Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive
A number sign (#) is used with this entry because autosomal recessive neuronal ceroid lipofuscinosis-4A (CLN4A) is caused by homozygous or compound heterozygous mutation in the CLN6 gene (606725) on chromosome 15q23.
Mutation in the CLN6 gene can also cause earlier onset of neuronal ceroid lipofuscinosis (CLN6; 601780) with ocular involvement.Description
Adult-onset neuronal ceroid lipofuscinosis, also known as Kufs disease, is a neurodegenerative disorder without retinal involvement. There are 2 overlapping phenotypes: type A, characterized by progressive myoclonic epilepsy, and type B, characterized by dementia and a variety of motor-system signs (summary by Arsov et al., 2011).
In general, the neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and progressive visual failure. The ultrastructural pattern of lipopigment in CLN4 comprises a mixed pattern of 'granular,' 'curvilinear,' and 'fingerprint' profiles (Mole et al., 2005).
For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730).Nomenclature
The CLNs were originally classified broadly according to age at onset. CLN4 is classically referred to as adult-onset CLN, but at least one other form of CLN (CLN1) can have onset in adulthood (Arsov et al., 2011).Clinical Features
Kufs (1925) reported a case of adult-onset neuronal ceroid lipofuscinosis with onset at age 26 and death at age 38. Fine et al. (1960) found reports of 18 complete histologic descriptions. Chou and Thompson (1970) reported the morphologic changes in a man who was well until age 17 and died at age 32. A sister was said to have died of a similar clinical picture characterized by seizures, intellectual deterioration, lack of motor control, and development of athetoid movements. The parents were well and were related as first cousins, indicating autosomal recessive inheritance.
Dom et al. (1979) described 2 brothers with Kufs disease. In both, the first manifestation took the form of generalized epileptic seizures, at ages 30 and 32, followed by a cerebellar syndrome with myoclonic jerks and extrapyramidal symptoms. Postmortem examination of 1 brother showed extensive storage of ceroid lipofuscin as curvilinear bodies in the central nervous system and in hepatocytes, heart muscle, and retina. The surviving younger brother showed lipofuscin accumulation on peroneal muscle biopsy. The eye grounds were normal.
Tobo et al. (1984) reported adult-onset CLN in a 49-year-old man and his 51-year-old sister, characterized by episodic stuporous and psychotic states, mental retardation, generalized convulsions, and ichthyosis vulgaris. Postmortem examination of the woman showed excessive accumulation of lipofuscin throughout the central nervous system, particularly in neurons of the thalamus, substantia nigra, inferior olivary nuclei, brainstem motor nuclei, and cerebral cortex.
Of 118 cases in the literature that had been reported as Kufs disease, Berkovic et al. (1988) concluded that only 50 cases fulfilled strict clinical and pathologic criteria for the diagnosis. The 68 cases that were excluded had inadequate data, evidence for a storage disease other than Kufs disease, or atypical clinical features. Berkovic et al. (1988) noted that diagnostic confusion in the earlier literature may have resulted from lipofuscin accumulation with normal aging or from the fact that electron microscopy was not yet available for definitive diagnosis. Berkovic et al. (1988) delineated 2 clinical phenotypes of Kufs disease: type A begins with a progressive myoclonic epilepsy, with later development of dementia and ataxia, and type B is characterized by dementia with cerebellar and/or extrapyramidal motor symptoms. Both types have onset around age 30 years, and both have absence of retinal degeneration or blindness.
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.
Nardocci et al. (1995) reported findings on 4 patients with adult-onset NCL evaluated at the National Neurological Institute of Milan from 1984 to 1993. Two patients were sibs and 2 were isolated cases. The sibs had onset at ages 38 and 40 years, and the 2 isolated cases had onset at ages 50 and 12 years. The older patients presented with mental deterioration and later developed dystonia, bradykinesia, and ataxia. The younger patient, who was considered to have an adolescent onset of Kufs disease, presented with seizures and myoclonus, and later developed ataxia and mental deterioration. In all patients, visual acuity and funduscopic findings were normal, and MRI showed cerebral and cerebellar atrophy within 6 years of disease onset. All patients showed fingerprint profiles in skin cells.
Sadzot et al. (2000) reported 2 brothers with Kufs disease who presented with progressive myoclonic epilepsy. The first manifestations occurred before age 20 years in both patients, but did not progress significantly until after age 20. Both patients developed dementia and were in a vegetative state by age 30. Postmortem examination of 1 patient showed characteristic autofluorescent storage material in neurons with fingerprint profiles and strong immunoreactivity against subunit c of mitochondrial ATP synthase (603192).
Arsov et al. (2011) reported 6 unrelated families with type A Kufs disease. Age at onset ranged from 16 to 51 years. Most had initial tonic-clonic seizures or action myoclonus, followed by cognitive decline or dementia. Some had ataxia.
Berkovic et al. (2019) studied 20 patients with type A Kufs disease from 13 unrelated families. Twelve patients had previously been reported, and follow-up information was provided for 9 of them. Mean age of onset was 28 years (range, 12-51 years). Patients typically presented with progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures. Patients became wheelchair-bound at a mean of 12 years after onset. Median survival time was 26 years (range, 8-31 years) from disease onset. Ataxia was the most prominent motor feature and dysarthria was also prominent. Dementia appeared to be invariable, although onset varied. In about a quarter of the patients, cognitive, behavioral or motor changes were present a few years before myoclonic seizures. Epileptiform discharges that were generalized, multifocal or posteriorly predominant were observed on EEG, with photosensitivity, often at low frequency, seen in 17 of 18 cases. None of the patients had retinal involvement. MRI showed progressive cerebral and cerebellar atrophy. Ultrastructural examination revealed fingerprint profiles as the characteristic inclusions, but they were not reliably seen in tissues other than the brain. Curvilinear profiles, which are seen in the late infantile form, were not a feature.Molecular Genetics
By genomewide mapping followed by candidate gene sequencing in 3 families with autosomal recessive Kufs disease, Arsov et al. (2011) identified homozygous or compound heterozygous mutations in the CLN6 gene (see, e.g., 606725.0011-606725.0014). Mutations were also found in affected members from 4 additional families with Kufs disease, yielding a total of 9 different pathogenic mutations in the CLN6 gene. All patients from the 7 families had progressive myoclonic epilepsy followed by dementia, consistent with a type A phenotype. There were no apparent genotype/phenotype correlations. Mutation in the CLN6 gene was not found in 1 family with a type B phenotype. Arsov et al. (2011) noted the striking phenotypic differences between patients with earlier onset CLN6 and patients with Kufs disease. Patients with CLN6 have retinal involvement, whereas none of the Kufs syndrome patients had retinal involvement. The authors suggested that Kufs syndrome patients may have some residual mutant protein function or that there are other disease modifiers.
In 13 unrelated families with neuronal ceroid lipofuscinosis (type A Kufs), Berkovic et al. (2019) identified homozygous CLN6 variants in 4 families and compound heterozygous variants in 9. Most pathogenic variants were predicted to result in amino acid substitutions; however, there were 4 heterozygous pathogenic variants predicting protein truncations, including 2 small deletions and/or insertions (indels), 1 large deletion, and 1 canonical splice site change. Compared to the variant late infantile form (see 601780), fewer of the variants predicted protein truncation. Certain heterozygous missense variants in the same amino acid position were found in both the variant late infantile form and adult-onset Kufs disease; whether onset was in late infancy or adulthood depended on the mutation severity of the second allele. Of the 13 families, 9 were of Italian ancestry. The authors noted that this was likely a product of these rare pathogenic variants being founder mutations in mainland Italy, Sicily, and Malta. The authors also noted that molecular diagnosis can now largely replace the previous 'gold standard' for diagnosis, ultrastructural examination of brain tissue.