Letter to the Editor
Clinical, biochemical, and molecular findings in a Colombian patient with Tay-Sachs disease
Caracterización clínica, bioquímica y molecular de una paciente colombiana con enfermedad de Tay-Sachs
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Posso Gomez, J.F. Gomez, V. Botero, H. Pachajoa" "autores" => array:4 [ 0 => array:3 [ "nombre" => "L.J." "apellidos" => "Posso Gomez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "J.F." "apellidos" => "Gomez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "V." "apellidos" => "Botero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:4 [ "nombre" => "H." "apellidos" => "Pachajoa" "email" => array:1 [ 0 => "hmpachajoa@icesi.edu.co" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras, Universidad ICESI, Cali, Colombia" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Fundación Clínica Valle de Lili, Cali, Colombia" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Caracterización clínica, bioquímica y molecular de una paciente colombiana con enfermedad de Tay-Sachs" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1732 "Ancho" => 2500 "Tamanyo" => 277283 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Comparative findings from nuclear MRI at age 14 months and at 4 years and 5 months.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Tay-Sachs disease is an autosomal recessive neurodegenerative disorder characterised by a mutation or deletion of the hexosaminidase A gene (<span class="elsevierStyleItalic">HEXA</span>), located at 15q23. The gene codes for the alpha subunit of hexosaminidase A, a lysosomal enzyme involved in ganglioside metabolism.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Tay-Sachs disease is a lysosomal storage disease and generally manifests after a period of normal neurological development. In this disease, gangliosides (GM2), a type of sphingolipid present in the membranes of cells of the central nervous system, are stored due to the lack of hexosaminidase A. The accumulation of gangliosides causes irreversible neurological damage and death at young ages.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">3,4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We present the case of a 5-year-old girl with clinical, biochemical, and molecular symptoms of Tay-Sachs disease.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Our patient was born in Colombia, and was the mother's second child; the older sibling was healthy. No alterations were observed during her gestation, except for the mother's subjective perception of reduced fetal movement. When she was 8 days old, she presented frequent vomiting with no food content and mobilisation of secretions which became persistent; no further relevant pathological findings were observed until 9 months of age, when initially distal and subsequently generalised myoclonic seizures appeared.</p><p id="par0025" class="elsevierStylePara elsevierViewall">At about 10 months of age, the patient showed some regression in developmental milestones: she did not follow objects with her eyes or grasp objects and had a weak suck. At 11 months of age, she suffered a tonic-clonic seizure which led her to convulsive status epilepticus and was transferred to an emergency department; a brain CT scan showed no alterations. A brain MRI scan was performed when she was 14 months old (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), revealing alterations in the myelination pattern, which affected the basal ganglia (mainly the putamen, globus pallidus, and caudate nucleus). A discrete component was observed in the posterior thalami and corticospinal tracts at the level of the midbrain. These findings were compatible with hypomyelination.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">From the age of 11 months, our patient began to display progressive neurological impairment and recurrent aspiration pneumonia, which led to the performance of a gastrostomy to decrease episodes of pulmonary aspiration. At the age of 3.5 years, she became completely disconnected from her environment, and hypotonia progressed to generalised spasticity; when the patient was 4 years of age, she presented central apnoea and underwent a tracheostomy connection to a continuous positive airway pressure system.