Publications by authors named "Tuula Lönnqvist"

67 Publications

Neurocognitive impairment, employment, and social status in radiotherapy-treated adult survivors of childhood brain tumors.

Neurooncol Pract 2021 Jun 22;8(3):266-277. Epub 2021 Jan 22.

Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.

Background: Little is known of the cognitive functions, employment, and social status in adult survivors of childhood brain tumor (BT). We aimed to determine the long-term neurocognitive profile of radiotherapy-treated adult survivors of childhood BT and the relationship between cognitive functions and employment and social status.

Methods: Neurocognitive profiles of survivors were assessed in a Finnish national cohort of 71 radiotherapy-treated survivors of childhood BT (median follow-up time: 21 years [range: 5-33 years]) using a cross-sectional design. Neurocognitive outcomes were compared to control (n = 45) and normative values. Tumor- and treatment-related data were collected from the patient files. Information on employment and social status was gathered.

Results: Survivors' (median age: 27 years [range: 16-43 years]) median verbal and performance intelligence quotient (IQ) was 90 (range: 49-121) and 87 (range: 43-119), respectively. The cognitive domains with the greatest impairment were executive functions (median score, -3.5 SD [range: -25.0 to 1.3 SD]), and processing speed and attention (median score, -2.5 SD [range: -24.9 to 0.5 SD]). Executive functions were associated with employment, educational level, living independently, having an intimate relationship, and having a driving license. Processing speed and attention were related to educational level, living independently, having an intimate relationship, and having a driving license. Performance IQ was associated with educational level and employment status. Working memory was associated with educational level and living independently.

Conclusions: Radiotherapy-treated adult survivors of childhood BT experience significant neurocognitive impairment, which is associated with difficulties related to employment and social status.
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http://dx.doi.org/10.1093/nop/npab004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153831PMC
June 2021

Diagnostic value of serum biomarkers FGF21 and GDF15 compared to muscle sample in mitochondrial disease.

J Inherit Metab Dis 2021 03 21;44(2):469-480. Epub 2020 Sep 21.

Research Programs Unit, Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

The aim of this study was to compare the value of serum biomarkers, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), with histological analysis of muscle in the diagnosis of mitochondrial disease. We collected 194 serum samples from patients with a suspected or known mitochondrial disease. Biomarkers were analyzed blinded using enzyme-labeled immunosorbent assay. Clinical data were collected using a structured questionnaire. Only 39% of patients with genetically verified mitochondrial disease had mitochondrial pathology in their muscle histology. In contrast, biomarkers were elevated in 62% of patients with genetically verified mitochondrial disease. Those with both biomarkers elevated had a muscle manifesting disorder and a defect affecting mitochondrial DNA expression. If at least one of the biomarkers was induced and the patient had a myopathic disease, a mitochondrial DNA expression disease was the cause with 94% probability. Among patients with biomarker analysis and muscle biopsy taken <12 months apart, a mitochondrial disorder would have been identified in 70% with analysis of FGF21 and GDF15 compared to 50% of patients whom could have been identified with muscle biopsy alone. Muscle findings were nondiagnostic in 72% (children) and 45% (adults). Induction of FGF21 and GDF15 suggest a mitochondrial etiology as an underlying cause of a muscle manifesting disease. Normal biomarker values do not, however, rule out a mitochondrial disorder, especially if the disease does not manifest in muscle. We suggest that FGF21 and GDF15 together should be first-line diagnostic investigations in mitochondrial disease complementing muscle biopsy.
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http://dx.doi.org/10.1002/jimd.12307DOI Listing
March 2021

Screening of hydrocephalus in infants using either WHO or population-based head circumference reference charts.

Acta Paediatr 2021 03 14;110(3):881-888. Epub 2020 Sep 14.

Department of Pediatrics, School of Medicine, University of Eastern Finland, Kuopio, Finland.

Aim: The aim was to compare the performances of the World Health Organization (WHO) and population-based (PB) references in the screening for hydrocephalus in infants aged <2 years.

Methods: We collected 341 longitudinal head circumference (HC) measurements of hydrocephalic infants and 120 181 measurements of 15 145 healthy infants from primary care. The measurements were converted into z-scores, and a new screening parameter, change in HC standard deviation score (SDS) over time (ΔHC SDS), was calculated. Comparisons were made using receiver operating characteristics analysis and linear mixed models.

Results: The mean HC SDS was 3.5 and the mean HC SDS was 2.9 in the hydrocephalic infants, and in healthy children, those numbers were 1.0 SDS and 0 SDS , respectively. The best screening accuracy was obtained with the PB reference in combination with the ΔHC SDS parameter (AUC 0.89). The accuracy of the WHO standard could be improved to a similar level by customising the screening cut-offs of HC SDS according to the population and combining screening parameters.

