Adult neuronal ceroid lipofuscinosis caused by deficiency in palmitoyl protein thioesterase 1

Abstract

The neuronal ceroid lipofuscinoses (NCLs) are the most common group of neurodegenerative diseases in children. Mutations in the CLN1 gene, which encodes the enzyme palmitoyl protein thioesterase 1 (PPT1), usually cause infantile-onset NCL (INCL) (Santavouri-Haltia disease, MIM 256730). 1 INCL has an age at onset of 8 to 18 months with rapid visual and psychomotor deterioration, ataxia, hypotonia, and seizures. 2 Retinal pigment aggregation does not usually occur. In all cases, a granular pattern of storage material in cells is observed by electron microscopy. However, in one family, onset was as late as adulthood. 3 We describe a second family with adult-onset NCL caused by a novel mutation in the CLN1/PPT1 gene.Case report. A 24-year-old woman with no significant family history was diagnosed with hypomanic episodes because of a 12-to 24-month history of "low self-esteem and mood, irritability, lack of interest, and bizarre behavior including a tendency to wander the streets" and thus treated with olanzapine and valproate. A few months later, she reported the inability to see properly. Ophthalmologic evaluation showed normal visual acuity, pupillary reaction, and normal optic discs and macular and retinal appearance in the presence of "extremely tubular" tunnel vision in both eyes when the automated visual field tests were performed but with inconsistent responses on Goldman's fields assessment. She had a history of declining academic abilities after age 18 years. She was emotionally labile, but no other neurologic abnormalities were detected.Brain MRI showed marked generalized cerebral and cerebellar atrophy with no focal abnormalities (figure) (see also figure E-1 on the Neurology Web site at www.neurology.org). Hematologic, biochemical, and vasculitic screens and standard lysosomal enzymes assays were normal. Visual evoked responses were delayed bilaterally. Flash electroretinograms were nondetectable (extinguished). Attenuated pattern electroretinograms (P50 and N95) were found. The EEG showed excess of slow activity with superimposed runs of medium voltage sharp and wave activity throughout the recording. Neuropsychological assessment revealed substantial dysfunction in intellectual ability, memory, language skills, visual processing, and executive functioning.Nearly 18 months after her presentation and with further but slow cognitive decline, she started to experience vivid and sometimes terrifying visual hallucinations. These included seeing huge snakes, elephants, and sometimes people. The introduction of risperidone did not resolve these symptoms. At 19 months' follow-up, a repeat MRI showed minor progression in the degree of brain atrophy. A repeat retinal examination then showed few but typical areas of retinitis pigmentosa (figure). There has been no evidence of seizures, myoclonic jerks, or other involuntary movements. Rectal and skin biopsy samples and blood were examined comprehensively by light microscopic techniques, and subsequently ultrastructural analysis was done by transmission electron mic...

Mass Spectrometry-based Protein Profiling to Determine the Cause of Lysosomal Storage Diseases of Unknown Etiology

“…22). The defective gene in the majority of ANCL cases remains to be identified, although several have been found to harbor mutations in PPT1 (23,24). In this study, we investigated four ANCL cases.…”

NCL diseases — clinical perspectives

“…Adult onset NCL due to CLN1 mutations is characterized by onset after 18 years of age [28]. Cognitive decline and depression are the initial manifestations followed by development of ataxia, parkinsonism, and vision loss.…”

Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations

“…In the first pipeline (P1), we employed Burrows-Wheeler alignment to map fastq files to the human reference genome (UCSC hg19) [11]. We called variants using Genome Analysis Tool Kit (GATK, version 1.4) [12] followed by functional annotation with Annovar [13] and SnpEff [14]. In the second pipeline (P2), we conducted alignment to UCSC hg19 by Short Oligonucleotide Analysis Package (SOAP, version2.21) [15], then used SOAPsnp (version 1.05) [16] to identify single nucleotide variants (SNVs) as well as GATK [12] to detect small insertion-deletions (indels).…”