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In the light of the clinical symptoms described, Tay-Sachs disease was suspected and a quantification of enzymatic activity of hexosaminidase in serum yielded normal levels; however, hexosaminidase A levels were critically diminished at 5.88% (reference values between 58% and 68%). The presence of lipids in neuronal cells was confirmed by magnetic resonance spectroscopy. Significantly reduced levels of N-acetyl aspartate and preserved levels of choline were observed (loss of N-acetyl aspartate is typical of demyelinating diseases). The brain nuclear MRI scan revealed greater hyperintensities in the thalami and involutionary changes secondary to the disease in comparison to the MRI scan performed at 14 months of age (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Given the laboratory test results, sequencing studies of the <span class="elsevierStyleItalic">HEXA</span> gene were requested and revealed a heterozygous pathogenic mutation of intron 9, with a change in the nucleotide c. 1073<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>1G<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>A. This mutation has previously been reported as pathological by Akli et al.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">5</span></a> in 1991.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Tay-Sachs disease, described in 1881 by Tay and in 1887 by Sachs, is currently one of the most widely studied sphingolipidoses within the context of lysosomal storage diseases.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">6</span></a> The characteristic inheritance pattern of this disease, as in most inborn errors of metabolism, follows an autosomal recessive inheritance pattern. Mutation of the <span class="elsevierStyleItalic">HEXA</span> gene is responsible for the disease.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">2</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Symptom onset occurs at 3-6 months of age; in our patient, the disease initially manifested as generalised tonic-clonic seizures at the age of 11 months. She later displayed progressive loss of the motor functions acquired until then; a significant swallowing disorder, generally leading to gastrostomy for total enteral nutrition; generalised spasticity; and invasive mechanical ventilation.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">7</span></a> Blindness due to optic atrophy, diagnosed at 2 years of age in our case, is another common pathological finding in this disease.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">8</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">One of the ophthalmological signs described in this disease are the cherry-red spots at the macula which correspond to the abnormal accumulation of metabolic products inside the retinal ganglion cells.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">9</span></a> However, in this particular case, these spots were not present, although the physical examination of the eye did reveal alterations in the fovea in a “bull's eye” shape, which may be secondary to drug-related toxicity or optical degeneration.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">10</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">A diagnosis of Tay-Sachs disease should be suspected upon onset of early symptoms of the disease, which range from an exaggerated acoustic startle reflex to the presence of psychomotor retardation and loss of previously acquired motor abilities, as in our patient. However, definitive diagnosis is established by the quantification of hexosaminidase A activity,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">11</span></a> which was markedly diminished in our case. Additionally, sequencing of the <span class="elsevierStyleItalic">HEXA</span> gene is recommended: results from our patient were positive for a single heterozygous mutation, which implies the presence of another mutation which was not identified by the molecular diagnostic methods used.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Prevalence of the disease is estimated at 1 case per 200<span class="elsevierStyleHsp" style=""></span>000 live births in the general population.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">12</span></a> However, there is a high prevalence among Ashkenazi Jews, at approximately 1 case per 4000 live births.