Ataxia telangiectasia differential diagnosis

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:

• Ataxia oculomotor apraxia type 1
• Ataxia oculomotor apraxia type 2
• Gaucher disease
• Hartnup disease
• Niemann-Pick disease
• Refsum disease

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	-	-	+	+	Progressive psychomotor regression Seizures External ophthalmoplegia Lactic acidosis Vomiting	Increased lactate levels in blood and CSF Genetic testing	MRI: abnormal white matter signal in the putamen, basal ganglia, and brainstem on T2 images
Niemann-Pick disease type C	-	-	+	+	Progressive neurodegeneration Hepatosplenomegaly Systemic involvement of liver, spleen, or lung preceedes neurologic symptoms	Abnormal liver function tests Fibroblast cell culture with filipin staining	MRI: Cerebral and cerebellar atrophy Thinning of the corpus callosum
Infantile Refsum disease	-	+	+	-	Abnormalities of the optic nerve and disc Retinitis pigmentosa Sensorineural hearing loss Hepatomegaly and cirrhosis Neurologic deterioration is slower than in Zellweger syndrome or ALD	Elevated plasma VLCFA levels	--
Adrenoleukodystrophy	+	-	-	-	Cognitive and behavioral abnormalities Adrenal insufficiency Hyperpigmented skin Gonadal dysfunction Neurologic deterioration progresses at a variable rate	Elevated plasma VLCFA levels Molecular genetic testing for mutations in the ABCD1 gene	--
Zellweger syndrome	-	+	-	-	Craniofacial dysmorphism Hepatomegaly Neonatal seizures Profound developmental delay MRI findings include cortical and white matter abnormalities Neurologic deterioration is rapid and infants rarely survive beyond six months of age	Elevated plasma VLCFA levels Elevated levels of phytanic acid, pristanic acid, and pipecolic acid in plasma and fibroblasts Reduced plasmalogen in erythrocytes Molecular genetic testing for mutations in the PEX1 or PEX6 genes	--
Pyruvate dehydrogenase deficiency	+	+	+	-	Lactic acidosis Seizures Intellectual disability	Elevated lactate and pyruvate levels in blood and CSF Abnormal PDH enzymatic activity in cultured fibroblasts	--
Arginase deficiency	+	-	-	-	Hyperammonemia Encephalopathy Respiratory alkalosis	Elevated ammonia level Elevated arginine level	--
Holocarboxylase synthetase deficiency	-	+	-	-	Ketoacidosis Dermatitis Alopecia Seizures Developmental delay	Elevated levels of: Beta-hydroxyisovalerate Beta-methylcrotonylglycine Beta-hydroxypropionate Methylcitrate Tiglylglycine	--
Glutaric aciduria type 1	-	-	-	+	Episodes of metabolic decompensation and encephalopathy often precipitated by infection and fever Rarely presents in the newborn period Microencephalic macrocephaly Seizures (approximately 20 percent) Cognitive function is preserved	Elevated levels of: glutaric acid 3-hydroxyglutaric acid	MRI: Frontal and temporal atrophy
Ataxia telangiectasia	-	-	+	-	Progressive cerebellar ataxia Abnormal eye movements Oculocutaneous telangiectasias Immune deficiency Increased risk of malignancy	Elevated serum alpha-fetoprotein level Low IgA and IgG levels Lymphopenia Genetic testing for mutation in the ATM gene	--
Pontocerebellar hypoplasias	-	+	-	-	Progressive muscle atrophy Microcephaly Developmental delay	Genetic testing for PCH gene mutations	MRI : Small cerebellum and brainstem including the pons
Metachromatic leukodystrophy	-	+	+	-	Regression of motor skills Seizures Optic atrophy Reduced or absent deep tendon reflexes Intellectual disability	Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts	--
Pelizaeus-Merzbacher	+	-	+	-	Nystagmus Cognitive impairment Onset in infancy Slowly progressive Language development may be normal	Genetic testing for mutations in PLP1 gene	MRI: White matter abnormalities
Angelman syndrome	-	-	+	-	Profound intellectual disability Postnatal microcephaly Typical abnormal behaviors (paroxysmal laughter, easily excitable)	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	+	-	-	+	Self-mutilating behavior Urinary stones due to hyperuricemia	Elevated uric acid level Abnormal enzymatic activity of HPRT in cultured fibroblasts Genetic testing for HPRT gene mutations	--
Miller-Dieker lissencephaly	+	+	-	-	Lissencephaly Microcephaly Dysmorphic features Seizures Failure to thrive	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:

