Ceroid Lipofuscinosis, Neuronal, 11

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

CLN6, TPP1, CLN3, ATP13A2, CLCN3, CLCN6, CLN5, CTSD, CLN8, PPT1, MFSD8, CTSF, PSEN1, DNAJC5, SCARB2, NCL

Drugs

Adeno-associated viral vector serotype 9 containing the human CLN1 gene, Brivaracetam, Gemfibrozil

Adeno-associated viral vector serotype 9 containing the human CLN1 gene, Brivaracetam, Gemfibrozil, Recombinant self-complementary adeno-associated viral vector serotype 9 containing the human CLN3 gene, recombinant self-complementary adeno-associated viral vector serotype 9 (AAV9) containing the human CLN3 gene, recombinant self-complementary adeno-associated viral vector serotype 9 containing the human CLN6 gene

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A number sign (#) is used with this entry because neuronal ceroid lipofuscinosis-11 (CLN11) is caused by homozygous mutation in the GRN gene (138945) on chromosome 17q.

Heterozygous mutation in the GRN gene causes frontotemporal lobar degeneration with TDP43-inclusions (607485).

Description

Neuronal ceroid lipofuscinosis-11 is an autosomal recessive neurologic disorder characterized by rapidly progressive visual loss due to retinal dystrophy, seizures, cerebellar ataxia, and cerebellar atrophy. Cognitive decline may also occur (summary by Smith et al., 2012).

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

Clinical Features

Smith et al. (2012) reported 2 Italian sibs with young-adult onset of neuronal ceroid lipofuscinosis. Their healthy parents, who were in their fifties, came from nearby villages in Lombardy, Italy, and were demonstrated to be distantly related. The proband was a 28-year-old man who presented with rapidly progressive visual failure at age 22, followed by major convulsions at age 25 and myoclonic seizures at age 26. He had mild cerebellar ataxia, early cognitive deterioration, and retinal dystrophy. Electroencephalogram (EEG) showed generalized polyspike wave discharges, electroretinogram showed severe attenuation of both rod and cone responses, and MRI showed cerebellar atrophy. Electron microscopic examination of a skin biopsy demonstrated numerous fingerprint profiles in membrane-bound structures in eccrine secretory cells and in endothelium, consistent with CLN. The proband's 26-year-old sister developed recurrent seizures at age 23 years, sometimes preceded by visual distortions, and she later had visual deterioration. Clinical examination showed cerebellar ataxia and retinal dystrophy. EEG results showed polyspike wave discharges with a posterior emphasis, and MRI indicated cerebellar atrophy.

Inheritance

The transmission pattern of adult-onset neuronal ceroid lipofuscinosis in the family reported by Smith et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

By exome sequencing of 2 Italian sibs with young-adult onset of CLN, Smith et al. (2012) identified a homozygous 4-bp deletion in the GRN gene (138945.0015). Heterozygosity for this mutation had previously been identified in patients with late-onset frontotemporal dementia (607485). Plasma progranulin levels in the homozygous patients were undetectable and were about 50% decreased in the heterozygous parents. Family history revealed 3 cases of late-onset dementia in both sides of the family, but DNA was not available from these patients. The healthy parents were in their fifties; the molecular findings suggested that they may be at risk for later-onset dementia. Smith et al. (2012) commented on the remarkable phenotypic differences between heterozygous and homozygous GRN mutations, and suggested that progranulin may have a lysosomal function.

Animal Model

Ahmed et al. (2010) found that Grn-null mice developed abnormal accumulation of abnormal intraneuronal ubiquitin-positive autofluorescent lipofuscin detected by light microscopy. Electron microscopic examination of fixed brain tissue from Grn-null showed abundant rectilinear profiles diagnostic of CLN (Smith et al., 2012).