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Methylmalonic aciduria and homocystinuria type cblF(cblF; MAHCF)

MedGen UID:
336373
Concept ID:
C1848578
Disease or Syndrome
Synonyms: COBALAMIN F DISEASE; COBALAMIN, DEFECT IN LYSOSOMAL RELEASE OF; METHYLMALONIC ACIDEMIA AND HOMOCYSTINURIA, cblF TYPE; METHYLMALONIC ACIDURIA DUE TO VITAMIN B12-RELEASE DEFECT; VITAMIN B12 LYSOSOMAL RELEASE DEFECT; VITAMIN B12 STORAGE DISEASE
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): LMBRD1 (6q13)
 
Monarch Initiative: MONDO:0010183
OMIM®: 277380
Orphanet: ORPHA79284

Disease characteristics

Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord. [from GeneReviews]
Authors:
Jennifer L Sloan  |  Nuria Carrillo  |  David Adams, et. al.   view full author information

Additional descriptions

From OMIM
Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC (MAHCC; 277400), cblD (MAHCD; 277410), cblF, and cblJ (MAHCJ; 614857).  http://www.omim.org/entry/277380
From MedlinePlus Genetics
Methylmalonic acidemia with homocystinuria is a disorder in which the body is unable to correctly process certain protein building blocks (amino acids), fat building blocks (fatty acids), and  cholesterol. The body is also unable to convert the amino acid homocysteine to another amino acid, methionine. Individuals with this disorder have a combination of features from two separate conditions, methylmalonic acidemia and homocystinuria. There are several forms of this combined condition, and the different forms have different genetic causes and signs and symptoms. The most common and best understood form, called cblC type (or cobalamin C disease), occurs in about 80 percent of affected individuals. 

The signs and symptoms of methylmalonic acidemia with homocystinuria usually develop in infancy, although they can begin at any age. When the condition begins early in life, affected individuals typically grow more slowly than expected. This sign is sometimes iedentified before the baby is born. These infants can also have difficulty feeding and have an abnormally pale appearance (pallor). Eye abnormalities and neurological problems, including weak muscle tone (hypotonia) and seizures, are also common in people with methylmalonic acidemia with homocystinuria. Many infants and children with this condition have delayed development and intellectual disability, and some have an unusually small head size (microcephaly). 

Some people with methylmalonic acidemia with homocystinuria develop a blood disorder called megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia), and the remaining red blood cells are larger than normal (megaloblastic). The signs and symptoms of early-onset methylmalonic acidemia with homocystinuria worsen over time, and the condition can be life-threatening if it is not treated.

When methylmalonic acidemia with homocystinuria begins in adolescence or adulthood, it may change an affected person's behavior and personality; the person may become less social and may experience hallucinations, delirium, and psychosis. In addition, these individuals can begin to lose previously acquired mental and physical abilities, resulting in a decline in school or work performance, difficulty controlling movements, memory problems, speech difficulties, a decline in intellectual function (dementia), or an extreme lack of energy (lethargy). Some people with methylmalonic acidemia with homocystinuria whose signs and symptoms begin later in life develop a condition called subacute combined degeneration of the spinal cord, which leads to numbness and weakness in the lower limbs, difficulty walking, and frequent falls.  https://medlineplus.gov/genetics/condition/methylmalonic-acidemia-with-homocystinuria

