Epidemiology of progressive intellectual and neurological deterioration in UK children.

ObjectivesTo report the findings of the UK study of childhood progressive intellectual and neurological deterioration (PIND), including variant Creutzfeldt-Jakob Disease (vCJD).MethodsActive surveillance of children with PIND commenced in May 1997,...

ObjectiveTo study the epidemiology of diseases that cause progressive intellectual and neurological deterioration (PIND) in UK children.DesignSince May 1997, the authors have performed active surveillance to search for variant Creutzfeldt–Jakob...

Variant Creutzfeldt-Jakob disease in UK children: a national surveillance study

AimTo report the differential diagnosis in children with progressive intellectual and neurological deterioration (PIND) in the UK.MethodSince 1997 the PIND Study has searched for variant Creutzfeldt‐Jakob disease (vCJD) in children, using the British Paediatric Surveillance Unit to perform prospective surveillance of those younger than 16 years with PIND.ResultsFrom May 1997 to October 2019, 2255 children meeting PIND criteria had been notified, of whom 2008 (1085 males, 923 females) had underlying diagnoses. There were over 220 different diseases, including six cases of vCJD. The numbers presenting in four age groups were: <1 year, 805 (40%); 1 to 4 years inclusive, 825 (41%); 5 to 9 years inclusive, 264 (13%); and 10 to 15 years inclusive, 114 (6%). The two largest ethnic groups were White and Pakistani (58.2% and 17% of diagnosed cases). The most common diseases in these two ethnic groups are shown for the four age groups. The distribution of diseases varied with age but was quite similar in White and Pakistani children.InterpretationThis paper provides a unique guide to the complex differential diagnosis of childhood PIND, showing considerable differences between four age groups, but similarities between ethnic groups. The PIND Study still provides the only systematic surveillance for vCJD in children in the UK.What this paper addsThe prevalence of diseases causing childhood progressive intellectual and neurological deterioration in the UK is low (approximately 0.1/1000 live births).There were more than 220 different disorders, mainly genetically determined.The majority of disorders presented early in childhood: 81% before the age of 5 years.There were similarities in the disease spectrum in White and Pakistani children.

Aims to describe the undiagnosed children in a UK study of progressive intellectual and neurological deterioration (PIND) and evaluate their investigations. Methods Since March 1997 this study has used the British Paediatric Surveillance Unit to identify UK children with PIND. Clinical data are gathered from paediatricians by questionnaire, telephone interview or site visit. The PIND Study Expert Group of specialists in paediatric neurology, neurometabolic disease and neurogenetics independently reviews the cases. Results By July 2016 4063 children with suspected PIND had been notified. There were 1958 finalised cases meeting the criteria for PIND; 1749 (89%) were diagnosed, a group of more than 190 different disorders. There were also 209 (11%) (111 male, 98 female) in whom investigations had failed to provide a diagnosis or who had died undiagnosed. Distribution by ethnicity was: White 104 (50%), Asian 85 (Pakistani 65, Indian 6, Bangladeshi 4, Asian unspecified 10) (41%), Black 5 (2%), other 7 (3%), not stated 8 (4%). There was a high rate of consanguinity: 90/209 (43%) over all (89% in the 65 Pakistani families). 72/209 (34%) had a similarly affected relative (57 of these were siblings). The undiagnosed cases had usually been very thoroughly investigated with, where appropriate, blood and urine metabolic tests, CSF examination, plasma white cell enzymes, EEG, ERG and VER, ECG, echocardiogram, skin biopsy, muscle biopsy, karyotype, DNA studies, CT and MRI brain scans. For example 174/ 209 (83%) had at least one MRI brain scan. 152/209 (73%) had died. Only 10 were known to have had full post mortem examinations, 4 had limited autopsies. 94 did not have post mortems (44 cases: not known). This low autopsy rate was also found in the diagnosed PIND cases where most diagnoses were made during life. Conclusion 11% of PIND children were undiagnosed despite intensive investigation. High rates of consanguinity (43%) and of a positive family history (34%) suggest that many had (currently unrecognised) neurometabolic diseases. Autopsies are rarely performed so storage of selected tissues for DNA and other analyses should be recommended in these undiagnosed cases. Acknowledgment independent research funded by Department of Health Policy Research Programme [121/6443].

