case reports 2020; 6(2)

https://doi.org/10.15446/cr.v6n2.83219 ATAXIA TELANGIECTASIA: A DIAGNOSTIC CHALLENGE. CASE REPORT

Keywords: Ataxia Telangiectasia; Neurodegenerative Diseases; Cerebellar Ataxia; Spinocerebellar Degenerations; Telangiectasia. Palabras clave: Ataxia telangiectasia; Enfermedades neurodegenerativas; Ataxia cerebelosa; Degeneraciones espinocerebelosa; Telangiectasia.

Natalia Martínez-Córdoba Universidad Militar Nueva Granada - Faculty of Medicine - Pediatric Neurology Research Group - Bogotá D.C. - Colombia. Hospital Militar Central - Pediatric Neurology Service - Bogotá D.C. - Colombia.

Eugenia Espinosa-García Universidad Militar Nueva Granada - Faculty of Medicine - Pediatric Neurology Research Group - Bogotá D.C. - Colombia. Hospital Militar Central - Pediatric Neurology Service - Bogotá D.C. - Colombia. Universidad del Rosario - Medical School - Bogotá D.C. - Colombia.

Corresponding author Natalia Martínez-Córdoba. Faculty of Medicine, Universidad Militar Nueva Granada. Bogotá D.C. Colombia. Email: [email protected].

Received: 28/10/2019 Accepted: 08/01/2020 case reports Vol. 6 No. 2: 109-17

110 RESUMEN ABSTRACT

Introducción. La ataxia-telangiectasia (AT) es Introduction: Ataxia-telangiectasia (AT) is a un síndrome neurodegenerativo con baja inciden- neurodegenerative syndrome with low incidence cia y prevalencia mundial que es causado por una and prevalence worldwide, which is caused by a mutación del gen ATM, es de herencia autosó- mutation of the ATM gene. It is an autosomal re- mica recesiva y se asocia a mecanismos defec- cessive disorder that is associated with defective tuosos en la regeneración y reparación del ADN. cell regeneration and DNA repair mechanisms. It Este síndrome se caracteriza por la presencia de is characterized by progressive cerebellar atax- ataxia cerebelosa progresiva, movimientos ocula- ia, abnormal eye movements, oculocutaneous res anormales, telangiectasias oculocutáneas e telangiectasias and immunodeficiency. Early inmunodeficiencia. El diagnóstico oportuno de la diagnosis is critical to initiate a timely interdis- AT es muy importante para poder iniciar un manejo ciplinary treatment, improve acute symptoms, interdisciplinario temprano, mejorar la sintomato- and control the multiple comorbidities of the logía aguda y controlar las múltiples comorbilida- disease. The following is the case of a patient des que causa. A continuación se presenta el caso who presented with the aforementioned char- de una paciente con las características clásicas acteristics and had an adequate response to de esta enfermedad y una adecuada respuesta the established medical treatment. y evolución al manejo médico instaurado. Case presentation: A 7-year-old female pa- Presentación de caso. Paciente femenina de tient from Bogotá, who presented clinical signs 7 años de edad, procedente de Bogotá, quien of global neurodevelopmental delay, cerebellar presentó cuadro clínico inicial de retraso global ataxia, frequent respiratory infections and ocu- del neurodesarrollo, ataxia cerebelosa, infec- lar telangiectasias. Symptoms were associated ciones respiratorias frecuentes y telangiectasias with elevation of alpha fetoprotein and immu- oculares. La sintomatología se asoció a elevación nodeficiency, which allowed for a diagnosis of de alfa fetoproteína e inmunodeficiencia, lo que AT and the initiation of a timely interdisciplinary permitió plantear el diagnóstico de AT e iniciar treatment. de manera oportuna el manejo interdisciplinario. Conclusion: AT is a chromosomal instability Conclusión. La AT es un síndrome de inestabili- syndrome with characteristic signs and symp- dad cromosómica con signos clínicos y síntomas toms. It is essential to know the etiopathogene- característicos, por lo que es primordial conocer la sis, clinical manifestations, diagnostic criteria, etiopatogenia, el cuadro clínico, los criterios diag- and therapeutic options, emphasizing that ear- nósticos y las propuestas terapéuticas, pues la ly detection and clinical suspicion could favor detección y la sospecha clínica temprana pueden the proper management of the comorbidities favorecer el manejo precoz de las diferentes co- and improve the progressive course of the morbilidades y mejorar el curso progresivo. disease. ataxia telangiectasia: a diagnostic challenge