Clinical features

From HPO
Homocystinuria
MedGen UID:
42485
Concept ID:
C0019880
Disease or Syndrome
Homocystinuria is an inherited disorder in which the body is unable to process certain building blocks of proteins (amino acids) properly. \n\nThe most common form of homocystinuria, called classic homocystinuria, is characterized by tall stature, nearsightedness (myopia), dislocation of the lens at the front of the eye, a higher risk of blood clotting disorders, and brittle bones that are prone to fracture (osteoporosis) or other skeletal abnormalities. Some affected individuals also have developmental delay and learning problems.\n\nLess common forms of homocystinuria can cause intellectual disability, slower growth and weight gain (failure to thrive), seizures, and problems with movement. They can also cause and a blood disorder called megaloblastic anemia, which occurs when a person has a low number of red blood cells (anemia), and the remaining red blood cells are larger than normal (megaloblastic).\n\nThe signs and symptoms of homocystinuria typically develop during childhood, although some mildly affected people may not show signs and symptoms until adulthood.
Cystathioninuria
MedGen UID:
66353
Concept ID:
C0220993
Disease or Syndrome
Cystathioninuria, an autosomal recessive phenotype with no striking pathologic features, is characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion. Because of the inconsistency and wide variety of disease associations, cystathioninuria is considered to be a benign biochemical anomaly (Mudd et al., 2001).
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Dextrocardia
MedGen UID:
4255
Concept ID:
C0011813
Congenital Abnormality
The heart is located in the right hand sided hemithorax. That is, there is a left-right reversal (or "mirror reflection") of the anatomical location of the heart in which the heart is locate on the right side instead of the left.
Patent ductus arteriosus
MedGen UID:
4415
Concept ID:
C0013274
Congenital Abnormality
In utero, the ductus arteriosus (DA) serves to divert ventricular output away from the lungs and toward the placenta by connecting the main pulmonary artery to the descending aorta. A patent ductus arteriosus (PDA) in the first 3 days of life is a physiologic shunt in healthy term and preterm newborn infants, and normally is substantially closed within about 24 hours after bith and completely closed after about three weeks. Failure of physiologcal closure is referred to a persistent or patent ductus arteriosus (PDA). Depending on the degree of left-to-right shunting, PDA can have clinical consequences.
Atrial septal defect
MedGen UID:
6753
Concept ID:
C0018817
Congenital Abnormality
Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.
Small for gestational age
MedGen UID:
65920
Concept ID:
C0235991
Finding
Smaller than normal size according to sex and gestational age related norms, defined as a weight below the 10th percentile for the gestational age.
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
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.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Microtia
MedGen UID:
57535
Concept ID:
C0152423
Congenital Abnormality
Underdevelopment of the external ear.
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.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.
Incoordination
MedGen UID:
141714
Concept ID:
C0520966
Finding
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.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Megaloblastic anemia
MedGen UID:
1527
Concept ID:
C0002888
Disease or Syndrome
Anemia characterized by the presence of erythroblasts that are larger than normal (megaloblasts).
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
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.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Tracheoesophageal fistula
MedGen UID:
21228
Concept ID:
C0040588
Anatomical Abnormality
An abnormal connection (fistula) between the esophagus and the trachea.
Stomatitis
MedGen UID:
52511
Concept ID:
C0038362
Disease or Syndrome
Stomatitis is an inflammation of the mucous membranes of any of the structures in the mouth.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Skin rash
MedGen UID:
1830322
Concept ID:
C5779628
Sign or Symptom
A red eruption of the skin.
Methylmalonic acidemia
MedGen UID:
120654
Concept ID:
C0268583
Disease or Syndrome
For this GeneReview, the term "isolated methylmalonic acidemia" refers to a group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine that result from the failure to isomerize (convert) methylmalonyl-coenzyme A (CoA) into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid. Isolated MMA is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, 5-deoxy-adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Prior to the advent of newborn screening, common phenotypes included: Infantile/non-B12-responsive form (mut0 enzymatic subtype, cblB), the most common phenotype, associated with infantile-onset lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds. Without appropriate treatment, the infantile/non-B12-responsive phenotype could rapidly progress to coma due to hyperammonemic encephalopathy. Partially deficient or B12-responsive phenotypes (mut– enzymatic subtype, cblA, cblB [rare], cblD-MMA), in which symptoms occur in the first few months or years of life and are characterized by feeding problems, failure to thrive, hypotonia, and developmental delay marked by episodes of metabolic decompensation. Methylmalonyl-CoA epimerase deficiency, in which findings range from complete absence of symptoms to severe metabolic acidosis. Affected individuals can also develop ataxia, dysarthria, hypotonia, mild spastic paraparesis, and seizures. In those individuals diagnosed by newborn screening and treated from an early age, there appears to be decreased early mortality, less severe symptoms at diagnosis, favorable short-term neurodevelopmental outcome, and lower incidence of movement disorders and irreversible cerebral damage. However, secondary complications may still occur and can include intellectual disability, tubulointerstitial nephritis with progressive impairment of renal function, "metabolic stroke" (bilateral lacunar infarction of the basal ganglia during acute metabolic decompensation), pancreatitis, growth failure, functional immune impairment, bone marrow failure, optic nerve atrophy, arrhythmias and/or cardiomyopathy (dilated or hypertrophic), liver steatosis/fibrosis/cancer, and renal cancer.
Cystathioninemia
MedGen UID:
75699
Concept ID:
C0268618
Disease or Syndrome
An increased concentration of cystathionine in the blood.
Decreased circulating adenosylcobalamin concentration
MedGen UID:
336369
Concept ID:
C1848556
Finding
The concentration of adenosylcobalam in the blood circulation is below the lower limit of normal. Adenosylcobalamin is one of the active forms of vitamin B12.
Decreased methionine synthase activity
MedGen UID:
376395
Concept ID:
C1848580
Finding
A reduction in methionine synthase activity.
Hyperhomocystinemia
MedGen UID:
812677
Concept ID:
C3806347
Finding
An increased concentration of homocystine in the blood.
Decreased circulating methylcobalamin concentration
MedGen UID:
867371
Concept ID:
C4021736
Finding
The concentration of methylcobalamin in the blood circulation is below the lower limit of normal. Methylcobalamin is a form of vitamin B12.
Elevated circulating propionylcarnitine concentration
MedGen UID:
1778397
Concept ID:
C5539596
Finding
Increased concentration of propionylcarnitine in the blood circulation.
Glossitis
MedGen UID:
6618
Concept ID:
C0017675
Disease or Syndrome
Inflammation of the tongue.
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).
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).

