Disease or Syndrome
Synonyms: FMRD; Fumarate Hydratase Deficiency; Fumaric aciduria
SNOMED CT: Fumarase deficiency (237983002); Fumarate hydratase deficiency (237983002)
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): FH (1q43)
 
Monarch Initiative: MONDO:0011730
OMIM®: 606812
Orphanet: ORPHA24

Disease characteristics

Excerpted from the GeneReview: Fumarate Hydratase Deficiency
Fumarate hydratase (FH) deficiency results in severe neonatal and early infantile encephalopathy that is characterized by poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Dysmorphic facial features include frontal bossing, depressed nasal bridge, and widely spaced eyes. Many affected individuals are microcephalic. A spectrum of brain abnormalities are seen on magnetic resonance imaging, including cerebral atrophy, enlarged ventricles and generous extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum, and an abnormally small brain stem. Brain malformations including bilateral polymicrogyria and absence of the corpus callosum can also be observed. Development is severely affected: most affected individuals are nonverbal and nonambulatory, and many die during early childhood. Less severely affected individuals with moderate cognitive impairment and long-term survival have been reported. [from GeneReviews]
Authors:
David Coman  |  Kamil R Kranc  |  John Christodoulou   view full author information

Additional descriptions

From OMIM
Fumarase deficiency (FMRD) is a severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy (summary by Kerrigan et al., 2000 and Mroch et al., 2012).  http://www.omim.org/entry/606812
From MedlinePlus Genetics
Fumarase deficiency is a condition that primarily affects the nervous system, especially the brain. Affected infants may have an abnormally small head size (microcephaly), abnormal brain structure, severe developmental delay, weak muscle tone (hypotonia), and failure to gain weight and grow at the expected rate (failure to thrive). They may also experience seizures. Some people with this disorder have unusual facial features, including a prominent forehead (frontal bossing), low-set ears, a small jaw (micrognathia), widely spaced eyes (ocular hypertelorism), and a depressed nasal bridge. An enlarged liver and spleen (hepatosplenomegaly) may also be associated with this disorder, as well as an excess of red blood cells (polycythemia) or deficiency of white blood cells (leukopenia) in infancy. Affected individuals usually survive only a few months, but a few have lived into early adulthood.  https://medlineplus.gov/genetics/condition/fumarase-deficiency