Conclusions: Auxology alone was not sufficient for the screening of hydrocephalus. The WHO standard should be validated in the population, and population-specific cut-offs for normality defined before its introduction.
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http://dx.doi.org/10.1111/apa.15533DOI Listing
March 2021

Radiation-induced accelerated aging of the brain vasculature in young adult survivors of childhood brain tumors.

Neurooncol Pract 2020 Jul 7;7(4):415-427. Epub 2020 Feb 7.

Department of Pediatrics and Adolescence, PEDEGO Research Unit and Medical Research Center, Oulu University Hospital, and University of Oulu, Oulu, Finland.

Background: Cranial radiotherapy may damage the cerebral vasculature. The aim of this study was to understand the prevalence and risk factors of cerebrovascular disease (CVD) and white matter hyperintensities (WMHs) in childhood brain tumors (CBT) survivors treated with radiotherapy.

Methods: Seventy CBT survivors who received radiotherapy were enrolled in a cross-sectional study at a median 20 years after radiotherapy cessation. The prevalence of and risk factors for CVD were investigated using MRI, MRA, and laboratory testing. Tumors, their treatment, and stroke-related data were retrieved from patients' files.

Results: Forty-four individuals (63%) had CVD at a median age of 27 years (range, 16-43 years). The prevalence rates at 20 years for CVD, small-vessel disease, and large-vessel disease were 52%, 38%, and 16%, respectively. Ischemic infarcts were diagnosed in 6 survivors, and cerebral hemorrhage in 2. Lacunar infarcts were present in 7, periventricular or deep WMHs in 34 (49%), and mineralizing microangiopathy in 21 (30%) survivors. Multiple pathologies were detected in 44% of the participants, and most lesions were located in a high-dose radiation area. Higher blood pressure was associated with CVD and a presence of WMHs. Higher cholesterol levels increased the risk of ischemic infarcts and WMHs, and lower levels of high-density lipoprotein and higher waist circumference increased the risk of lacunar infarcts.

Conclusions: Treating CBTs with radiotherapy increases the risk of early CVD and WMHs in young adult survivors. These results suggest an urgent need for investigating CVD prevention in CBT patients.
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http://dx.doi.org/10.1093/nop/npaa002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393284PMC
July 2020

Genetic background of ataxia in children younger than 5 years in Finland.

Neurol Genet 2020 Aug 5;6(4):e444. Epub 2020 Jun 5.

Department of Child Neurology (E.I., P.I., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital; Research Programs Unit, Stem Cells and Metabolism, Faculty of Medicine (E.I., P.I., M.P., S.O., V.B., E.P., A.S.), Institute for Molecular Medicine Finland (FIMM) (P.L.), Neuroscience Center (A.S.), HiLife, University of Helsinki, Finland; and Genetics Research Centre (C.J.C.), Molecular and Clinical Sciences Research Institute, St. George's, University of London, United Kingdom.

Objective: To characterize the genetic background of molecularly undefined childhood-onset ataxias in Finland.

Methods: This study examined a cohort of patients from 50 families with onset of an ataxia syndrome before the age of 5 years collected from a single tertiary center, drawing on the advantages offered by next generation sequencing. A genome-wide genotyping array (Illumina Infinium Global Screening Array MD-24 v.2.0) was used to search for copy number variation undetectable by exome sequencing.

Results: Exome sequencing led to a molecular diagnosis for 20 probands (40%). In the 23 patients examined with a genome-wide genotyping array, 2 additional diagnoses were made. A considerable proportion of probands with a molecular diagnosis had de novo pathogenic variants (45%). In addition, the study identified a de novo variant in a gene not previously linked to ataxia: MED23. Patients in the cohort had medically actionable findings.

Conclusions: There is a high heterogeneity of causative mutations in this cohort despite the defined age at onset, phenotypical overlap between patients, the founder effect, and genetic isolation in the Finnish population. The findings reflect the heterogeneous genetic background of ataxia seen worldwide and the substantial contribution of de novo variants underlying childhood ataxia.
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http://dx.doi.org/10.1212/NXG.0000000000000444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323479PMC
August 2020

Attitudes towards genetic testing and information: does parenthood shape the views?

J Community Genet 2020 Oct 4;11(4):461-473. Epub 2020 Apr 4.

Research Programs Unit, Stem Cells and Metabolism, University of Helsinki, Helsinki, Finland.