Disorder	Defect (Mechanism of Development)	Characteristic Features	Clinical Presentation	Laboratory Findings
X-Linked (Bruton) Agammaglobulinemia	Defect in tyrosine kinase gene (BTK) B cells fail to mature	X-linked recessive pattern of inheritance Increased prevalence in males	Recurrent bacterial and enteroviral infections after 6 months of age Pre-disposition to development of infections by encapsulated organisms Pre-disposition to development of Giardia infections Absent lymph nodes and tonsils	Normal CD19+ B cell count Decreased pro-B cells Increased pre-B cells Decreased immunoglobulins of all classes
Selective IgA Deficiency	Stem cell defect (Transferrable with marrow transplant) Lack of IL-4, IL-6, IL-7, IL-10, TGF-β, and IL-21 Mutations in transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI, TNFRSF13B)	Most common primary immune deficiency	Majority of the cases are asymptomatic Respiratory and gastrointestinal infections (mucosal infections) Associated with autoimmune diseases Atopy Anaphylaxis to IgA containing products	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	May present with other autoimmune diseases Associated with bronchiectasis Associated with lymphoma Associated with sinopulmonary infections (Bacterial, enteroviral and parasitic such as Giardia)	Decreased plasma cells Decreased immunoglobulins
Autosomal dominant hype IgE syndrome (Job's Syndrome)	Defieciency of Th17 cells due to STAT3 mutation Impaired neutrophils to sites of infection	Distinctive coarse facies Cold (non-inflammatory) Staphylococcal abscesses Retained primary teeth Eczema		Increased levels of IgE Decreased levels of interferon gamma (IFN-gamma)
Severe combined immunodeficiency (SCID)	Defective interleukin-2 receptor gamma chain Adenosine deaminase deficiency Reg 1 and Reg 2 nonsense mutations	IL-2R disease is X-linked ADA deficiency and reg mutations are typically autosomal recessive	Failure to thrive Chronic diarrhea Thrush Recurrent bacterial, viral and protozoal infections Treatment is bone marrow transplant	Decreased T cell receptor excision circles (TRECs) Abscence of thymic shadow on chest X-Ray Absent germinal centers of lymph node biopsy Absent T cells on flow cytometry
Ataxia Telangiectasia	Defect in ATM gene DNA double stranded breaks leading to cell cycle arrest	Hypersensitivity to X-Rays	Triad of: Ataxia Spider angiomas (Nests of distended capillaries) IgA deficiency	Increased alpha fetoprotein (AFP) Decreased IgA, IgG and IgE Lymphopenia Cerebellar atrophy
Hyper IgM Syndrome	Defective CD40L (CD40 ligand) on Th cells leading to class switching defect	X-linked recessive pattern of inheritance	Severe pyogenic infections in early life Opportunistic infection with: Pneumocystis jiroveci Cryptosporidium Cytomegalovirus (CMV)	Increased IgM Decreased IgG, IgA and IgE No germinal centers
Wiskott-Aldrich Syndrome	Mutation in WAS gene T cells unable to reorganize actin microfilaments (microfilament defect)	X-linked recessive pattern of inheritance Increased risk of autoimmune disease and malignancy	Thrombocytopenic purpura Eczema Recurrent infections	Decreased to normal IgG and IgM Increased IgE and IgA Fewer and smaller platelets

• Malignancy: can cause the reduction in the immunoglobulin production.

• 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.
• Other causes of primary humoral immunodeficiencies.
• Smoking: may cause IgG2 subclass deficiency.
• Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.