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Lipoyl transferase 1 deficiency(LIPT1D)

MedGen UID:
904073
Concept ID:
C4225379
Disease or Syndrome
Synonym: Lipoyltransferase 1 deficiency
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): LIPT1 (2q11.2)
 
Monarch Initiative: MONDO:0014576
OMIM®: 616299
Orphanet: ORPHA401862

Definition

Lipoyl transferase 1 deficiency is a very rare inborn error of metabolism disorder, with a highly variable phenotype, typically characterized by neonatal to infancy-onset of seizures, psychomotor delay, and abnormal muscle tone that may include hypo- and/or hypertonia, resulting in generalized weakness, dystonic movements, and/or progressive respiratory distress, associated with severe lactic acidosis and elevated lactate, ketoglutarate and 2-oxoacids in urine. Additional manifestations may include dehydration, vomiting, signs of liver dysfunction, extrapyramidal signs, spastic tetraparesis, brisk deep tendon reflexes, speech impairment, swallowing difficulties, and pulmonary hypertension. [from ORDO]

Clinical features

From HPO
Lacticaciduria
MedGen UID:
871116
Concept ID:
C4025585
Finding
An increased concentration of lactic acid in the urine.
Hyperglutaminuria
MedGen UID:
1372576
Concept ID:
C4476741
Finding
An increased concentration of glutamine in the urine.
Alaninuria
MedGen UID:
1696785
Concept ID:
C5139067
Finding
An increased level of alanine in the urine.
Bradycardia
MedGen UID:
140901
Concept ID:
C0428977
Finding
A slower than normal heart rate (in adults, slower than 60 beats per minute).
Pulmonary arterial hypertension
MedGen UID:
425404
Concept ID:
C2973725
Disease or Syndrome
Pulmonary hypertension is defined mean pulmonary artery pressure of 25mmHg or more and pulmonary capillary wedge pressure of 15mmHg or less when measured by right heart catheterisation at rest and in a supine position.
Decreased liver function
MedGen UID:
65430
Concept ID:
C0232744
Finding
Reduced ability of the liver to perform its functions.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
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.
Spastic tetraparesis
MedGen UID:
658719
Concept ID:
C0575059
Disease or Syndrome
Spastic weakness affecting all four limbs.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Abnormal cerebral white matter morphology
MedGen UID:
181756
Concept ID:
C0948163
Pathologic Function
An abnormality of the cerebral white matter.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
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.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Hyperprolinemia
MedGen UID:
75690
Concept ID:
C0268528
Disease or Syndrome
An increased concentration of proline in the blood.
Increased total bilirubin
MedGen UID:
152856
Concept ID:
C0741494
Finding
Increased concentration of total (conjugated and unconjugated) bilirubin in the blood.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Hyperglutaminemia
MedGen UID:
326901
Concept ID:
C1839533
Finding
An increased concentration of glutamine in the blood.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVLipoyl transferase 1 deficiency

Recent clinical studies

Etiology

Talaverón-Rey M, Álvarez-Córdoba M, Villalón-García I, Povea-Cabello S, Suárez-Rivero JM, Gómez-Fernández D, Romero-González A, Suárez-Carrillo A, Munuera-Cabeza M, Cilleros-Holgado P, Reche-López D, Piñero-Pérez R, Sánchez-Alcázar JA
Orphanet J Rare Dis 2023 Apr 12;18(1):80. doi: 10.1186/s13023-023-02687-5. PMID: 37046296Free PMC Article
Nagy B, Polak M, Ozohanics O, Zambo Z, Szabo E, Hubert A, Jordan F, Novaček J, Adam-Vizi V, Ambrus A
Biochim Biophys Acta Gen Subj 2021 Jun;1865(6):129889. Epub 2021 Mar 5 doi: 10.1016/j.bbagen.2021.129889. PMID: 33684457
Paredes F, Sheldon K, Lassègue B, Williams HC, Faidley EA, Benavides GA, Torres G, Sanhueza-Olivares F, Yeligar SM, Griendling KK, Darley-Usmar V, San Martin A
Proc Natl Acad Sci U S A 2018 Feb 20;115(8):1789-1794. Epub 2018 Feb 6 doi: 10.1073/pnas.1720693115. PMID: 29434038Free PMC Article
Baker PR 2nd, Friederich MW, Swanson MA, Shaikh T, Bhattacharya K, Scharer GH, Aicher J, Creadon-Swindell G, Geiger E, MacLean KN, Lee WT, Deshpande C, Freckmann ML, Shih LY, Wasserstein M, Rasmussen MB, Lund AM, Procopis P, Cameron JM, Robinson BH, Brown GK, Brown RM, Compton AG, Dieckmann CL, Collard R, Coughlin CR 2nd, Spector E, Wempe MF, Van Hove JL
Brain 2014 Feb;137(Pt 2):366-79. Epub 2013 Dec 11 doi: 10.1093/brain/awt328. PMID: 24334290Free PMC Article
Athappilly FK, Hendrickson WA
Structure 1995 Dec 15;3(12):1407-19. doi: 10.1016/s0969-2126(01)00277-5. PMID: 8747466