INTRODUCTION CASE PRESENTATION 111

Ataxia-telangiectasia (AT), also known as Bod- Mestizo, female patient, 7 years old, from Bogotá er-Sedgwick syndrome or Louis-Bar syndrome, D.C., Colombia, and the product of a second is a multisystemic, neurodegenerative, autoso- pregnancy by young, non-blood related, mid- mal recessive disease associated with the ATM dle-class parents. The girl had no significant pre- gene mutation (A-T-mutated), which is located natal history and was born by cesarean section at on the long arm of chromosome 11 (11q22-23). 35 weeks of gestation. Her weight at birth was (1) This syndrome affects multiple organs of the 1 800gr and her size was 40cm; the APGAR body and has moderate and severe long-term score was 4/10, 7/10 and 7/10 at 1 minute, sequelae. 5 minutes and 10 minutes, respectively. She AT is characterized by progressive neu- also presented with neonatal hypoxia, requiring rological dysfunction with multisystemic mechanical ventilation for 24 hours and hospi- alterations and predisposition to cancer. The talization in the neonatal intensive care unit for characteristic symptoms of this disease usually 20 days. appear early in childhood and include cere- The child’s psychomotor development was bellar ataxia, oculomotor apraxia, chorea, and normal until the age of 20 months, at which cognitive impairment. (2) Moreover, the cells time it was evident that there was language of AT patients present chromosomal instability, delay, café-au-lait spots and unsteady gait. At hypersensitivity to X-rays, propensity to lym- 31 months, she was referred to the Neuropedi- phoid neoplasms, variable immunodeficiency, atrics Service, which requested magnification and susceptibility to infections, which cause and brain magnetic resonance imaging (MRI) systemic symptoms such as endocrinopathies, studies; management with physical and lan- leukemias, radiosensitivity and ocular telangi- guage therapy was initiated. ectasias. (3,4) At 5 years of age, the patient was taken to While over 400 mutations of the ATM gene the emergency department due to a possible have been detected, it has been reported that focal onset impaired awareness seizure. During AT has an incidence of 1 between 40 000 and the interview, psychomotor and language delays 100 000 people (5) and that its frequency of were observed, as well as multiple respirato- heterozygosity in the mutant allele is 1.4% to ry and gastrointestinal tract infections. The 2% in the general population. (1,3) neurological examination revealed bradylalia, This disease is usually diagnosed late, as it bradypsychia, ataxic gait with enlargement of is only identifiable when patients have severe the support polygon, presence of oculomotor symptoms that begin with alterations in the apraxia, dysmetria and telangiectasias in sclera motor system. In addition, it is often misdiag- (Figure 1), so more specific tests were requested. nosed as cerebral palsy. (6) Finally, since MRI showed cerebellar atrophy So far there is no specific treatment for AT, (Figure 2), video-electroencephalography so its management is palliative and supportive. (EGG) was normal, alpha-fetoprotein (AFP) (7) Patients with this disease should participate levels were elevated, and immunological tests in daily and social integration activities, always were altered (Table 1), a diagnosis of AT was trying to maintain their quality of life. suggested. case reports Vol. 6 No. 2: 109-17

112

Figure 1. Patient with sclera telangiectasia. Source: Document obtained during the study.

Figure 2. Brain MRI showing cerebellar vermian atrophy. A) Sagittal plane / T1 sequence; B) Coronal plane / FLAIR sequence. Source: Document obtained during the study.

Table 1. Laboratory tests performed during patient follow-up. First sample Second sample Third sample Reference Test (11/09/2017) (09/05/2018) (04/06/2019) values IgA mg/dL 94 77.3 76.9 58-311 IgM mg/dL 157 147 174.5 84-383 IgG1 mg/dL 6.34 6.34 7.97 3.06-9.450 IgG2 mg/dL 0.56 2.34 3.05 0.605-3.450 IgG3 mg/dL 0.57 0.44 0.41 0.099-1.221 IgG4 mg/dL 0.01 0.10 0.15 0.018-1.125 CD3 669 672 778 1400-3700 CD4 282 265 256 700-2200 CD8 639 301 443 490-1300 Alpha- Fetoprotein (ng/mL) 69 74 69.4 0.89-8.78 Source: Own elaboration. ataxia telangiectasia: a diagnostic challenge

