PED WITH OR WITHOUT EPILEPSY AND/OR HEMOLYTIC ANEMIA
PAROXYSMAL EXERCISE-INDUCED DYSKINESIA WITH OR WITHOUT EPILEPSY AND/OR HEMOLYTIC ANEMIA
GLUT1DS2
PAROXYSMAL EXERTION-INDUCED DYSTONIA WITH OR WITHOUT EPILEPSY AND/OR HEMOLYTIC ANEMIA
PED
DYT18
dystonia 18
GLUT1 deficiency syndrome-2 is an autosomal dominant disorder characterized primarily by onset in childhood of paroxysmal exercise-induced dyskinesia. The dyskinesia involves transient abnormal involuntary movements, such as dystonia and choreoathetosis, induced by exercise or exertion, and affecting the exercised ...GLUT1 deficiency syndrome-2 is an autosomal dominant disorder characterized primarily by onset in childhood of paroxysmal exercise-induced dyskinesia. The dyskinesia involves transient abnormal involuntary movements, such as dystonia and choreoathetosis, induced by exercise or exertion, and affecting the exercised limbs. Some patients may also have epilepsy, most commonly childhood absence epilepsy, with an average onset of about 2 to 3 years. Mild mental retardation may also occur. One family has been reported with the additional feature of hemolytic anemia (Weber et al., 2008). GLUT1 deficiency syndrome-2 shows wide clinical variability both within and between affected families. The disorder, which results from a defect in the GLUT1 glucose transporter causing decreased glucose concentration in the central nervous system, is part of a spectrum of neurologic phenotypes resulting from GLUT1 deficiency. GLUT1 deficiency syndrome-1 (606777) represents the more severe end of the phenotypic spectrum. Correct diagnosis of GLUT1 deficiency is important because a ketogenic diet often results in marked clinical improvement in motor and seizure symptoms (reviews by Pascual et al., 2004 and Brockmann, 2009)
Plant et al. (1984) reported a mother and daughter with exercise-induced paroxysmal dystonia. The mother first developed involuntary movements of the legs after walking at age 8 years. Involvement of the upper limbs sometimes occurred with stress or continuous ...Plant et al. (1984) reported a mother and daughter with exercise-induced paroxysmal dystonia. The mother first developed involuntary movements of the legs after walking at age 8 years. Involvement of the upper limbs sometimes occurred with stress or continuous writing. The attacks could also be elicited with other stimuli, including passive movement and vibration. The patient's daughter was similarly affected. Margari et al. (2000) reported a family in which 6 members had paroxysmal exertion-induced dyskinesia with onset in childhood. Other precipitating factors included fasting and stress. The attacks were characterized by involuntary flexing and extending movements and alternately twisting movements of the upper and lower limbs lasting between 10 and 40 minutes. All patients also had absence seizures or partial complex seizures, which spontaneously resolved with age. One patient had generalized tonic-clonic seizures. Some had mild learning disabilities and irritable behavior with aggressive or impulsive outbursts. The dyskinesias showed decreased frequency with age. Detailed neurophysiologic studies suggested hyperexcitability at the muscular and brain cell membrane levels, and Margari et al. (2000) postulated a defect in an ion channel. Munchau et al. (2000) reported a family in which 4 members had paroxysmal exercise-induced dystonia with a mean age at onset of 12 years (range, 9-15 years). Attacks of PED in affected members were predominantly dystonic and lasted between 15 and 30 minutes. They were consistently precipitated by walking but could also occur after other exercise. Three patients also had migraine without aura. Overweg-Plandsoen et al. (2003) reported a 6-year-old boy with delayed psychomotor development, moderate mental retardation, horizontal nystagmus, dysarthria, limb ataxia, hyperreflexia, and dystonic posturing of the limbs. He had never had seizures. The motor activity and coordination fluctuated throughout the day, which was unrelated to food intake. Laboratory studies showed hypoglycorrhachia and low CSF lactate. Genetic analysis identified a de novo heterozygous mutation in the GLUT1 gene (N34I; 138140.0011). A ketogenic diet helped with the motor symptoms. Wang et al. (2005) reported 3 patients with an atypical phenotype of GLUT1 deficiency syndrome without infantile seizures. Two had a phenotype consistent with that reported in a child by Overweg-Plandsoen et al. (2003): all had mental retardation, dysarthria, dystonia, and ataxia, but no seizures. The third patient with an atypical phenotype reported by Wang et al. (2005) had choreoathetosis, dystonia, paroxysmal episodes of blinking, and abnormal head and eye movements, which ceased at age 3 years. He also had hypotonia, dysarthria, and developmental delay. Biochemical analysis showed that all patients had