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Methylmalonic aciduria and homocystinuria type cblD(MAHCD)

MedGen UID:
341253
Concept ID:
C1848552
Disease or Syndrome
Synonyms: cblD (variant 1); cblD (variant 2); MAHCD; Methylmalonic acidemia with homocystinuria cblD; METHYLMALONIC ACIDEMIA, cblH TYPE; Methylmalonic aciduria with homocystinuria cblD type
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): MMADHC (2q23.2)
 
Monarch Initiative: MONDO:0010185
OMIM®: 277410
Orphanet: ORPHA79283

Definition

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]

Additional descriptions

From OMIM
Methylmalonic aciduria (MMA) and homocystinuria type cblD (MAHCD) is an autosomal recessive disorder of cobalamin (cbl; vitamin B12) metabolism. Affected individuals typically present in infancy or early childhood with variable neurologic abnormalities, including developmental delay, encephalopathy, seizures, poor feeding, impaired intellectual development, and nystagmus. Onset of symptoms in the teenage years has also been reported. Most patients also have megaloblastic anemia. Laboratory studies show methylmalonic aciduria and homocystinuria (Coelho et al., 2008). The metabolic 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) (Coelho et al., 2008; review by Watkins and Rosenblatt, 2022). Genetic Heterogeneity of Methylmalonic Aciduria and Homocystinuria Different forms of combined methylmalonic aciduria and homocystinuria have been classified historically according to complementation groups of cells in vitro: cblC (MAHCC; 277400), cblD, cblF (MAHCF; 277380), cblJ (MAHCJ; 614857), and cblL (MAHCL; 620940).  http://www.omim.org/entry/277410
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\nThe signs and symptoms of homocystinuria typically develop during childhood, although some mildly affected people may not show signs and symptoms until adulthood.\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).
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
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.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
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.
Spastic ataxia
MedGen UID:
376528
Concept ID:
C1849156
Disease or Syndrome
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Megaloblastic anemia
MedGen UID:
1527
Concept ID:
C0002888
Disease or Syndrome
Anemia characterized by the presence of erythroblasts that are larger than normal (megaloblasts).
Increased mean corpuscular volume
MedGen UID:
81303
Concept ID:
C0302845
Finding
Larger than normal size of erythrocytes.
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).
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.
Hypomethioninemia
MedGen UID:
336368
Concept ID:
C1848555
Finding
A decreased concentration of methionine 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 methylmalonyl-CoA mutase activity
MedGen UID:
336374
Concept ID:
C1848579
Finding
An abnormality of Krebs cycle metabolism that is characterized by a decreased rate of methylmalonyl-CoA mutase activity.
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.
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.

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
Haarmann A, Mayr M, Kölker S, Baumgartner ER, Schnierda J, Hopfer H, Devuyst O, Baumgartner MR
Mol Genet Metab 2013 Dec;110(4):472-6. Epub 2013 Sep 17 doi: 10.1016/j.ymgme.2013.08.021. PMID: 24095221

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
Haarmann A, Mayr M, Kölker S, Baumgartner ER, Schnierda J, Hopfer H, Devuyst O, Baumgartner MR
Mol Genet Metab 2013 Dec;110(4):472-6. Epub 2013 Sep 17 doi: 10.1016/j.ymgme.2013.08.021. PMID: 24095221

Prognosis

Haarmann A, Mayr M, Kölker S, Baumgartner ER, Schnierda J, Hopfer H, Devuyst O, Baumgartner MR
Mol Genet Metab 2013 Dec;110(4):472-6. Epub 2013 Sep 17 doi: 10.1016/j.ymgme.2013.08.021. PMID: 24095221
Coelho D, Suormala T, Stucki M, Lerner-Ellis JP, Rosenblatt DS, Newbold RF, Baumgartner MR, Fowler B
N Engl J Med 2008 Apr 3;358(14):1454-64. doi: 10.1056/NEJMoa072200. PMID: 18385497

Clinical prediction guides

Coelho D, Suormala T, Stucki M, Lerner-Ellis JP, Rosenblatt DS, Newbold RF, Baumgartner MR, Fowler B
N Engl J Med 2008 Apr 3;358(14):1454-64. doi: 10.1056/NEJMoa072200. PMID: 18385497

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    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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