This study examines how parents of pediatric patients might differ in their views and attitudes towards genetic technology and information when compared to adult patients. There is surprisingly little evidence on how parents compare to other parts of population in their attitudes. Previous empirical studies often relate health-related preferences and attitudes to factors such as age, education, and income instead of parental status, thus evading comparison of parents to others as health-related decision makers. Findings related to the parental status can be useful when implementing genetic technology in clinical practice. We conducted a survey of views on genetic technology and information for groups of adult neurology patients (n = 68) and parents of pediatric neurology patients (n = 31) to shed some light on this issue. In addition to our own survey instrument, we conducted other surveys to gain insight on psychosocial factors that might affect these attitudes. The results suggest that parents are more concerned about their children's genetic risk factors when compared to the attitudes of adult patients about their own risk. For both groups, negative emotional state was associated with more concerns towards genetic information. Our study provides insights on how parental views might affect the acceptance of genetic technology and information.
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http://dx.doi.org/10.1007/s12687-020-00462-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475141PMC
October 2020

Viral shedding, and distribution of cytomegalovirus glycoprotein H (UL75), glycoprotein B (UL55), and glycoprotein N (UL73) genotypes in congenital cytomegalovirus infection.

J Clin Virol 2020 04 11;125:104287. Epub 2020 Feb 11.

Department of Pediatric Infectious Diseases, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: Children with congenital CMV infection (cCMV) shed virus in urine and saliva for prolonged periods of time. Outcome of cCMV varies from asymptomatic infection with no sequelae in most cases, to severe longterm morbidity. The factors associated with asymptomatic cCMV are not well defined. We evaluated the viral shedding in a cohort of infants with cCMV identified on newborn screening. In addition, we describe the distribution of viral genotypes in our cohort of asymptomatic infants and previous cohorts of cCMV children in the literature.

Methods: Study population consisted of 40 children with cCMV identified in screening of 19,868 infants, a prevalence of 2/1000. The viral shedding was evaluated at 3 and 18 months of age by real-time CMV-PCR of saliva and plasma, and CMV culture of urine. CMV positive saliva samples were analyzed for genotypes for CMV envelope glycoproteins gB (UL55), and gH (UL75) by genotype specific real-time PCR, and gN (UL73) by cloning and sequencing RESULTS: At 3 months age 40/40 saliva and urine samples, and 19/40 plasma samples were positive for CMV. At 18 months age all urine samples tested (33/33), 9/37 of saliva samples, and 2/34 plasma samples were positive for CMV. The genotype distribution did not differ from the published data CONCLUSIONS: The urinary virus shedding is more persistent than salivary shedding in children with cCMV. The genotype distribution was similar to previous literature and does not explain the low disease burden of cCMV in our population.
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http://dx.doi.org/10.1016/j.jcv.2020.104287DOI Listing
April 2020

The spectrum of acute central nervous system symptoms during the treatment of childhood acute lymphoblastic leukaemia.

Pediatr Blood Cancer 2020 02 1;67(2):e27999. Epub 2019 Nov 1.

Division of Pediatric Hematology and Oncology and Stem Cell Transplantation, Helsinki University Hospital and Helsinki University, Helsinki, Finland.

Background: Children with central nervous system (CNS) toxicity during therapy for acute lymphoblastic leukaemia (ALL) are at risk for treatment modifications, long-term sequelae and even higher mortality. A better understanding of CNS symptoms and their complications improves the potential to prevent and treat them.

Methods: Patient files from 649 children treated with Nordic Society of Pediatric Hematology and Oncology ALL92 and ALL2000 protocols in Finland were reviewed retrospectively for any acute CNS symptom. Detailed data on symptoms, examinations and treatment of the underlying CNS complications were collected from the medical records. Disease-related and outcome data were retrieved from the Nordic leukaemia registry.

Results: Altogether, 13% (86) of patients with ALL had acute CNS symptoms. Most symptoms (64%) occurred during the first 2 months of therapy. Posterior reversible encephalopathy syndrome was the most frequent complication (4.5%). Cerebrovascular events were diagnosed in 10 cases (1.6%), while methotrexate-related stroke-like syndrome (SLS) was observed in only one patient (0.2%). CNS symptoms due to systemic or unclear conditions, especially sepsis, were important for differential diagnosis. CNS leukaemia was associated with CNS symptoms (hazard ratio [HR] = 4.03; P = .003), and epilepsy was a common sequel of CNS complications (19%).

Conclusions: Acute CNS symptoms are common during ALL therapy, occurring mainly during the first 2 months of treatment. Patients with CNS leukaemia at diagnosis are at a higher risk for CNS toxicity. Despite intensive CNS-directed methotrexate treatment, SLS was diagnosed extremely rarely in our series.
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http://dx.doi.org/10.1002/pbc.27999DOI Listing
February 2020

Radiation-Induced Meningiomas After Childhood Brain Tumor: A Magnetic Resonance Imaging Screening Study.