decreased CSF glucose and decreased glucose uptake into erythrocytes compared to controls. Kamm et al. (2007) reported a German family in which 4 individuals spanning 3 generations had paroxysmal exercise-induced dystonia, 2 of whom also had clinical seizures. Onset of PED ranged from 2 to 10 years and affected the legs. One woman had generalized seizures during pregnancy at age 22 years, and a boy had onset of frequent absence seizures at age 3.5 years. EEG studies showed abnormalities in all 4 patients, even those without seizures, as well as in 2 unaffected family members. EEG findings were variable, and included synchronous and hypersynchronous spike-wave complexes, sharp waves, and rhythmic theta- and delta-activity. Two individuals had speech and developmental delay, and 1 had migraine with visual aura. Joshi et al. (2008) reported a 13-year-old boy with a history of ataxia since early childhood who was diagnosed with GLUT1 deficiency syndrome after onset of epilepsy at age 11 years. He had delayed psychomotor development, early-onset ataxia, and hyperreflexia. He first developed a seizure disorder at age 11 years, with staring spells, head jerking, eye rolling, and loss of tone, which progressed to absence, myoclonic, and atonic seizures. His cognitive and motor skills deteriorated during this period. EEG showed moderate background slowing. Laboratory studies showed decreased CSF glucose and lactate, consistent with GLUT1 deficiency syndrome. Genetic analysis identified a heterozygous mutation in the SLC2A1 gene (R93W; 138140.0013). A ketogenic diet resulted in complete seizure control with motor and cognitive improvement. Zorzi et al. (2008) reported 3 unrelated Italian females with GLUT1 deficiency associated with paroxysmal movement disorders diagnosed in early adulthood. None had a positive family history. All had global developmental delay noted in infancy, and 2 had seizures beginning in the first 6 months of life (myoclonic absence and complex partial seizures, respectively). All had microcephaly, dysarthria, spasticity, and moderate mental retardation. Paroxysmal movements included myoclonic jerks, stiffening, and dystonic posturing. Two had exercise-induced dystonia, 1 with choreoathetosis. Zorzi et al. (2008) noted that the abnormal movements were consistent with paroxysmal dyskinesia, thus expanding the phenotype associated with GLUT1 deficiency. Suls et al. (2008) reported a 5-generation Belgian family segregating paroxysmal exercise-induced dyskinesia and epilepsy. Three additional smaller unrelated families with a similar phenotype were also observed. Of the 22 affected individuals from all families, 19 (76%) had a history of PED and 14 (56%) had a history of epilepsy; 11 (44%) had a history of both. Three SLC2A1 mutation carriers were asymptomatic, indicating reduced penetrance. The median age at onset of PED was 8 years (range, 3-30), and all patients had involvement of the legs. Precipitating factors included exertion (89%), particularly prolonged brisk walking, stress (39%), starvation (28%) and sleep deprivation (6%). All patients had involvement of the legs: 9 (50%) reported involuntary movements suggestive of choreoathetosis alone, 3 (17%) of dystonia, and 6 (33%) of both. Choreoathetosis was described as uncontrollable rapid movements, and dystonia as stiffening and cramps. PED made walking impossible and caused falls in some individuals. The 14 mutation carriers with epilepsy had a median age at onset of 2 years (range, 0-19). The seizure types could be classified as absence (64%), generalized tonic-clonic seizures without focal onset (50%), and complex and simple partial seizures (14%). Most patients had seizure remission with antiepileptic drug treatment. Most mutation carriers were of average intelligence or had mild mental retardation. Four patients underwent formal neuropsychologic testing and had a median IQ of 65 (45-79). EEG studies were often normal (43%), but some showed interictal generalized epileptic discharges (29%) and/or background slowing (5-10%). The mean CSF glucose level was 44 mg/dl (range, 34-64) and the mean CSF:plasma glucose was 0.52 (range, 0.47-0.60), indicating a mild decrease compared to controls. PET studies suggested that disordered glucose metabolism in the corticostriate pathways plays a role in PED, and that disordered glucose metabolism in the frontal lobes plays a role in epilepsy. Three patients were successfully treated with a ketogenic diet. Most patients reported that PED and epilepsy became less severe when they grew older. The findings indicated that both PED without epilepsy and PED with epilepsy can be caused by mutations in the SLC2A1 gene. Suls et al. (2008) suggested that attacks of PED may be caused by reduced glucose transport across the blood-brain barrier, possibly when the energy demand of the brain overcomes its supply