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D-Glyceric aciduria

MedGen UID:
452447
Concept ID:
C0342765
Disease or Syndrome
Synonyms: D-Glycerate kinase deficiency; D-Glycericacidemia; Deficiency of glycerate kinase; GLYCERATE KINASE DEFICIENCY; Non ketotic hyperglycinemia syndrome
SNOMED CT: D-Glyceric aciduria (237980004)
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): GLYCTK (3p21.2)
 
Monarch Initiative: MONDO:0009070
OMIM®: 220120
Orphanet: ORPHA941

Definition

D-glyceric aciduria is a rare autosomal recessive metabolic disorder with a highly variable phenotype. Some patients have an encephalopathic presentation, with severe mental retardation, seizures, microcephaly, and sometimes early death, whereas others have a mild phenotype with only mild speech delay or even normal development (summary by Sass et al., 2010). [from OMIM]

Clinical features

From HPO
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Single transverse palmar crease
MedGen UID:
96108
Concept ID:
C0424731
Finding
The distal and proximal transverse palmar creases are merged into a single transverse palmar crease.
Patent ductus arteriosus
MedGen UID:
4415
Concept ID:
C0013274
Congenital Abnormality
In utero, the ductus arteriosus (DA) serves to divert ventricular output away from the lungs and toward the placenta by connecting the main pulmonary artery to the descending aorta. A patent ductus arteriosus (PDA) in the first 3 days of life is a physiologic shunt in healthy term and preterm newborn infants, and normally is substantially closed within about 24 hours after bith and completely closed after about three weeks. Failure of physiologcal closure is referred to a persistent or patent ductus arteriosus (PDA). Depending on the degree of left-to-right shunting, PDA can have clinical consequences.
Bradycardia
MedGen UID:
140901
Concept ID:
C0428977
Finding
A slower than normal heart rate (in adults, slower than 60 beats per minute).
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.
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 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.
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.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
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.
Status epilepticus
MedGen UID:
11586
Concept ID:
C0038220
Disease or Syndrome
Status epilepticus is a type of prolonged seizure resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Opisthotonus
MedGen UID:
56246
Concept ID:
C0151818
Sign or Symptom
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
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.
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of irregular spikes. There is continuous (during wakefulness), high-amplitude (>200 Hz), generalized polymorphic slowing with no organized background and multifocal spikes demonstrated by electroencephalography (EEG).
Focal clonic seizure
MedGen UID:
155749
Concept ID:
C0752323
Disease or Syndrome
A focal clonic seizure is a type of focal motor seizure characterized by sustained rhythmic jerking, that is regularly repetitive.
Tongue thrusting
MedGen UID:
473491
Concept ID:
C1829460
Finding
Pressing forward of the tongue in the mouth, a retained motoric habit from infantile swallowing patterns
Brisk reflexes
MedGen UID:
382164
Concept ID:
C2673700
Finding
Tendon reflexes that are noticeably more active than usual (conventionally denoted 3+ on clinical examination). Brisk reflexes may or may not indicate a neurological lesion. They are distinguished from hyperreflexia by the fact that hyerreflexia is characterized by hyperactive repeating (clonic) reflexes, which are considered to be always abnormal.
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.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Appendicular spasticity
MedGen UID:
937224
Concept ID:
C4313257
Finding
A type of spasticity that affects one or more limbs (arms or legs).
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Elevated CSF D-glyceric acid concentration
MedGen UID:
1053624
Concept ID:
CN376968
Finding
The concentration of D-carboxylic acid in the cerebrospinal fluid (CSF) is above the upper limit of normal.
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.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Neonatal respiratory distress
MedGen UID:
924182
Concept ID:
C4281993
Finding
Respiratory difficulty as newborn.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Non-ketotic hyperglycinemia
MedGen UID:
155625
Concept ID:
C0751748
Disease or Syndrome
Nonketotic hyperglycinemia (NKH) is the inborn error of glycine metabolism defined by deficient activity of the glycine cleavage enzyme system (GCS), which results in accumulation of large quantities of glycine in all body tissues including the brain. Based on ultimate outcome NKH is categorized into severe NKH (no developmental progress and intractable epilepsy) and attenuated NKH (variable developmental progress and treatable or no epilepsy). The majority of children with NKH have onset in the neonatal period manifest as progressive lethargy evolving into profound coma and marked hypotonia; 85% have severe NKH and 15% attenuated NKH. Those with onset between two weeks and three months typically present with hypotonia; 50% have severe NKH and 50% attenuated NKH. Those with onset after age three months have attenuated NKH. Severe versus attenuated NKH is consistent within families, but the degree of developmental progress in those with attenuated NKH can vary.
Reduced hepatic D-glycerate kinase activity
MedGen UID:
1841847
Concept ID:
C5826599
Finding
Activity of D-glycerate kinase in the liver below the lower limit of normal.
Elevated circulating D-glyceric concentration
MedGen UID:
1053966
Concept ID:
CN376967
Finding
The concentration of D-gyceric acid in the blood circulation is above the upper limit of normal.
Optic nerve hypoplasia
MedGen UID:
137901
Concept ID:
C0338502
Disease or Syndrome
Underdevelopment of the optic nerve.
Deeply set eye
MedGen UID:
473112
Concept ID:
C0423224
Finding
An eye that is more deeply recessed into the plane of the face than is typical.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVD-Glyceric aciduria