J Adolesc Young Adult Oncol 2019 10 7;8(5):593-601. Epub 2019 May 7.

Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.

Childhood brain tumors (CBTs) and their treatment increase the risk of secondary neoplasms (SNs). We studied the incidence of secondary craniospinal tumors with magnetic resonance imaging (MRI) screening in a national cohort of survivors of CBT treated with radiotherapy, and we analyzed the Finnish Cancer Registry (FCR) data on SNs in survivors of CBT with radiotherapy registered as a part of the primary tumor treatment. A total of 73 survivors of CBT participated in the MRI study (mean follow-up of 19 ± 6.2 years). The incidence of SNs in a cohort of CBT patients ( = 569) was retrieved from the FCR (mean follow-up of 11 ± 12.9 years). Brain tumors were diagnosed at age ≤16 years between the years 1970 and 2008 in the clinical study and the years 1963 and 2010 in the FCR population. Secondary brain tumors, meningiomas in all and schwannoma in one, were found in 6 of the 73 (8.2%) survivors with a mean of 23 ± 4.3 years after the diagnosis of the primary tumor. The cumulative incidence was 10.2% (95% confidence interval [CI] 3.9-25.1) in 25 years of follow-up. In the FCR data, the 25-year cumulative incidence of SNs was 2.4% (95% CI 1.3-4.1); only two brain tumors, no meningiomas, were registered. Survivors of CBT treated with radiotherapy have a high incidence of meningiomas, which are rarely registered in the FCR.
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http://dx.doi.org/10.1089/jayao.2019.0010DOI Listing
October 2019

Bedside neurophysiological tests can identify neonates with stroke leading to cerebral palsy.

Clin Neurophysiol 2019 05 15;130(5):759-766. Epub 2019 Mar 15.

Department of Clinical Neurophysiology, Children's Hospital, HUS Medical Imaging Center, University of Helsinki and Helsinki University Hospital (HUH), Helsinki, Finland.

Objective: The unspecific symptoms of neonatal stroke still challenge its bedside diagnosis. We studied the accuracy of routine electroencephalography (EEG) and simultaneously recorded somatosensory evoked potentials (EEG-SEP) for diagnosis and outcome prediction of neonatal stroke.

Methods: We evaluated EEG and EEG-SEPs from a hospital cohort of 174 near-term neonates with suspected seizures or encephalopathy, 32 of whom were diagnosed with acute ischemic or hemorrhagic stroke in MRI. EEG was scored for background activity and seizures. SEPs were classified as present or absent. Developmental outcome of stroke survivors was evaluated from medical records at 8- to 18-months age.

Results: The combination of continuous EEG and uni- or bilaterally absent SEP (n = 10) was exclusively seen in neonates with a middle cerebral artery (MCA) stroke (specificity 100%). Moreover, 80% of the neonates with this finding developed with cerebral palsy. Bilaterally present SEPs did not exclude stroke, but predicted favorable neuromotor outcome in stroke survivors (positive predictive value 95%).

Conclusions: Absent SEP combined with continuous EEG background in near-term neonates indicates an MCA stroke and a high risk for cerebral palsy.

Significance: EEG-SEP offers a bedside method for diagnostic screening and a reliable prediction of neuromotor outcome in neonates suspected of having a stroke.
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http://dx.doi.org/10.1016/j.clinph.2019.02.017DOI Listing
May 2019

Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers.

EMBO Mol Med 2018 12;10(12)

Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland

Mitochondrial disorders (MDs) are inherited multi-organ diseases with variable phenotypes. Inclusion body myositis (IBM), a sporadic inflammatory muscle disease, also shows mitochondrial dysfunction. We investigated whether primary and secondary MDs modify metabolism to reveal pathogenic pathways and biomarkers. We investigated metabolomes of 25 mitochondrial myopathy or ataxias patients, 16 unaffected carriers, six IBM and 15 non-mitochondrial neuromuscular disease (NMD) patients and 30 matched controls. MD and IBM metabolomes clustered separately from controls and NMDs. MDs and IBM showed transsulfuration pathway changes; creatine and niacinamide depletion marked NMDs, IBM and infantile-onset spinocerebellar ataxia (IOSCA). Low blood and muscle arginine was specific for patients with m.3243A>G mutation. A four-metabolite blood multi-biomarker (sorbitol, alanine, myoinositol, cystathionine) distinguished primary MDs from others (76% sensitivity, 95% specificity). Our omics approach identified pathways currently used to treat NMDs and mitochondrial stroke-like episodes and proposes nicotinamide riboside in MDs and IBM, and creatine in IOSCA and IBM as novel treatment targets. The disease-specific metabolic fingerprints are valuable "multi-biomarkers" for diagnosis and promising tools for follow-up of disease progression and treatment effect.
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http://dx.doi.org/10.15252/emmm.201809091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284386PMC
December 2018

Evaluation of SEPs in asphyxiated newborns using a 4-electrode aEEG brain monitoring set-up.

