Miriam Nickel

Brain iron quantification by MRI in mitochondrial membrane protein-associated neurodegeneration under iron-chelating therapy

Therapeutic trials for Neurodegeneration with Brain Iron Accumulation have aimed at a reduction of cerebral iron content. A 13‐year‐old girl with mitochondrial membrane protein‐associated neurodegeneration treated with an iron‐chelating agent was monitored by R2 relaxometry, R2* relaxometry, and quantitative susceptibility mapping to estimate the brain iron content. The highly increased brain iron content slowly decreased in the substantia nigra but remained stable for globus pallidus. The estimated iron content was higher by R2* compared to R2 and quantitative susceptibility mapping, a finding not previously observed in the brain of healthy volunteers. A hypothesis explaining this discrepancy is offered.

POLR3A and POLR3B Mutations in Unclassified Hypomyelination

OBJECTIVE This study aims to ascertain frequency of mutations in POLR3A or POLR3B, which are associated with 4H leukodystrophy, in a cohort of patients with unclassified hypomyelination. METHODS AND RESULTS In a cohort of 22 patients with the magnetic resonance imaging (MRI) diagnosis of unclassified hypomyelination and without typical clinical signs, we evaluated clinical and MRI features. Developmental delay or intellectual disability, ataxia, and spasticity were frequent symptoms. POLR3A and POLR3B were sequenced. A compound heterozygote mutation in POLR3B was found in only one patient. Additional investigations allowed a definitive diagnosis in 10 patients. CONCLUSION Mutations in POLR3A or POLR3B are rare in patients with unclassified hypomyelination, and alternative diagnoses should be considered first.

Novel morphological macular findings in juvenile CLN3 disease.

Aims Juvenile CLN3 disease, one of the most common forms of a group of lysosomal storage diseases called neuronal ceroid lipofuscinoses (NCLs), is a progressive neurodegenerative disorder with initial visual deterioration. The objective of this study was to analyse the retinal phenotype of patients with CLN3 disease with the help of recent ophthalmic imaging modalities to distinguish CLN3 disease from other inherited retinal dystrophies. Methods Patients underwent ophthalmic evaluations, including anterior and posterior segment examinations, optical coherence tomography, fundus autofluorescence, near infrared imaging and fundus photography. Patients were also assessed according to the Hamburg juvenile NCL (JNCL) score. Each ophthalmic finding was assessed by three independent examiners and assigned to a clinical severity score. Results 22 eyes of 11 patients were included. The mean age at examination was 14.4 years (range 11.8–26.4 years), with an average age at initial diagnosis of 8 years (range 4.5–11 years). The mean Hamburg JNCL score was 7.3 (range 0–13). All patients showed a specific macular striation pattern on optical coherence tomography that was independent of age and progression of the disease. Other previously described retinal features of CLN3 disease were classified into four severity grades. Conclusions This study represents the first prospective observational case series documenting retinal abnormalities in CLN3 disease with the aid of the spectral domain optical coherence tomography. The major finding was a characteristic, striated macular pattern in all patients studied. Particularly in early disease cases, macular striae can potentially help to discriminate CLN3 disease from other inherited forms of retinitis pigmentosa.

Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study

BACKGROUND Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, characterised by rapid psychomotor decline and epilepsy, is caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1. We aimed to analyse the characteristics and rate of progression of CLN2 disease in an international cohort of patients. METHODS We did an observational cohort study using data from two independent, international datasets of patients with untreated genotypically confirmed CLN2 disease: the DEM-CHILD dataset (n=74) and the Weill Cornell Medical College (WCMC) dataset (n=66). Both datasets included quantitative rating assessments with disease-specific clinical domain scores, and disease course was measured longitudinally in 67 patients in the DEM-CHILD cohort. We analysed these data to determine age of disease onset and diagnosis, as well as disease progression-measured by the rate of decline in motor and language summary scores (on a scale of 0-6 points)-and time from first symptom to death. FINDINGS In the combined DEM-CHILD and WCMC dataset, median age was 35·0 months (IQR 24·0-38·5) at first clinical symptom, 37·0 months (IQR 35·0 -42·0) at first seizure, and 54·0 months (IQR 47·5-60·0) at diagnosis. Of 74 patients in the DEM-CHILD dataset, the most common first symptoms of disease were seizures (52 [70%]), language difficulty (42 [57%]), motor difficulty (30 [41%]), behavioural abnormality (12 [16%]), and dementia (seven [9%]). Among the 41 patients in the DEM-CHILD dataset for whom longitudinal assessments spanning the entire disease course were available, a rapid annual decline of 1·81 score units (95% CI 1·50-2·12) was seen in motor-language summary scores from normal (score of 6) to no function (score of 0), which occurred over approximately 30 months. Among 53 patients in the DEM-CHILD cohort with available data, the median time between onset of first disease symptom and death was 7·8 years (SE 0·9) years. INTERPRETATION In view of its natural history, late-infantile CLN2 disease should be considered in young children with delayed language acquisition and new onset of seizures. CLN2 disease has a largely predictable time course with regard to the loss of language and motor function, and these data might serve as historical controls for the assessment of current and future therapies. FUNDING EU Seventh Framework Program, German Ministry of Education and Research, EU Horizon2020 Program, National Institutes of Health, Nathans Battle Foundation, Cures Within Reach Foundation, Noahs Hope Foundation, Hope4Bridget Foundation.

OP48 – 2893: The DEM-CHILD NCL Patient Database: A tool for the evaluation of therapies in neuronal ceroid lipofuscinoses (NCL)

Objective The aims of the DEM-CHILD NCL Patient Database are (i) to collect patients with different NCL forms in participating countries in order to measure the prevalence of each type of NCL, (ii) to establish an NCL patient registry to enable retrospective and prospective patient data collection and to precisely describe the clinical course and its variability in the different forms of NCL, (iii) to correlate the genotype of patients with their phenotype by linking clinical and genetic mutation data, (iv) to establish a tool for evaluation of experimental therapy studies, as well as palliative therapies. Methods Two categories of patient data have been collected: Static data, which are derived from the medical history of a patient and dynamic data, which are related to the patients age. Data collection was performed both retrospectively (static data) and prospectively (dynamic data) during regular visits in NCL specialty centers throughout Europe. Results In the DEM-CHILD project, NCL expert clinicians from Finland, UK, Italy and Germany have collaborated to establish an online NCL patient database. To date, extensive natural history data from more than 200 patients with different NCL forms have been collected. Analysis on genotype-phenotype variability has been performed based on longitudinal clinical scoring data, MRI-based brain volumetry and other clinical information. Prevalence figures for the genetic types CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN8, and CLN10 have been obtained for the participating countries. The database consortium has now expanded beyond the DEM-CHILD partners with currently 12 countries participating. Conclusion The large collection in the DEM-CHILD database of comprehensive sets of data on the natural history of different NCL forms is an indispensable tool for the evaluation of therapies. Its data are already being used for this purpose in current clinical trials.

Unexplained loss of vision in a child: consider bilateral primary optic nerve sheath meningioma.

A 4-year-old girl gradually lost her vision to become practically blind at the age of 10 years. Examinations at several medical centers had been unable to establish an etiology. Traditional investigation using cerebral magnetic resonance imaging (MRI) initially showed normal results; however, later on it showed progressive atrophy of both optical nerves without recognizable cause. Subsequently, MRI including adequate orbital sequences, contrast-enhanced sequences, and fat suppression demonstrated bilateral primary optic nerve sheath meningioma, a rare but treatable tumor of childhood. The patient underwent neurosurgery and to date retains minimal vision. Adequate neuroradiological investigation of unexplained optic atrophy is advocated.

Considering Valproate as a Risk Factor for Rapid Exacerbation of Complex Movement Disorder in Progressed Stages of Late-Infantile CLN2 Disease.

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease, OMIM 204500) is a rare autosomal-recessive lysosomal storage disorder. It is one of the most common neurodegenerative disorders in childhood. Symptoms include epilepsy, rapid motor and language regression, dementia, visual loss, and a complex movement disorder in later stages of the disease. We report on two children with genetically confirmed late-infantile CLN2 disease who developed a severe exacerbation of their complex movement disorder leading to hyperthermia, hyper-CK-emia and decreased level of consciousness over several weeks despite different therapeutic approaches. Both patients were on long-term antiepileptic treatment with valproate and only after the withdrawal of valproate, the movement disorder disappeared and level of consciousness improved. These observations emphasize that valproate has to be considered as a possible risk factor in patients in later stages of late-infantile CLN2 disease who develop a rapidly progressive complex movement disorder.

PP03.8 – 2898: Late language acquisition and unexplained epilepsy are indicators of easily detectable CLN2 disease

Objective Late-infantile CLN2 disease is caused by a deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) and is characterized by rapid psychomotor decline and epilepsy. Although the disease is presently incurable, early diagnosis is desirable for family planning and upcoming experimental therapies. In our patients, diagnosis was frequently delayed by two or more years after the onset of striking symptoms (epilepsy and ataxia). We were looking for ways to shorten the time to diagnosis. Methods We reviewed systematically the early development of 28 CLN2 patients, looking for possible forerunners of overt disease and focussing on language acquisition. We also used a dry blood spot (DBS) test for TPP1 activity in a group of children investigated mainly in Turkey and Brazil for unexplained epilepsy and/or ataxia. Results Two thirds of CLN2 patients had never achieved language capacities in the normal range for age. Most of these children had been classified as “late talkers”. Among 142 patients with unexplained epilepsy and/or ataxia, six were shown to have CLN2 disease. Conclusion “Late talkers” and children with unclear epilepsy and/or ataxia have a significant risk of being CLN2 patients. The availability of a simple and cheap enzymatic DBS test helps clarifying a suspicion of this severe genetic disease fast and conveniently.

The unified Batten disease rating scale (UBDRS): Validation and reliability in an independent sample

• Validity of the UBDRS physical subscale in this independent sample was assessed by comparison with previously published results. CLN2 disease and CLN3 disease each have a characteristic movement disorder Subject # Evaluator Trainer A B C D 1 6 8 5 5 8 2 45 48 46 47 42 3 53 54 54 53 55 4 1 1 1 1 1 5 53 52 54 53 56 6 31 33 34 32 30 7 61 61 61 61 58 8 42 44 44 44 38 9 20 19 19 17 21 10 13 13 11 9 16 11 5 6 3 3 8 12 26 28 26 26 30 13 8 8 8 8 10 UBDRS Physical Subscale Scores by Subject and Rater

An Adapted Clinical Measurement Tool for the Key Symptoms of CLN2 Disease

Neuronal ceroid lipofuscinosis type-2 (CLN2) disease is a rare, autosomal recessive, pediatric-onset, neurodegenerative lysosomal storage disease caused by mutations in the TPP1 gene. Cerliponase a...