Leukoencephalopathies in childhood : Delineation of phenotypes

Within the last 15 years, several new leukoencephalopathies have been recognized. However, more than half of children with cerebral white matter abnormalities still have no specific diagnosis. Our aim was to classify unknown leukoencephalopathies and to identify new diseases among them. During the study, three subgroups of patients were delineated and examined further. First, we evaluated 38 patients with unknown leukoencephalopathy. Brain MRI findings were grouped into seven categories according to the predominant location of the abnormalities. The largest subgroups were myelination abnormalities (n=20) and periventricular white matter abnormalities (n=12). Six patients had uniform MRI findings with signal abnormalities in hemispheric white matter and in selective brain stem and spinal cord tracts. Magnetic resonance spectroscopy (MRS) showed elevated lactate and decreased N-acetylaspartate in the abnormal white matter. The patients presented with ataxia, tremor, distal spasticity, and signs of dorsal column dysfunction. This phenotype - leukoencephalopathy with brain stem and spinal cord involvement and elevated white matter lactate (LBSL) - was first published elsewhere in 2003. A new finding was development of a mild axonal neuropathy. The etiopathogenesis of this disease is unknown, but elevated white matter lactate in MRS suggests a mitochondrial disorder. Secondly, we studied 22 patients with 18q deletions. Clinical and MRI findings were correlated with molecularly defined size of the deletion. All patients with deletions between markers D18S469 and D18S1141 (n=18) had abnormal myelination in brain MRI, while four patients with interstitial deletions sparing that region, had normal myelination pattern. Haploinsufficiency of myelin basic protein is suggested to be responsible for this dysmyelination. Congenital aural atresia/stenosis was found in 50% of the cases and was associated with deletions between markers D18S812 (at 18q22.3) and D18S1141 (at q23). Last part of the study comprised 13 patients with leukoencephalopathy and extensive cerebral calcifications. They showed a spectrum of findings, including progressive cerebral cysts, retinal telangiectasias and angiomas, intrauterine growth retardation, skeletal and hematologic abnormalities, and severe intestinal bleeding, which overlap with features of the previously reported patients with "Coats plus" syndrome and "leukoencephalopathy with calcifications and cysts", suggesting that these disorders are related. All autopsied patients had similar neuropathologic findings showing calcifying obliterative microangiopathy. Our patients may represent an autosomally recessively inherited disorder because there were affected siblings and patients of both sexes. We have started genealogic and molecular genetic studies of this disorder.Väitöskirjan tavoitteena oli selvittää, millaisia uusia sairauksia löytyy lapsipotilailta, joilla magneettikuvaus paljastaa muutoksia aivojen valkeassa aineessa. Valkean aineen sairaudet ovat harvinaisia, usein perinnöllisiä ja oireiltaan eteneviä. Useita uusia sairauksia on tunnistettu magneettikuvauksen yleistyttyä viimeksi kuluneen 15 vuoden aikana, mutta edelleen yli puolet muutoksista jää vaille selitystä. Kartoitimme tuntemattomia aivojen valkean aineen muutoksia 43 potilaallamme, joiden muutokset oli todettu lapsuusiällä, vuosien 1990-2005 välisenä aikana. Seurasimme potilaiden oireiden kehitystä ja aivomuutoksia sekä mittasimme aivokudoksen aineenvaihduntaa magneettispektroskopialla. Tutkittavien joukosta erottui kaksi uutta taudinkuvaa. Kuudella potilaalla oli aivorungon sekä selkäytimen valkean aineen hermoratojen muutoksia ja aivokudokseen kertyi maitohappoa. Heillä oli tasapainovaikeuksia, alaraajojen jäykkyyttä, vapinaa ja asento- sekä värinätunnon heikentymistä. Oireiden alkamisikä vaihteli leikki-iästä murrosikään. Samanlaisia potilaita kuvattiin kirjallisuudessa ensimmäisen kerran vuonna 2003 nimellä LBSL (Leukoencephalopathy with Brainstem and Spinal cord involvement and elevated white matter Lactate). Syyskuussa 2006 potilaita oli raportoitu maailmanlaajuisesti yhteensä 20, suomalaiset potilaat mukaan lukien. Harvinaisuudestaan huolimatta tämä sairaus näyttää kuuluvan yleisimpiin ns. uusiin aivojen valkean aineen sairauksiin Suomessa ja tautia sairastavia löytyy todennäköisesti enemmän, kun tämä suhteellisen lieväoireinen sairaus tulee tunnetuksi. Toisen ryhmän muodostivat potilaat, joilla valkean aineen muutosten lisäksi todettiin laajoja aivokalkkeutumia. Osalla heistä oli poikkeavuuksia myös silmien verkkokalvon verisuonissa, luuston rakenteessa ja verenkuvassa. Perehdyimme lisäksi aiemmin samanlaiseen sairauteen menehtyneiden suomalaisten potilaiden neuropatologisiin löydöksiin, joissa havaittiin muutoksia ensisijaisesti aivojen pienissä verisuonissa. Kirjallisuudessa on aiemmin kuvattu yksittäisiä tai muutaman potilaan aineistoja, yhteensä alle 20 potilasta, jotka todennäköisesti edustavat samaa oireyhtymää. Oma 13 potilaan sarjamme on suurin kuvatuista ja kattaa koko oirekirjon. Jatkotutkimusten tavoitteena on tunnistaa edellä mainittujen perinnöllisten sairauksien taustalla olevat geenivirheet. Kolmannen tutkimusryhmän muodostivat 22 potilasta, joilla oli todettu kromosomin 18 pitkän haaran osittainen häviämä eli deleetio. Puuttuvan alueen koko tutkittiin molekyyligeneettisesti. Aivojen valkea aine kehittyi poikkeavasti vain niillä potilailla, joiden kromosomista 18 puuttuva alue sisälsi aivojen valkean aineen tärkeän proteiinin (MBP) geenin. Tulos vahvisti aikaisempia päätelmiä MBP:n osuudesta 18q- oireyhtymässä todettuun valkean aineen poikkeavuuteen