Clin Neurophysiol Pract 2018 30;3:122-126. Epub 2018 Jun 30.

Department of Clinical Neurophysiology, Children's Hospital, HUS Medical Imaging Center, University of Helsinki and Helsinki University Hospital (HUH), Helsinki, Finland.

Objective: To evaluate the reliability of recording cortical somatosensory evoked potentials (SEPs) in asphyxiated newborns using the 4-electrode setup applied in routine long-term amplitude-integrated EEG (aEEG) brain monitoring and to assess the number of averages needed for reliably detecting the cortical responses.

Methods: We evaluated median nerve SEPs in 50 asphyxiated full-term newborns. The SEP interpretation (present or absent) from the original recordings with 21-electrodes and approximately 600 trials served as the reference. This was compared to SEP classification (absent, present, or unreliable) based on a reduced (300 or 150) number of averages, and to classification based on only four electrodes (F3, P3, F4, P4).

Results: Compared to the original classification, cortical SEPs were uniformly interpreted as present or absent in all 50 newborns with the 4-electrode setup and 600 averages. Reducing number of averages to 300 still resulted in correct SEP interpretation in 49/50 newborns with 21-electrode setup, and 46/50 newborns with 4-electrode setup.

Conclusions: Evaluation of early cortical neonatal SEPs is reliable from the 4-electrode setup commonly used in aEEG monitoring. SEP is discernible in most newborns with 300 averages.

Significance: Adding SEP into routine aEEG monitoring offers an additional tool for early neonatal neurophysiological evaluation.
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http://dx.doi.org/10.1016/j.cnp.2018.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134187PMC
June 2018

The Burden of Congenital Cytomegalovirus Infection: A Prospective Cohort Study of 20 000 Infants in Finland.

J Pediatric Infect Dis Soc 2019 Jul;8(3):205-212

Department of Pediatric Infectious Diseases, Childrens Hospital.

Background: Congenital cytomegalovirus (cCMV) infection is the most common congenital infection and causes significant morbidity. This study was undertaken to evaluate the benefits of screening newborns for cCMV and to understand the cCMV disease burden in Finland.

Methods: Infants born in Helsinki area hospitals were screened for CMV by testing their saliva with a real-time polymerase chain reaction assay. The CMV-positive infants and matched controls were monitored to determine their neurodevelopmental, audiological, and ophthalmological outcomes at 18 months of age. Griffiths Mental Development Scales, otoacoustic emission and sound field audiometry, and ophthalmologic examination were performed.

Results: Of the 19868 infants screened, 40 had confirmed cCMV infection (prevalence, 2 in 1000 [95% confidence interval, 1.4-2.6 in 1000]). Four (10%) infants had symptomatic cCMV. Griffiths general quotients did not differ significantly between the CMV-positive (mean, 101.0) and control (mean, 101.6) infants (P = .557), nor did quotients for any of the Griffiths subscales (locomotion, personal-social, hearing and language, eye and hand, performance) (P = .173-.721). Four of 54 CMV-positive ears and 6 of 80 CMV-negative ears failed otoacoustic emission testing (P = 1.000). The mean minimal response levels over the frequencies 500 Hz to 4 kHz in the sound field audiometry did not differ between CMV-positive (mean, 34.31-dB hearing level) and control (mean, 32.73-dB hearing level) infants (P = .338). No CMV-related ophthalmologic findings were observed.

Conclusions: The prevalence of cCMV was low, and outcomes at 18 months of age did not differ between the infected infants and healthy control infants. With such a low burden in Finland, universal newborn screening for cCMV seems unwarranted.
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http://dx.doi.org/10.1093/jpids/piy027DOI Listing
July 2019

Reply to 'Letter to Editor by Finsterer J and Zarrouk-Mahjoub S: Phenotypic manifestations of the m.8969G>A variant'.

Neurogenetics 2018 05 26;19(2):133-134. Epub 2018 Feb 26.

Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1007/s10048-018-0542-zDOI Listing
May 2018

Defective mitochondrial ATPase due to rare mtDNA m.8969G>A mutation-causing lactic acidosis, intellectual disability, and poor growth.

Neurogenetics 2018 01 19;19(1):49-53. Epub 2018 Jan 19.

Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.

