Epidemiological, clinical, and genetic characteristics of paediatric genetic white matter disorders in Northern Finland.

Oula A Knuutinen,Johanna M Uusimaa,Jaakko H Oikarainen,Tytti M‐L Pokka,Reetta M L Hinttala,Salla M Kangas,Jukka S Moilanen,Elisa J Rahikkala,Maria H Suo‐Palosaari,Päivi M Vieira

doi:10.1111/dmcn.14884

Abstract

To examine the epidemiological, clinical, and genetic characteristics of paediatric patients with genetic white matter disorders (GWMDs) in Northern Finland. A longitudinal population-based cohort study was conducted in the tertiary catchment area of Oulu University Hospital from 1990 to 2019. Patients were identified retrospectively by International Statistical Classification of Diseases and Related Health Problems codes in hospital records and prospectively by attending physicians. Inclusion criteria were children younger than 18 years with defined GWMDs or genetic disorders associated with white matter abnormalities (WMAs) on brain magnetic resonance imaging. Eighty patients (mean age [SD] at the end of the study 11y [8y 6mo], range 0-35y; 45 males, 35 females) were diagnosed with a defined GWMD. The cumulative childhood incidence was 30 per 100000 live births. Regarding those patients with 49 distinct GWMDs, 20% had classic leukodystrophies and 80% had genetic leukoencephalopathies. The most common leukodystrophies were cerebral adrenoleukodystrophy, Krabbe disease, and Salla disease. Additionally, 29 patients (36%) had genetic aetiologies not previously associated with brain WMAs or they had recently characterised GWMDs, including SAMD9L- and NHLRC2-related neurological disorders. Aetiology was mitochondrial in 21% of patients. The most common clinical findings were motor developmental delay, intellectual disability, hypotonia, and spasticity. The cumulative childhood incidence of childhood-onset GWMDs was higher than previously described. Comprehensive epidemiological and natural history data are needed before future clinical trials are undertaken. What this paper adds Forty-nine distinct genetic white matter disorders (GWMDs) were identified, with 20% of cases being classic leukodystrophies. The cumulative childhood incidence of GWMDs was higher than described previously. A considerable proportion (36%) of GWMDs were previously undefined or recently characterised GWMDs. Mitochondrial aetiology was more common (21%) than previously reported.

Highlights

The inclusion criteria were patients younger than 18 years at the time of clinical evaluation, who were living in the tertiary catchment area of Oulu University Hospital and who had a genetic white matter disorders (GWMDs) associated with white matter abnormalities (WMAs) either previously or as identified in the current study
Eight patients (10%) with disorders belonging to the Finnish disease heritage were identified
Twenty-nine patients (36%) with 20 disorders had a defined genetic aetiology not previously associated with brain WMAs or a recently characterised GWMD, including ataxia-pancytopenia syndrome (MIM no. 159550; SAMD9L; n=3),[16] fibrosis, neurodegeneration, and cerebral angiomatosis disease (MIM no. 618278; NHLRC2; n=3),[17] Lujan–Fryns syndrome (MIM no. 309520; MED12; n=2), spastic paraplegia 4, autosomal dominant (MIM no. 182601; SPAST; n=2), and TAF1C-related disorder (TAF1C)-related neurological

Summary

Introduction

29 patients (36%) had genetic aetiologies not previously associated with brain WMAs or they had recently characterised GWMDs, including SAMD9L- and NHLRC2-related neurological disorders.

Results

Conclusion