Diagnostic methods and emerging treatments for adult neuronal ceroid lipofuscinoses (Kufs disease)

ABSTRACT

Introduction: Adult-onset neuronal ceroid lipofuscinoses (ANCL) are a group of rare inherited neurodegenerative diseases of early adulthood, named after the presence of intralysosomal autofluorescent lipopigment with characteristic ultrastructural features in neurons and other cell types. Over the last decade, six ANCL genes have been identified, three of them being related to exclusively adult-onset phenotypes, the remaining three shared with childhood-onset NCL (CNCL).

Areas covered: Even in the molecular era, the contribution of neuropathological assessment is essential since genetic heterogeneity foresees new genes to be detected and validated. No disease-modifying therapy (DMT) is available for neuronal ceroid lipofuscinoses (NCL), but patients may benefit from improved symptomatic and supportive treatments, and recent advances in cellular and molecular biology (utilizing both cellular and animal models of the disease) have provided important contributions to the knowledge of NCL pathophysiology. DMT strategies aim to prevent storage formation and/or deplete accumulated substrate; few of them have already been translated into clinical practice in CNCL only.

Expert opinion: The complexity of pathophysiological mechanisms underlying NCL, such as neuronal excitotoxicity, unfavourable condition of the neuropil and enhanced vulnerability of the affected cells, requires the identification of multiple targets suitable for treatments to prevent neuronal progressive dysfunction and death.

KEYWORDS:

• Adult-onset neuronal ceroid lipofuscinosis
• ANCL diagnosis
• NCL
• neuropathology
• Parry disease
• therapeutic strategies
• treatment

Article highlights

• ANCL are a group of rare, inherited, lysosomal storage diseases characterized by different combinations of progressive neurocognitive impairment, refractory epileptic seizures and movement disorders. The major clinical phenotypes of ANCL are referred to as Kufs disease type A and B.

• The neuropathological hallmark of ANCL is the accumulation of autofluorescent PAS- and Sudan black B-positive lipopigments with characteristic ultrastructural features in the cytoplasm of neurons and other cell types.

• Pathogenic variants in six genes (CLN1, CLN4, CLN5, CLN6, CLN11, CLN13) have been recognized as responsible for ANCL to date.

• Diagnosis of ANCL is based on clinical and pathological criteria. Molecular tools allow genetic confirmation in some cases.

• No disease-modifying treatment for ANCL are available until now. Emerging therapeutic approaches include enzyme replacement therapy, stem cell transplantation, lysosome modulation, gene therapy and the use of anti-inflammatory or RNA/DNA modulating compounds.

• Current therapeutic approach to ANCL includes symptomatic treatment and general supportive care.

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Declaration of interest

A Simonati has received honoraria for consultation by Biomarin Pharmaceuticals Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper is funded by Ministero dell’Istruzione, dell’Università e della Ricerca, FUR contribution to A Simonati.