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

Abstract

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.

Leukodystrophies

“…Children affected by Canavan disease have delayed development in the first year of life followed by a neurologic regression. 77 Most children have profound hypotonia, although this can occur in combination with appendicular spasticity. Additional unique features include the presence of abnormal eye movements (especially nystagmus) and macrocephaly.…”

Gene Therapy for Rare Neurological Disorders

“…[5][6][7] Particularly, conditions with infantile or early childhood onset, e.g., spinal muscular atrophy (SMA), Tay-Sachs disease (TSD), Sandhoff 's disease (SD), or CD, show overlapping symptoms, such as muscular hypotonia or developmental delay, and can lead to a challenging search until a diagnosis is found. 5,8,9 Thus, natural history studies are essential to developing diagnostic criteria, particularly in rare conditions. This cannot be emphasized enough because clinical trials depend on a clear understanding of the disease progression where natural history data might function as a nontreatment control group.…”

“…While the age of onset can provide an important clue, e.g., ALS or Huntington's disease (HD) vs. Canavan's disease (CD), presenting symptoms can be relatively indeterminate, with a wide range of signs and symptoms. [5][6][7] Particularly, conditions with infantile or early childhood onset, e.g., spinal muscular atrophy (SMA), Tay-Sachs disease (TSD), Sandhoff 's disease (SD), or CD, show overlapping symptoms, such as muscular hypotonia or developmental delay, and can lead to a challenging search until a diagnosis is found. 5,8,9 Thus, natural history studies are essential to developing diagnostic criteria, particularly in rare conditions.…”

Ablating the Transporter Sodium‐Dependent Dicarboxylate Transporter 3 Prevents Leukodystrophy in Canavan Disease Mice

“…Occasionally, the clinical onset is delayed until later in childhood. 1 Magnetic resonance imaging shows alterations in brain signals indicative of cytotoxic edema and diffusion restriction 2 ; proton magnetic resonance spectroscopy demonstrates a marked elevation in brain NAA concentration ([NAA B ]) 3 ; and neuropathological studies reveal "spongiform" vacuoles arising within myelin and astroglia. 4 No therapies presently available prevent or reverse Canavan disease.…”

“…The disease usually presents in infancy, with ataxia, hypotonia, and failure to acquire developmental milestones, often in association with macrocephaly, blindness, nystagmus, and seizures. Occasionally, the clinical onset is delayed until later in childhood 1 . Magnetic resonance imaging shows alterations in brain signals indicative of cytotoxic edema and diffusion restriction 2 ; proton magnetic resonance spectroscopy demonstrates a marked elevation in brain NAA concentration ([NAA B ]) 3 ; and neuropathological studies reveal “spongiform” vacuoles arising within myelin and astroglia 4 .…”