Diagnosis

Choi M, Lee J, Jeong K, Pak Y
Biochim Biophys Acta Mol Basis Dis 2024 Jun;1870(5):167173. Epub 2024 Apr 16 doi: 10.1016/j.bbadis.2024.167173. PMID: 38631410
Paredes F, Sheldon K, Lassègue B, Williams HC, Faidley EA, Benavides GA, Torres G, Sanhueza-Olivares F, Yeligar SM, Griendling KK, Darley-Usmar V, San Martin A
Proc Natl Acad Sci U S A 2018 Feb 20;115(8):1789-1794. Epub 2018 Feb 6 doi: 10.1073/pnas.1720693115. PMID: 29434038Free PMC Article
Baker PR 2nd, Friederich MW, Swanson MA, Shaikh T, Bhattacharya K, Scharer GH, Aicher J, Creadon-Swindell G, Geiger E, MacLean KN, Lee WT, Deshpande C, Freckmann ML, Shih LY, Wasserstein M, Rasmussen MB, Lund AM, Procopis P, Cameron JM, Robinson BH, Brown GK, Brown RM, Compton AG, Dieckmann CL, Collard R, Coughlin CR 2nd, Spector E, Wempe MF, Van Hove JL
Brain 2014 Feb;137(Pt 2):366-79. Epub 2013 Dec 11 doi: 10.1093/brain/awt328. PMID: 24334290Free PMC Article

Therapy

Talaverón-Rey M, Álvarez-Córdoba M, Villalón-García I, Povea-Cabello S, Suárez-Rivero JM, Gómez-Fernández D, Romero-González A, Suárez-Carrillo A, Munuera-Cabeza M, Cilleros-Holgado P, Reche-López D, Piñero-Pérez R, Sánchez-Alcázar JA
Orphanet J Rare Dis 2023 Apr 12;18(1):80. doi: 10.1186/s13023-023-02687-5. PMID: 37046296Free PMC Article
Hao JW, Wang J, Guo H, Zhao YY, Sun HH, Li YF, Lai XY, Zhao N, Wang X, Xie C, Hong L, Huang X, Wang HR, Li CB, Liang B, Chen S, Zhao TJ
Nat Commun 2020 Sep 21;11(1):4765. doi: 10.1038/s41467-020-18565-8. PMID: 32958780Free PMC Article

Prognosis

Fredericks GJ, Hoffmann FW, Rose AH, Osterheld HJ, Hess FM, Mercier F, Hoffmann PR
Proc Natl Acad Sci U S A 2014 Nov 18;111(46):16478-83. Epub 2014 Nov 3 doi: 10.1073/pnas.1417176111. PMID: 25368151Free PMC Article
Edmonds MJ, Morgan A
BMC Genomics 2014 Oct 2;15(1):841. doi: 10.1186/1471-2164-15-841. PMID: 25277130Free PMC Article
Baker PR 2nd, Friederich MW, Swanson MA, Shaikh T, Bhattacharya K, Scharer GH, Aicher J, Creadon-Swindell G, Geiger E, MacLean KN, Lee WT, Deshpande C, Freckmann ML, Shih LY, Wasserstein M, Rasmussen MB, Lund AM, Procopis P, Cameron JM, Robinson BH, Brown GK, Brown RM, Compton AG, Dieckmann CL, Collard R, Coughlin CR 2nd, Spector E, Wempe MF, Van Hove JL
Brain 2014 Feb;137(Pt 2):366-79. Epub 2013 Dec 11 doi: 10.1093/brain/awt328. PMID: 24334290Free PMC Article
Athappilly FK, Hendrickson WA
Structure 1995 Dec 15;3(12):1407-19. doi: 10.1016/s0969-2126(01)00277-5. PMID: 8747466

Clinical prediction guides

Nagy B, Polak M, Ozohanics O, Zambo Z, Szabo E, Hubert A, Jordan F, Novaček J, Adam-Vizi V, Ambrus A
Biochim Biophys Acta Gen Subj 2021 Jun;1865(6):129889. Epub 2021 Mar 5 doi: 10.1016/j.bbagen.2021.129889. PMID: 33684457
Paredes F, Sheldon K, Lassègue B, Williams HC, Faidley EA, Benavides GA, Torres G, Sanhueza-Olivares F, Yeligar SM, Griendling KK, Darley-Usmar V, San Martin A
Proc Natl Acad Sci U S A 2018 Feb 20;115(8):1789-1794. Epub 2018 Feb 6 doi: 10.1073/pnas.1720693115. PMID: 29434038Free PMC Article
Habarou F, Hamel Y, Haack TB, Feichtinger RG, Lebigot E, Marquardt I, Busiah K, Laroche C, Madrange M, Grisel C, Pontoizeau C, Eisermann M, Boutron A, Chrétien D, Chadefaux-Vekemans B, Barouki R, Bole-Feysot C, Nitschke P, Goudin N, Boddaert N, Nemazanyy I, Delahodde A, Kölker S, Rodenburg RJ, Korenke GC, Meitinger T, Strom TM, Prokisch H, Rotig A, Ottolenghi C, Mayr JA, de Lonlay P
Am J Hum Genet 2017 Aug 3;101(2):283-290. Epub 2017 Jul 27 doi: 10.1016/j.ajhg.2017.07.001. PMID: 28757203Free PMC Article
Fredericks GJ, Hoffmann FW, Rose AH, Osterheld HJ, Hess FM, Mercier F, Hoffmann PR
Proc Natl Acad Sci U S A 2014 Nov 18;111(46):16478-83. Epub 2014 Nov 3 doi: 10.1073/pnas.1417176111. PMID: 25368151Free PMC Article
Edmonds MJ, Morgan A
BMC Genomics 2014 Oct 2;15(1):841. doi: 10.1186/1471-2164-15-841. PMID: 25277130Free PMC Article