The child was assessed by the Pediatric the findings on physical examination and the 113 Immunology Service, which considered cellular associated comorbidities. and humoral immunodeficiency (IgG2 and At the time of preparation of this case report, IgG4 deficiency), so she started treatment the patient had undergone a global evaluation with gamma globulin IV every 28 days. She of the disease (AFP levels, immunological was also assessed by the pediatric hema- tests, video telemetry and blood counts) which tology-oncology service due to bicytopenia showed, on the one hand, an adequate response (leukopenia+thrombocytopenia) during a to the treatment and, on the other, the absence hospital stay without evidence of neoplastic of new alterations or comorbidities. It is worth alteration. The patient continued attending mentioning that, despite the poor and uncertain child psychiatry and physical, occupational prognosis that AT usually has, the child did not and language therapy. present significant clinical deterioration and had The specialties of pediatric neurology and adequate school performance, good participation clinical genetics gathered and concluded that it in daily activities and adequate social integration. was not necessary to perform a genetic study Furthermore, the number of hospitalizations due since AT could be diagnosed due to the elevat- to infections and comorbidities associated with ed AFP levels, the evolution of the symptoms, basic pathology decreased (Figure 3).

5 Years Hospitalization Neonatal Period 31 Months · Ataxic gait · Cesarean section at 35 weeks · Altered standing balance · Sclereal telangiectasia · · Apgar Score: 4-7-7 · Poor language development Ocular apraxia · · BW: 1 800gr · Unsteady gait with frequent falls Dysmetria · · · Diagnosis of AT SB: 40cm Café-au-lait spots · · NICU for 20 days Cerebellar atrpphy on MRI · · Elevated AFP levels NIV for 24 hours · Immunide ciency Multiple respiratory infections

20 Months 5 years At the time of

· Language delay · Psycchomotr, developmental and preparation of this · Alteration of the motor system language delay case report · Unsteady gait · Paroxysmal events · Multidisciplonary assessment · Focal onset seizures with altered · Treatment with inhalers and · state of consciousness monthly IV immunoglobulin · Hospitalization

Treatment with occupational, speech and physical therapy Figure 3. Patient follow-up timeline. BW: birth weight; SB: size at birth; NICU: neonatal intensive care unit; NIV: non-invasive ventilation; AT: ataxia telangiectasia; AFP: Alternative Names: Alpha-fetoprotein; MRI - nuclear magnetic resonance. Source: Own elaboration.

DISCUSSION multisystemic disorder affecting especially the neurological and immunological areas. AT is a progressive, rare, autosomal recessive According to Delfino et al., (8) AT was first neurodegenerative disorder consisting of a described in 1926 by Syllaba and Henner, who case reports Vol. 6 No. 2: 109-17

114 observed progressive choreoathetosis and ocular both humoral and cellular immunodeficiency telangiectasia in three family members. Later, (in approximately 70% of the patients). (19) in 1941, Louis-Bar (9) reported progressive Associated systemic findings include lung dis- cerebellar ataxia and cutaneous telangiecta- ease, radiation sensitivity, neurodevelopmental sias in a Belgian boy, but it was not until 1957 delay, skin conditions (hypertrichosis, seborrheic that Boder, Sedwick and Biedmond described dermatitis, vitiligo, acanthosis nigricans), insu- it as a distinct clinical entity characterized by lin-resistant diabetes mellitus and increased abnormalities of organic development, neu- incidence of malignancy. (5) rological disorders and recurrent pulmonary AT can appear in three different forms: infections. (10,11) Pure A-T, where patients have all or almost all The product of the ATM gene is a protein of the diagnostic symptoms; attenuated or type associated to the DNA repair process and the II T-A, where patients lack some of the typical cell cycle, and it has multiple mechanisms of findings but have radio sensitivity; and carrier action. These include the phosphorylation of T-A, where patients with a single ATM gene different substances such as the p53 tumor mutation are at increased risk of developing suppressor protein, which is responsible for cancer. (20) stopping the cell cycle or apoptosis; (12) the Regarding diagnostic criteria, Delfino et al. protein tyrosine kinase c-Abl, involved in the (8) and Lazo-Rivera & Pastor-Vizcarra, (21) in repair of DNA after ionizing radiation; (13) the accordance with the Lederman’s group from the tumor suppressor BRCA1, involved in breast Ataxia-telangiectasia Clinical Center, established cancer (11,13-15); and the protein phospha- three characteristic neurological findings of AT: tase 2A, which regulates the nuclear import of A) ataxic gait at the ages of 2-3; B) dysarthria histone deacetylase 4 (HDAC4) and neuronal and oculomotor disorders such as apraxia; and gene expression. (16,17) C) associated movement disorders, progressive Abnormalities in ATM-mediated functions ataxia, hypomimia, swallowing disorders and damage DNA by poor cell repair, accumu- peripheral neuropathy. These authors, together lation of somatic mutations, and increased with Cabana et al., (22) also stated that at least sensitivity to ionizing radiation, and this may one of the following conditions must be met: cause increased risk of cancer, early aging, ocular telangiectasia, elevated AFP level, and and neurodegeneration. (6) Similarly, thymo- spontaneous or X-ray-induced chromosome cytes, immature B-lymphocytes, Purkinje cells breakage. of the cerebellum, and vascular endothelium In this sense, the diagnosis is made based are compromised by the presence of these on clinical findings, identification of mutations abnormalities. (1,8) in the ATM gene, elevated levels of AFP of at The clinical presentation of AT usually least 2 standard deviations (which was found begins with progressive cerebellar ataxia as- in the case presented here with a sensitivity of sociated with deterioration of fine and gross 95%), humoral and/or cellular immunodeficiency motor skills, oculomotor apraxia, nystagmus, and increased chromosomal breakage after and delayed onset and speed of speech. (18) exposure to radiation, besides the semiological Telangiectasias appear between the ages of characteristics exposed. (3) three and five, mainly in the bulbar conjunctiva, This report presents the case of a patient nose, face, neck, and palate veil, as well as with classic AT phenotype, ataxic gait from an ataxia telangiectasia: a diagnostic challenge