Mutations in mitochondrial ATP synthase 6 (MT-ATP6) are a frequent cause of NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) or Leigh syndromes, especially a point mutation at nucleotide position 8993. M.8969G>A is a rare MT-ATP6 mutation, previously reported only in three individuals, causing multisystem disorders with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia or IgA nephropathy. We present two siblings with the m.8969G>A mutation and a novel, substantially milder phenotype with lactic acidosis, poor growth, and intellectual disability. Our findings expand the phenotypic spectrum and show that mtDNA mutations should be taken account also with milder, stable phenotypes.
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http://dx.doi.org/10.1007/s10048-018-0537-9DOI Listing
January 2018

Posterior Reversible Encephalopathy Syndrome: Risk Factors and Impact on the Outcome in Children With Acute Lymphoblastic Leukemia Treated With Nordic Protocols.

J Pediatr Hematol Oncol 2018 01;40(1):e13-e18

Astrid Lindgren Children's Hospital, Karolinska University Hospital, and the Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Posterior reversible encephalopathy syndrome (PRES) in children with acute lymphoblastic leukemia has been increasingly recognized as a clinicoradiological entity. Our aim was to describe the incidence of PRES in pediatric patients with ALL, identify its risk factors, and examine its prognostic importance. For this research, we conducted a systematic, retrospective review of the patient records in a population-based series of children with acute lymphoblastic leukemia (n=643) treated in Finland from 1992 to 2008. Of the patients with ALL, 4.5% (n=29) developed radiologically confirmed PRES, of which 28 cases occurred during induction. Hypertension (P=0.006; odds ratio [OR], 4.10, confidence interval [CI], 1.50-11.25), constipation (P=0.001; OR, 5.60; CI, 2.02-15.52), and >14 days of alkalinization (P=0.017; OR, 3.27; CI, 1.23-8.68) were significant independent risk factors for PRES. One-third of the patients developed epilepsy. Relapses occurred significantly more often in those patients with PRES (P=0.001), which was associated with worse overall survival (P=0.040; 5-year survival=75.9% [60.3%-91.4%] vs. 88.4% [85.8%-90.9%]). Using NOPHO-ALL 92/2000 protocols, PRES is a significant early complication of therapy in ALL, and was associated with a poorer prognosis and significant neurological morbidity.
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http://dx.doi.org/10.1097/MPH.0000000000001009DOI Listing
January 2018

Phenotype-genotype correlations in Leigh syndrome: new insights from a multicentre study of 96 patients.

J Med Genet 2018 01 3;55(1):21-27. Epub 2017 Nov 3.

Department of Pediatrics, The Queen Silvia Children's Hospital, University of Gothenburg, Gothenburg, Sweden.

Background: Leigh syndrome is a phenotypically and genetically heterogeneous mitochondrial disorder. While some genetic defects are associated with well-described phenotypes, phenotype-genotype correlations in Leigh syndrome are not fully explored.

Objective: We aimed to identify phenotype-genotype correlations in Leigh syndrome in a large cohort of systematically evaluated patients.

Methods: We studied 96 patients with genetically confirmed Leigh syndrome diagnosed and followed in eight European centres specialising in mitochondrial diseases.

Results: We found that ataxia, ophthalmoplegia and cardiomyopathy were more prevalent among patients with mitochondrial DNA defects. Patients with mutations in and genes with complex I deficiency shared common phenotypic features, such as early development of central nervous system disease, followed by high occurrence of cardiac and ocular manifestations. The cerebral cortex was affected in patients with mutations significantly more often than the rest of the cohort. Patients with the m.8993T>G mutation in gene had more severe clinical and radiological manifestations and poorer disease outcome compared with patients with the m.8993T>C mutation.

Conclusion: Our study provides new insights into phenotype-genotype correlations in Leigh syndrome and particularly in patients with complex I deficiency and with defects in the mitochondrial ATP synthase.
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http://dx.doi.org/10.1136/jmedgenet-2017-104891DOI Listing
January 2018

Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.

Am J Hum Genet 2017 Nov;101(5):856-865

Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA.

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs102] and c.920delG [p.Gly307Alafs11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.
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http://dx.doi.org/10.1016/j.ajhg.2017.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673666PMC
November 2017

PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature.

J Med Genet 2018 02 2;55(2):104-113. Epub 2017 Nov 2.

Department of Pediatric Neurology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.

Background: De novo mutations in have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia.

Objectives: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations.

Methods: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of -derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes.

Results: We report mutations in (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes.

Conclusion: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.
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http://dx.doi.org/10.1136/jmedgenet-2017-104946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800346PMC
February 2018

Cerebellar mutism syndrome in children with brain tumours of the posterior fossa.

BMC Cancer 2017 Jun 21;17(1):439. Epub 2017 Jun 21.

Department of Neurosurgery, Rigshospitalet, Copenhagen, Denmark.

Background: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined.

Methods: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre-operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles.

Discussion: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition.

