Letter to the Editor
Periventricular heterotopia: broadening of the clinical spectrum of the clathrin 1 gene (CLTC) pathogenic variants
Heterotopías periventriculares: ampliación del espectro clínico de las variantes patogénicas del gen de la clatrina 1 (CLTC)
D. Martín Fernández-Mayoralasa,
, N. Muñoz Jareñob, A. Alba Menéndezc, A. Fernández-Jaéna,d
Corresponding author
a Departamento de Neuropediatría, Hospital Universitario Quirónsalud, Madrid, Spain
b Hospital Quirónsalud Sur, Alcorcón, Madrid, Spain
c Genómica y Medicina, Instituto de Estudios Celulares y Moleculares, Lugo, Spain
d Facultad de Medicina, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain
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Slightly elongated face, long palpebral fissures, midface hypoplasia, deep philtrum, and bulbous tip of the nose.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">CLTC</span> gene encodes the clathrin heavy chain 1 (CHC1) protein.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">1,2</span></a> This structure enables the formation of lattices in clathrin-coated vesicles by facilitating the intracellular membrane traffic of receptors, endocytosis of certain macromolecules, and stability of the mitotic spindle during the metaphase.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> This protein is expressed in greater abundance in the developing brain.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a> Loss-of-function (LoF) mutations of the <span class="elsevierStyleItalic">CLTC</span> gene are associated with autosomal dominant mental retardation-56 (MIM#617854), although they have also been reported in patients with epilepsy and other neurodevelopmental disorders.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">3–5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">We present the case of a girl with a previously unreported de novo mutation of the gene and periventricular heterotopia detected with a brain magnetic resonance imaging (MRI) study.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Our patient is a girl with no relevant family history, and personal history of patent ductus arteriosus and bone alterations (spina bifida occulta and mild rib hypoplasia). Head circumference has consistently been in the 10th percentile. <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> shows the phenotype. At the age of 5, she began to present epileptic seizures (typical absence and generalised tonic-clonic seizures), which were controlled with ethosuximide and valproic acid; seizures returned when the drug was withdrawn when the patient was 7 years old. An EEG performed before treatment revealed 3-Hz spike-and-wave discharges triggered by hyperventilation, which lasted 9<span class="elsevierStyleHsp" style=""></span>seconds. An MRI scan showed periventricular heterotopia (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The patient showed difficulties with attention, language, and reading. Her intelligence quotient according to the Wechsler Intelligence Scale for Children (fifth edition) was 68, with working memory and attention abilities being particularly impaired.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">A whole-genome sequencing (WGS) study revealed heterozygous presence of a de novo nonsense mutation in exon 23 of the <span class="elsevierStyleItalic">CLTC</span> gene (hg19; chr 17: 57760140; NM_004859.3; c.3751C>T, p.Arg1251*). The mutation, which was subsequently confirmed by Sanger sequencing, was not listed on any genetic database and had not previously been reported in the literature.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The literature includes nearly 30 cases of de novo LoF variants of the <span class="elsevierStyleItalic">CLTC</span> gene.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a> The phenotype is characterised by subtle but consistent dysmorphic features, which can be observed in the patient we present.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a> One of these features is bulbous tip of the nose.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a> Bone deformities have been described previously.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a> The degree of intellectual disability is variable, from borderline intelligence quotient to moderate disability.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">1,5</span></a> Delayed language acquisition and attention deficit/hyperactivity disorder are very frequent.