Ceroid Lipofuscinosis, Neuronal, 4b, Autosomal Dominant

A number sign (#) is used with this entry because neuronal lipofuscinosis-4B (CLN4B) is caused by heterozygous mutation in the DNAJC5 gene (611203) on chromosome 20q13.

Description

Neuronal ceroid lipofuscinosis-4B is an autosomal dominant neurodegenerative disorder characterized by onset of symptoms in adulthood. It belongs to a group of progressive neurodegenerative diseases characterized by accumulation of intracellular autofluorescent lipopigment storage material in the brain and other tissues. Several different forms have been described according to age of onset (see, e.g., CLN3, 204200). Individuals with the adult form, sometimes referred to as Kufs disease, develop psychiatric manifestations, seizures, cerebellar ataxia, and cognitive decline. Retinal degeneration is usually not present (summary by Benitez et al., 2011 and Velinov et al., 2012).

For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730).

Clinical Features

Boehme et al. (1971) reported a family (named Parry) in which 11 individuals over 4 generations were affected with adult-onset neuronal ceroid lipofuscinosis (NCL) in an autosomal dominant pattern of inheritance. The strikingly consistent clinical picture was onset of a cerebellar syndrome at about age 31 years, followed by seizures, myoclonic jerks, and progressive dementia. Pathologic features included neuronal loss and accumulation of lipopigment in remaining neurons. No curvilinear or fingerprint patterns were apparent on ultrastructural examination. Armstrong et al. (1974) studied 3 sibs from Boehme's family and found that all 3 had low peroxidase although only 2 were clinically affected. Brodner and Noh (1976) and Brodner et al. (1976) studied a 24-year-old man from the family reported by Boehme et al. (1971). Cortical biopsy at the time of craniotomy for removal of astrocytoma showed changes indicative of Kufs disease. Velinov et al. (2012) reported follow-up of the Parry family reported by Boehme et al. (1971). The 49-year-old female proband developed psychiatric problems, including irritability and obsessive-compulsive manifestations, in her mid-twenties. EEG showed recurrent burst of 4- to 6-Hz slow waves, and she later developed overt seizures. This was followed by progressive memory loss and gait ataxia. In her forties, she reported progressive visual disturbances, described as 'yellow blinding lights.' Electron microscopic analysis of patient lymphocytes showed no lysosomal inclusions at age 26 years, but changes consistent with granular osmiophilic deposits and curvilinear profiles were observed at age 34.

Ferrer et al. (1980) reported a family with autosomal dominant Kufs disease with 6 affected individuals in 2 generations. Disease onset ranged from age 33 to 37 years and was characterized by progressive dementia and involuntary movements of the face and neck. One affected individual had seizures. Brain biopsy showed mild neuronal loss and the accumulation of a granular, membrane-bound product resembling lipofuscin with occasional dense compact rectilinear profiles, but no fingerprint or curvilinear profiles.

Goebel and Braak (1989) provided a detailed review of adult-onset NCL. Psychiatric and behavioral changes, mental deterioration, seizures, extrapyramidal symptoms, and ataxia dominate the clinical picture, while ocular symptoms are conspicuously absent.

Josephson et al. (2001) reported a family of English ancestry in which 10 members over 5 generations had Kufs disease. Age of onset ranged from 32 to 40 years, with the initial manifestation being new-onset seizures. Dementia developed in all affected members within 3 years of seizure onset and was characterized by impaired episodic memory, visual/spatial abilities, and executive function. Motor symptoms included myoclonus and extrapyramidal symptoms. Detailed postmortem examination of 1 patient showed cortical atrophy and autofluorescent granular accumulations in neurons of the cortex, basal ganglia, thalamus, brainstem, and cerebellum. Ultrastructural examination of the granular deposits did not show fingerprint or curvilinear profiles.

Nijssen et al. (2002) reported a Dutch family with autosomal dominant Kufs disease. There were 6 affected individuals in 3 generations, with an age of onset ranging from 24 to 46 years. Clinical features were similar to previously reported cases, including seizures, myoclonus, and dementia. Parkinsonian features such as rigidity, short-stepped gait, masked face, and stooped posture were also present in later stages of the disease. Some individuals also had hearing impairment. Neuropathologic examination of some affected individuals showed ballooned cells with autofluorescent and PAS-positive intraneuronal storage material and granular osmiophilic deposits.

Burneo et al. (2003) reported a family from Alabama with the disorder in which at least 4 generations were affected. In addition to seizures, dementia, and myoclonus, several affected individuals also had parkinsonism. Noskova et al. (2011) had excluded a mutation in the DNAJC5 gene in the family reported by Burneo et al. (2003), but Cadieux-Dion et al. (2013) did find a DNAJC5 mutation (611203.0001) in this family.

Noskova et al. (2011) reported a 3-generation Czech family with autosomal dominant adult-onset CLN. The proband presented at age 30 with myoclonic epilepsy, generalized tonic-clonic seizures, and progressive cognitive deterioration with depression; these symptoms were followed by progressive motor neurologic symptoms leading to death at age 37 years. Neuropathologic examination of postmortem brain tissue showed characteristic neurolysosomal storage of autofluorescent material with ultrastructural appearance corresponding to granular osmiophilic deposits (GROD). Other family members showed a similar clinical course.

Inheritance

The transmission pattern of adult-onset NCL in the family reported by Boehme et al. (1971) was consistent with autosomal dominant inheritance.

Mapping

By linkage analysis of the large family with adult-onset NCL reported by Boehme et al. (1971), Cadieux-Dion et al. (2013) found linkage to a 3.8-Mb region on chromosome 20q13.33 (maximum multipoint lod score of 5.3 at SNP rs11204451).

Molecular Genetics

In a Czech family with autosomal dominant adult-onset ceroid neuronal lipofuscinosis-4B, Noskova et al. (2011) identified a heterozygous deletion mutation in the DNAJC5 gene (346_348del; 611203.0001). The mutation was found by a combination of linkage analysis, copy-number analysis, gene-expression analysis, and exome sequencing of candidate genes. Screening of this gene in 20 additional families identified pathogenic mutations in 4 (346_348del or L115R, 611203.0002). Two of the families had been reported by Josephson et al. (2001) and Nijssen et al. (2002).

In patients with CLN4B, Benitez et al. (2011) and Velinov et al. (2012) found the same 2 heterozygous mutations in the DNCJC5 gene as those reported by Noskova et al. (2011), thus confirming the findings. Benitez et al. (2011) studied the family originally reported by Josephson et al. (2001), and Velinov et al. (2012) studied the Parry family originally reported by Boehme et al. (1971).

By linkage analysis combined with exome sequencing in the large family (Parry) reported by Boehme et al. (1971), Cadieux-Dion et al. (2013) identified heterozygosity for the same deletion in the DNAJC5 gene that had previously been identified (611203.0001). The mutation was confirmed by Sanger sequencing, was not found in 380 control chromosomes, and segregated with the disorder in the family. The American patient reported by Noskova et al. (2011) who carried this mutation was found to be from the Parry family. Cadieux-Dion et al. (2013) also identified the deletion mutation in affected members of a family from Alabama reported by Burneo et al. (2003), even though the mutation in this family had not been found by Noskova et al. (2011). Haplotype analysis did not show a founder effect between the 2 families, suggesting that it is a recurrent mutation. Cadieux-Dion et al. (2013) also identified a heterozygous L115R mutation in 1 of 6 additional patients with the disorder; this patient had no family history. Overall, DNAJC5 mutations accounted for 38% of cases with unexplained adult-onset NCL in their cohort, with the mutations occurring at mutational hotspots.