Trial Registration: Clinicaltrials.gov : NCT02300766 , date of registration: November 21, 2014.
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http://dx.doi.org/10.1186/s12885-017-3416-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480181PMC
June 2017

MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability.

Brain 2017 Aug;140(8):2093-2103

Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.

Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.
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http://dx.doi.org/10.1093/brain/awx138DOI Listing
August 2017

Evoked potentials recorded during routine EEG predict outcome after perinatal asphyxia.

Clin Neurophysiol 2017 07 11;128(7):1337-1343. Epub 2017 May 11.

Department of Clinical Neurophysiology, Children's Hospital, HUS Medical, Imaging Center, University of Helsinki and Helsinki University Hospital (HUH), Helsinki, Finland.

Objective: To evaluate the added value of somatosensory (SEPs) and visual evoked potentials (VEPs) recorded simultaneously with routine EEG in early outcome prediction of newborns with hypoxic-ischemic encephalopathy under modern intensive care.

Methods: We simultaneously recorded multichannel EEG, median nerve SEPs, and flash VEPs during the first few postnatal days in 50 term newborns with hypoxic-ischemic encephalopathy. EEG background was scored into five grades and the worst two grades were considered to indicate poor cerebral recovery. Evoked potentials were classified as absent or present. Clinical outcome was determined from the medical records at a median age of 21months. Unfavorable outcome included cerebral palsy, severe mental retardation, severe epilepsy, or death.

Results: The accuracy of outcome prediction was 98% with SEPs compared to 90% with EEG. EEG alone always predicted unfavorable outcome when it was inactive (n=9), and favorable outcome when it was normal or only mildly abnormal (n=17). However, newborns with moderate or severe EEG background abnormality could have either favorable or unfavorable outcome, which was correctly predicted by SEP in all but one newborn (accuracy in this subgroup 96%). Absent VEPs were always associated with an inactive EEG, and an unfavorable outcome. However, presence of VEPs did not guarantee a favorable outcome.

Conclusions: SEPs accurately predict clinical outcomes in newborns with hypoxic-ischemic encephalopathy and improve the EEG-based prediction particularly in those newborns with severely or moderately abnormal EEG findings.

Significance: SEPs should be added to routine EEG recordings for early bedside assessment of newborns with hypoxic-ischemic encephalopathy.
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http://dx.doi.org/10.1016/j.clinph.2017.04.025DOI Listing
July 2017

ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss.

Brain 2017 05;140(5):1267-1279

The Folkhälsan Institute of Genetics, Haartmaninkatu 8, 00290 Helsinki, Finland.

Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of-function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development.
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http://dx.doi.org/10.1093/brain/awx040DOI Listing
May 2017

Neonatal somatosensory evoked potentials persist during hypothermia.

Acta Paediatr 2017 Jun 5;106(6):912-917. Epub 2017 Apr 5.

Department of Clinical Neurophysiology, Children's Hospital, HUS Medical Imaging Center, University of Helsinki and Helsinki University Hospital (HUH), Helsinki, Finland.

Aim: Treatment with therapeutic hypothermia has challenged the use of amplitude-integrated electroencephalography in predicting outcomes after perinatal asphyxia. In this study, we assessed the feasibility and gain of somatosensory evoked potentials (SEP) during hypothermia.

Methods: This retrospective study comprised neonates from 35 + 6 to 42 + 2 gestational weeks and treated for asphyxia or hypoxic-ischaemic encephalopathy at Helsinki University Hospital between 14 February 2007 and 23 December 2009. This period was partly before the introduction of routine therapeutic hypothermia, which enabled us to include normothermic neonates who would these days receive hypothermia treatment. We analysed SEPs from 47 asphyxiated neonates and compared the results between 23 normothermic and 24 hypothermic neonates.

Results: Our data showed that hypothermia led to SEP latencies lengthening by a few milliseconds, but the essential gain for predicting outcomes by SEPs was preserved during hypothermia. Of the 24 hypothermic neonates, bilaterally absent SEPs were associated with poor outcome in 2/2 neonates, normal SEPs were associated with good outcomes in 13/15 neonates and 5/7 neonates with unilaterally absent or grossly delayed SEPs had a poor outcome.

Conclusion: Our findings indicated that SEPs were a reliable tool for evaluating the somatosensory system in asphyxiated neonates in both normothermic and hypothermic conditions.
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http://dx.doi.org/10.1111/apa.13813DOI Listing
June 2017

ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia.

Hum Mol Genet 2017 04;26(8):1432-1443

Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.