Background: Progressive intellectual and neurological deterioration (PIND) is a rare but severe childhood disorder characterized by loss of intellectual or developmental abilities, and requires quick diagnosis to ensure timely treatment to prevent possible irreversible neurological damage. Inborn errors of metabolism (IEMs) constitute a group of more than 1,000 monogenic conditions in which the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease, resulting in either accumulation of toxic metabolites and/or shortage of energy and building blocks for the cells. Many IEMs are amenable to treatment with the potential to improve outcomes. With this literature review we aim to create an overview of IEMs presenting with PIND in children, to aid clinicians in accelerating the diagnostic process.Methods: We performed a PubMed search on IEMs presenting with PIND in individuals aged 0–18 years. We applied stringent selection criteria and subsequently derived information on encoding genes, pathways, clinical and biochemical signs and diagnostic tests from IEMbase (www.iembase.org) and other sources.Results: The PubMed search resulted in a total of 2,152 articles and a review of references added another 19 articles. After applying our selection criteria, a total of 85 IEMs presenting with PIND remained, of which 57 IEMs were reported in multiple unrelated cases and 28 in single families. For 44 IEMs (52%) diagnosis can be achieved through generally accessible metabolic blood and urine screening tests; the remainder requires enzymatic and/or genetic testing. Treatment targeting the underlying pathophysiology is available for 35 IEMs (41%). All treatment strategies are reported to achieve stabilization of deterioration, and a subset improved seizure control and/or neurodevelopment.Conclusions: We present the first comprehensive overview of IEMs presenting with PIND, and provide a structured approach to diagnosis and overview of treatability. Clearly IEMs constitute the largest group of genetic PIND conditions and have the advantage of detectable biomarkers as well as amenability to treatment. Thus, the clinician should keep IEMs at the forefront of the diagnostic workup of a child with PIND. With the ongoing discovery of new IEMs, expanded phenotypes, and novel treatment strategies, continuous updates to this work will be required.

Our aim was to study the clinical presentation, mode of diagnosis, and epidemiology of mitochondrial disorders in children from the UK who have progressive intellectual and neurological deterioration (PIND). Since April 1997, we have identified patients aged 16 years or younger with suspected PIND through the monthly notification card sent to all UK consultant paediatricians by the British Paediatric Surveillance Unit. Clinical details obtained from reporting paediatricians are classified by an Expert Group. By July 2008, 2493 cases of PIND had been reported, among which there were 112 children (69 males, 43 females) with mitochondrial diseases presenting between birth and 14 years 7 months (median 12mo), divided into 13 subgroups. In some instances, clinical features were characteristic of mitochondrial disease, but many children presented non-specifically with combinations of developmental delay, hypotonia, failure to thrive, and seizures; 16 children had multisystem disease at presentation. Mortality was high: 40 children had died. Blood and/or cerebrospinal fluid lactate measurements were abnormal in 87 children, and 47 of 78 brain magnetic resonance images showed increased basal ganglia signal. Definite diagnoses were usually made by muscle enzyme or genetic studies. This is a unique population-based study of the mitochondrial disorders that cause childhood neurodegenerative disease. It provides detailed information about the clinical presentation and investigation of these complex cases.

ObjectiveTo determine whether any children in the UK had variant Creutzfeldt-Jakob disease (vCJD).DesignThis active prospective epidemiological study used the British Paediatric Surveillance Unit, asking UK paediatricians to notify all childhood...