Professional guidelines

PubMed

Inoue Y, Shinka T, Ohse M, Kuhara T
J Chromatogr B Analyt Technol Biomed Life Sci 2005 Aug 25;823(1):2-6. Epub 2005 Apr 25 doi: 10.1016/j.jchromb.2005.03.036. PMID: 16055048

Recent clinical studies

Etiology

Zehavi Y, Mandel H, Eran A, Ravid S, Abu Rashid M, Jansen EEW, Wamelink MMC, Saada A, Shaag A, Elpeleg O, Spiegel R
Metab Brain Dis 2019 Apr;34(2):557-563. Epub 2019 Jan 12 doi: 10.1007/s11011-019-0384-x. PMID: 30637540
Swanson MA, Garcia SM, Spector E, Kronquist K, Creadon-Swindell G, Walter M, Christensen E, Van Hove JLK, Sass JO
Mol Genet Metab 2017 Jun;121(2):80-82. Epub 2017 Apr 20 doi: 10.1016/j.ymgme.2017.04.009. PMID: 28462797
Dimer NW, Schuck PF, Streck EL, Ferreira GC
An Acad Bras Cienc 2015 Aug;87(2 Suppl):1409-14. Epub 2015 Aug 4 doi: 10.1590/0001-3765201520150021. PMID: 26247153
Topcu M, Saatci I, Haliloglu G, Kesimer M, Coskun T
Neuropediatrics 2002 Feb;33(1):47-50. doi: 10.1055/s-2002-23600. PMID: 11930278
Van Schaftingen E
FEBS Lett 1989 Jan 30;243(2):127-31. doi: 10.1016/0014-5793(89)80113-9. PMID: 2537226

Diagnosis

Zehavi Y, Mandel H, Eran A, Ravid S, Abu Rashid M, Jansen EEW, Wamelink MMC, Saada A, Shaag A, Elpeleg O, Spiegel R
Metab Brain Dis 2019 Apr;34(2):557-563. Epub 2019 Jan 12 doi: 10.1007/s11011-019-0384-x. PMID: 30637540
Swanson MA, Garcia SM, Spector E, Kronquist K, Creadon-Swindell G, Walter M, Christensen E, Van Hove JLK, Sass JO
Mol Genet Metab 2017 Jun;121(2):80-82. Epub 2017 Apr 20 doi: 10.1016/j.ymgme.2017.04.009. PMID: 28462797
Dimer NW, Schuck PF, Streck EL, Ferreira GC
An Acad Bras Cienc 2015 Aug;87(2 Suppl):1409-14. Epub 2015 Aug 4 doi: 10.1590/0001-3765201520150021. PMID: 26247153
Topcu M, Saatci I, Haliloglu G, Kesimer M, Coskun T
Neuropediatrics 2002 Feb;33(1):47-50. doi: 10.1055/s-2002-23600. PMID: 11930278
Van Schaftingen E
FEBS Lett 1989 Jan 30;243(2):127-31. doi: 10.1016/0014-5793(89)80113-9. PMID: 2537226

Therapy

Bonham JR, Stephenson TJ, Carpenter KH, Rattenbury JM, Cromby CH, Pollitt RJ, Hull D
Pediatr Res 1990 Jul;28(1):38-41. doi: 10.1203/00006450-199007000-00009. PMID: 2165585

Prognosis

Kalim A, Fitzsimons P, Till C, Fernando M, Mayne P, Sass JO, Crushell E
Brain Dev 2017 Jun;39(6):536-538. Epub 2017 Feb 9 doi: 10.1016/j.braindev.2017.01.005. PMID: 28190537
Sass JO, Fischer K, Wang R, Christensen E, Scholl-Bürgi S, Chang R, Kapelari K, Walter M
Hum Mutat 2010 Dec;31(12):1280-5. Epub 2010 Nov 9 doi: 10.1002/humu.21375. PMID: 20949620

Clinical prediction guides

Swanson MA, Garcia SM, Spector E, Kronquist K, Creadon-Swindell G, Walter M, Christensen E, Van Hove JLK, Sass JO
Mol Genet Metab 2017 Jun;121(2):80-82. Epub 2017 Apr 20 doi: 10.1016/j.ymgme.2017.04.009. PMID: 28462797
Kalim A, Fitzsimons P, Till C, Fernando M, Mayne P, Sass JO, Crushell E
Brain Dev 2017 Jun;39(6):536-538. Epub 2017 Feb 9 doi: 10.1016/j.braindev.2017.01.005. PMID: 28190537
Rashed MS, Aboul-Enein HY, AlAmoudi M, Jakob M, Al-Ahaideb LY, Abbad A, Shabib S, Al-Jishi E
Biomed Chromatogr 2002 May;16(3):191-8. doi: 10.1002/bmc.126. PMID: 11920944

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