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Growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome(COXPD18)

MedGen UID:
816331
Concept ID:
C3810001
Disease or Syndrome
Synonym: Combined oxidative phosphorylation deficiency 18
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): SFXN4 (10q26.11)
 
Monarch Initiative: MONDO:0014261
OMIM®: 615578
Orphanet: ORPHA391348

Definition

Combined oxidative phosphorylation deficiency-18 (COXPD18) is an autosomal recessive disorder of mitochondrial function characterized by intrauterine growth retardation, hypotonia, visual impairment, speech delay, and lactic acidosis associated with decreased mitochondrial respiratory chain activity. Affected patients may also show hematologic abnormalities, mainly macrocytic anemia (summary by Hildick-Smith et al., 2013). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060). [from OMIM]

Clinical features

From HPO
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Dysmetria
MedGen UID:
68583
Concept ID:
C0234162
Finding
A type of ataxia characterized by the inability to carry out movements with the correct range and motion across the plane of more than one joint related to incorrect estimation of the distances required for targeted movements.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Delayed fine motor development
MedGen UID:
869257
Concept ID:
C4023681
Finding
A type of motor delay characterized by a delay in acquiring the ability to control the fingers and hands.
Macrocytic anemia
MedGen UID:
1920
Concept ID:
C0002886
Disease or Syndrome
A type of anemia characterized by increased size of erythrocytes with increased mean corpuscular volume (MCV) and increased mean corpuscular hemoglobin (MCH).
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.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Difficulty running
MedGen UID:
108251
Concept ID:
C0560346
Finding
Reduced ability to run.
Hypersegmentation of neutrophil nuclei
MedGen UID:
870828
Concept ID:
C4025288
Finding
An excessive division of the lobes of the nucleus of a neutrophil.
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.
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).
Oligohydramnios
MedGen UID:
86974
Concept ID:
C0079924
Pathologic Function
Diminished amniotic fluid volume in pregnancy.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.
Decreased activity of mitochondrial complex I
MedGen UID:
393796
Concept ID:
C2677650
Finding
A reduction in the activity of the mitochondrial respiratory chain complex I, which is part of the electron transport chain in mitochondria.
Increased mitochondrial number
MedGen UID:
868101
Concept ID:
C4022492
Finding

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome in Orphanet.

Recent clinical studies

Etiology

M-Osman MA, B-Abd-Elrehim GA, Abdelkreem E, Abosdera MM, Kassem MA
Turk J Pediatr 2023;65(4):611-619. doi: 10.24953/turkjped.2022.688. PMID: 37661676
Hikmat O, Isohanni P, Keshavan N, Ferla MP, Fassone E, Abbott MA, Bellusci M, Darin N, Dimmock D, Ghezzi D, Houlden H, Invernizzi F, Kamarus Jaman NB, Kurian MA, Morava E, Naess K, Ortigoza-Escobar JD, Parikh S, Pennisi A, Barcia G, Tylleskär KB, Brackman D, Wortmann SB, Taylor JC, Bindoff LA, Fellman V, Rahman S
Ann Clin Transl Neurol 2021 Nov;8(11):2155-2165. Epub 2021 Oct 18 doi: 10.1002/acn3.51470. PMID: 34662929Free PMC Article
Magner M, Dvorakova V, Tesarova M, Mazurova S, Hansikova H, Zahorec M, Brennerova K, Bzduch V, Spiegel R, Horovitz Y, Mandel H, Eminoğlu FT, Mayr JA, Koch J, Martinelli D, Bertini E, Konstantopoulou V, Smet J, Rahman S, Broomfield A, Stojanović V, Dionisi-Vici C, van Coster R, Morava E, Sperl W, Zeman J, Honzik T
J Inherit Metab Dis 2015 May;38(3):417-26. Epub 2014 Oct 18 doi: 10.1007/s10545-014-9774-8. PMID: 25326274
Alter BP
Pediatr Clin North Am 2002 Oct;49(5):973-88. doi: 10.1016/s0031-3955(02)00031-7. PMID: 12430621
Vohr BR, Bell EF, Oh W
Am J Dis Child 1982 May;136(5):443-7. doi: 10.1001/archpedi.1982.03970410061015. PMID: 6177239