Aims To review the cases referred to this UK-wide study of children with progressive intellectual and neurological deterioration (PIND) and analyse the differential diagnoses in these children by age at presentation. Methods Children meeting the case definition for PIND were identified via the British Paediatric Surveillance Unit. Data were obtained by standard questionnaire, with additional information from hospital records and laboratory reports, allowing validation of diagnoses and estimation of the age of presentation to clinicians. Results Between April 1997 and October 2019, 4612 children had been notified to the study. 2072 were found not to meet the PIND case definition. 2009 had an underlying diagnosis to explain their deterioration; of these the numbers presenting by age were: Conclusion Since 1997 the PIND Study has provided unique epidemiological data about neurodegenerative diseases in UK children. It shows that children meeting the criteria for PIND tend to present early in life (over 80% before the age of 5 years) – not surprising because of the inherited basis for so many of these disorders. The study provides a differential diagnosis for PIND children by age and remains the only means of performing systematic surveillance of the neurodegenerative diseases that make up the differential diagnosis of vCJD. Acknowledgement Independent research funded by the Department of Health (DH) Policy Research Programme [PR-ST-1216-10001]. Views expressed are not necessarily those of DH.

An 11-month old girl is presented to you for developmental delay. The child started to roll over at four months of age and sit independently at approximately seven months of age. Afterwards, she gradually regressed and could no longer achieve these motor milestones. In the past few weeks, she lost the ability to hold her head straight or bear weight on her legs. Her babbling and smiling have decreased, and she does not seem to be interested in her surroundings. The pregnancy and delivery were uneventful, and there is no history of neonatal complications, febrile illnesses or head injuries. The family reports that she received her first three pentavalent immunizations. An analysis of family history was negative for developmental delay; however, the parents are distant cousins. On examination, the child was unable to sit, roll or bear weight on her legs. Her eyes fixed poorly on objects and she did not reach for them. Her trunk and limb muscular tone was poor, while the muscle bulk remained normal. Deep tendon reflexes were hard to obtain. In view of the developmental deterioration and abnormal neurological examination, the patient was referred to a paediatric neurologist. LEARNING POINTS Primary health care providers treating children with progressive intellectual and neurological deterioration (PIND) are facing a challenging task, because a myriad of neurodegenerative disorders can present in a similar fashion. Regression of developmental milestones or PIND should alert primary health care providers of the need to conduct a detailed history and physical examination. ○ When clinically indicated, investigations such as magnetic resonance imaging, electroencephalogram, evoked potentials, biochemical studies, genetic investigations (cytogenetic studies and molecular testing) and biochemical evaluations should be considered. ○ A definitive diagnosis may require further investigations and more invasive testing (1,2). The two-year surveillance study (3) on PIND was used to enhance monitoring for the possibility of Creutzfeldt-Jakob disease (CJD) and variant-CJD. While CJD is rare, the occurrence of variant-CJD in Canada would signal an important change in its epidemiology. Canadian Paediatric Surveillance Program participants reported 99 possible PIND cases; 59 of these were confirmed. The three most frequent diagnoses were mitochondrial disorders, ceroid lipofuscinosis and mucopolysaccharidosis. One case of iatrogenic CJD was confirmed; however, no cases of the variant form were reported. Of note, there were no cases with toxic etiologies (4,5). A definitive etiological diagnosis could not be attained in eight cases, even after exhaustive investigations and review by an expert panel consisting of four paediatric neurologists, a medical geneticist and a paediatric neuropathologist. Support for ongoing research and surveillance on PIND disorders is essential to advance knowledge and provide useful public health information about trends occurring in rare neurological disorders.

ObjectivesTo report investigations performed in children with progressive neurodegenerative diseases reported to this UK study.DesignSince 1997 paediatric surveillance for variant Creutzfeldt-Jakob disease (vCJD) has been performed by identifying children aged...

