Niemann-Pick type C as a cause of progressive intellectual and neurological deterioration in childhood.

AIM: 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. METHOD: Paediatricians notified cases via the British Paediatric Surveillance Unit between 1997 and 2015. RESULTS: 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. INTERPRETATION: 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.

Leukodystrophies and genetic leukoencephalopathies in childhood: a national epidemiological study.

AIM: To report on the epidemiology of the brain white matter disorders of children identified via a national prospective study. METHOD: 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. RESULTS: 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. INTERPRETATION: 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.

Clinical features of narcolepsy in children vaccinated with AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in England.

AIM: The aim of this study was to investigate whether children in England with narcolepsy who received the ASO3 adjuvanted pandemic A/H1N1 2009 influenza vaccine (Pandemrix) differed clinically from unvaccinated patients. METHOD: A retrospective review was conducted in children with narcolepsy diagnosed by sleep centres and paediatric neurologists in 16 English hospitals. The inclusion criteria were patient age 4 to 18 years, onset of narcolepsy after January 2008, and diagnosis by the time of the key data-gathering visit in 2011. Clinical data came from hospital notes and general practitioner questionnaires. An expert panel validated the diagnoses. RESULTS: Seventy-five patients with narcolepsy were identified (43 males, 32 females; mean age at onset 10y 4mo, range 3-18y). Of these patients, 11 received the Pandemrix vaccine before narcolepsy onset. On first presentation, there were more frequent reports of cataplexy, among other features, in vaccinated than in unvaccinated patients (82% vs 55%), but only excessive weight gain (55% vs 20%) was significantly more frequent (p=0.03). Facial hypotonia (p=0.03) and tongue protrusion (p=0.01) were eventually seen more frequently in vaccinated children. When considering patients diagnosed within a year of onset, vaccinated children were not diagnosed more rapidly than unvaccinated children. INTERPRETATION: Some symptoms and signs of narcolepsy were more frequently reported in Pandemrix-vaccinated patients. There was no evidence of the more rapid diagnosis in vaccinated patients that has been reported in Finland and Sweden.

Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis.

OBJECTIVE: To evaluate the risk of narcolepsy in children and adolescents in England targeted for vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine (Pandemrix) from October 2009. DESIGN: Retrospective analysis. Clinical information and results of sleep tests were extracted from hospital notes between August 2011 and February 2012 and reviewed by an expert panel to confirm the diagnosis. Vaccination and clinical histories were obtained from general practitioners. SETTING: Sleep centres and paediatric neurology centres in England. PARTICIPANTS: Children and young people aged 4-18 with onset of narcolepsy from January 2008. MAIN OUTCOME MEASURES: The odds of vaccination in those with narcolepsy compared with the age matched English population after adjustment for clinical conditions that were indications for vaccination. The incidence of narcolepsy within six months of vaccination compared with the incidence outside this period measured with the self controlled cases series method. RESULTS: Case notes for 245 children and young people were reviewed; 75 had narcolepsy (56 with cataplexy) and onset after 1 January 2008. Eleven had been vaccinated before onset; seven within six months. In those with a diagnosis by July 2011 the odds ratio was 14.4 (95% confidence interval 4.3 to 48.5) for vaccination at any time before onset and 16.2 (3.1 to 84.5) for vaccination within six months before onset. The relative incidence from the self controlled cases series analysis in those with a diagnosis by July 2011 with onset from October 2008 to December 2010 was 9.9 (2.1 to 47.9). The attributable risk was estimated as between 1 in 57,500 and 1 in 52,000 doses. CONCLUSION: The increased risk of narcolepsy after vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine indicates a causal association, consistent with findings from Finland. Because of variable delay in diagnosis, however, the risk might be overestimated by more rapid referral of vaccinated children.

GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed.

