An exploration of the diagnostic journey of children with Neuronal Ceroid Lipofuscinosis (NCL)

Alanna Gayko –

alanna.gayko@uon.edu.au

University of Newcastle, Australia

This research would not have proceeded without the support of the families affected by Batten disease in Australia and New Zealand, and the Australian chapter of Batten Disease Support and Research Association. The assistance of Lysosomal Diseases New Zealand and Genetics Alliance Australia for advertising the study is also acknowledged. A median two-year diagnostic delay was identified in 26 children diagnosed with NCL and half of this delay occurred before investigations were initiated. A younger sibling’s diagnosis of NCL was confirmed in a shorter timeframe. These families have provided their personal insight of their children’s diagnosis of this rare life-limiting disease. They have revealed a small window into their lives regarding diagnosis and left us with a greater understanding and respect for their personal circumstances during the diagnostic journey of NCL.

Neuronal Ceroid Lipofuscinosis (NCL) or Batten disease, is a group of predominantly recessively-inherited neurodegenerative diseases that mostly affect children. It is the most common genetic cause of dementia in children, yet a rare cause of dementia in adults. Although NCL remains life-limiting, clinical trials are in development for specific disease types. NCL has a low Australian and New Zealand incidence, but a devastating impact on affected children and their families. Currently, neither country participates in an international NCL patient registry that leaves these families isolated from potential research and therapeutic agents. As recently as 2017, a historical milestone was passed with the approval of the first disease-modifying enzyme replacement therapy – Brineura® for ceroid lipofuscinosis, neuronal 2 or CLN2.

Research has consistently identified a protracted diagnostic period of NCL. Retrospectively identifying the earliest onset of the disease could feasibly impact future diagnostic delays. Subtle early signs and symptoms merge with other rare or common diseases and can be missed. This study describes the early phase of NCL in this cohort of A&NZ children. It uses parent-report to retrospectively identify the earliest sign or symptom that led to the diagnosis or that should have led to the diagnosis with hindsight. To achieve this aim, the parents’ experiences, and any facilitators of a timely diagnosis of NCL were also explored.

Databases including PubMed and manual searches of reference lists provided a comprehensive historical and contemporary literature review, focused on the onset of NCL. Specific research of the initial presentation of NCL during childhood was limited; however, themes of early signs and symptoms were identified. Corresponding with the literature, the mnemonic ‘NEURONS’ was devised by the student researcher to incorporate the early signs and symptoms of childhood-onset NCL diseases. These include Neurological stalling and/or Epilepsy. Ultrastructural features are distinctive but not unique to each disease. Regression of milestones and abilities become evident. Ophthalmic signs with visual loss behaviour and vacuolated lymphocytes are associated with CLN3. New-onset ataxia and early Speech delays are aligned with specific diseases such as CLN2.

After gaining University of Newcastle Human Research Ethics Committee approval [No. H-2018-0059], a purposive sample was obtained. Participation was offered to all A&NZ parents/legal guardians of children, alive or deceased, diagnosed with any NCL disease in the past five decades. Recruitment was initiated through the Australian chapter of the Batten Disease Research Association (BDSRA) family support group, two alternate organisations, and snowball recruitment. There were two phases of the study: The consultative phase comprised of key informant consultation in the design of the quantitative survey regarding children with an NCL diagnosis. The survey phase incorporated a structured cross-sectional survey devised by the research team. Potential participants were invited to complete the REDCap® on-line survey, using links on the Australian BDSRA Facebook® page or website. The anonymous survey asked parents to retrospectively explore the diagnosis of their child’s disease in a chronological format, with an option to provide additional text.

Facilitators and hindrances of childhood-onset NCL diagnosis were identified. Pre-genetic clinical, enzymatic, and/or genetic diagnoses were categorised. There were 29 A&NZ parent participants of children with either CLN1, CLN2, CLN3, or CLN5 disease. Predominantly, the parents identified the earliest changes and prompted investigation of their child. Initial misdiagnoses included up to four alternate diagnoses. The primary outcome of the study identified a two-year median diagnostic delay, including a one-year delay before investigations were initiated. A cohort of 26 children of index cases with a confirmed age of onset, did not include two facilitated pre-symptomatic diagnoses.

The diagnostic ‘odyssey’ discussed in the rare disease literature, was similarly identified in this A&NZ study. The longest delay determined in this study was a recent protracted diagnosis of nine years and nine months for a child with CLN3. Early signs and symptoms were aligned with the NEURONS model based on the literature. Speech pathologists or ophthalmologists reviewed these children with either speech delays and/or loss or a new onset visual loss, associated with the early sign of clumsiness. Education programmes may increase specific health professionals’ awareness of NCL, reduce future diagnostic delays for NCL, and improve family access to emerging clinical trials and available treatments.

An exploration of the diagnostic journey of children with Neuronal Ceroid Lipofuscinosis (NCL)