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Three Siblings with Progressive Encephalopathy and Destructive ® Journal of the International OPEN JICNA Child Neurology Association ACCESS A peer reviewed open access e-journal in Child Neurology CASE REPORT Three Siblings with Progressive Encephalopathy and Destructive White Matter Lesions Helen Franckx1; Katriens Stouffs1; Tim Vanderhasselt1; Sara Seneca1; Alexander Gheldof1; Linda De Meirleir1 1University Hospital Brussels Corresponding author: Helen Franckx; Email: [email protected]; Telephone number: 0032 (0)2 474 95 63 ABSTRACT Intellectual disability is an important health issue, with a prevalence estimated at 1%. Autosomal genes are increasingly identified as an important cause, although still few of them are known. Most cases are of recessive origin and are found in large consanguineous families in the Middle East. Mutations in the TRAPPC9 gene have been reported in different families and are associated with a nonsyndromic form of intellectual disability, although phenotypic abnormalities such as a specific facial appearance, obesity, hypotonia and consistent brain abnormalities were linked to these mutations. Here, we describe three siblings of consanguineous Algerian parents with a homozygous c.1708C>T, p. Arg570* mutation in the TRAPPC9 gene. Initially, a relatively normal development was seen until the age of 12-18 months, with from then on a progressive degradation of their mental and motor state and the presence of convulsions in two of them. This, in combination with progressive white matter lesions seen on repetitive magnetic resonance imaging, suggests that this TRAPPC9 mutation should not only be considered as a form of intellectual disability but also as a neurodegenerative disease. Keywords: Intellectual disability, TRAPPC9, homozygous mutation, neurodegenerative disease © 2018 Franckx et al.; licensee JICNA INTRODUCTION PATIENTS Intellectual disability (ID) is a neurodevelopmental disorder Three siblings (two boys and one girl) were referred to the characterized by the impairment of skills manifested during paediatric neurologist because of neurodevelopmental de- the developmental period, which contribute to the overall lay. Their parents were healthy consanguineous (cousins) of level of intelligence. The prevalence is estimated at 1% [1]. Algerian ethnicity. ID can present as nonsyndromic (ID is the sole clinical The two brothers were followed for many years in our feature) or syndromic (with additional symptoms), although center. They both were born at term after an uneventful this distinction is not always obvious [2]. Due to the high pregnancy. During the first year of life, no pronounced ab- male-to-female ratio, X-linked ID has been extensively ex- normalities were found. It was only in their second year that amined. This has led to the discovery of more than 80 genes both boys presented with similar symptoms of neurodevel- associated with ID on the X chromosome (of which 30 cause opmental delay and epilepsy. Phenotypically some peculiar nonsyndromic ID). Since the X chromosome represents only similarities were found, including pronounced microcephaly, about 5% of the human genome there is increasing evidence flat occiput, brittle hair and syndactyly of the second and that there are many autosomal–recessive loci involved in ID third toe. (Figure 1) [3]. It is estimated that autosomal-recessive ID accounts In the following years, it became clear that their develop- for 40% of all individuals with nonsyndromic forms, and is mental delay was severe. They presented with general hypo- extremely prevalent in consanguineous populations [4]. Re- tonia and were never able to walk unsupported. Intellectually cently, over 300 genes have been identified to play a role in they were severely disabled with an almost absent speech. autosomal-recessive forms of ID. More than 97% of them Both developed autistic traits with prominent behavioral have a role in a recessive disorder that includes ID as one problems and stereotypic movements, which needed treat- of their symptoms, only a few genes are identified as giving ment by different antipsychotic drugs. Partial epileptic sei- ID as the main phenotype [5]. One of these is the TRAP- zures were seen during childhood and were successfully PC9 gene. Homozygous mutations have been described treated with sodium valproate. in several families and are linked with moderate-to-severe Extensive etiological work-up was performed in both. ID associated with typical facial appearance, obesity, early Electrophysiological tests consisted of an electroenceph- onset hypotonia and brain anomalies [6]. Here, we describe alogram (EEG), Brainstem Evoked Response Audiometry three siblings in whom a homozygous nonsense mutation of (BERA) and somatosensory evoked potentials (SSEP). EEG TRAPPC9 was identified using exome sequencing analysis. showed low voltage and little variability. BERA and SSEP Previously described phenotypical features were found in were normal. A complete metabolic profile using blood, urine combination with progressive encephalopathy and destruc- and cerebrospinal fluid or muscle and skin biopsies did not tive white matter lesions, suggesting a neurodegenerative identify any abnormalities. Genetic work-up showed a nor- disease. 