Final Diagnosis -- Neuronal Intranuclear Inclusion Disease (NIID), Juvenile-sporadic

FINAL DIAGNOSIS:

NEURONAL INTRANUCLEAR INCLUSION DISEASE (NIID), JUVENILE-SPORADIC.

DISCUSSION:

Neuronal intranuclear inclusion disease (NIID) is a rare, slowly progressive and fatal neurodegenerative disorder characterized by the presence of eosinophilic neuronal intranuclear inclusions (NII) of the central, peripheral, and autonomic nervous systems with glial inclusions described in some cases. Neuronal loss and gliosis have been described in brainstem, cerebellar and spinal regions without relationship to NII. There are approximately 30 case reports of this condition reported in the literature. Infantile, juvenile, and adult-onset cases have been described. The majority of cases are sporadic but several examples of familial occurrence have been reported. There is no obvious mode of inheritance although apparent autosomal dominant transmission has been found in some families. Given the variability in clinical and pathological findings it is unlikely that all these descriptions represent one disease.

Clinically, most cases of NIID present as a multisystem neurodegenerative process beginning in the second decade and progressing to death in 10 to 20 years. Neurological signs and symptoms vary widely, but usually include ataxia, extra-pyramidal signs such as tremor and oculogyral crises, lower motor neuron findings such as absent deep tendon reflexes, weakness, muscle wasting, foot deformities and less apparent behavioral or cognitive difficulties. Patients eventually become incapacitated and die of repeated lower respiratory infections. Electrophysiological studies often show evidence of chronic denervation of muscle and reduced nerve conduction velocities. Imaging may show cerebral and/or cerebellar atrophy. There are no known specific laboratory findings besides histological analysis. Reported adult-onset cases are characterized by dementia and may represent a different pathological entity.

Macroscopic examination of the brain may be normal or show a mild reduction in cortical ribbon thickness with sparing of white matter volume. Mild to moderate cerebellar atrophy, more pronounced in the vermis, may also be evident. The substantia nigra is often nonpigmented. On light microscopy, the most striking histological feature is the widespread presence of well demarcated, round, eosinophilic NII, 2 to 6 microns in diameter on average. On ultrastructural examination, NII are non-membrane bound and consist of densely packed, randomly arranged filaments 8 to 15 nanometers in diameter with granular aggregates. Focal, severe neuronal loss is usually present in the substantia nigra, cerebellar Purkinje cell layer, dentate nucleus, red nucleus, and anterior horns. This is associated with mild to moderate gliosis. Investigators have noted that the distribution of neuronal loss, rather than the ubiquitous presence of intranuclear inclusions, correlates with clinical manifestations.

NII are immunoreactive for ubiquitin and Thioflavin S and show variable autofluorescence. They are not immunoreactive for tau, neurofilament, amyloid precursor protein, glial fibrillary acidic protein (GFAP), or alpha- or beta-tubulin. Occasional inclusions have been shown to be weakly positive for polyglutamine . Because of this, and clinical and morphologic similarities between NIID and certain CAG repeat polyglutamine diseases, it has been suggested NIID is caused by a CAG expansion in an unknown gene. However, NIID inclusions do not show the ubiquitous, strong immunopositivity for polyglutamine observed in known CAG repeat disorders. NIID inclusions do consistently stain for ataxin-3. More recently Pountney et al. 2003 have found NII in familial, adult-onset cases to be consistently immunoreactive for SUMO-1. This case is the first report of SUMO-1 positivity in juvenile, sporadic NIID. Finding abundant SUMO-1 in NII in both familial and sporadic NIID raises the possibility that the primary defect is one of aberrant SUMOylation leading to nuclear proteins resistant to degradation

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Contributed by Kate McFadden, MD and Clayton Wiley, MD, PhD