early age, oculomotor apraxia and dysarthria, telangiectasias (at three to five years of age). 115 who developed ocular telangiectasias at the age However, the disease should be confirmed by of 5. This allowed to suspect the AT diagnosis, verifying elevated levels of AFP and, if neces- which was later confirmed with the elevation in sary, a genetic study, all in order to generate an AFP levels (69 mg/dL); given the findings it was appropriate clinical approach to better guide the not necessary to do ATM gene sequencing. It management and prognosis of patients. should be noted that the only ataxia associated Although no curative therapy exists, symp- with elevated AFP is ataxia-telangiectasia, a tomatic treatment for AT should be timely and fact known for over thirty years and reported interdisciplinary and should include physical in over 95% of patients with this disease. (23) therapy, occupational therapy, speech therapy Although cellular or humoral immunodefi- and pediatric immunology, pediatric hematolo- ciency are not diagnostic criteria for AT, they gy-oncology, physiatry, nutrition, child psychiatry, may lead to this diagnosis; in this patient, it and pediatric neurology services. was possible to identify them because of the associated recurrent respiratory infections. INFORMED CONSENT Furthermore, regarding AT, the literature also reports defects in the T- and B-lymphocyte This case report was elaborated after the pa- system, thymic hypoplasia, absence of IgA and tient’s parents gave their consent, always main- IgE (in 70% and 80% of patients, respectively) taining privacy and anonymity. and IgG deficiency (predominantly G2). (7) AT increases cancer susceptibility by CONFLICT OF INTEREST increasing radiosensitivity and chromosomal instability, causing a genetic and telomeric None stated by the authors. break. (16) Therefore, although no neoplas- tic alterations were detected in the reported FUNDING patient, the hematology-oncology service should monitor her since the early detection None stated by the authors. of oncological problems is important for the prognosis and follow-up of cancer. ACKNOWLEDGEMENTS Finally, it should be noted that since the population mentioned is not representative, None stated by the authors. no epidemiological data can be generated or generalized about the semiology or clinical REFERENCES benefit of treatment for AT. 1. Martínez-Grau I, Vargas-Díaz J. Inmunodefi- CONCLUSIONS ciencia con ataxia telangiectasia. Reporte de un caso. Inmunología. 2009;28(1):12-8. http://doi. The diagnosis of AT is based on clinical semiol- org/fk8ngm. ogy and should be considered in patients with 2. Rothblum-oviatt C, Wright J, Lefton-greif early-onset cerebellar ataxia, altered language MA, Mcgrath-morrow SA, Crawford TO, development, and subsequent appearance of Lederman HM. Ataxia telangiectasia: a review. case reports Vol. 6 No. 2: 109-17