1 Franckx et al. - JICNA 2018, 18:110 Figure 1. Phenotype of the three siblings. Figure 2. MRI of the oldest boy. Figure 3. MRI of the youngest boy. Figure 4. MRI of the sister. 2 Franckx et al. - JICNA 2018, 18:110 mal male karyotype, no 22q11 deletion and the absence of complete absence of the TRAPPC9 protein in skin fibro- fragile X-syndrome. blasts [7]. Repetitive magnetic resonance imaging (MRI) was per- In Table 1 the clinical signs associated with TRAPPC9 mu- formed in both. As shown in figure 2, the MRI of the oldest tation are summarized. Several of them are variably present boy demonstrated colpocephaly, mega cisterna magna, par- in our patients. Unlike the previously reported happy dispo- tial agenesis of the corpus callosum, cerebellar medio-inferi- sition as a psychiatric symptom, we see that in our patients or hypoplasia, thin white matter, abnormal signal intensity in behavioral manifestations were more severe with the need the occipito-temporal white matter, normal cortical morphol- for antipsychotic drugs. The ID in our patients was extensive ogy and no brainstem involvement. with the almost complete absence of spoken language and In the youngest boy, MRI demonstrated mega cisterna the inability to walk alone. magna, hypoplasia of the corpus callosum, cerebellar infe- rior hypoplasia, abnormal bilateral postero-parietal and oc- CATEGORY SUBCATEGORY FEATURES cipital white matter, white matter hypoplasia, mild ventricular dilatation, no basal ganglia involvement and a normal brain- Growth Weight • Truncal obesity stem. In both the repeated MRI’s showed progressive ven- Head and Head • Microcephaly tricular dilatation with decrease of white matter and cortical neck Face • Short, smooth phil- atrophy (Figure 3). trum The first 2 images show the first MRI, the second 2 imag- Eyes • Wide nasal bridge es show the progression. • Hypertelorism After giving birth to two healthy sisters, a third sibling girl • Hypotelorism was born with similar symptoms. She was born at term af- • Hypoplastic supraor- ter an uneventful pregnancy. She was first examined at one bital ridges year of age. The mother reported slight hypotonia during the Mouth • Straight eyebrows first months of life, with the inability to sit or crawl. Pheno- Teeth • Downturned mouth typically she demonstrated the same distinctive craniofacial Neck • Clefth lip appearance with microcephaly and flat occiput (Figure 1). In • Prominent central the following years, the hypotonia continued with inability to incisors walk unsupported. She was also intellectually disabled with • Short neck almost absent speech and demonstrated autistic traits with Skeletal Hands • Long, thin fingers stereotypic movements which needed treatment by antipsy- chotic drugs. No epileptic activity was seen. MRI showed Neurologic Central nervous • Mental retardation, similarities with those of her brothers with hypoplasia of the system moderate to severe corpus callosum, a delayed myelination and abnormal bilat- • Language develop- ment limited to a few eral white matter (Figure 4). words Since first genetic and metabolic work-up was negative, a • Seizures whole exome sequencing was performed according to stan- • Delayed walking dard procedures for one of the sibs. This revealed a homozy- • Hypotonia gous c.1708C>T, p. Arg570 mutation in the TRAPPC9 gene. • Absent continence The same mutation was also found by Sanger sequencing in • Thin corpus callosum both brothers, and the parents were heterozygous carriers of • Decreased volume the mutation. The two unaffected sisters were not carrying of the cerebral white the mutation. No other homozygous or compound hetero- matter zygous mutation could be detected that might explain the • White matter abnor- phenotype of the patients. (Figure 5) malities • Hypoplasia of the inferior cerebellar vermis Behavioral • Happy disposition Psychiatric • Hyperactivity Manifestations • Stereotypic move- ments Miscella- • Onset in infancy neous Figure 5. Family pedigree Table 1. Summary of the clinical signs associated with TRAPPC9-related ID [2-4][6-8] DISCUSSION The MRI abnormalities as noted above are consistent To date, autosomal recessive nonsyndromic ID caused by with earlier reports. Since the two brothers were followed homozygous TRAPPC9 mutations have been reported in for more than two decades, it was possible to
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