De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G > A (p.G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral palsy, both with disease onset in childhood. HSP is a clinically and genetically heterogeneous disorder of the upper motor neurons. Symptoms beginning in early childhood may resemble spastic cerebral palsy. The function of ATAD3A, a mitochondrial inner membrane AAA ATPase, is yet undefined. AAA ATPases form hexameric rings, which are catalytically dependent on the co-operation of the subunits. The dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity. We further show that overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass. Similarly, we observed altered dynamics of the mitochondrial network and increased lysosomes in patient fibroblasts and neurons derived through differentiation of patient-specific induced pluripotent stem cells. These alterations were verified in patient fibroblasts to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including HSP, with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity.
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http://dx.doi.org/10.1093/hmg/ddx042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393146PMC
April 2017

Primary versus non-primary maternal cytomegalovirus infection as a cause of symptomatic congenital infection - register-based study from Finland.

Infect Dis (Lond) 2017 Jun 24;49(6):445-453. Epub 2017 Jan 24.

i Infectious Diseases , Children's Hospital, University of Helsinki and Helsinki University Hospital , Helsinki , Finland.

Background: Both primary and non-primary maternal cytomegalovirus (CMV) infection during pregnancy can lead to vertical transmission. We evaluated the proportion of maternal primary/non-primary infections among 26 babies with symptomatic congenital CMV infection born in Finland from 2000 to 2012.

Methods: We executed a database search on hospital records from all five university hospitals in Finland to identify infants with congenital CMV infection. The preserved maternal serum samples drawn at the end of the first trimester were analysed for CMV antibodies. Maternal infection was classified to be non-primary, if there was high avidity CMV immunoglobulin G (IgG) in the early pregnancy samples. Infection was considered primary in the case of either low avidity IgG (primary infection in the first trimester or near conception) or absent CMV IgG at the end of the first trimester (primary infection in the second or third trimester).

Results: The majority of the symptomatic congenital CMV infections (54%) were due to maternal non-primary infection, 27% due to maternal primary infection in the first trimester or near conception, and 19% during the second or third trimester. Long-term sequelae occurred in 59% of patients: in 6/7 after primary infection in the first trimester, in 0/5 after primary infection in the second or third trimester, and in 9/14 after non-primary infection.

Conclusions: In this register-based cohort, non-primary infections caused the majority of symptomatic congenital CMV infections, and resulted in significant morbidity.
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http://dx.doi.org/10.1080/23744235.2017.1279344DOI Listing
June 2017

Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.

Am J Hum Genet 2016 09 18;99(3):735-743. Epub 2016 Aug 18.

Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany.

SQSTM1 (sequestosome 1; also known as p62) encodes a multidomain scaffolding protein involved in various key cellular processes, including the removal of damaged mitochondria by its function as a selective autophagy receptor. Heterozygous variants in SQSTM1 have been associated with Paget disease of the bone and might contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Using exome sequencing, we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation. Our findings expand the SQSTM1-associated phenotypic spectrum and lend further support to the concept of disturbed selective autophagy pathways in neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.ajhg.2016.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010644PMC
September 2016

Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy.

Neurol Genet 2016 Feb 21;2(1):e46. Epub 2016 Jan 21.

Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.

Objective: To identify the molecular genetic basis of a syndrome characterized by rapidly progressing cerebral atrophy, intractable seizures, and intellectual disability.

Methods: We performed exome sequencing in the proband and whole-genome single nucleotide polymorphism genotyping (copy number variant analysis) in the proband-parent trio. We used heterologous expression systems to study the functional consequences of identified mutations.

Results: The search for potentially deleterious recessive or de novo variants yielded compound heterozygous missense (c.1202G>A, p.Cys401Tyr) and frameshift deletion (c.2396delG, p.Ser799IlefsTer96) mutations in ADAM22, which encodes a postsynaptic receptor for LGI1. The deleterious effect of the mutations was observed in cell surface binding and immunoprecipitation assays, which revealed that both mutant proteins failed to bind to LGI1. Furthermore, immunoprecipitation assays showed that the frameshift mutant ADAM22 also did not bind to the postsynaptic scaffolding protein PSD-95.

Conclusions: The mutations identified abolish the LGI1-ADAM22 ligand-receptor complex and are thus a likely primary cause of the proband's epilepsy syndrome, which is characterized by unusually rapidly progressing cortical atrophy starting at 3-4 months of age. These findings are in line with the implicated role of the LGI1-ADAM22 complex as a key player in nervous system development, specifically in functional maturation of postnatal synapses. Because the frameshift mutation affects an alternatively spliced exon with highest expression in postnatal brain, the combined effect of the mutations is likely to be hypomorphic rather than complete loss of function. This is compatible with the longer survival of the patient compared to Lgi1 (-/-) and Adam22 (-/-) mice, which develop lethal seizures during the first postnatal weeks.
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http://dx.doi.org/10.1212/NXG.0000000000000046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817901PMC
February 2016
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