To report on the epidemiology of the brain white matter disorders of children identified via a national prospective study. Since 1997 a study of UK children with progressive intellectual and neurological deterioration (PIND) has used the British Paediatric Surveillance Unit system to identify children with progressive neurodegenerative disease. This paper reports on children in the study with brain white matter disorders. Between May 1997 and November 2014 the PIND study identified 349 children with diagnosed leukodystrophies, giving an estimated UK lifetime risk of 31/million live births. There were 18 specific diseases in the group and relatively large numbers of affected children came from consanguineous Pakistani families. In addition there were 454 children with genetic leukoencephalopathies - in this group there were 38 diseases. 5.8% of children with scan evidence of brain white matter disorders did not receive a specific diagnosis. These unique prospectively-obtained national data avoid the selection bias inherent in reports from single centres. White matter disorders of the central nervous system comprise more than half of UK paediatric neurodegenerative diseases meeting the PIND criteria. This paper reports the lifetime risk/million live births for the commonest leukodystrophies, providing a basis for comparison with future studies.

Background and aims: To report the distribution of leukoencephalopathies in children identified by this prospective population-based study. Methods: 2802 children with suspected progressive intellectual and neurological deterioration (PIND) were notified via the British Paediatric Surveillance Unit (BPSU) between 1997 and 2009. An expert group reviewed clinical data and confirmed diagnoses where possible. An independent expert reviewed the available scans of children with unclassified leukoencephalopathies. Results: 1132 of the PIND children had an underlying diagnosis and of these 295 had one of the leukoencephalopathies. The distribution of diagnosed leukoencephalopathies was as follows: metachromatic leukodystrophy 62, X-linked adrenoleukodystrophy 60, Krabbe disease 39, Canavan disease 16, Alexander disease 13, leukoencephalopathy with vanishing white matter 12, Aicardi-Goutieres syndrome 12, Pelizaeus-Merzbacher disease 11, megalencephalic leukoencephalopathy with subcortical cysts 8, multiple sulphatase deficiency 6, multiple sclerosis 3, peroxisomal bifunctional D-protein deficiency 2, peroxisomal biogenesis defect 1. There were 50 children in the unclassified leukoencephalopathy group. In 32 the scans were reviewed and 19 were placed in a hypomyelination sub-group, the other 13 remaining in the unclassified leukoencephalopathy group with the 18 whose scans could not be reviewed. Conclusions: Leukoencephalopathies comprised 26% of PIND children with a known diagnosis. This population based study gives the relative frequency of the different leukoencephalopathies, providing an aid to diagnosis in children with abnormal white matter on brain imaging. After rigorous investigation 16% (50/295) remained in an unclassified group, but this situation is evolving.

To describe the cases of Niemann-Pick type C (NP-C) disease in a United Kingdom epidemiological study of progressive intellectual and neurological deterioration in childhood. Paediatricians notified cases via the British Paediatric Surveillance Unit between 1997 and 2015. Fifty-three NP-C patients were identified: 29 females, 24 males. Fifteen cases had a systemic presentation (neonatal jaundice and/or hepatosplenomegaly). Thirty-eight had a neurological onset, the commonest presenting symptom being gait disturbance/ataxia (29 cases, 76%). Forty-nine cases eventually had neurological problems, the commonest were school/cognitive difficulties (40, 82%), seizures (33, 67%), dysphagia (20, 41%), dysarthria (18, 37%), cataplexy (17, 35%), and visual deterioration (8, 16%); their commonest abnormal physical signs were vertical supranuclear gaze palsy (35, 71%), hypotonia (19, 39%) and hepatosplenomegaly (19, 39%). The median diagnostic delay in the 38 neurological onset cases was 3 years (range 0.3-12.8). Confirmatory investigations included filipin staining of skin fibroblasts (42 cases), bone marrow examination in 30 (the last in 2011), and increasingly DNA studies, mutations in NP-C1 being found in 20 cases. NP-C should be considered in children with progressive neurological deterioration. Subtle neurological problems combined with a history of prolonged neonatal jaundice and/or hepatosplenomegaly may provide early evidence of the disease.

Perspective on the paper by Verity et al (see page608) Dr Verity and his colleagues publish the results of their continuing study of progressive intellectual and neurological deterioration (PIND) in...