Kannabidioli epilepsian hoidossa

VertaisarvioituKannabidioli on yksi kannabiskasvin yhdisteistä. Se on osoittautunut lumelääkettä tehokkaammaksi kolmessa kontrolloidussa tutkimuksessa vaikean epilepsian hoidossa. Puhtaalle kannabidiolille haetaan parhaillaan myyntilupaa Euroopassa. Muihin indikaatioihin tarkoitetut Suomessa saatavilla olevat lääkekannabisvalmisteet sisältävät enemmän delta-9-tetrahydrokannabinoli THC:tä kuin kannabidiolia, eivätkä ne siten sovellu epilepsian hoitoon.Peer reviewe

De novo variants in neurodevelopmental disorders with epilepsy

Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.Peer reviewe

Intrafamilial variability in SLC6A1-related neurodevelopmental disorders

Epilepsy; Intellectual disability; Intrafamilial variabilityEpilepsia; Discapacidad intelectual; Variabilidad intrafamiliarEpilèpsia; Discapacitat intel·lectual; Variabilitat intrafamiliarIntroduction: Phenotypic spectrum of SLC6A1-related neurodevelopmental disorders (SLC6A1-NDD) includes intellectual disability (ID), autistic spectrum disorders (ASD), epilepsy, developmental delay, beginning from early infancy or after seizure onset, and other neurological features such as hypotonia and movement disorders. Data on familial phenotypic heterogeneity have been rarely reported, thus in our study we aimed to investigate intrafamilial phenotypic variability in families with SLC6A1 variants. Methods: We collected clinical, laboratory and genetic data on 39 individuals, including 17 probands, belonging to 13 families harboring inherited variants of SLC6A1. Data were collected through an international network of Epilepsy and Genetic Centers. Results: Main clinical findings in the whole cohort of 39 subjects were: (a) epilepsy, mainly presenting with generalized seizures, reported in 71% of probands and 36% of siblings or first/second-degree relatives. Within a family, the same epilepsy type (generalized or focal) was observed; (b) ID reported in 100% and in 13% of probands and siblings or first/second-degree relatives, respectively; (c) learning disabilities detected in 28% of the SLC6A1 carriers, all of them were relatives of a proband; (d) around 51% of the whole cohort presented with psychiatric symptoms or behavioral disorders, including 82% of the probands. Out of the 19 patients with psychiatric symptoms, ASD were diagnosed in 40% of them; (e) neurological findings (primarily tremor and speech difficulties) were observed 38.5% of the whole cohort, including 10 probands. Our families harbored 12 different SLC6A1 variants, one was a frameshift, two stop-gain, while the remaining were missense. No genotype–phenotype associations were identified. Discussion: Our study showed that first-or second-degree relatives presented with a less severe phenotype, featuring mainly mild intellectual and/or learning disabilities, at variance with the probands who suffered from moderate to severe ID, generalized, sometimes intractable, epileptic seizures, behavioral and psychiatric disorders. These findings may suggest that a proportion of individuals with mild SLC6A1-NDD might be missed, in particular those with an older age where genetic testing is not performed. Further studies on intrafamilial phenotypic variability are needed to confirm our results and possibly to expand the phenotypic spectrum of these disorders and benefit genetic counseling

High-resolution SNP array analysis of patients with developmental disorder and normal array CGH result (vol 13, 84, 2012)

Peer reviewe

High-resolution SNP array analysis of patients with developmental disorder and normal array CGH results

Erratum to: high-resolution SNP array analysis of patients with developmental disorder and normal array CGH result BMC Medical Genetics 2014, 15:124 10.1186/s12881-014-0124-3Peer reviewe

Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland

The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case.Peer reviewe

Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy

The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBAS, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBAS variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.A1a371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg5SHis, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.A1a371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufml in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.A1a371Thr variant in trans with a loss-of-function allele in UBAS underlies a severe infantile-onset encephalopathy.Peer reviewe

The spectrum of intermediate SCN8A-related epilepsy

Objective: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies. Methods: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.Peer reviewe

Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland

The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case