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Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness(TRMA)

MedGen UID:
83338
Concept ID:
C0342287
Congenital Abnormality
Synonyms: Rogers syndrome; THIAMINE METABOLISM DYSFUNCTION SYNDROME 1 (MEGALOBLASTIC ANEMIA, DIABETES MELLITUS, AND DEAFNESS TYPE); Thiamine-responsive anemia syndrome; Thiamine-Responsive Megaloblastic Anemia Syndrome; Thiamine-responsive myelodysplasia; TRMA
SNOMED CT: Thiamine-responsive megaloblastic anemia syndrome (237617006); Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness (237617006); Rogers syndrome (237617006)
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): SLC19A2 (1q24.2)
 
Monarch Initiative: MONDO:0009575
OMIM®: 249270
Orphanet: ORPHA49827

Disease characteristics

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus. Onset of megaloblastic anemia occurs between infancy and adolescence. The anemia is corrected with thiamine treatment, but the red cells remain macrocytic and anemia can recur if treatment is withdrawn. Progressive sensorineural hearing loss often occurs early and can be detected in toddlers; hearing loss is irreversible and may not be prevented by thiamine treatment. The diabetes mellitus is non-type I in nature, with age of onset from infancy to adolescence. Thiamine treatment may reduce insulin requirement and delay onset of diabetes in some individuals. [from GeneReviews]
Authors:
Shuhei Sako  |  Toshiki Tsunogai  |  Kimihiko Oishi   view full author information

Additional descriptions

From OMIM
Thiamine-responsive megaloblastic anemia syndrome (TRMA) comprises megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Onset is typically between infancy and adolescence, but all of the cardinal findings are often not present initially. The anemia, and sometimes the diabetes, improves with high doses of thiamine. Other more variable features include optic atrophy, congenital heart defects, short stature, and stroke (summary by Bergmann et al., 2009). Genetic Heterogeneity of Disorders Due to Thiamine Metabolism Dysfunction See also episodic encephalopathies due to defects in thiamine metabolism: biotin-responsive basal ganglia disease (THMD2; 607483), caused by mutation in the SLC19A3 gene (606152) on chromosome 2q36; Amish-type microcephaly (THMD3; 607196) and bilateral striatal necrosis and progressive polyneuropathy (THMD4; 613710), both caused by mutation in the SLC25A19 gene (606521) on chromosome 17q25; and THMD5 (614458), caused by mutation in the TPK1 gene (606370) on chromosome 7q35.  http://www.omim.org/entry/249270
From MedlinePlus Genetics
Thiamine-responsive megaloblastic anemia syndrome is a rare condition characterized by hearing loss, diabetes, 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 symptoms of this blood disorder may include decreased appetite, lack of energy, headaches, pale skin, diarrhea, and tingling or numbness in the hands and feet. Individuals with thiamine-responsive megaloblastic anemia syndrome begin to show symptoms of megaloblastic anemia between infancy and adolescence. This syndrome is called "thiamine-responsive" because the anemia can be treated with high doses of vitamin B1 (thiamine).

People with thiamine-responsive megaloblastic anemia syndrome develop hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss)

during early childhood. It remains unclear whether thiamine treatment can improve hearing or prevent hearing loss.

Diabetes becomes apparent in affected individuals sometime between infancy and adolescence. Although these individuals develop diabetes during childhood, they do not have the form of the disease that develops most often in children, called type 1 (autoimmune) diabetes. People with thiamine-responsive megaloblastic anemia syndrome usually require insulin to treat their diabetes. In some cases, treatment with thiamine can reduce the amount of insulin a person needs.

Some individuals with thiamine-responsive megaloblastic anemia syndrome develop optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain. Heart and blood vessel (cardiovascular) problems such as heart rhythm abnormalities and heart defects have also been reported in some people with this syndrome.  https://medlineplus.gov/genetics/condition/thiamine-responsive-megaloblastic-anemia-syndrome

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Cardiac arrhythmia
MedGen UID:
2039
Concept ID:
C0003811
Finding
Any cardiac rhythm other than the normal sinus rhythm. Such a rhythm may be either of sinus or ectopic origin and either regular or irregular. An arrhythmia may be due to a disturbance in impulse formation or conduction or both.
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.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Stroke disorder
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
Sudden impairment of blood flow to a part of the brain due to occlusion or rupture of an artery to the brain.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Situs inversus
MedGen UID:
1642262
Concept ID:
C4551493
Congenital Abnormality
A left-right reversal (or "mirror reflection") of the anatomical location of the major thoracic and abdominal organs.
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).
Gastroesophageal reflux
MedGen UID:
1368658
Concept ID:
C4317146
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised 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.
Sideroblastic anemia
MedGen UID:
8067
Concept ID:
C0002896
Disease or Syndrome
Sideroblastic anemia results from a defect in the incorporation of iron into the heme molecule. A sideroblast is an erythroblast that has stainable deposits of iron in cytoplasm (this can be demonstrated by Prussian blue staining).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Thiamine-responsive megaloblastic anemia
MedGen UID:
488839
Concept ID:
C0271972
Disease or Syndrome
A type of megaloblastic anemia (i.e., anemia characterized by the presence of erythroblasts that are larger than normal) that improves upon the administration of thiamine.
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Hoarse voice
MedGen UID:
5602
Concept ID:
C0019825
Sign or Symptom
Hoarseness refers to a change in the pitch or quality of the voice, with the voice sounding weak, very breathy, scratchy, or husky.
Abnormality of the skin
MedGen UID:
11449
Concept ID:
C0037268
Congenital Abnormality
An abnormality of the skin.
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.
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.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells.
Visual loss
MedGen UID:
784038
Concept ID:
C3665386
Finding
Loss of visual acuity (implying that vision was better at a certain time point in life). Otherwise the term reduced visual acuity should be used (or a subclass of that).
Cone-rod dystrophy
MedGen UID:
896366
Concept ID:
C4085590
Disease or Syndrome
The first signs and symptoms of cone-rod dystrophy, which often occur in childhood, are usually decreased sharpness of vision (visual acuity) and increased sensitivity to light (photophobia). These features are typically followed by impaired color vision (dyschromatopsia), blind spots (scotomas) in the center of the visual field, and partial side (peripheral) vision loss. Over time, affected individuals develop night blindness and a worsening of their peripheral vision, which can limit independent mobility. Decreasing visual acuity makes reading increasingly difficult and most affected individuals are legally blind by mid-adulthood. As the condition progresses, individuals may develop involuntary eye movements (nystagmus).\n\nThere are more than 30 types of cone-rod dystrophy, which are distinguished by their genetic cause and their pattern of inheritance: autosomal recessive, autosomal dominant, and X-linked. Additionally, cone-rod dystrophy can occur alone without any other signs and symptoms or it can occur as part of a syndrome that affects multiple parts of the body.\n\nCone-rod dystrophy is a group of related eye disorders that causes vision loss, which becomes more severe over time. These disorders affect the retina, which is the layer of light-sensitive tissue at the back of the eye. In people with cone-rod dystrophy, vision loss occurs as the light-sensing cells of the retina gradually deteriorate.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMegaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness
Follow this link to review classifications for Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness in Orphanet.

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PubMed

Di Candia F, Di Iorio V, Tinto N, Bonfanti R, Iovino C, Rosanio FM, Fedi L, Iafusco F, Arrigoni F, Malesci R, Simonelli F, Rigamonti A, Franzese A, Mozzillo E
Ital J Pediatr 2023 Nov 30;49(1):158. doi: 10.1186/s13052-023-01553-1. PMID: 38037112Free PMC Article
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Recent clinical studies

Etiology

Habeb AM, Flanagan SE, Zulali MA, Abdullah MA, Pomahačová R, Boyadzhiev V, Colindres LE, Godoy GV, Vasanthi T, Al Saif R, Setoodeh A, Haghighi A, Haghighi A, Shaalan Y; International Neonatal Diabetes Consortium, Hattersley AT, Ellard S, De Franco E
Diabetologia 2018 May;61(5):1027-1036. Epub 2018 Feb 15 doi: 10.1007/s00125-018-4554-x. PMID: 29450569Free PMC Article
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Valerio G, Franzese A, Poggi V, Tenore A
Diabetes Care 1998 Jan;21(1):38-41. doi: 10.2337/diacare.21.1.38. PMID: 9538968

Diagnosis

Marcé-Grau A, Martí-Sánchez L, Baide-Mairena H, Ortigoza-Escobar JD, Pérez-Dueñas B
J Inherit Metab Dis 2019 Jul;42(4):581-597. Epub 2019 Jun 24 doi: 10.1002/jimd.12125. PMID: 31095747
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Bay A, Keskin M, Hizli S, Uygun H, Dai A, Gumruk F
Int J Hematol 2010 Oct;92(3):524-6. Epub 2010 Sep 11 doi: 10.1007/s12185-010-0681-y. PMID: 20835854
Ristow M
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Therapy

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J Inherit Metab Dis 2019 Jul;42(4):581-597. Epub 2019 Jun 24 doi: 10.1002/jimd.12125. PMID: 31095747
Argun M, Baykan A, Hatipoğlu N, Akın L, Şahin Y, Narin N, Kurtoğlu S
Turk J Pediatr 2018;60(3):348-351. doi: 10.24953/turkjped.2018.03.021. PMID: 30511554
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Bay A, Keskin M, Hizli S, Uygun H, Dai A, Gumruk F
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Prognosis

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Moulin V, Grandoni F, Castioni J, Lu H
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Diabetes Care 1998 Jan;21(1):38-41. doi: 10.2337/diacare.21.1.38. PMID: 9538968

Clinical prediction guides

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Akın L, Kurtoğlu S, Kendirci M, Akın MA, Karakükçü M
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