Ataxia telangiectasia differential diagnosis: Difference between revisions

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Comparison of the clinical features, biomarkers and brain imaging between ataxia telangiectasia (AT), ataxiatelangiectasia-like disorder type 1 (ATLD1) and ataxia telangiectasia-like disorder type 2 (ATLD2)
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! style="width: 200px; background: #4479BA;" | {{fontcolor|#FFF|Clinical Features}}
! style="width: 300px; background: #4479BA;" | {{fontcolor|#FFF|AT (ATM)}}
! style="width: 400px; background: #4479BA;" | {{fontcolor|#FFF|ATLD1 (MRE11A)}}
! style="width: 500px; background: #4479BA;" | {{fontcolor|#FFF|ATLD2 (PCNA)}}
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Ataxia
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Dysarthria
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Telangiectasia
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Eye movement disorders
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Photophobia and photosensitivity
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Movement disorders (choreoathetosis, dystonia, myoclonus, tremor)
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Cognitive dysfunction
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Sensorineural hearing loss
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Skin abnormalities
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Microcephaly
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Short stature, developmental delay
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Lymphoid tumors predisposition
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Unknown
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Recurrent infections
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Increased levels of alpha-fetoprotein
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Unknown
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Reduced levels of Immunoglobulin
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| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Cerebellar atrophy
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AT, ataxia telangiectasia; ATLD1, ataxia telangiectasia-like disorder type 1; ATLD2, ataxia telangiectasia-like disorder type 2.
==Differentiating Ataxia Telangiectasia From Other Disorders Causing Humoral Immunodeficiency==
==Differentiating Ataxia Telangiectasia From Other Disorders Causing Humoral Immunodeficiency==
Ataxia Telangiectasia should also be differentiated from other disorders leading to [[hypogammaglobulinemia]] and defects of [[humoral immunity]]. The following conditions may be considered as differentials:<ref name="pmid17910333">{{cite journal |vauthors=Agarwal S, Cunningham-Rundles C |title=Assessment and clinical interpretation of reduced IgG values |journal=Ann. 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Immunol. |volume=27 |issue=3 |pages=308–16 |date=May 2007 |pmid=17510807 |doi=10.1007/s10875-007-9075-1 |url=}}</ref><ref name="pmid26564081">{{cite journal |vauthors=Nissenkorn A, Ben-Zeev B |title=Ataxia telangiectasia |journal=Handb Clin Neurol |volume=132 |issue= |pages=199–214 |date=2015 |pmid=26564081 |doi=10.1016/B978-0-444-62702-5.00014-7 |url=}}</ref><ref name="pmid27884168">{{cite journal |vauthors=Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM |title=Ataxia telangiectasia: a review |journal=Orphanet J Rare Dis |volume=11 |issue=1 |pages=159 |date=November 2016 |pmid=27884168 |pmc=5123280 |doi=10.1186/s13023-016-0543-7 |url=}}</ref><ref name="pmid9874856">{{cite journal |vauthors=Crawford TO |title=Ataxia telangiectasia |journal=Semin Pediatr Neurol |volume=5 |issue=4 |pages=287–94 |date=December 1998 |pmid=9874856 |doi= |url=}}</ref><ref name="pmid2415689">{{cite journal |vauthors=Boder E |title=Ataxia-telangiectasia: an overview |journal=Kroc Found Ser |volume=19 |issue= |pages=1–63 |date=1985 |pmid=2415689 |doi= |url=}}</ref><ref name="pmid22614068">{{cite journal |vauthors=Hoche F, Seidel K, Theis M, Vlaho S, Schubert R, Zielen S, Kieslich M |title=Neurodegeneration in ataxia telangiectasia: what is new? What is evident? |journal=Neuropediatrics |volume=43 |issue=3 |pages=119–29 |date=June 2012 |pmid=22614068 |doi=10.1055/s-0032-1313915 |url=}}</ref><ref name="pmid13542097">{{cite journal |vauthors=BODER E, SEDGWICK RP |title=Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection |journal=Pediatrics |volume=21 |issue=4 |pages=526–54 |date=April 1958 |pmid=13542097 |doi= |url=}}</ref><ref name="pmid24683014">{{cite journal |vauthors=Sahama I, Sinclair