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Systemic degenerations of the extrapyramidal nuclei have been classified by Jellinger into 4 groups124:

  1. Pure pallidal atrophy (PA), with lesions found only in the efferent pallidal system.
  2. Pure pallidoluysian atrophy (PLA).
  3. Pallidal degeneration with involvement of the striatum or Substantia Nigra (PLNA).
  4. Combinations of the first 3 types with other “cerebrospinal degenerations” such as pallidoluysiodentate atrophy (PLDA).

Myoclonic epilepsy has not been associated with PA, PLA or PLNA, but is described in the group of PLDA.

There are two early reports of pathological system degenerations of the pallido-Luysian and dentato-rubral pathways:

  1. In 1946 Titica and Van Bogaert described a patient with progressive dementia and “hemiballismus”, described as “ involuntary contorting movements of the left arm and grimacing”, associated with visual loss125.  His older sister had cataracts, marked intention tremor, and progressive ataxia. 
  2. Smith described a patient with dysarthria, choreoathetosis and cerebellar signs126.  Autopsy showed changes predominantly in the cerebellofugal and extrapyramidal systems with marked neuronal loss in the dentate nuclei, loss of Purkinje cells, and marked demyelination of the subthalamic nuclei and the globus pallidus. 


Although two cases of familial PME from Japan were described in 1965, with pathology involving the brainstem and cerebellum 127 , the condition known as DRPLA, and characterized by AD inheritance, was first described in Japan in 1977.  There were four cases from three separate Japanese families with AD myoclonic epilepsy, with pathological findings of degeneration of the dentate nuclei, superior cerebellar peduncles, and the pallido-luysian system (128 cited in 129).  DRPLA was first described in the Western literature in 1978 by Takahata130.


1.10.2 Clinical Manifestations

In 1982, Naito described five different families with myoclonus, epilepsy, ataxia, dementia and choreoathetosis, all of whom had degeneration of the dentatorubral and pallidoluysian systems2.  He noted that this was a new neurologic disease, “hereditary dentatorubral-pallidoluysian atrophy”, with the following unique features2:

(1) A PME syndrome with or without cerebellar ataxia or choreathetosis or both.

(2) Pathological findings of dentatorubral-pallidoluysian atrophy.

(3) AD heredity. 

Iizuka et al expanded the clinical phenotype, and distinguished two clinical types of DRPLA (1984) in addition to PME129:

  1. Ataxo-choreoathetoid type: ataxia was prominent in the ataxo-choreoathetoid type in the early stages of the illness, and choreoathetoid movements more prominent with disease progression.  Disturbances of external ocular momements were commonly observed129.
  2. Pseudo-Huntington type: Choreic movenents and dementia were always predominant, and ataxia was mild or latent throughout the course.


The disorder has been most commonly reported from Japan, but cases have been described in Europe131.  Age of onset varies from childhood to late adulthood.  The differential diagnosis includes Huntington’s disease, Parkinson’s disease, mitochondrial encephalopathies and cerebellar ataxias132.  Myoclonus, epilepsy and cerebellar features, which include ataxia, postural and intention tremor, are characteristic of DRPLA131.  Hyperkinetic involuntary movements and rigidity may be related to involvement of the pallidofugal system, and may be difficult to distinguish from Huntington disease, possibly since they may mask the cerebellar signs131.

In general, patients with disease of early onset have a more rapid progression and manifest as PME, whereas those presenting later have cerebellar ataxia, choreoathetosis and dementia, although there are exceptions to this in families of non-Japanese descent2 133. Inheritance

DRPLA is inherited as an autosomal dominant disorder, and in common with many triplet codon repeat disorders, there is a correlation between repeat number and age of onset of the illlness134 and anticipation is present130. Special Investigations

MRI may demonstrate atrophy of the cerebellum and brainstem, correlating with the size of the trincucleotide CAG repeat expansion 135.  T-2 weighted high intensity signal change is also in the white matter and brainstem136. Neuropathology

There is neuronal loss in the cortex, thalamus and chromatolytic changes in the neurons of the pons, locus ceruleus, hypoglossal and dorsal vagal nuclei.  In the cerebellum, the dentate nuclei showed neuronal loss and chromatolytic changes, and reduction in the number of Purkinje cells130.  Some patients also showed neuronal loss in the globus pallidus and gliosis of the subthalamic nucleus130;130.  Patients may have severe degeneration of the dentate and axonal loss in the superior cerebellar peduncle2;137. Genetics

The gene locus for DRPLA is located at chromosome 12p13.31 and the gene codes for a protein termed atrophin 1.  DRPLA is due to expansion of an unstable trinucleotide (CAG) repeat138.  In the Japanese population the number of repeats is highly polymorphic with a distinct, bimodal distribution of normal and expanded alleles134.  In normal individuals allele sizes vary between 7 and 23 copies, whereas patients with DRPLA have expansions in the range of 49 to 75 repeats139. Epidemiology

DRPLA is described worldwide, although is commonest in Japan, where the incidence is 0.2-0.7 per 100 000 140;141.