Diagnosis

M-Osman MA, B-Abd-Elrehim GA, Abdelkreem E, Abosdera MM, Kassem MA
Turk J Pediatr 2023;65(4):611-619. doi: 10.24953/turkjped.2022.688. PMID: 37661676
Whyte MP
Bone 2023 Apr;169:116684. Epub 2023 Jan 27 doi: 10.1016/j.bone.2023.116684. PMID: 36709914
Baker RA, Priestley JRC, Wilstermann AM, Reese KJ, Mark PR
Am J Med Genet A 2019 Mar;179(3):373-380. Epub 2018 Dec 24 doi: 10.1002/ajmg.a.61019. PMID: 30582773
David S, De Waele K, De Wilde B, Faes F, Vanakker O, Walraedt S, Prytuła A
Acta Clin Belg 2019 Dec;74(6):460-464. Epub 2018 Dec 3 doi: 10.1080/17843286.2018.1551743. PMID: 30501482
Alter BP
Pediatr Clin North Am 2002 Oct;49(5):973-88. doi: 10.1016/s0031-3955(02)00031-7. PMID: 12430621

Therapy

De Clerck M, Vande Walle J, Dhont E, Dehoorne J, Keenswijk W
Paediatr Int Child Health 2018 Nov;38(4):277-280. Epub 2017 May 30 doi: 10.1080/20469047.2017.1329889. PMID: 28557682
Vohr BR, Bell EF, Oh W
Am J Dis Child 1982 May;136(5):443-7. doi: 10.1001/archpedi.1982.03970410061015. PMID: 6177239
Friedman J, Lewy JE
Pediatr Ann 1978 Nov;7(11):767-73. PMID: 105338

Prognosis

Keshavan N, Rahman S
Mol Genet Metab 2024 Sep-Oct;143(1-2):108554. Epub 2024 Jul 24 doi: 10.1016/j.ymgme.2024.108554. PMID: 39079226
Hikmat O, Isohanni P, Keshavan N, Ferla MP, Fassone E, Abbott MA, Bellusci M, Darin N, Dimmock D, Ghezzi D, Houlden H, Invernizzi F, Kamarus Jaman NB, Kurian MA, Morava E, Naess K, Ortigoza-Escobar JD, Parikh S, Pennisi A, Barcia G, Tylleskär KB, Brackman D, Wortmann SB, Taylor JC, Bindoff LA, Fellman V, Rahman S
Ann Clin Transl Neurol 2021 Nov;8(11):2155-2165. Epub 2021 Oct 18 doi: 10.1002/acn3.51470. PMID: 34662929Free PMC Article
Peter B, Waddington CL, Oláhová M, Sommerville EW, Hopton S, Pyle A, Champion M, Ohlson M, Siibak T, Chrzanowska-Lightowlers ZMA, Taylor RW, Falkenberg M, Lightowlers RN
Hum Mol Genet 2018 May 15;27(10):1743-1753. doi: 10.1093/hmg/ddy080. PMID: 29518248Free PMC Article
Magner M, Dvorakova V, Tesarova M, Mazurova S, Hansikova H, Zahorec M, Brennerova K, Bzduch V, Spiegel R, Horovitz Y, Mandel H, Eminoğlu FT, Mayr JA, Koch J, Martinelli D, Bertini E, Konstantopoulou V, Smet J, Rahman S, Broomfield A, Stojanović V, Dionisi-Vici C, van Coster R, Morava E, Sperl W, Zeman J, Honzik T
J Inherit Metab Dis 2015 May;38(3):417-26. Epub 2014 Oct 18 doi: 10.1007/s10545-014-9774-8. PMID: 25326274
Vohr BR, Bell EF, Oh W
Am J Dis Child 1982 May;136(5):443-7. doi: 10.1001/archpedi.1982.03970410061015. PMID: 6177239

Clinical prediction guides

Keshavan N, Rahman S
Mol Genet Metab 2024 Sep-Oct;143(1-2):108554. Epub 2024 Jul 24 doi: 10.1016/j.ymgme.2024.108554. PMID: 39079226
Hussain SI, Muhammad N, Khan N, Khan M, Fardous F, Tahir R, Yasin M, Khan SA, Saleha S, Muhammad N, Wasif N, Khan S
J Gene Med 2024 Jan;26(1):e3591. Epub 2023 Sep 18 doi: 10.1002/jgm.3591. PMID: 37721116
Baker RA, Priestley JRC, Wilstermann AM, Reese KJ, Mark PR
Am J Med Genet A 2019 Mar;179(3):373-380. Epub 2018 Dec 24 doi: 10.1002/ajmg.a.61019. PMID: 30582773
Peter B, Waddington CL, Oláhová M, Sommerville EW, Hopton S, Pyle A, Champion M, Ohlson M, Siibak T, Chrzanowska-Lightowlers ZMA, Taylor RW, Falkenberg M, Lightowlers RN
Hum Mol Genet 2018 May 15;27(10):1743-1753. doi: 10.1093/hmg/ddy080. PMID: 29518248Free PMC Article
Alter BP
Pediatr Clin North Am 2002 Oct;49(5):973-88. doi: 10.1016/s0031-3955(02)00031-7. PMID: 12430621

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