Anti-Zic4 antibodies

Synonyms: none

Clinical associations:
The main neurologic disorder associated with Zic4 antibodies is paraneoplastic cerebellar degeneration in the context of SCLC. If Zic4 antibodies develop concurrently with other SCLC-related onconeuronal antibodies (see immunologic associations) the neurologic disorder is paraneoplastic encephalomyelitis.

The frequency of Zic4 antibodies in SCLC patients without paraneoplastic disorders is 16%.

Tumor associations:

Detection of anti-Zic4 antibodies has a strong association with SCLC. In a study of 49 patients with anti-Zic4 associated paraneoplastic syndromes, 44 had SCLC, 1 adenocarcinoma of the lung in a patient with anti-Hu antibodies (likely representing a mixed tumor), 1 neuroblastoma, 1 Merkel cell tumor, 2 patients with radiographic evidence of a lung tumor or mediastinal adenopathies.

Screening test:
Using immunohistochemistry of frozen brain sections (human, rabbit, rat, mouse) the anti-Zic4 antibodies show predominant reactivity with the nuclei of neurons of the granular layer of the cerebellum (Figure 1 panels A and B), and less intense reactivity with other neurons, including in descending order Purkinje cells, and neurons of deep cerebellar nuclei, brainstem and brain. The immunohistochemical detection of Zic4 antibodies may be complicated by the frequent association with other onconeuronal antibodies (Hu, CV2 or CRMP5, Ri).

Figure 1

Confirmatory test:
The definite demonstration of Zic4 antibodies is made using recombinant Zic4 protein (Figure 2 panel A).Of note, immunoblot of human neuronal proteins is not a good confirmatory tests because most patients sera show reactivity with multiple neuronal proteins, likely corresponding to reactivity with multiple Zic proteins (Figure 2 panel B)

Immunologic Associations:
Because the Zic proteins are highly homologous to each other, the sera of patients with anti-Zic4 antibodies almost always react with Zic1, and less frequently with Zic2.

Patients with paraneoplastic disorders and anti-Zic4 antibodies often develop concurrent antibodies to other onconeuronal antigens associated with SCLC, including anti-Hu, anti-CV2/CRMP5 and less frequently anti-Ri. In a study of 49 patients with paraneoplastic encephalitis or cerebellar degeneration associated with anti-Zic4 antibodies 40 patients had concurrent anti-Hu (=29), anti-CV2/CRMP5 (=2) or all three antibodies (=9). Patients with isolated Zic4 antibodies were more likely to develop pure cerebellar dysfunction than patients with several antibodies, who usually developed encephalomyelitis.

Zic antigens:
The Zic proteins have important roles in the development of the nervous system, and comprise a family of 5 zinc-finger proteins with extensive sequence homology (range 52%-62% identity). In animal studies, mutations of different Zic genes result in an extensive array of neurologic abnormalities, including cerebellar malformation, holoprosencephaly, spina bifida, and sensorimotor gait abnormalities. Mutant Zic1 mice are regarded as models of the Joubert’s syndrome, a human autosomal recessive disorder characterized by hindbrain and cerebellar malformation.

References:

-Bataller L, Wade DF, Graus F, Stacey HD, Rosenfeld MR, Dalmau J. Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer. Neurology 2004; 62: 778-82.
- Aruga J, Minowa O, Yaginuma H, et al. Mouse Zic1 is involved in cerebellar development. J Neurosci 1998;18:284-293.
- Aruga J, Yozu A, Hayashizaki Y, Okazaki Y, Chapman VM, Mikoshiba K. Identification and characterization of Zic4, a new member of the mouse Zic gene family. Gene 1996;172:291-294.

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