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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
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)
SNOMED CT: Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness (237617006); Rogers syndrome (237617006)
 
Gene (location): SLC19A2 (1q24.2)
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is corrected with thiamine treatment, but the red cells remain macrocytic, and anemia can recur when treatment is withdrawn. Progressive sensorineural hearing loss has generally been 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 delay onset of diabetes in some individuals. [from GeneReviews]
Authors:
Kimihiko Oishi  |  George A Diaz   view full author information

Additional descriptions

From OMIM
Thiamine-responsive megaloblastic anemia syndrome 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 lethal 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 GHR
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://ghr.nlm.nih.gov/condition/thiamine-responsive-megaloblastic-anemia-syndrome

Clinical features

Refractory sideroblastic anemia
MedGen UID:
8067
Concept ID:
C0002896
Disease or Syndrome
A type of sideroblastic anemia that is not responsive to treatment.
Cardiac arrhythmia
MedGen UID:
2039
Concept ID:
C0003811
Finding
A disorder in which there is abnormal electrical activity in the heart.
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Sensorineural hearing impairment
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.
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.
Hoarse voice
MedGen UID:
5602
Concept ID:
C0019825
Sign or Symptom
An unnaturally deep or rough quality of voice.
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)
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
A disorder characterized by loss of optic nerve fibers. It may be inherited or acquired. Acquired causes include ischemia, optic nerve neuropathy, glaucoma, trauma, radiation, brain tumors, and multiple sclerosis. It leads to vision disturbances.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A deterioration of the retina. This nonspecific term is retained here because of its wide use in the literature, but if possible new annotations should indicate the precise type of retinal abnormality.
Abnormality of the skin
MedGen UID:
11449
Concept ID:
C0037268
Congenital Abnormality
A skin abnormality that is present at birth or detected in the neonatal period.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A laboratory test result indicating that there is an abnormally small number of platelets in the circulating blood.
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
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.
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).
Visual loss
MedGen UID:
784038
Concept ID:
C3665386
Finding
Disturbance of eyesight.
Cone-rod dystrophy
MedGen UID:
896366
Concept ID:
C4085590
Disease or Syndrome
Cone-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.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).There 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.

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.

Recent clinical studies

Etiology

Setoodeh A, Haghighi A, Saleh-Gohari N, Ellard S, Haghighi A
Gene 2013 May 1;519(2):295-7. Epub 2013 Feb 20 doi: 10.1016/j.gene.2013.02.008. PMID: 23454484Free PMC Article
Yilmaz Agladioglu S, Aycan Z, Bas VN, Peltek Kendirci HN, Onder A
Genet Couns 2012;23(2):149-56. PMID: 22876572
Borgna-Pignatti C, Azzalli M, Pedretti S
J Pediatr 2009 Aug;155(2):295-7. doi: 10.1016/j.jpeds.2009.01.062. PMID: 19619756
Ganesh R, Ezhilarasi S, Vasanthi T, Gowrishankar K, Rajajee S
Indian J Pediatr 2009 Mar;76(3):313-4. Epub 2009 Apr 6 doi: 10.1007/s12098-009-0058-5. PMID: 19347672
Valerio G, Franzese A, Poggi V, Tenore A
Diabetes Care 1998 Jan;21(1):38-41. PMID: 9538968

Diagnosis

Mikstiene V, Songailiene J, Byckova J, Rutkauskiene G, Jasinskiene E, Verkauskiene R, Lesinskas E, Utkus A
Am J Med Genet A 2015 Jul;167(7):1605-9. Epub 2015 Feb 23 doi: 10.1002/ajmg.a.37015. PMID: 25707023
Akbari MT, Zare Karizi S, Mirfakhraie R, Keikhaei B
Eur J Pediatr 2014 Dec;173(12):1663-5. Epub 2013 Dec 20 doi: 10.1007/s00431-013-2237-7. PMID: 24357267
Yilmaz Agladioglu S, Aycan Z, Bas VN, Peltek Kendirci HN, Onder A
Genet Couns 2012;23(2):149-56. PMID: 22876572
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
Ganesh R, Ezhilarasi S, Vasanthi T, Gowrishankar K, Rajajee S
Indian J Pediatr 2009 Mar;76(3):313-4. Epub 2009 Apr 6 doi: 10.1007/s12098-009-0058-5. PMID: 19347672

Therapy

Mikstiene V, Songailiene J, Byckova J, Rutkauskiene G, Jasinskiene E, Verkauskiene R, Lesinskas E, Utkus A
Am J Med Genet A 2015 Jul;167(7):1605-9. Epub 2015 Feb 23 doi: 10.1002/ajmg.a.37015. PMID: 25707023
Yilmaz Agladioglu S, Aycan Z, Bas VN, Peltek Kendirci HN, Onder A
Genet Couns 2012;23(2):149-56. PMID: 22876572
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
Borgna-Pignatti C, Azzalli M, Pedretti S
J Pediatr 2009 Aug;155(2):295-7. doi: 10.1016/j.jpeds.2009.01.062. PMID: 19619756
Ganesh R, Ezhilarasi S, Vasanthi T, Gowrishankar K, Rajajee S
Indian J Pediatr 2009 Mar;76(3):313-4. Epub 2009 Apr 6 doi: 10.1007/s12098-009-0058-5. PMID: 19347672

Prognosis

Astuti D, Sabir A, Fulton P, Zatyka M, Williams D, Hardy C, Milan G, Favaretto F, Yu-Wai-Man P, Rohayem J, López de Heredia M, Hershey T, Tranebjaerg L, Chen JH, Chaussenot A, Nunes V, Marshall B, McAfferty S, Tillmann V, Maffei P, Paquis-Flucklinger V, Geberhiwot T, Mlynarski W, Parkinson K, Picard V, Bueno GE, Dias R, Arnold A, Richens C, Paisey R, Urano F, Semple R, Sinnott R, Barrett TG
Hum Mutat 2017 Jul;38(7):764-777. Epub 2017 Jun 1 doi: 10.1002/humu.23233. PMID: 28432734Free PMC Article
Yilmaz Agladioglu S, Aycan Z, Bas VN, Peltek Kendirci HN, Onder A
Genet Couns 2012;23(2):149-56. PMID: 22876572
Borgna-Pignatti C, Azzalli M, Pedretti S
J Pediatr 2009 Aug;155(2):295-7. doi: 10.1016/j.jpeds.2009.01.062. PMID: 19619756
Ganesh R, Ezhilarasi S, Vasanthi T, Gowrishankar K, Rajajee S
Indian J Pediatr 2009 Mar;76(3):313-4. Epub 2009 Apr 6 doi: 10.1007/s12098-009-0058-5. PMID: 19347672
Meire FM, Van Genderen MM, Lemmens K, Ens-Dokkum MH
Ophthalmic Genet 2000 Dec;21(4):243-50. PMID: 11135496

Clinical prediction guides

Astuti D, Sabir A, Fulton P, Zatyka M, Williams D, Hardy C, Milan G, Favaretto F, Yu-Wai-Man P, Rohayem J, López de Heredia M, Hershey T, Tranebjaerg L, Chen JH, Chaussenot A, Nunes V, Marshall B, McAfferty S, Tillmann V, Maffei P, Paquis-Flucklinger V, Geberhiwot T, Mlynarski W, Parkinson K, Picard V, Bueno GE, Dias R, Arnold A, Richens C, Paisey R, Urano F, Semple R, Sinnott R, Barrett TG
Hum Mutat 2017 Jul;38(7):764-777. Epub 2017 Jun 1 doi: 10.1002/humu.23233. PMID: 28432734Free PMC Article
Srikrupa NN, Meenakshi S, Arokiasamy T, Murali K, Soumittra N
Ophthalmic Genet 2014 Jun;35(2):119-24. Epub 2013 May 2 doi: 10.3109/13816810.2013.793363. PMID: 23638917
Meire FM, Van Genderen MM, Lemmens K, Ens-Dokkum MH
Ophthalmic Genet 2000 Dec;21(4):243-50. PMID: 11135496
Raz T, Barrett T, Szargel R, Mandel H, Neufeld EJ, Nosaka K, Viana MB, Cohen N
Hum Genet 1998 Oct;103(4):455-61. PMID: 9856490
Neufeld EJ, Mandel H, Raz T, Szargel R, Yandava CN, Stagg A, Fauré S, Barrett T, Buist N, Cohen N
Am J Hum Genet 1997 Dec;61(6):1335-41. doi: 10.1086/301642. PMID: 9399900Free PMC Article

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