K, Pannek K, Lavin M, Rose S |title=Radiological imaging in ataxia telangiectasia: a review |journal=Cerebellum |volume=13 |issue=4 |pages=521–30 |date=August 2014 |pmid=24683014 |doi=10.1007/s12311-014-0557-4 |url=}}</ref><ref name="pmid23886747">{{cite journal |vauthors=Lin DD, Barker PB, Lederman HM, Crawford TO |title=Cerebral abnormalities in adults with ataxia-telangiectasia |journal=AJNR Am J Neuroradiol |volume=35 |issue=1 |pages=119–23 |date=January 2014 |pmid=23886747 |pmc=4106125 |doi=10.3174/ajnr.A3646 |url=}}</ref><ref name="pmid15069401">{{cite journal |vauthors=Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM |title=Immunodeficiency and infections in ataxia-telangiectasia |journal=J. Pediatr. |volume=144 |issue=4 |pages=505–11 |date=April 2004 |pmid=15069401 |doi=10.1016/j.jpeds.2003.12.046 |url=}}</ref>
Ataxia Telangiectasia should also be differentiated from other disorders leading to [[hypogammaglobulinemia]] and defects of [[humoral immunity]]. The following conditions may be considered as differentials:<ref name="pmid17910333">{{cite journal |vauthors=Agarwal S, Cunningham-Rundles C |title=Assessment and clinical interpretation of reduced IgG values |journal=Ann. 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Immunol. |volume=162 |issue=11 |pages=6690–700 |date=June 1999 |pmid=10352287 |doi= |url=}}</ref><ref name="pmid8993019">{{cite journal |vauthors=Hayward AR, Levy J, Facchetti F, Notarangelo L, Ochs HD, Etzioni A, Bonnefoy JY, Cosyns M, Weinberg A |title=Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM |journal=J. Immunol. |volume=158 |issue=2 |pages=977–83 |date=January 1997 |pmid=8993019 |doi= |url=}}</ref><ref name="pmid20180797">{{cite journal |vauthors=Davies EG, Thrasher AJ |title=Update on the hyper immunoglobulin M syndromes |journal=Br. J. Haematol. |volume=149 |issue=2 |pages=167–80 |date=April 2010 |pmid=20180797 |pmc=2855828 |doi=10.1111/j.1365-2141.2010.08077.x |url=}}</ref><ref name="pmid20101521">{{cite journal |vauthors=Yel L |title=Selective IgA deficiency |journal=J. Clin. 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Immunol. |volume=27 |issue=3 |pages=308–16 |date=May 2007 |pmid=17510807 |doi=10.1007/s10875-007-9075-1 |url=}}</ref><ref name="pmid26564081">{{cite journal |vauthors=Nissenkorn A, Ben-Zeev B |title=Ataxia telangiectasia |journal=Handb Clin Neurol |volume=132 |issue= |pages=199–214 |date=2015 |pmid=26564081 |doi=10.1016/B978-0-444-62702-5.00014-7 |url=}}</ref><ref name="pmid27884168">{{cite journal |vauthors=Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM |title=Ataxia telangiectasia: a review |journal=Orphanet J Rare Dis |volume=11 |issue=1 |pages=159 |date=November 2016 |pmid=27884168 |pmc=5123280 |doi=10.1186/s13023-016-0543-7 |url=}}</ref><ref name="pmid9874856">{{cite journal |vauthors=Crawford TO |title=Ataxia telangiectasia |journal=Semin Pediatr Neurol |volume=5 |issue=4 |pages=287–94 |date=December 1998 |pmid=9874856 |doi= |url=}}</ref><ref name="pmid2415689">{{cite journal |vauthors=Boder E |title=Ataxia-telangiectasia: an overview |journal=Kroc Found Ser |volume=19 |issue= |pages=1–63 |date=1985 |pmid=2415689 |doi= |url=}}</ref><ref name="pmid22614068">{{cite journal |vauthors=Hoche F, Seidel K, Theis M, Vlaho S, Schubert R, Zielen S, Kieslich M |title=Neurodegeneration in ataxia telangiectasia: what is new? What is evident? |journal=Neuropediatrics |volume=43 |issue=3 |pages=119–29 |date=June 2012 |pmid=22614068 |doi=10.1055/s-0032-1313915 |url=}}</ref><ref name="pmid13542097">{{cite journal |vauthors=BODER E, SEDGWICK RP |title=Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection |journal=Pediatrics |volume=21 |issue=4 |pages=526–54 |date=April 1958 |pmid=13542097 |doi= |url=}}</ref><ref name="pmid24683014">{{cite journal |vauthors=Sahama I, Sinclair K, Pannek K, Lavin M, Rose S |title=Radiological imaging in ataxia telangiectasia: a review |journal=Cerebellum |volume=13 |issue=4 |pages=521–30 |date=August 2014 |pmid=24683014 |doi=10.1007/s12311-014-0557-4 |url=}}</ref><ref name="pmid23886747">{{cite journal |vauthors=Lin DD, Barker PB, Lederman HM, Crawford TO |title=Cerebral abnormalities in adults with ataxia-telangiectasia |journal=AJNR Am J Neuroradiol |volume=35 |issue=1 |pages=119–23 |date=January 2014 |pmid=23886747 |pmc=4106125 |doi=10.3174/ajnr.A3646 |url=}}</ref><ref name="pmid15069401">{{cite journal |vauthors=Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM |title=Immunodeficiency and infections in ataxia-telangiectasia |journal=J. 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Latest revision as of 10:27, 28 July 2021