Clinical features

From HPO
Cutaneous leiomyoma
MedGen UID:
87533
Concept ID:
C0346064
Neoplastic Process
The presence of leiomyoma of the skin.
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Increased urine succinate level
MedGen UID:
1771435
Concept ID:
C5421603
Finding
The concentration of succinate in the urine, normalized for urine concentration, is above the upper limit of normal.
Elevated urine fumaric acid level
MedGen UID:
1842100
Concept ID:
C5826557
Finding
The concentration of fumaric acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Perimembranous ventricular septal defect
MedGen UID:
87490
Concept ID:
C0344925
Congenital Abnormality
A ventricular septal defect that is confluent with and involves the membranous septum and is bordered by an atrioventricular valve, not including the type 3 VSDs.
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.
Ascites
MedGen UID:
416
Concept ID:
C0003962
Disease or Syndrome
Accumulation of fluid in the peritoneal cavity.
Intrahepatic cholestasis
MedGen UID:
3042
Concept ID:
C0008372
Disease or Syndrome
Impairment of bile flow due to obstruction in the small bile ducts within the liver.
Liver failure
MedGen UID:
88444
Concept ID:
C0085605
Disease or Syndrome
A disorder characterized by the inability of the liver to metabolize chemicals in the body. Causes include cirrhosis and drug-induced hepatotoxicity. Signs and symptoms include jaundice and encephalopathy. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic dehydrogenase, and alkaline phosphatase.
Necrotizing enterocolitis
MedGen UID:
105440
Concept ID:
C0520459
Disease or Syndrome
Inflammation of the intestine leading to bacterial invasion causing cellular damage and death which causes necrosis of the colon and intestine.
Status epilepticus
MedGen UID:
11586
Concept ID:
C0038220
Disease or Syndrome
Status epilepticus is a type of prolonged seizure resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.
Corpus callosum, agenesis of
MedGen UID:
104498
Concept ID:
C0175754
Congenital Abnormality
The corpus callosum is the largest fiber tract in the central nervous system and the major interhemispheric fiber bundle in the brain. Formation of the corpus callosum begins as early as 6 weeks' gestation, with the first fibers crossing the midline at 11 to 12 weeks' gestation, and completion of the basic shape by age 18 to 20 weeks (Schell-Apacik et al., 2008). Agenesis of the corpus callosum (ACC) is one of the most frequent malformations in brain with a reported incidence ranging between 0.5 and 70 in 10,000 births. ACC is a clinically and genetically heterogeneous condition, which can be observed either as an isolated condition or as a manifestation in the context of a congenital syndrome (see MOLECULAR GENETICS and Dobyns, 1996). Also see mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600). Schell-Apacik et al. (2008) noted that there is confusion in the literature regarding radiologic terminology concerning partial absence of the corpus callosum, where various designations have been used, including hypogenesis, hypoplasia, partial agenesis, or dysgenesis.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Lissencephaly
MedGen UID:
78604
Concept ID:
C0266463
Finding
A spectrum of malformations of cortical development caused by insufficient neuronal migration that subsumes the terms agyria, pachygyria and subcortical band heterotopia. See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
Polymicrogyria
MedGen UID:
78605
Concept ID:
C0266464
Congenital Abnormality
Polymicrogyria is a congenital malformation of the cerebral cortex characterized by abnormal cortical layering (lamination) and an excessive number of small gyri (folds).
Choroid plexus cyst
MedGen UID:
87376
Concept ID:
C0338597
Finding
A cyst occurring within the choroid plexus within a cerebral ventricle.
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.
Hypoplasia of the brainstem
MedGen UID:
334226
Concept ID:
C1842688
Finding
Underdevelopment of the brainstem.
Open operculum
MedGen UID:
436570
Concept ID:
C2675973
Finding
Underdevelopment of the operculum.
Intellectual disability, profound
MedGen UID:
892508
Concept ID:
C3161330
Mental or Behavioral Dysfunction
Profound mental retardation is defined as an intelligence quotient (IQ) below 20.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Abnormal speech pattern
MedGen UID:
1853271
Concept ID:
C3687424
Finding
An abnormality in the sound (volume) or cadence (rate) of speech.
Polycythemia
MedGen UID:
18552
Concept ID:
C0032461
Disease or Syndrome
Polycythemia is diagnosed if the red blood cell count, the hemoglobin level, and the red blood cell volume all exceed the upper limits of normal.
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.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Relative macrocephaly
MedGen UID:
338607
Concept ID:
C1849075
Congenital Abnormality
A relatively mild degree of macrocephaly in which the head circumference is not above two standard deviations from the mean, but appears dysproportionately large when other factors such as body stature are taken into account.
Reduced subcutaneous adipose tissue
MedGen UID:
387876
Concept ID:
C1857657
Finding
A reduced amount of fat tissue in the lowest layer of the integument. This feature can be appreciated by a reduced skinfold thickness.
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.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Hyperbilirubinemia
MedGen UID:
86321
Concept ID:
C0311468
Finding
An increased amount of bilirubin in the blood.
Decreased fumarate hydratase activity
MedGen UID:
343007
Concept ID:
C1853903
Finding
An abnormality of Krebs cycle metabolism that is characterized by a decreased rate of fumarate hydratase activity.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Conjunctival icterus
MedGen UID:
537025
Concept ID:
C0240962
Finding
Conjunctival icterus is a condition where there is yellowing of the whites of the eyes. This is most commonly seen in patients who have liver disease.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Pallor
MedGen UID:
69133
Concept ID:
C0241137
Finding
Abnormally pale skin.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Bilateral fetal pyelectasis
MedGen UID:
869105
Concept ID:
C4023523
Disease or Syndrome
A bilateral form of fetal pyelectasis.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.
Mitochondrial swelling
MedGen UID:
7664
Concept ID:
C0026244
Cell or Molecular Dysfunction
The mitochondrial matrix refers to the substance occupying the space enclosed by the inner membrane of a mitochondrion, which contains enzymes, DNA, granules, and inclusions of protein crystals, glycogen, and lipid. Mitochondrial swelling refers to an increase in size of the mitochondrial matrix. This phenomenon is thought to be related to a permeabilized inner membrane that originates a large swelling in the mitochondrial matrix. Mitochondrial swelling may distend the outer membrane until it ruptures.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVFumarase deficiency
Follow this link to review classifications for Fumarase deficiency in Orphanet.