after prolonged periods of exercise. Rotstein et al. (2009) reported a 10-year-old boy with GLUT1 deficiency syndrome who presented at age 2 years with onset of episodic ataxia and slurred speech associated with unilateral muscle weakness. Laboratory studies showed significantly decreased CSF glucose levels. He showed gradual cognitive decline, progressive microcephaly, and ataxia during childhood. Studies in patient erythrocytes showed about a 50% decrease in glucose uptake compared to controls. Genetic analysis identified a de novo heterozygous R93W mutation in the SLC2A1 gene (138140.0013). Rotstein et al. (2009) noted that the phenotype in this patient was reminiscent of alternating hemiplegia of childhood (104290). Perez-Duenas et al. (2009) reported a 7-year-old girl with GLUT1 deficiency syndrome-2. She had delayed psychomotor development from infancy, and presented at age 5 years with episodic flaccidity and loss of ambulation. The episodes continued and were accompanied by gait ataxia, dysarthria, dyskinesias, and choreic movements. Milder features included action tremor, upper limb dysmetria, and ataxia. Brain MRI showed moderately severe supratentorial cortico-subcortical atrophy, and EEG showed mild diffuse slowing. CSF glucose was decreased. Institution of a ketogenic diet resulted in clinical improvement of the movement disorder and increased brain growth, although cognitive skills did not improve. Genetic analysis identified a heterozygous de novo mutation in the SLC2A1 gene (138140.0017). - Clinical Variability Weber et al. (2008) reported a 3-generation family in which 4 members had childhood onset of episodic involuntary exertion-induced dystonic, choreoathetotic, and ballistic movements associated with macrocytic hemolytic anemia with reticulocytosis. One woman reported less frequent symptoms since the age of 35, which disappeared completely after the age of 45. Neuropsychologic evaluation revealed slight deficits in attention concerning complex tasks and verbal memory in the 2 adults, mild developmental delay in 1 child, and decreased cognitive function with an IQ of 77 in the second child. The 2 younger patients developed seizures in infancy and childhood, respectively, that were more frequent in the morning before breakfast and improved after carbohydrate intake. Ketogenic diets were beneficial in the younger patients. Electron microscopy of the patients' red cells showed echinocytes, and erythrocytes of all affected individuals had increased sodium and decreased potassium. CSF revealed glucose levels at or below the lower limit of normal. Mullen et al. (2010) reported significant intrafamilial clinical variability of GLUT1 deficiency syndrome in 2 unrelated families, one with 9 mutation carriers spanning 2 generations and the other with 6 mutation carriers spanning 2 generations. Of 15 patients with SLC2A1 mutations, 12 had epilepsy, most commonly absence epilepsy, with onset between ages 3 and 34 years. Eight patients had idiopathic generalized epilepsies with absence seizures, 2 had myoclonic-astatic epilepsy, and 2 had focal epilepsy. Seven patients had subtle paroxysmal exertional dyskinesia as the only manifestation, and 2 mutation carriers were unaffected. Only 3 of 15 patients had mild intellectual disabilities. Mullen et al. (2010) emphasized the phenotypic overlap with common forms of idiopathic generalized epilepsy (see EIG12, 614847)
In affected members of the families reported by Margari et al. (2000) and Munchau et al. (2000), Weber et al. (2008) identified 2 different heterozygous mutations in the SLC2A1 gene (138140.0009 and 138140.0010, respectively). Two additional families with PED ...In affected members of the families reported by Margari et al. (2000) and Munchau et al. (2000), Weber et al. (2008) identified 2 different heterozygous mutations in the SLC2A1 gene (138140.0009 and 138140.0010, respectively). Two additional families with PED did not have SLC2A1 mutations, suggesting genetic heterogeneity. In affected members of a large Belgian family segregating PED and epilepsy, Suls et al. (2008) identified a heterozygous missense mutation in the GLUT1 gene (S95I; 138140.0012). In affected members of a family with PED and hemolytic anemia, Weber et al. (2008) identified a deletion in the SLC2A1 gene (138140.0008). Weber et al. (2008) concluded that the dyskinesias resulted from an exertion-induced energy deficit causing episodic dysfunction in the basal ganglia. The hemolysis was demonstrated in vitro to result from alterations in intracellular electrolytes caused by a cation leak through mutant SLC2A1. Schneider et al. (2009) identified 2 different de novo heterozygous mutations in the GLUT1 gene (see, e.g., 138140.0015) in 2 of 10 unrelated Caucasian patients with paroxysmal exercise-induced dyskinesias. One of the patients had childhood onset of absence epilepsy