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]}

Differential Diagnosis

Ataxia telangiectasia like disorder (ATLD) is an extremely rare condition which could be considered as a differential diagnosis to AT. ATLD patients are very similar to AT patients in showing a progressive cerebellar ataxia, hypersensitivity to ionising radiation and genomic instability. However, ATLD can be distinguished from AT by the absence of telangiectasias, normal immunoglobulin levels, a later onset of the condition and a slower progression of the disease. It is not known whether ATLD individuals are also predisposed to tumours. The gene mutated in ATLD is hMre11 and is located on chromosome 11q21.

Nijmegen breakage syndrome (NBS), also known as ataxia telangiectasia variant 1, is a very rare syndrome which could be considered as a differential diagnosis to AT. People with Nijmegen breakage syndrome show the same immunodeficiency, radiosensitivity and risk of cancer as AT but do not have any ataxia or oculo-cutaneous telangiectasia. Nijmegen breakage syndrome sufferers also show microcephaly. The gene associated with Nijmegen syndrome (Nbs1) is known to be located on 8q21.

Interestingly, the proteins expressed by the hMre11 and Nbs1 genes exist in the cell as a complex, along with a third protein expressed by the hRad50 gene. This complex, known as the MRN complex, plays an important role in DNA damage repair and signalling and is required to recruit ATM to the sites of DNA double strand breaks. Mre11 and Nbs1 are also targets for phosphorylation by the ATM kinase. Thus, the similarity of the three diseases can be explained in part by the fact that the protein products of the three genes mutated in these disorders interact in common pathways in the cell.

In the early ataxic stages children may be diagnosed with cerebral palsy.

Other differential diagnoses are:

Differential diagnosis

Ataxia telangiectasia must be differentiated from other diseases that cause neurological manifestations in infants.

