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Methylcobalamin deficiency type cblG(HMAG)

MedGen UID:
344426
Concept ID:
C1855128
Disease or Syndrome
Synonyms: Functional methionine synthase deficiency type cblG; HMAG; HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblG COMPLEMENTATION TYPE; HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG COMPLEMENTATION TYPE; HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG 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): MTR (1q43)
 
Monarch Initiative: MONDO:0009609
OMIM®: 250940
Orphanet: ORPHA2170

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 description

From OMIM
Homocystinuria and megaloblastic anemia is an autosomal recessive inborn error of metabolism resulting from defects in the cobalamin (vitamin B12)-dependent pathway that converts homocysteine to methionine, which is catalyzed by methionine synthase. Clinical features are somewhat variable, but include delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia, all of which respond to cobalamin supplementation. Methylmalonic aciduria is not present. Two complementation groups have been described based on fibroblast studies: CblE (236270) and CblG (Watkins and Rosenblatt, 1988). Most patients present in early infancy, but some patients with CblG have shown later onset (Outteryck et al., 2012). Cells from patients with CblE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent. Cells from patients with CblG have defects in the methionine synthase enzyme under both conditions (summary by Leclerc et al., 1996). CblE is caused by mutation in the MTRR gene (602568). Watkins and Rosenblatt (1989) commented on the clinical and biochemical heterogeneity in patients with cblE and cblG.  http://www.omim.org/entry/250940

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.
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Pes planus
MedGen UID:
42034
Concept ID:
C0016202
Anatomical Abnormality
A foot where the longitudinal arch of the foot is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced.
Slender finger
MedGen UID:
387832
Concept ID:
C1857482
Finding
Fingers that are disproportionately narrow (reduced girth) for the hand/foot size or build of the individual.
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).
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
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.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.
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.
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.
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.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
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.
Generalized-onset seizure
MedGen UID:
115963
Concept ID:
C0234533
Disease or Syndrome
A generalized-onset seizure is a type of seizure originating at some point within, and rapidly engaging, bilaterally distributed networks. The networks may include cortical and subcortical structures but not necessarily the entire cortex.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
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.
Poor coordination
MedGen UID:
107874
Concept ID:
C0563243
Finding
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
Severe global developmental delay
MedGen UID:
332436
Concept ID:
C1837397
Finding
A severe delay in the achievement of motor or mental milestones in the domains of development of a child.
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.
Megaloblastic anemia
MedGen UID:
1527
Concept ID:
C0002888
Disease or Syndrome
Anemia characterized by the presence of erythroblasts that are larger than normal (megaloblasts).
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.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Hypomethioninemia
MedGen UID:
336368
Concept ID:
C1848555
Finding
A decreased concentration of methionine in the blood.
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.
Abnormal circulating vitamin B12 concentration
MedGen UID:
866685
Concept ID:
C4021032
Finding
A deviation from the normal concentration of cobalamin (vitamin B12) in the blood. Vitamin B12 is one of the eight B vitamins.
Abnormal blood folate concentration
MedGen UID:
866690
Concept ID:
C4021037
Finding
Any deviation from the normal concentration of folate in the blood circulation.
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.
Rotary nystagmus
MedGen UID:
116106
Concept ID:
C0240595
Disease or Syndrome
A form of nystagmus in which the eyeball makes rotary motions around the axis.
Blindness
MedGen UID:
99138
Concept ID:
C0456909
Disease or Syndrome
Blindness is the condition of lacking visual perception defined as a profound reduction in visual perception. On the 6m visual acuity scale, blindness is defined as less than 3/60. On the 20ft visual acuity scale, blindness is defined as less than 20/400. On the decimal visual acuity scale, blindness is defined as less than 0.05. Blindness is typically characterized by a visual field of no greater than 10 degrees in radius around central fixation.

Professional guidelines

PubMed

Kripps KA, Sremba L, Larson AA, Van Hove JLK, Nguyen H, Wright EL, Mirsky DM, Watkins D, Rosenblatt DS, Ketteridge D, Berry SA, McCandless SE, Baker PR 2nd
J Inherit Metab Dis 2022 Mar;45(2):157-168. Epub 2021 Oct 21 doi: 10.1002/jimd.12448. PMID: 34625984
Vaisbich MH, Braga A, Gabrielle M, Bueno C, Piazzon F, Kok F
Pediatr Nephrol 2017 Jun;32(6):1089-1092. Epub 2017 Feb 16 doi: 10.1007/s00467-017-3615-6. PMID: 28210839

Recent clinical studies

Etiology

Kripps KA, Sremba L, Larson AA, Van Hove JLK, Nguyen H, Wright EL, Mirsky DM, Watkins D, Rosenblatt DS, Ketteridge D, Berry SA, McCandless SE, Baker PR 2nd
J Inherit Metab Dis 2022 Mar;45(2):157-168. Epub 2021 Oct 21 doi: 10.1002/jimd.12448. PMID: 34625984
Vaisbich MH, Braga A, Gabrielle M, Bueno C, Piazzon F, Kok F
Pediatr Nephrol 2017 Jun;32(6):1089-1092. Epub 2017 Feb 16 doi: 10.1007/s00467-017-3615-6. PMID: 28210839

Diagnosis

Kripps KA, Sremba L, Larson AA, Van Hove JLK, Nguyen H, Wright EL, Mirsky DM, Watkins D, Rosenblatt DS, Ketteridge D, Berry SA, McCandless SE, Baker PR 2nd
J Inherit Metab Dis 2022 Mar;45(2):157-168. Epub 2021 Oct 21 doi: 10.1002/jimd.12448. PMID: 34625984
Kasapkara ÇS, Yılmaz-Keskin E, Özbay-Hoşnut F, Akçaboy M, Polat E, Olgaç A, Zorlu P
Turk J Pediatr 2019;61(2):282-285. doi: 10.24953/turkjped.2019.02.021. PMID: 31951343
Vaisbich MH, Braga A, Gabrielle M, Bueno C, Piazzon F, Kok F
Pediatr Nephrol 2017 Jun;32(6):1089-1092. Epub 2017 Feb 16 doi: 10.1007/s00467-017-3615-6. PMID: 28210839

Therapy

Ghemrawi R, Arnold C, Battaglia-Hsu SF, Pourié G, Trinh I, Bassila C, Rashka C, Wiedemann A, Flayac J, Robert A, Dreumont N, Feillet F, Guéant JL, Coelho D
Metabolism 2019 Dec;101:153992. Epub 2019 Oct 28 doi: 10.1016/j.metabol.2019.153992. PMID: 31672445
Vaisbich MH, Braga A, Gabrielle M, Bueno C, Piazzon F, Kok F
Pediatr Nephrol 2017 Jun;32(6):1089-1092. Epub 2017 Feb 16 doi: 10.1007/s00467-017-3615-6. PMID: 28210839
Stokes MB, Zviti R, Lin F, D'Agati VD
Pediatr Nephrol 2016 Dec;31(12):2263-2264. Epub 2016 Mar 15 doi: 10.1007/s00467-016-3344-2. PMID: 26980088

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