Ceroid Lipofuscinosis, Neuronal, 10

A number sign (#) is used with this entry because neuronal ceroid lipofuscinosis-10 (CLN10) is caused by homozygous or compound heterozygous mutation in the cathepsin D gene (CTSD; 116840) on chromosome 11p15.

Description

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 (Mole et al., 2005).

For a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis, see CLN1 (256730).

Clinical Features

Steinfeld et al. (2006) identified a patient with cathepsin D deficiency in a group of 25 infants and children with a nonidentified genetic cause of a CLN-like disorder. The affected child had normal early psychomotor development and first showed neurodegenerative symptoms, namely ataxia and visual disturbances, at early school age. The ocular fundus showed retinitis pigmentosa, and cranial MRI scans showed cerebral and cerebellar atrophy. In the course of disease, she developed progressive cognitive decline, loss of speech, retinal atrophy, and loss of motor functions. At the age of 17 years, she was wheelchair-bound and severely mentally retarded. Ultrastructural examination of skin biopsy material revealed granular osmiophilic-like deposits and myelin-like lamellar structures in nonmyelinated Schwann cells. In comparison with the granular deposits characteristic of CLN1 (256730), these granular inclusions appeared more heterogeneous and were less abundant within cells. The myelin-like lamellar structures are less specific for CLN, being often found in other storage diseases such as the mucopolysaccharidoses. Inclusions were not found in patient endothelial cells, fibroblasts, sweat glands, or peripheral lymphocytes.

Hersheson et al. (2014) reported 4 sibs, born of consanguineous Somali parents, with juvenile-onset CLN10. The patients presented at around 15 years of age with cerebellar ataxia and retinitis pigmentosa, which progressed to significant motor impairment and cognitive decline. Brain imaging showed cerebellar atrophy. One patient had a sensory axonal neuropathy confirmed by neurophysiologic studies. Two of the sibs died in their thirties. An unrelated Somali boy with CLN10 had onset of similar features at age 8 years; he also had a sensory axonal neuropathy. Muscle biopsy of 1 patient from the first family and of the unrelated boy showed granulovacuolar material in angular atrophic fibers as well as granular osmiophilic deposits consistent with CLN. Neither of these patients was reported to have a clinical myopathy, but a sib of the patient in the first family had cardiomyopathy.

Congenital Neuronal Ceroid Lipofuscinosis

Barohn et al. (1992) noted that the clinical expression of CLN rarely occurs at birth, the so-called 'congenital' form.

Norman and Wood (1941) and Brown et al. (1954) reported 2 sibs with congenital CLN. The patient reported by Norman and Wood (1941) had microcephaly and respiratory difficulties and died at age 18 days. Postmortem examination showed multiple intracellular lipoid inclusions throughout the brain and less so in the reticuloendothelial system. The patient reported by Brown et al. (1954) showed microcephaly, rigidity, and apnea from birth and died at 7 weeks of age. Postmortem examination showed a small, firm brain with neuronal lipoid inclusions.

Sandbank (1968) reported the findings in 2 infants, born to a consanguineous couple, who died at ages 24 and 48 hours. Six other children of this couple had reportedly died within 48 hours of delivery. The 2 infants, a male and a female, showed hyperkinetic movements, tremor of the hands and legs, absence of pupillary reactions, and absence of Moro and grasping reflexes. The brains of both infants were small and firm with severe loss of neurons and extensive gliosis. There were multiple large cells in the brain with an eosinophilic, intracellular material; similar material was observed in cells of the reticuloendothelial system. Sandbank (1968) noted the similarities to the patient reported by Norman and Wood (1941).

Humphreys et al. (1985) reported an affected infant who died at age 29 hours from respiratory failure. The brain was small and firm with marked neuronal loss and gliosis. Granular lipopigment material was identified in astrocytes, macrophages, and residual neurons. Similar material was observed in cells from the liver, spleen, thymus, and lung. Humphreys et al. (1985) noted similarities to infantile and juvenile Batten disease (see, e.g., CLN3, 204200).

Barohn et al. (1992) reported an affected infant who was microcephalic and had generalized seizures at birth. He developed cyanosis and bradycardia and died 36 hours after birth. Neuropathologic examination showed severe cerebral atrophy and diffuse ballooning of neurons with autofluorescent lipid accumulation. The white matter was gliotic, and no myelin was observed.

Siintola et al. (2006) reported a Pakistani child, born of first-cousin parents, with congenital CLN. He had 2 affected brothers. All 3 affected fetuses demonstrated deceleration of head growth in the last trimester and were born microcephalic with overriding sutures and obliterated fontanels. Other dysmorphic features included low-set ears and broad nasal bridge. The infants showed seizures, spasticity, and central apnea from birth and died at ages 10, 1, and 4 days, respectively. Siintola et al. (2006) also reported a fourth similarly affected infant from an unrelated family who died within 29 hours after birth. Neuropathologic examination of 3 of the patients showed severe neuronal loss in the cerebral and cerebellar cortices, glial activation, and white matter almost devoid of axons and myelin. Immunostaining for the cathepsin D protein was almost absent in brain tissue. In 1 affected infant from the first family, Siintola et al. (2006) identified a homozygous null mutation in the CTSD gene (116840.0003).

Molecular Genetics

In a patient with cathepsin D deficiency manifesting as a CLN-like disorder, Steinfeld et al. (2006) identified compound heterozygosity for missense mutations in the CTSD gene. The maternal allele carried a phe229-to-ile substitution (F229I; 116840.0001), and the paternal allele a trp383-to-cys substitution (W383C; 116840.0002). The mutations caused markedly reduced proteolytic activity, and a diminished amount of cathepsin D was found in patient fibroblasts.

In a Pakistani infant with severe congenital NCL, Siintola et al. (2006) identified a homozygous null mutation in the CTSD gene (116840.0003). The extreme clinical phenotype, including postnatal apnea, seizures, and early death, were consistent with complete inactivation of the cathepsin D protein.

In 4 sibs, born of consanguineous Somali parents, with juvenile-onset CLN10, Hersheson et al. (2014) identified a homozygous missense mutation in the CTSD gene (G149V; 116840.0004). The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. An unrelated Somali boy with a similar disorder carried a different homozygous missense mutation (A399H; 116840.0005). In both families, patient fibroblasts showed significantly decreased cathepsin D activity (11% of control values).