Diseases Type of motor abnormality Clinical findings Laboratory findings and diagnostic tests Radiographic findings
Spasticity Hypotonia Ataxia Dystonia
Leigh syndrome - - + +
Niemann-Pick disease type C - - + +
  • Abnormal liver function tests
  • Fibroblast cell culture with filipin staining
Infantile Refsum disease - + + - Elevated plasma VLCFA levels --
Adrenoleukodystrophy + - - -
  • Elevated plasma VLCFA levels
  • Molecular genetic testing for mutations in the ABCD1 gene
--
Zellweger syndrome - + - - --
Pyruvate dehydrogenase deficiency + + + -
  • Elevated lactate and pyruvate levels in blood and CSF
  • Abnormal PDH enzymatic activity in cultured fibroblasts
--
Arginase deficiency + - - - --
Holocarboxylase synthetase deficiency - + - - Elevated levels of:
  • Beta-hydroxyisovalerate
  • Beta-methylcrotonylglycine
  • Beta-hydroxypropionate
  • Methylcitrate
  • Tiglylglycine
--
Glutaric aciduria type 1 - - - + Elevated levels of:
Ataxia telangiectasia - - + - --
Pontocerebellar hypoplasias - + - - Genetic testing for PCH gene mutations
Metachromatic leukodystrophy - + + -
  • Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts
--
Pelizaeus-Merzbacher + - + -
Angelman syndrome - - + -
  • Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations
--
Rett syndrome + - - +
  • Occurs almost exclusively in females
  • Normal development during first six months followed by regression and loss of milestones
  • Loss of speech capability
  • Stereotypic hand movements
  • Seizures
  • Autistic features
  • Clinical diagnosis
  • Genetic testing for MECP2 mutations
--
Lesch-Nyhan syndrome + - - + --
Miller-Dieker lissencephaly + + - -
  • Cytogenetic testing for 17p13.3 microdeletion
--
Dopa-responsive dystonia + - - +
  • Onset in early childhood
  • Symptoms worsen with fatigue and exercise
  • Positive response to a trial of levodopa
--


Comparison of the clinical features, biomarkers and brain imaging between ataxia telangiectasia (AT), ataxiatelangiectasia-like disorder type 1 (ATLD1) and ataxia telangiectasia-like disorder type 2 (ATLD2)

Clinical Features AT (ATM) ATLD1 (MRE11A) ATLD2 (PCNA)
Ataxia + + +
Dysarthria + + +
Telangiectasia + - +
Eye movement disorders + + -
Photophobia and photosensitivity - - +
Movement disorders (choreoathetosis, dystonia, myoclonus, tremor) + + -
Cognitive dysfunction + + +
Sensorineural hearing loss - - +
Skin abnormalities + - +
Microcephaly - - +
Short stature, developmental delay + + +
Lymphoid tumors predisposition + - Unknown
Recurrent infections + - -
Increased levels of alpha-fetoprotein + - Unknown
Reduced levels of Immunoglobulin + - -
Cerebellar atrophy + + +

AT, ataxia telangiectasia; ATLD1, ataxia telangiectasia-like disorder type 1; ATLD2, ataxia telangiectasia-like disorder type 2.

Differentiating Ataxia Telangiectasia From Other Disorders Causing Humoral Immunodeficiency

Ataxia Telangiectasia should also be differentiated from other disorders leading to hypogammaglobulinemia and defects of humoral immunity. The following conditions may be considered as differentials:[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][24][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]

Disorder Defect (Mechanism of Development) Characteristic Features Clinical Presentation Laboratory Findings
X-Linked (Bruton) Agammaglobulinemia
Selective IgA Deficiency
  • Serum IgA < 7 mg/dl
  • Normal IgG and IgM levels
Common Variable Immunodeficiency
  • Defective B cell differentiation
  • May be acquired in 20-30 years of age
Autosomal dominant hype IgE syndrome (Job's Syndrome)
  • Distinctive coarse facies
  • Cold (non-inflammatory) Staphylococcal abscesses
  • Retained primary teeth
  • Eczema
Severe combined immunodeficiency (SCID)
Ataxia Telangiectasia
Hyper IgM Syndrome
Wiskott-Aldrich Syndrome
  • Malignancy: can cause the reduction in the immunoglobulin production.[51]
  • Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia..
  • Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.[52]
  • Other causes of primary humoral immunodeficiencies.
  • Smoking: may cause IgG2 subclass deficiency.[53]
  • Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.

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