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METHYLCOBALAMIN DEFICIENCY, cblG TYPE(HMAG)

MedGen UID:
344426
Concept ID:
C1855128
Disease or Syndrome
Synonyms: HMAG; HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblG COMPLEMENTATION TYPE; HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG COMPLEMENTATION TYPE; METHIONINE SYNTHASE DEFICIENCY
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): MTR (1q43)
OMIM®: 250940
Orphanet: ORPHA2170

Definition

The clinical manifestations of disorders of intracellular cobalamin metabolism can be highly variable even within a single complementation group. The prototype and best understood is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range, including: Newborns, who can have intrauterine growth retardation (IUGR) and microcephaly; Infants, who can have poor feeding, failure to thrive, pallor, and neurologic signs, and occasionally hemolytic uremic syndrome (HUS) and/or seizures including infantile spasms; Toddlers, who can have failure to thrive, poor head growth, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures; and Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, and/or subacute combined degeneration of the spinal cord. [from GTR]

Additional descriptions

From GeneReviews
The clinical manifestations of disorders of intracellular cobalamin metabolism can be highly variable even within a single complementation group. The prototype and best understood is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range, including: Newborns, who can have intrauterine growth retardation (IUGR) and microcephaly; Infants, who can have poor feeding, failure to thrive, pallor, and neurologic signs, and occasionally hemolytic uremic syndrome (HUS) and/or seizures including infantile spasms; Toddlers, who can have failure to thrive, poor head growth, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures; and Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, and/or subacute combined degeneration of the spinal cord.  https://www.ncbi.nlm.nih.gov/books/NBK1328
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

Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. (Adams et al., Principles of Neurology, 6th ed, p272)
Blindness
MedGen UID:
99138
Concept ID:
C0456909
Finding
Blindness is the condition of lacking visual perception due to physiological or neurological factors.
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. There are multiple forms of homocystinuria, which are distinguished by their signs and symptoms and genetic cause. The most common form of homocystinuria is characterized by nearsightedness (myopia), dislocation of the lens at the front of the eye, an increased risk of abnormal blood clotting, and brittle bones that are prone to fracture (osteoporosis) or other skeletal abnormalities. Some affected individuals also have developmental delay and learning problems.Less common forms of homocystinuria can cause intellectual disability, failure to grow and gain weight at the expected rate (failure to thrive), seizures, problems with movement, and 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 homocystinuria typically develop within the first year of life, although some mildly affected people may not develop features until later in childhood or adulthood.
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Seizure Disorders
MedGen UID:
4506
Concept ID:
C0014544
Disease or Syndrome
A brain disorder characterized by episodes of abnormally increased neuronal discharge resulting in transient episodes of sensory or motor neurological dysfunction, or psychic dysfunction. These episodes may or may not be associated with loss of consciousness or convulsions.
Cerebral degeneration
MedGen UID:
56343
Concept ID:
C0154671
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Poor coordination
MedGen UID:
107874
Concept ID:
C0563243
Finding
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
A finding referring to walking difficulties.
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
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.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Megaloblastic anemia
MedGen UID:
1527
Concept ID:
C0002888
Disease or Syndrome
A disorder characterized by the presence of ANEMIA, abnormally large red blood cells (megalocytes or macrocytes), and MEGALOBLASTS.
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. There are multiple forms of homocystinuria, which are distinguished by their signs and symptoms and genetic cause. The most common form of homocystinuria is characterized by nearsightedness (myopia), dislocation of the lens at the front of the eye, an increased risk of abnormal blood clotting, and brittle bones that are prone to fracture (osteoporosis) or other skeletal abnormalities. Some affected individuals also have developmental delay and learning problems.Less common forms of homocystinuria can cause intellectual disability, failure to grow and gain weight at the expected rate (failure to thrive), seizures, problems with movement, and 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 homocystinuria typically develop within the first year of life, although some mildly affected people may not develop features until later in childhood or adulthood.
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
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. There are multiple forms of homocystinuria, which are distinguished by their signs and symptoms and genetic cause. The most common form of homocystinuria is characterized by nearsightedness (myopia), dislocation of the lens at the front of the eye, an increased risk of abnormal blood clotting, and brittle bones that are prone to fracture (osteoporosis) or other skeletal abnormalities. Some affected individuals also have developmental delay and learning problems.Less common forms of homocystinuria can cause intellectual disability, failure to grow and gain weight at the expected rate (failure to thrive), seizures, problems with movement, and 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 homocystinuria typically develop within the first year of life, although some mildly affected people may not develop features until later in childhood or adulthood.
Methylmalonic acidemia
MedGen UID:
120654
Concept ID:
C0268583
Disease or Syndrome
Isolated methylmalonic acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut(0) enzymatic subtype or mut(–) enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; “metabolic stroke” (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy.
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.
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Hyperhomocystinemia
MedGen UID:
812677
Concept ID:
C3806347
Finding
An increased concentration of homocystine in the blood.
Decreased methylcobalamin
MedGen UID:
867371
Concept ID:
C4021736
Finding
Decreased concentration of methylcobalamin. Methylcobalamin is a form of vitamin B12.

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