  124.   Jellinger K. Pallidal, pallidonigral and pallidoluysionigral degenerations including association with thalamic and dentate degenerations. In: Vinken PJ, Bruyn GW, Klawans HL, eds. Handbook of Clinical Neurology. Elsevier 1986: 445-63.

  125.   Titica J, Van Bogaert L. Heredo-degenerative Hemiballismus. Brain 1946;69:251-63.

  126.   Smith JK, Gonda VE, Malamud N. Unusual form of cerebellar ataxia combined dentato-rubral and pallido-Luysian degeneration. Neurology 1950;8:205-9.

  127.   Yokoi S, Kobori H, Yoshihara H. Clinical and Neuropathological Studies of Myoclonic Epilepsy. Acta Neuropathologica 1965;4:370-9.

  128.   Naito H, Tanaka M, Hirose Y, Oyanagi S. Clinicopathological study on two autopsied cases of degenerative types of myoclonus epilepsy with choreo-athetoid movement: Proposal of hereditary dentate and pallidal system atrophy. Psychiatr Neurol Jpn 1977;79:193-204.

  129.   Iizuka R, Hirayama K, Maehara KA. Dentato-rubro-pallido-luysian atrophy: a clinico-pathological study. Journal of Neurology, Neurosurgery & Psychiatry 1984;47:1288-98.

  130.   Takahata N, Ito K, Yoshimura Y, Nishihori K, Suzuki H. Familial chorea and myoclonus epilepsy. Neurology 1978;28:913-9.

  131.   Nielsen JE, Sorensen SA, Hasholt L, Norremolle A. Dentatorubral-pallidoluysian atrophy. Clinical features of a five-generation Danish family. Mov Disord. 1996;11:533-41.

  132.   Munoz, E, Mila, M, Sanchez, A, Latorre, P, Ariza, M, Codina, M, Ballesta, F, and Tolosa, E. Dentatorubropallidoluysian atrophy in a Spanish family: a clinical, radiological, pathological, and genetic study. Journal of Neurology, Neurosurgery & Psychiatry 67, 811-814. 1999.
Ref Type: Journal (Full)

  133.   Takahashi, H., Ohama, E., Naito, H., Takeda, S., Nakashima, S., Makifuchi, T., and Ikuta, F. Hereditary dentatorubral-pallidoluysian atrophy: Clinical and pathological variants in a family. Neurology 38, 1065-1070. 1988.
Ref Type: Journal (Full)

  134.   Potter NT, Meyer MA, Zimmerman AW, Eisenstadt ML, Anderson IJ. Molecular and clinical findings in a family with dentatorubral- pallidoluysian atrophy. Annals of Neurology 1995;37:273-7.

  135.   Tsuji S. Dentatorubral-pallidoluysian atrophy: clinical aspects and molecular genetics. Adv.Neurol. 2002;89:231-9.

  136.   Yoshii F, Tomiyasu H, Shinohara Y. Fluid attenuation inversion recovery (FLAIR) images of dentatorubropallidoluysian atrophy: case report. J Neurol Neurosurg Psychiatry 1998;65:396-9.

  137.   Goto I, Tobimatsu S, Ohta M, Hosokawa S, Shibasaki H, Kuroiwa Y. Dentatorubropallidoluysian degeneration: clinical, neuro-ophthalmologic, biochemical, and pathologic studies on autosomal dominant form. Neurology 1982;32:1395-9.

  138.   Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, Takahashi H, Kondo R, Ishikawa A, Hayashi T, . Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat.Genet. 1994;6:9-13.

  139.   Delgado-Escueta AV, Serratosa JM, Liu A, Weissbecker K, Medina MT, Gee, M, Treiman LJ, Sparkes RS. Progress in mapping human epilepsy genes. [Review] [65 refs]. Epilepsia 1994;35 Suppl 1:S29-40.

  140.   Koide R, Onodera O, Ikeuchi T, Kondo R, Tanaka H, Tokiguchi S, Tomoda A, Miike T, Isa F, Beppu H, Shimizu N, Watanabe Y, Horikawa Y, Shimohata T, Hirota K, Ishikawa A, Tsuji S. Atrophy of the cerebellum and brainstem in dentatorubral pallidoluysian atrophy. Influence of CAG repeat size on MRI findings. Neurology 1997;49:1605-12.

  141.   Warner TT, Williams L, Harding AE. DRPLA in Europe. Nat.Genet. 1994;6:225.