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Ataxia-telangiectasia-like disorder 2(ATLD2)

MedGen UID:
863113
Concept ID:
C4014676
Disease or Syndrome
Synonym: ATLD2
SNOMED CT: PCNA-related progressive neurodegenerative photosensitivity syndrome (1228871002); Proliferating cell nuclear antigen-related progressive neurodegenerative photosensitivity syndrome (1228871002)
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): PCNA (20p12.3)
 
Monarch Initiative: MONDO:0014399
OMIM®: 615919
Orphanet: ORPHA438134

Definition

Ataxia-telangiectasia-like disorder-2 is an autosomal recessive syndrome resulting from defects in DNA excision repair. Affected individuals have a neurodegenerative phenotype characterized by developmental delay, ataxia, and sensorineural hearing loss. Other features include short stature, cutaneous and ocular telangiectasia, and photosensitivity (summary by Baple et al., 2014). For a discussion of genetic heterogeneity of ATLD, see ATLD1 (604391). [from OMIM]

Clinical features

From HPO
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
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).
Absent pubertal growth spurt
MedGen UID:
1373047
Concept ID:
C4476965
Finding
The abrupt and transient increase in the annual growth rate normally observed in adolescent individuals does not occur.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
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.
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).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Neurodegeneration
MedGen UID:
17999
Concept ID:
C0027746
Cell or Molecular Dysfunction
Progressive loss of neural cells and tissue.
Photophobia
MedGen UID:
43220
Concept ID:
C0085636
Sign or Symptom
Excessive sensitivity to light with the sensation of discomfort or pain in the eyes due to exposure to bright light.
Unsteady gait
MedGen UID:
68544
Concept ID:
C0231686
Finding
A shaky or wobbly manner of walking.
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.
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.
Joint contracture
MedGen UID:
3228
Concept ID:
C0009918
Anatomical Abnormality
A limitation in the passive range of motion of the elbow resulting from loss of elasticity in the periarticular tissues owing to structural changes of non-bony tissues, such as muscles, tendons, ligaments, joint capsules or skin. A contracture prevents movement of the associated body part.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Congenital diaphragmatic hernia
MedGen UID:
68625
Concept ID:
C0235833
Congenital Abnormality
The presence of a hernia of the diaphragm present at birth.
Progressive muscle weakness
MedGen UID:
68704
Concept ID:
C0240421
Finding
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Conjunctival telangiectasia
MedGen UID:
66780
Concept ID:
C0239105
Disease or Syndrome
The presence of small (ca. 0.5-1.0 mm) dilated blood vessels near the surface of the mucous membranes of the conjunctiva.
Cutaneous photosensitivity
MedGen UID:
87601
Concept ID:
C0349506
Pathologic Function
An increased sensitivity of the skin to light. Photosensitivity may result in a rash upon exposure to the sun (which is known as photodermatosis). Photosensitivity can be diagnosed by phototests in which light is shone on small areas of skin.
Progeroid facial appearance
MedGen UID:
341830
Concept ID:
C1857710
Finding
A degree of wrinkling of the facial skin that is more than expected for the age of the individual, leading to a prematurely aged appearance.
Cutaneous telangiectasia
MedGen UID:
1047582
Concept ID:
CN371974
Finding
Dilated blood vessels on the skin.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAtaxia-telangiectasia-like disorder 2

Recent clinical studies

Etiology

Worm C, Schambye MER, Mkrtchyan GV, Veviorskiy A, Shneyderman A, Ozerov IV, Zhavoronkov A, Bakula D, Scheibye-Knudsen M
Aging (Albany NY) 2024 Feb 9;16(3):2026-2046. doi: 10.18632/aging.205537. PMID: 38345566Free PMC Article
Unterholzner L
Immunobiology 2013 Nov;218(11):1312-21. Epub 2013 Jul 29 doi: 10.1016/j.imbio.2013.07.007. PMID: 23962476
Finsterer J
Can J Neurol Sci 2009 Jul;36(4):409-28. doi: 10.1017/s0317167100007733. PMID: 19650351
Liu W, Narayanan V
Semin Pediatr Neurol 2008 Dec;15(4):216-20. doi: 10.1016/j.spen.2008.10.014. PMID: 19073331
Le Ber I, Brice A, Dürr A
Curr Neurol Neurosci Rep 2005 Sep;5(5):411-7. doi: 10.1007/s11910-005-0066-4. PMID: 16131425

