The natural history of Canavan disease: 23 new cases and comparison with patients from literature

TY - JOUR

T1 - The natural history of Canavan disease: 23 new cases and comparison with patients from literature

AU - Bley, Annette

AU - Denecke, Jonas

AU - Kohlschütter, Alfried

AU - Schön, Gerhard

AU - Hischke, Sandra

AU - Guder, Philipp

AU - Bierhals, Tatjana

AU - Lau, Heather

AU - Hempel, Maja

AU - Eichler, Florian S

PY - 2021/5/19

Y1 - 2021/5/19

N2 - BACKGROUND: Canavan disease (CD, MIM # 271900) is a rare and devastating leukodystrophy of early childhood. To identify clinical features that could serve as endpoints for treatment trials, the clinical course of CD was studied retrospectively and prospectively in 23 CD patients. Results were compared with data of CD patients reported in three prior large series. Kaplan Meier survival analysis including log rank test was performed for pooled data of 82 CD patients (study cohort and literature patients).RESULTS: Onset of symptoms was between 0 and 6 months. Psychomotor development of patients was limited to abilities that are usually gained within the first year of life. Macrocephaly became apparent between 4 and 18 months of age. Seizure frequency was highest towards the end of the first decade. Ethnic background was more diverse than in studies previously reported. A CD severity score with assessment of 11 symptoms and abilities was developed.CONCLUSIONS: Early hallmarks of CD are severe psychomotor disability and macrocephaly that develop within the first 18 months of life. While rare in the first year of life, seizures increase in frequency over time in most patients. CD occurs more frequently outside Ashkenazi Jewish communities than previously reported. Concordance of phenotypes between siblings but not patients with identical ASPA mutations suggest the influence of yet unknown modifiers. A CD severity score may allow for assessment of CD disease severity both retrospectively and prospectively.

AB - BACKGROUND: Canavan disease (CD, MIM # 271900) is a rare and devastating leukodystrophy of early childhood. To identify clinical features that could serve as endpoints for treatment trials, the clinical course of CD was studied retrospectively and prospectively in 23 CD patients. Results were compared with data of CD patients reported in three prior large series. Kaplan Meier survival analysis including log rank test was performed for pooled data of 82 CD patients (study cohort and literature patients).RESULTS: Onset of symptoms was between 0 and 6 months. Psychomotor development of patients was limited to abilities that are usually gained within the first year of life. Macrocephaly became apparent between 4 and 18 months of age. Seizure frequency was highest towards the end of the first decade. Ethnic background was more diverse than in studies previously reported. A CD severity score with assessment of 11 symptoms and abilities was developed.CONCLUSIONS: Early hallmarks of CD are severe psychomotor disability and macrocephaly that develop within the first 18 months of life. While rare in the first year of life, seizures increase in frequency over time in most patients. CD occurs more frequently outside Ashkenazi Jewish communities than previously reported. Concordance of phenotypes between siblings but not patients with identical ASPA mutations suggest the influence of yet unknown modifiers. A CD severity score may allow for assessment of CD disease severity both retrospectively and prospectively.

KW - Amidohydrolases/genetics

KW - Canavan Disease/genetics

KW - Humans

KW - Infant

KW - Mutation

KW - Phenotype

KW - Retrospective Studies

U2 - 10.1186/s13023-020-01659-3

DO - 10.1186/s13023-020-01659-3

M3 - SCORING: Journal article

C2 - 34011350

VL - 16

SP - 227

JO - ORPHANET J RARE DIS

JF - ORPHANET J RARE DIS

SN - 1750-1172

IS - 1

ER -