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">1,5</span></a> Gait alterations (ataxic, hypotonic, or spastic) may also present.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">4,5</span></a> Some patients develop parkinsonism in adulthood.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a> Corpus callosum hypoplasia is the most frequent structural brain anomaly,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a> although microcephalus (10th percentile in our patient), other anomalies (especially of neuronal migration), and epilepsy, as in our patient and other published cases, are also frequent.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">1,4,5</span></a> Absence seizures, as observed in our patient, have previously been described in another patient with a de novo frameshift mutation of the <span class="elsevierStyleItalic">CLTC</span> gene.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> The literature includes reports of adequate seizure control with valproic acid.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> The phenotypic variability observed in patients with LoF variants of this gene is associated with allelic heterogeneity, although the correlation with the type of mutation or the affected segment of clathrin is not well established.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">1,4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In conclusion, we report a new pathogenic variant of the <span class="elsevierStyleItalic">CLTC</span> gene, to our knowledge never previously reported, in a patient who also presents periventricular heterotopia, contributing to further expansion of the clinical spectrum of mutations of this gene and their association with alterations in neuronal migration.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0035" class="elsevierStylePara elsevierViewall">The authors have received no funding for this study.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 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: Martín Fernández-Mayoralas D, Muñoz Jareño N, Alba Menéndez A, Fernández-Jaén A. Heterotopías periventriculares: ampliación del espectro clínico de las variantes patogénicas del gen de la clatrina 1 <span class="elsevierStyleItalic">(CLTC)</span>. Neurología. 2021;36:327–329.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1205 "Ancho" => 905 "Tamanyo" => 194448 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Phenotype of the patient at the age of 11. Slightly elongated face, long palpebral fissures, midface hypoplasia, deep philtrum, and bulbous tip of the nose.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1018 "Ancho" => 905 "Tamanyo" => 74609 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Brain magnetic resonance imaging sequence study performed when the patient was 5 years old. Axial T2-weighted sequence. Periventricular heterotopia.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.J. Nabais Sa" 1 => "H. Venselaar" 2 => "L. Wiel" 3 => "A. Trimouille" 4 => "E. Lasseaux" 5 => "S. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 9 | 0 | 9 |
| 2024 October | 58 | 2 | 60 |
| 2024 September | 75 | 20 | 95 |
| 2024 August | 73 | 7 | 80 |
| 2024 July | 68 | 8 | 76 |
| 2024 June | 62 | 7 | 69 |
| 2024 May | 62 | 3 | 65 |
| 2024 April | 52 | 11 | 63 |
| 2024 March | 85 | 5 | 90 |
| 2024 February | 64 | 4 | 68 |
| 2024 January | 70 | 7 | 77 |
| 2023 December | 82 | 13 | 95 |
| 2023 November | 86 | 6 | 92 |
| 2023 October | 84 | 9 | 93 |
| 2023 September | 44 | 7 | 51 |
| 2023 August | 35 | 9 | 44 |
| 2023 July | 46 | 6 | 52 |
| 2023 June | 65 | 6 | 71 |
| 2023 May | 55 | 10 | 65 |
| 2023 April | 57 | 3 | 60 |
| 2023 March | 55 | 7 | 62 |
| 2023 February | 53 | 2 | 55 |
| 2023 January | 67 | 9 | 76 |
| 2022 December | 35 | 9 | 44 |
| 2022 November | 49 | 10 | 59 |
| 2022 October | 27 | 6 | 33 |
| 2022 September | 32 | 20 | 52 |
| 2022 August | 43 | 17 | 60 |
| 2022 July | 28 | 9 | 37 |
| 2022 June | 31 | 13 | 44 |
| 2022 May | 20 | 9 | 29 |
| 2022 April | 25 | 11 | 36 |
| 2022 March | 33 | 9 | 42 |
| 2022 February | 37 | 5 | 42 |
| 2022 January | 50 | 13 | 63 |
| 2021 December | 27 | 11 | 38 |
| 2021 November | 21 | 7 | 28 |
| 2021 October | 35 | 9 | 44 |
| 2021 September | 31 | 6 | 37 |
| 2021 August | 56 | 13 | 69 |
| 2021 July | 27 | 5 | 32 |
| 2021 June | 19 | 5 | 24 |
| 2021 May | 45 | 9 | 54 |
| 2021 April | 8 | 11 | 19 |
| 2021 March | 4 | 9 | 13 |
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