Professional guidelines

PubMed

Strauss TS, Boniferro E, Brockhoff E, Johnson A, Schneider E, Grubman O, Cole D, Hussain F, Ashmead G, Al-Ibraheemi Z, Brustman L
Am J Obstet Gynecol MFM 2023 Mar;5(3):100820. Epub 2022 Nov 28 doi: 10.1016/j.ajogmf.2022.100820. PMID: 36455867

Recent clinical studies

Etiology

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Tregoning S, Salter W, Thorburn DR, Durkie M, Panayi M, Wu JY, Easterbrook A, Coman DJ
Twin Res Hum Genet 2013 Dec;16(6):1117-20. Epub 2013 Nov 4 doi: 10.1017/thg.2013.72. PMID: 24182348
Ottolenghi C, Hubert L, Allanore Y, Brassier A, Altuzarra C, Mellot-Draznieks C, Bekri S, Goldenberg A, Veyrieres S, Boddaert N, Barbier V, Valayannopoulos V, Slama A, Chrétien D, Ricquier D, Marret S, Frebourg T, Rabier D, Munnich A, de Keyzer Y, Toulhoat H, de Lonlay P
Hum Mutat 2011 Sep;32(9):1046-52. Epub 2011 Jul 12 doi: 10.1002/humu.21534. PMID: 21560188
De Vivo DC
Brain Dev 1993 Jan-Feb;15(1):1-22. doi: 10.1016/0387-7604(93)90002-p. PMID: 8338207
DiMauro S, Bonilla E, Zeviani M, Servidei S, DeVivo DC, Schon EA
J Inherit Metab Dis 1987;10 Suppl 1:113-28. doi: 10.1007/BF01812852. PMID: 2824920

Diagnosis

Kimonis VE, Steller J, Sahai I, Grange DK, Shoemaker J, Zelaya BM, Mandell R, Shih K, Shih V
Mol Genet Metab 2012 Sep;107(1-2):241-2. Epub 2012 Apr 20 doi: 10.1016/j.ymgme.2012.04.010. PMID: 22595425
Allegri G, Fernandes MJ, Scalco FB, Correia P, Simoni RE, Llerena JC Jr, de Oliveira ML
J Inherit Metab Dis 2010 Aug;33(4):411-9. Epub 2010 Jun 15 doi: 10.1007/s10545-010-9134-2. PMID: 20549362
De Meirleir L
J Child Neurol 2002 Dec;17 Suppl 3:3S26-33; discussion 3S33-4. PMID: 12597053
Coughlin EM, Christensen E, Kunz PL, Krishnamoorthy KS, Walker V, Dennis NR, Chalmers RA, Elpeleg ON, Whelan D, Pollitt RJ, Ramesh V, Mandell R, Shih VE
Mol Genet Metab 1998 Apr;63(4):254-62. doi: 10.1006/mgme.1998.2684. PMID: 9635293
Remes AM, Rantala H, Hiltunen JK, Leisti J, Ruokonen A
Pediatrics 1992 Apr;89(4 Pt 2):730-4. PMID: 1557269

Therapy

Kimonis VE, Steller J, Sahai I, Grange DK, Shoemaker J, Zelaya BM, Mandell R, Shih K, Shih V
Mol Genet Metab 2012 Sep;107(1-2):241-2. Epub 2012 Apr 20 doi: 10.1016/j.ymgme.2012.04.010. PMID: 22595425

Prognosis

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Hum Mutat 2011 Sep;32(9):1046-52. Epub 2011 Jul 12 doi: 10.1002/humu.21534. PMID: 21560188
Deschauer M, Gizatullina Z, Schulze A, Pritsch M, Knöppel C, Knape M, Zierz S, Gellerich FN
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Mol Genet Metab 1998 Apr;63(4):254-62. doi: 10.1006/mgme.1998.2684. PMID: 9635293
Bourgeron T, Chretien D, Poggi-Bach J, Doonan S, Rabier D, Letouzé P, Munnich A, Rötig A, Landrieu P, Rustin P
J Clin Invest 1994 Jun;93(6):2514-8. doi: 10.1172/JCI117261. PMID: 8200987Free PMC Article

Clinical prediction guides

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J Coll Physicians Surg Pak 2017 Apr;27(4):218-221. PMID: 28492150
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Hum Mutat 2011 Sep;32(9):1046-52. Epub 2011 Jul 12 doi: 10.1002/humu.21534. PMID: 21560188
Allegri G, Fernandes MJ, Scalco FB, Correia P, Simoni RE, Llerena JC Jr, de Oliveira ML
J Inherit Metab Dis 2010 Aug;33(4):411-9. Epub 2010 Jun 15 doi: 10.1007/s10545-010-9134-2. PMID: 20549362
Coughlin EM, Christensen E, Kunz PL, Krishnamoorthy KS, Walker V, Dennis NR, Chalmers RA, Elpeleg ON, Whelan D, Pollitt RJ, Ramesh V, Mandell R, Shih VE
Mol Genet Metab 1998 Apr;63(4):254-62. doi: 10.1006/mgme.1998.2684. PMID: 9635293
Bourgeron T, Chretien D, Poggi-Bach J, Doonan S, Rabier D, Letouzé P, Munnich A, Rötig A, Landrieu P, Rustin P
J Clin Invest 1994 Jun;93(6):2514-8. doi: 10.1172/JCI117261. PMID: 8200987Free PMC Article

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