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">13</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Finally, Tay-Sachs disease must be included in the differential diagnosis of paediatric neurological disorders causing regression of developmental milestones. It is important to include molecular testing as part of diagnostic protocols for the disease and genetic counselling as a means to prevent familial recurrences of the disease.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">This study has not been published in any other journal nor has it been submitted for publication to any other journal. All authors cited have reviewed this manuscript and endorsed its publication. The authors have no conflicts of interest to declare.</p><p id="par0075" class="elsevierStylePara elsevierViewall">This study was financed by ICESI University.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Posso Gomez LJP, Gomez JF, Botero V, Pachajoa H. Caracterización clínica, bioquímica y molecular de una paciente colombiana con enfermedad de Tay-Sachs. Neurología. 2018;33:61–63.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1732 "Ancho" => 2500 "Tamanyo" => 277283 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Comparative findings from nuclear MRI at age 14 months and at 4 years and 5 months.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:13 [ 0 => array:3 [ "identificador" => "bib0070" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R.A. Gravel" 1 => "J.T.R. Clarke" 2 => "M.M. Kaback" 3 => "D. Mahuran" 4 => "K. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 34 | 1 | 35 |
| 2024 October | 108 | 11 | 119 |
| 2024 September | 111 | 11 | 122 |
| 2024 August | 63 | 9 | 72 |
| 2024 July | 47 | 12 | 59 |
| 2024 June | 78 | 5 | 83 |
| 2024 May | 83 | 8 | 91 |
| 2024 April | 100 | 18 | 118 |
| 2024 March | 76 | 11 | 87 |
| 2024 February | 107 | 2 | 109 |
| 2024 January | 138 | 6 | 144 |
| 2023 December | 180 | 21 | 201 |
| 2023 November | 197 | 11 | 208 |
| 2023 October | 231 | 26 | 257 |
| 2023 September | 87 | 3 | 90 |
| 2023 August | 61 | 10 | 71 |
| 2023 July | 118 | 25 | 143 |
| 2023 June | 133 | 10 | 143 |
| 2023 May | 196 | 11 | 207 |
| 2023 April | 168 | 26 | 194 |
| 2023 March | 133 | 16 | 149 |
| 2023 February | 117 | 11 | 128 |
| 2023 January | 127 | 5 | 132 |
| 2022 December | 133 | 11 | 144 |
| 2022 November | 150 | 9 | 159 |
| 2022 October | 119 | 12 | 131 |
| 2022 September | 94 | 37 | 131 |
| 2022 August | 98 | 18 | 116 |
| 2022 July | 71 | 10 | 81 |
| 2022 June | 124 | 15 | 139 |
| 2022 May | 156 | 9 | 165 |
| 2022 April | 160 | 15 | 175 |
| 2022 March | 246 | 21 | 267 |
| 2022 February | 238 | 17 | 255 |
| 2022 January | 297 | 32 | 329 |
| 2021 December | 221 | 31 | 252 |
| 2021 November | 198 | 30 | 228 |
| 2021 October | 219 | 15 | 234 |
| 2021 September | 92 | 19 | 111 |
| 2021 August | 113 | 25 | 138 |
| 2021 July | 88 | 19 | 107 |
| 2021 June | 115 | 13 | 128 |
| 2021 May | 190 | 14 | 204 |
| 2021 April | 497 | 37 | 534 |
| 2021 March | 320 | 18 | 338 |
| 2021 February | 230 | 11 | 241 |
| 2021 January | 183 | 18 | 201 |
| 2020 December | 246 | 22 | 268 |
| 2020 November | 210 | 23 | 233 |
| 2020 October | 90 | 12 | 102 |
| 2020 September | 91 | 10 | 101 |
| 2020 August | 103 | 12 | 115 |
| 2020 July | 84 | 18 | 102 |
| 2020 June | 91 | 12 | 103 |
| 2020 May | 149 | 23 | 172 |
| 2020 April | 226 | 19 | 245 |
| 2020 March | 255 | 13 | 268 |
| 2020 February | 274 | 17 | 291 |
| 2020 January | 210 | 17 | 227 |
| 2019 December | 257 | 17 | 274 |
| 2019 November | 281 | 19 | 300 |
| 2019 October | 196 | 10 | 206 |
| 2019 September | 122 | 3 | 125 |
| 2019 August | 73 | 3 | 76 |
| 2019 July | 134 | 19 | 153 |
| 2019 June | 237 | 10 | 247 |
| 2019 May | 266 | 25 | 291 |
| 2019 April | 162 | 7 | 169 |
| 2019 March | 62 | 3 | 65 |
| 2019 February | 43 | 5 | 48 |
| 2019 January | 60 | 5 | 65 |
| 2018 December | 32 | 7 | 39 |
| 2018 November | 38 | 6 | 44 |
| 2018 October | 59 | 14 | 73 |
| 2018 September | 77 | 4 | 81 |
| 2018 August | 12 | 0 | 12 |
| 2018 July | 16 | 2 | 18 |
| 2018 June | 17 | 11 | 28 |
| 2018 May | 50 | 3 | 53 |
| 2018 April | 22 | 3 | 25 |
| 2018 March | 13 | 6 | 19 |
| 2018 February | 6 | 1 | 7 |
| 2018 January | 2 | 4 | 6 |
| 2017 December | 2 | 5 | 7 |
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