Diagnosis

Worm C, Schambye MER, Mkrtchyan GV, Veviorskiy A, Shneyderman A, Ozerov IV, Zhavoronkov A, Bakula D, Scheibye-Knudsen M
Aging (Albany NY) 2024 Feb 9;16(3):2026-2046. doi: 10.18632/aging.205537. PMID: 38345566Free PMC Article
Fiévet A, Bellanger D, Valence S, Mobuchon L, Afenjar A, Giuliano F, Dubois d'Enghien C, Parfait B, Pedespan JM, Auger N, Rieunier G, Collet A, Burglen L, Stoppa-Lyonnet D, Stern MH
Hum Mutat 2019 Oct;40(10):1690-1699. Epub 2019 May 15 doi: 10.1002/humu.23773. PMID: 31033087
Tzur-Gilat A, Ziv Y, Mittelman L, Barzilai A, Shiloh Y
Mech Ageing Dev 2013 Oct;134(10):496-505. Epub 2013 Apr 9 doi: 10.1016/j.mad.2013.04.001. PMID: 23583690
Liu W, Narayanan V
Semin Pediatr Neurol 2008 Dec;15(4):216-20. doi: 10.1016/j.spen.2008.10.014. PMID: 19073331
Fernet M, Gribaa M, Salih MA, Seidahmed MZ, Hall J, Koenig M
Hum Mol Genet 2005 Jan 15;14(2):307-18. Epub 2004 Dec 1 doi: 10.1093/hmg/ddi027. PMID: 15574463

Therapy

Uchisaka N, Takahashi N, Sato M, Kikuchi A, Mochizuki S, Imai K, Nonoyama S, Ohara O, Watanabe F, Mizutani S, Hanada R, Morio T
J Pediatr 2009 Sep;155(3):435-8. doi: 10.1016/j.jpeds.2009.02.037. PMID: 19732584

Prognosis

Oba D, Hayashi M, Minamitani M, Hamano S, Uchisaka N, Kikuchi A, Kishimoto H, Takagi M, Morio T, Mizutani S
Acta Neuropathol 2010 Apr;119(4):513-20. Epub 2010 Jan 20 doi: 10.1007/s00401-010-0639-4. PMID: 20087742
Uchisaka N, Takahashi N, Sato M, Kikuchi A, Mochizuki S, Imai K, Nonoyama S, Ohara O, Watanabe F, Mizutani S, Hanada R, Morio T
J Pediatr 2009 Sep;155(3):435-8. doi: 10.1016/j.jpeds.2009.02.037. PMID: 19732584

Clinical prediction guides

Völkening L, Vatselia A, Asgedom G, Bastians H, Lavin M, Schindler D, Schambach A, Bousset K, Dörk T
FASEB J 2020 Feb;34(2):2812-2820. Epub 2019 Dec 31 doi: 10.1096/fj.201902318R. PMID: 31908056
Fiévet A, Bellanger D, Valence S, Mobuchon L, Afenjar A, Giuliano F, Dubois d'Enghien C, Parfait B, Pedespan JM, Auger N, Rieunier G, Collet A, Burglen L, Stoppa-Lyonnet D, Stern MH
Hum Mutat 2019 Oct;40(10):1690-1699. Epub 2019 May 15 doi: 10.1002/humu.23773. PMID: 31033087
Unterholzner L
Immunobiology 2013 Nov;218(11):1312-21. Epub 2013 Jul 29 doi: 10.1016/j.imbio.2013.07.007. PMID: 23962476
Khan AO, Oystreck DT, Koenig M, Salih MA
J AAPOS 2008 Apr;12(2):186-9. Epub 2007 Dec 21 doi: 10.1016/j.jaapos.2007.09.016. PMID: 18083591
Lee JH, Ghirlando R, Bhaskara V, Hoffmeyer MR, Gu J, Paull TT
J Biol Chem 2003 Nov 14;278(46):45171-81. Epub 2003 Sep 8 doi: 10.1074/jbc.M308705200. PMID: 12966088

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