AIM: To report the demographic, phenotypic, and time-to-diagnosis characteristics of children with GM2 gangliosidosis referred to the UK study of Progressive Intellectual and Neurological Deterioration. METHOD: Case notification is made via monthly surveillance card, administered by the British Paediatric Surveillance Unit to all UK-based paediatricians; children with GM2 gangliosidosis were identified from cases satisfying inclusion in the UK study of Progressive Intellectual and Neurological Deterioration and analysed according to phenotypic and biochemical categories. RESULTS: Between May 1997 and January 2010, 73 individuals with GM2 gangliosidoses were reported: 40 with Tay-Sachs disease, 31 with Sandhoff disease, and two with GM2 activator protein deficiency. Together they account for 6% (73/1164) of all diagnosed cases of progressive intellectual and neurological deterioration. The majority (62/73) were sporadic index cases with no family history. Children of Pakistani ancestry were overrepresented in all subtypes, particularly juvenile Sandhoff disease, accounting for 10 of 11 notified cases. Infantile-onset variants predominated (55/73); the mean age at onset of symptoms was 6.2 and 4.7 months for infantile-onset Tay-Sachs and Sandhoff disease respectively, and 26.2 and 34.7 months for the corresponding juvenile-onset variants. Time to diagnosis averaged 7.4 months and 28.0 months in infantile- and juvenile-onset disease respectively. INTERPRETATION: GM2 gangliosidosis is a significant cause of childhood neurodegenerative disease; timely diagnosis relies upon improved clinical recognition, which may be increasingly important as specific therapies become available. There is a potential benefit from the introduction of screening programmes for high-risk ethnic groups.

Is there evidence of vertical transmission of variant Creutzfeldt-Jakob disease?

OBJECTIVES: The possibility of vertical transmission of variant Creutzfeldt-Jakob disease (vCJD) has been raised because of the widespread distribution of infectivity in vCJD and the demonstration that this condition can be transmitted through blood transfusion. The aim of this study is to search for evidence of this type of transmission of vCJD. METHODS: A national surveillance system for CJD has been established in the UK since 1990. Through this register, details were extracted of all children born to vCJD cases up to March 2009. This list was checked against the CJD register and cases identified through the UK study of Progressive Intellectual and Neurological Deterioration in children to determine whether any of the children of vCJD cases had themselves developed a progressive neurological disorder or vCJD. RESULTS: 125 children were born to parents with a diagnosis of vCJD. Nine of these children were born to females with vCJD who were symptomatic at conception, birth or within a year of clinical onset. Only one woman was known to have breast fed her child. None of the children of vCJD cases have been referred to the National CJD Surveillance Unit as suspected vCJD and none have been classified as suffering from a progressive neurodegenerative disorder through the Progressive Intellectual and Neurological Deterioration study. One of the children has been investigated by the National Prion Unit (see accompanying case report). INTERPRETATION: To date there is no evidence of vertical transmission of vCJD. However, the incubation period through this mechanism might be prolonged and it will be many years before observational data can exclude this possibility.

The epidemiology of progressive intellectual and neurological deterioration in childhood.

OBJECTIVE: To study the epidemiology of diseases that cause progressive intellectual and neurological deterioration (PIND) in UK children. DESIGN: Since May 1997, the authors have performed active surveillance to search for variant Creutzfeldt-Jakob Disease (vCJD) among the many diseases that cause neurological deterioration in children, using the monthly surveillance card sent to all UK consultant paediatricians by the British Paediatric Surveillance Unit. The authors obtain clinical details from reporting paediatricians by questionnaire or site visit, and an Expert Group then independently classifies the cases. RESULTS: After 12 years, 2636 patients less than 16 years old with suspected PIND had been reported, of whom 1114 had a confirmed diagnosis to explain their deterioration: in these children, there were 147 different diseases. These were the six commonest diagnostic groups: leukoencephalopathies (183 cases), neuronal ceroid lipofuscinoses (141 cases), mitochondrial diseases (122 cases), mucopolysaccharidoses (102 cases), gangliosidoses (100 cases) and peroxisomal disorders (69 cases). Relatively large numbers of PIND children were reported from parts of the UK where there are high rates of consanguinity. Only six children with vCJD (four definite, two probable) had been identified. CONCLUSIONS: Although this study does not ascertain all UK cases, it provides a novel insight into the epidemiology of the neurodegenerative diseases that cause PIND in children. It is reassuring that in general these children are carefully investigated and that active surveillance has found only six children with vCJD. However, there is concern that more childhood vCJD cases may appear, possibly with a different genotype from those identified so far.

The clinical presentation of mitochondrial diseases in children with progressive intellectual and neurological deterioration: a national, prospective, population-based study.

AIM: 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). METHOD: 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. RESULTS: 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. INTERPRETATION: 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.