Dystonia 9

A number sign (#) is used with this entry because dystonia-9 (DYT9) is caused by heterozygous mutation in the SLC2A1 gene (138140), also referred to as GLUT1, on chromosome 1p34.

Allelic disorders with overlapping features include GLUT1 deficiency syndrome-1 (GLUT1DS1; 606777), GLUT1DS2 (612126), and idiopathic generalized epilepsy-12 (EIG12; 614847).

Description

Dystonia-9 is an autosomal dominant neurologic disorder characterized by childhood onset of paroxysmal choreoathetosis and progressive spastic paraplegia. Most show some degree of cognitive impairment. Other variable features may include seizures, migraine headaches, and ataxia (summary by Weber et al., 2011).

Clinical Features

Auburger et al. (1996) described a large German pedigree with autosomal dominant paroxysmal choreoathetosis and spasticity. A total of 18 affected and 11 unaffected family members were clinically evaluated. Age of onset ranged from 2 to 15 years, with most individuals presenting clear symptoms before attending school. Patients complained of episodes of involuntary movements, dystonic posture of toes, legs, and arms, imbalance, dysarthria, paresthesias periorally and on the lower limbs, and double vision, sometimes accompanied or followed by headache. Cerebellar ataxia was not seen in the episodes observed. The episodes lasted approximately 20 minutes, and occurred at frequencies ranging from twice a day to twice a year. Physical exercise, emotional stress, lack of sleep, and alcohol consumption were mentioned as precipitating factors. While physical examination was usually normal in the clinical interval, 5 patients exhibited constant spastic paraplegia as evidenced by spastic leg tone, increased tendon reflexes, and pyramidal signs in the lower limbs, without increased latencies on motor evoked potential analysis. Affected individuals were described as good natured and simple minded; 1 patient was 'analphabetic.'

Weber et al. (2011) reported Australian adult monozygotic twin brothers with DYT9 and mental retardation. They presented with paroxysmal choreoathetosis and progressive spastic paraparesis; ataxia was not observed. As toddlers, they both developed episodic stereotyped, abnormal movements mainly affecting the limbs. The movements progressed to vigorous choreatic movements without impairment of consciousness. Episodes lasted between 5 minutes and 2 hours, and occurred several times weekly. Precipitating factors included prolonged exercise or physical exhaustion, dehydration, caffeine, alcohol, and anticipation of food. Medication was not beneficial for these episodes. In addition, both had a persistent gait disturbance due to progressive spastic paraparesis since later childhood, with markedly increased tone, sustained clonus, pyramidal pattern weakness, brisk reflexes, and extensor plantar responses.

Inheritance

The transmission pattern of paroxysmal choreoathetosis in the family reported by Auburger et al. (1996) was consistent with autosomal dominant inheritance.

Clinical Management

Bain et al. (1992) demonstrated a rise in pH in the cerebellum with (31)P nuclear magnetic resonance spectroscopy in 6 affected members of 2 unrelated families with familial periodic cerebellar ataxia consistent with ataxia (see 108500). Consistent with this finding, acetazolamide stopped or alleviated symptoms. In contrast, Auburger et al. (1996) found no clear elevation of pH in their family. They stated, however, that episodes ceased in one patient after administration of acetazolamide and phenytoin and were ameliorated in a second patient by acetazolamide but continued in a third patient despite treatment with a range of agents.

Mapping

By linkage analysis in a large pedigree with paroxysmal choreoathetosis with episodic ataxia and spasticity, Auburger et al. (1996) concluded that the gene for this disorder probably lies in a 2-cM region between D1S443 and D1S197. They noted that a cluster of potassium channel genes is located on 1p.

Molecular Genetics

In affected members of the family with DYT9 originally reported by Auburger et al. (1996), Weber et al. (2011) identified a heterozygous mutation in the SLC2A1 gene (R232C; 138140.0018). Two Australian brothers with the disorder carried a different heterozygous mutation (R126C; 138140.0014).

Nomenclature

Muller et al. (1998) referred to this disorder as dystonia-9 and suggested that it is closely related to paroxysmal dystonic choreoathetosis (PDC; 118800), which they referred to as dystonia-8. The involuntary movements and dystonia in DYT9 are similar to those in PDC, which maps to chromosome 2. In both disorders, episodes can be induced by alcohol, fatigue, and emotional stress; however, in DYT9, physical exercise can precipitate the episodes, and 5 of the 18 patients studied by Auburger et al. (1996) had spastic paraplegia both during and between episodes of dyskinesia.