116 Orphanet J Rare Dis. 2016;11(159):159. http:// International; Congress of Neurological Sciences. doi.org/dt6m. London: Pergamon Press; 1957. p. 206. 3. Teive HAG, Moro A, Moscovich M, Arruda 12. Khanna KK, Keating KE, Kozlov S, Scott S, WA, Munhoz RP, Raskin S, et al. Ataxia - te- Gatei M, Hobson K, et al. ATM associates with langiectasia - a historical review and a proposal for and phosphorylates p53 : mapping the region of a new designation: ATM syndrome. J Neurol Sci. interaction. Nat Genet. 1998;20(4):398-400. 2015;355(1-2):3-6. http://doi.org/f3g582. http://doi.org/cxd2dp. 4. Chun HH, Gatti RA. Ataxia - telangiectasia, 13. Baskaran R, Wood LD, Whitaker LL, Can- an evolving phenotype. DNA Repair (Amst). man CE, Morgan SE, Xu Y, et al. Ataxia telan- 2004;3(8-9):1187-96. http://doi.org/b9snsc. giectasia mutant protein activates c-Abl tyrosine 5. Celiksoy MH, Cubuk PO, Guner SN, Yildiran kinase in response to ionizing radiation. Nature. A. A Case of Ataxia-telangiectasia Presented With 1997;387(6632):516-9. http://doi.org/cnwq3p. Hemophagocytic Syndrome. J Pediatr Hematol 14. Cortez D, Wag Y, Qin J, Elledge Sj. Require- Oncol. 2018;40(8):547-9. http://doi.org/gfmzqf. ment of ATM-Dependent Phosphorylation of Brcal 6. Navratil M, Đuranovic´ V, Nogalo B, Švigir A, in the DNA Damage Response to Double-Strand Dumbovic-Dubravcic´ I, Turkalj M. Ataxia-Te- Breaks. Science. 2000;286(5442):1162-6. langiectasia Presenting as Cerebral Palsy and Re- http://doi.org/fnh4cx. current Wheezing: A Case Report. Am J Case Rep. 15. Chen J. Advances in Brief Ataxia Telangiecta- 2015;16:631-6. http://doi.org/gcbtcq. sia-related Protein Is Involved in the Phosphoryla- 7. Perlman S, Becker-Catania S, Gatti RA. tion of BRCA1 following Deoxyribonucleic Acid Ataxia-Telangiectasia: Diagnosis and Treatment. Damage. Cancer Res. 2000;60(18):5037-9. Semin Pediatr Neurol. 2003;10(3):173-82. 16. Li J, Chen J, Ricupero CL, Hart RP, Schwartz http://doi.org/br9td9. MS, Kusnecov A, et al. Nuclear accumulation 8. Delfino M, Bruzzone R, Rey A, Delfino A, Pírez of HDAC4 in ATM deficiency promotes neuro- MC. Ataxia-telangiectasia (síndrome de Louis- degeneration in ataxia telangiectasia. Nat Med. Bar). Arch. Pediatr. Urug. 2006;77(2):154-9. 2012;18(5):783-90. http://doi.org/f3x3cf. 9. Louis-Bar D. Sur un syndrome progresiff com- 17. Amirifar P, Ranjouri MR, Yazdani R, Abol- prenant des télangiectasies capillaries cutanées hassani H, Aghamohammadi A. Ataxia-te- et conjontivales symétriques à disposition nae- langiectasia: A review of clinical features and voîde et des troubles cérébelleux. Confin Neurol. molecular pathology. Pediatr Allergy Immunol. 1941;2(1):33-42. 2019;30(3):277-88. http://doi.org/dt6n. 10. Boder E, Sedwick RP. Ataxia telangiecta- 18. Perlman SL, Deceased EB, Sedgewick RP, sia; a familial syndrome of progressive cere- Gatti RA. Ataxia-telangiectasia. Handb Clin Neu- bellar ataxia, oculocutaneous telangiectasia rol. 2012;103(3):307-32. http://doi.org/b7d8fh. and frequent pulmonary infection. Pediatrics. 19. Chopra C, Davies G, Taylor M, Anderson M, 1958;21(4):526-54. Bainbridge S, Tighe P, et al. Immune deficiency 11. Biemond A. Paleocerebellar atrophy with ex- in Ataxia-Telangiectasia: a longitudinal study of 44 trapyramidal manifestations in association with patients. Cin Exp Inmmunol. 2014;176(2):275- bronchiectasis and telangiectasis of the conjunc- 82. http://doi.org/f5467j. tiva bulbi as a familial syndrome. In: van Bogaert 20. Hadi-Babikir HE. Classic ataxia-telangiectasia in L, Radermecker J, eds. Proceeding of the First a Sudanese boy : Case report and review of the lite- ataxia telangiectasia: a diagnostic challenge

117 rature. Sudan J Paediatr. 2011;11(1):60-3. ces of the delayed diagnosis of Ataxia-Telan- 21. Lazo-Rivera E, Pastor-Vizcarra LF. Ataxia-Te- giectasia. Pediatrics. 1998;102(1 Pt I):98-100. langiectasia: Reporte de caso. Rev Neuropsiquiatr. http://doi.org/dvz7z2. 2014;77(4):283-7. 23. Waldmann TA, Mcintire KR. Serum-Alpha-Feto- 22. Cabana MD, Crawford TO, Winkelstein JA, protein Levels in Patients With Ataxia-Telangiectasia. Christensen JR, Lederman HM. Consequen- Lancet. 1972;2(7787):1112-5. http://doi.org/cv6tc2.