Differential diagnosis of progressive intellectual and neurological deterioration in children

Abstract

Aim: To report the differential diagnosis in children with progressive intellectual and neurological deterioration (PIND) in the UK.

Method: Since 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.

Results: From 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.

Interpretation: This 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 adds: The 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.

Figure 1

rogressive intellectual and neurological deterioration diagnoses in (a) White and (b) Pakistani children <1y. Eleven most common diagnoses in White (n=302) and Pakistani (n=107) children age <1y. The White (n=150) and Pakistani (n=62) children with ‘other’ diagnoses are shown in Table S1. AGS, Aicardi‐Goutières syndrome; GM1, GM1 gangliosidosis; Leuk, unclassified leukoencephalopathies; Mito, mitochondrial disorders; Mo co‐fact def, molybdenum co‐factor deficiency; MPS I, mucopolysaccharidosis type I; Zellweger spectrum, Zellweger spectrum disorder (includes Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease).

Figure 2

Progressive intellectual and neurological deterioration diagnoses in (a) White and (b) Pakistani children 1–4y. Ten most common diagnoses in White (n=381) and Pakistani (n=97) children age 1–4y. The White (n=96) and Pakistani (n=37) children with ‘other’ diagnoses are shown in Table S2. ALD, adrenoleukodystrophy; A‐T, ataxia‐telangiectasia; Leuk, unclassified leukoencephalopathies; Mito, mitochondrial disorders; MLD, metachromatic leukodystrophy; MPS III, mucopolysaccharidosis type III; NCL, neuronal ceroid lipofuscinoses; NP‐C, Niemann‐Pick type C; PKAN, pantothenate kinase‐associated neurodegeneration; PLAN, PLA2G6‐associated neurodegeneration; VWMD, vanishing white matter disease.

Figure 3

Progressive intellectual and neurological deterioration diagnoses in (a) White and (b) Pakistani children 5–9y. Twelve most common diagnoses in White (n=145) children age 5–9y and four most common diagnoses in Pakistani (n=17) children age 5–9y. The White (n=18) and Pakistani (n=10) children with ‘other’ diagnoses are shown in Table S3. ALD, adrenoleukodystrophy; Hypomyelin, hypomyelination; Juv, juvenile; Mito, mitochondrial disorders; MLD, metachromatic leukodystrophy; NCL, neuronal ceroid lipofuscinoses; NP‐C, Niemann‐Pick type C; PKAN, pantothenate kinase‐associated neurodegeneration; SSPE, subacute sclerosing panencephalitis.

Figure 4

Progressive intellectual and neurological deterioration diagnoses in (a) White and (b) Pakistani children 10–15y. Fourteen most common diagnoses in White (n=65) children age 10–15y and six most common diagnoses in Pakistani (n=10) children age 10–15y. The White (n=12) children with ‘other’ diagnoses are shown in Table S4. ALD, adrenoleukodystrophy; Astro, astrocytoma; Cobal, cobalamin deficiency; Juv, juvenile; Leuk, unclassified leukoencephalopathies; Mito, mitochondrial disorders; MLD, metachromatic leukodystrophy; NCL, neuronal ceroid lipofuscinoses; NP‐C, Niemann‐Pick type C; PKAN, pantothenate kinase‐associated neurodegeneration; SSPE, subacute sclerosing panencephalitis; vCJD, variant Creutzfeldt‐Jakob disease.