Term Hierarchy

Follow this link to review classifications for Methylmalonic aciduria and homocystinuria type cblF in Orphanet.

Recent clinical studies

Etiology

Hwang N, Jang JH, Cho EH, Choi R, Choi SJ, Park HD
Mol Genet Genomic Med 2021 Nov;9(11):e1838. Epub 2021 Oct 16 doi: 10.1002/mgg3.1838. PMID: 34655177Free PMC Article
Bonafede L, Ficicioglu CH, Serrano L, Han G, Morgan JI, Mills MD, Forbes BJ, Davidson SL, Binenbaum G, Kaplan PB, Nichols CW, Verloo P, Leroy BP, Maguire AM, Aleman TS
Invest Ophthalmol Vis Sci 2015 Dec;56(13):7875-87. doi: 10.1167/iovs.15-17857. PMID: 26658511Free PMC Article
Armour CM, Brebner A, Watkins D, Geraghty MT, Chan A, Rosenblatt DS
Pediatrics 2013 Jul;132(1):e257-61. Epub 2013 Jun 17 doi: 10.1542/peds.2013-0105. PMID: 23776111

Diagnosis

Hwang N, Jang JH, Cho EH, Choi R, Choi SJ, Park HD
Mol Genet Genomic Med 2021 Nov;9(11):e1838. Epub 2021 Oct 16 doi: 10.1002/mgg3.1838. PMID: 34655177Free PMC Article
Pillai NR, Miller D, Pierpont EI, Berry SA, Aggarwal A
Am J Med Genet A 2021 Jun;185(6):1870-1874. Epub 2021 Mar 17 doi: 10.1002/ajmg.a.62170. PMID: 33729671
Wu C, Sun Q, Fan D
JAMA Neurol 2018 Mar 1;75(3):374-375. doi: 10.1001/jamaneurol.2017.4527. PMID: 29340559
Fettelschoss V, Burda P, Sagné C, Coelho D, De Laet C, Lutz S, Suormala T, Fowler B, Pietrancosta N, Gasnier B, Bornhauser B, Froese DS, Baumgartner MR
J Biol Chem 2017 Jul 14;292(28):11980-11991. Epub 2017 Jun 1 doi: 10.1074/jbc.M117.784819. PMID: 28572511Free PMC Article
Armour CM, Brebner A, Watkins D, Geraghty MT, Chan A, Rosenblatt DS
Pediatrics 2013 Jul;132(1):e257-61. Epub 2013 Jun 17 doi: 10.1542/peds.2013-0105. PMID: 23776111

Therapy

Armour CM, Brebner A, Watkins D, Geraghty MT, Chan A, Rosenblatt DS
Pediatrics 2013 Jul;132(1):e257-61. Epub 2013 Jun 17 doi: 10.1542/peds.2013-0105. PMID: 23776111

Prognosis

Pillai NR, Miller D, Pierpont EI, Berry SA, Aggarwal A
Am J Med Genet A 2021 Jun;185(6):1870-1874. Epub 2021 Mar 17 doi: 10.1002/ajmg.a.62170. PMID: 33729671
Armour CM, Brebner A, Watkins D, Geraghty MT, Chan A, Rosenblatt DS
Pediatrics 2013 Jul;132(1):e257-61. Epub 2013 Jun 17 doi: 10.1542/peds.2013-0105. PMID: 23776111

Clinical prediction guides

Bonafede L, Ficicioglu CH, Serrano L, Han G, Morgan JI, Mills MD, Forbes BJ, Davidson SL, Binenbaum G, Kaplan PB, Nichols CW, Verloo P, Leroy BP, Maguire AM, Aleman TS
Invest Ophthalmol Vis Sci 2015 Dec;56(13):7875-87. doi: 10.1167/iovs.15-17857. PMID: 26658511Free PMC Article

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C3 Acylcarnitine, Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA), 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Propionic and Methylmalonic Acidemia: C3 Elevated, 2022

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