ORPHA: 314404; DO: 0050968;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.2 | Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant | 604121 | Autosomal dominant | 3 | DNMT1 | 126375 |
A number sign (#) is used with this entry because of evidence that autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCADN) is caused by heterozygous mutation in the DNMT1 gene (126375) on chromosome 19p13.
ADCADN is an autosomal dominant neurologic disorder characterized by adult onset of progressive cerebellar ataxia, narcolepsy/cataplexy, sensorineural deafness, and dementia. More variable features include optic atrophy, sensory neuropathy, psychosis, and depression (summary by Winkelmann et al., 2012).
Melberg et al. (1995) reported a 4-generation Swedish pedigree in which 5 individuals had cerebellar ataxia and sensorineural deafness. Four of the 5 patients also had narcolepsy. Among the 4, 2 had diabetes mellitus which was present in 2 otherwise healthy members of the family. Optic atrophy, other neurologic abnormalities, and psychiatric symptoms developed as the disorder progressed. Biochemical investigation of muscle biopsy in 1 case indicated mitochondrial dysfunction with decreased ATP production for substrates that normally give the highest rates. Inheritance was autosomal dominant.
Melberg et al. (1999) provided a follow-up of 4 members of the Swedish family reported by Melberg et al. (1995). After age 50 years, 1 of the patients had developed primitive reflexes, pseudobulbar signs, incontinence, hyperreflexia, and extensor plantar responses. He had optic atrophy, cataracts, nystagmus, ataxia, spasticity, head tremor, resting tremor, and mental deterioration. He also had sensorimotor polyneuropathy. The disease had progressed in the other 3 patients as well. Serial brain imaging revealed rapidly progressing cerebellar and cerebral atrophy. There was also brainstem atrophy, pronounced enlargement of the third ventricle, loss of the olivary bulges, and disappearance of cortical-white matter differentiation. Postmortem examination of 1 patient showed increased iron content in the basal ganglia and thalami and neuronal loss in the brainstem and cerebellum. Molecular analysis of CAG repeat expansions in several candidate genes was negative.
Winkelmann et al. (2012) reported 3 additional kindreds with autosomal dominant cerebellar ataxia, deafness, and narcolepsy. One family was from the United States and 2 were Italian. One of the Italian probands had sporadic disease with no previous family history of a similar disorder. This Italian patient developed narcolepsy/cataplexy at age 42 years, followed by hearing loss, memory problems and depression, lower limb lymphedema, cerebellar ataxia at age 46, peripheral sensory neuropathy at age 47, and optic atrophy at age 55. Cerebrospinal fluid (CSF) hypocretin-1 (HCRT; 602358) was low and CSF tau protein (MAPT; 157140) was high. One of his 3 daughters had narcolepsy.
The transmission pattern of cerebellar ataxia, deafness, and narcolepsy in the family reported by Melberg et al. (1995) was consistent with autosomal dominant inheritance.
In affected members of 4 families with autosomal dominant cerebellar ataxia, deafness, and narcolepsy, Winkelmann et al. (2012) identified 3 different heterozygous mutations in exon 21 of the DNMT1 gene (126375.0003-126375.0005). The first mutations were identified by exome sequencing. One of the families was the Swedish family previously reported by Melberg et al. (1995, 1999).
Melberg, A., Dahl, N., Hetta, J., Valind, S., Nennesmo, I., Lundberg, P. O., Raininko, R. Neuroimaging study in autosomal dominant cerebellar ataxia, deafness, and narcolepsy. Neurology 53: 2190-2192, 1999. [PubMed: 10599806] [Full Text: https://doi.org/10.1212/wnl.53.9.2190]
Melberg, A., Hetta, J., Dahl, N., Nennesmo, I., Bengtsson, M., Wibom, R., Grant, C., Gustavson, K. H., Lundberg, P. O. Autosomal dominant cerebellar ataxia deafness and narcolepsy. J. Neurol. Sci. 134: 119-129, 1995. [PubMed: 8747854] [Full Text: https://doi.org/10.1016/0022-510x(95)00228-0]
Winkelmann, J., Lin, L., Schormair, B., Kornum, B. R., Faraco, J., Plazzi, G., Melberg, A., Cornelio, F., Urban, A. E., Pizza, F., Poli, F., Grubert, F., Wieland, T., Graf, E., Hallmayer, J., Strom, T. M., Mignot, E. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum. Molec. Genet. 21: 2205-2210, 2012. [PubMed: 22328086] [Full Text: https://doi.org/10.1093/hmg/dds035]