In other species: crab-eating macaque , pig

Categories: Lysosomal storage disease , Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 204500 (trait) , 607998 (gene) , 609270 (trait)

Links to relevant human diseases in MONDO:

• MONDO:0008769: neuronal ceroid lipofuscinosis 2

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2006

Cross-species summary: One of several variants of neuronal ceroid lipofuscinosis (NCL) or Batten disease: CLN2; NCL2

Species-specific description: The neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases characterized by intraneuronal accumulation of fluorescent granules, early neuronal death, and progressive neurodegeneration of the central nervous system. NCL2 is an early-onset disease of miniature long-haired dachshunds. Early signs include progressive loss of vision under dim light, decreased menace response, tremors of the head, myoclonus, and cerebellar ataxia. Signs appear in young dogs and progress rapidly, with death by 12 months of age., as no effective treatment has been identified. The mode of inheritance is autosomal recessive. Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT Kick et al. (2023) "A study using the dog model was performed to evaluate the efficacy of ocular gene therapy to provide a continuous, long-term source of human TPP1 (hTPP1) to the retina, inhibit retinal degeneration and preserve retinal function. ... Intravitreal administration of AAV2.CAG.hTPP1 resulted in stable, widespread expression of hTPP1 throughout the inner retina, prevented disease-related declines in retinal function and inhibited disease-related cell loss and storage body accumulation in the retina for at least 6 months. Uveitis occurred in eyes treated with the hTPP1 vector, but this did not prevent therapeutic efficacy."

Mapping: CFA21

Molecular basis: The causative mutation is a single nucleotide deletion (c.325delC) in exon 4 of TPP1, which causes an amino acid codon frameshift and a premature stop codon (Awano et al., 2006). There is an analogous disease in humans (OMIM# 204500).

Clinical features: Progressive loss of vision under dim light begins in affected dogs at 6-7 months of age (Sanders et al., 2011). Unilaterally decreased menace response begins at 8 months of age, followed by intention and resting tremors of the head, and myoclonus. Cerebellar ataxia (dysmetria, incoordination) began at 9-10 months of age. Other neurological signs include altered cognitive function, motor dysfunction, and myoclonus. Tests of cognitive ability were significantly different from normal dogs at 6 months of age (Sanders et al., 2011). Other signs reported include seizures, hyperactivity, howling, aggressive behavior, hypermetria, circling, and diarrhea (Awano et al., 2006). No effective treatment has been identified, and affected dogs die by 12 months of age (Awano et al., 2006). Intrathecal administration of TPP1 caused a robust immune response and did not improve the overall function of treated dogs (Vuillemenot et al., 2011).

Pathology: Affected dogs have less than 1% TPP1 activity in the cerebral cortex (Awano et al., 2006). Autofluorescent lysosomal storage occurs throughout the central nervous system. Some cerebral cortex cells have large storage bodies, but most have little to none. Storage material is present in all layers of the cerebellum, but only moderate in Purkinje cells. In the spinal cord, most autofluorescent storage is in large motor neurons. Curvilinear aggregates in the lysosomes are identified by electron microscopy (Awano et al., 2006, Vuillemenot et al., 2011). Histopathology of the cerebellum includes white matter depletion, decreased numbers of cortical neurons, a narrowed molecular layer, a sparsely populated internal granular layer, and irregularly spaced Purkinje cells. Larger neurons in the cerebrum and spinal cord contain coarse eosinophilic, PAS positive cytoplasmic granules (Awano et al., 2006).

Prevalence: The mutation appears to be uncommon among miniature long-haired dachshunds (Awano et al., 2006).

Control: Parents of affected dogs are obligate carriers. Siblings of affected animals should be tested. Breeding of affected or carrier dogs is not recommended.

Genetic testing: A test is available to detect the causative mutation in miniature long-haired dachshunds.

Breed: Dachshund (Dog) (VBO_0200406).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: