A syndrome of autosomal dominant alternating hemiplegia: clinical presentation mimicking intractable epilepsy; chromosomal studies; and physiologic investigations.

We report the familial occurrence and apparent autosomal dominant inheritance of alternating hemiplegia of childhood. The proband, a 9-year-old boy, presented with developmental retardation, rare tonic-clonic seizures, and frequent episodes of flaccid alternating hemiplegia that had been presumed to represent postictal paralysis. The hemiplegia spells, which started in his first year, did not respond to multiple antiepileptics. Between attacks, there was choreoathetosis and dystonic posturing. Father, brother, paternal uncle, and paternal grandmother had similar histories of alternating hemiplegia. Investigations included negative CT, metabolic, and coagulation studies. EEG and SPECT 99mTc exametazime scanning failed to reveal any significant slowing or any major changes in cortical perfusion during hemiplegia as compared with nonhemiplegic periods. The karyotype revealed a balanced reciprocal translocation, 46,XY,t(3;9)(p26;q34) in the patient, in all the affected living relatives, and in one apparently unaffected sibling. The asymptomatic mother had a normal karyotype. Analysis of DNA markers was consistent with the karyotype results. Both affected siblings were treated with and responded to flunarizine therapy, with a greater than 70% decrease in attack frequency. Documented flunarizine trough serum concentrations were 28.9 ng/ml in the proband and 6.6 ng/ml in his brother.     

Familial hemiplegic migraine,nystagmus, and cerebellar atrophy

Familial hemiplegic migraine (FHM) is an autosomal dominant disorder characterized by transient hemiplegia during the aura phase of a migraine attack. Nystagmus has been reported in individuals affected with this disorder, but the origin of the ocular motility findings is unknown. A three-generation family with FHM is described and clinical histories are outlined. Ocular motility evaluations were performed on 7 family members, 5 with a history of hemiplegic migraine and 2 without history of migraine. All affected family members had abnormal eye movements consistent with vestibulocerebellar dysfunction. Magnetic resonance imaging scans in affected family members revealed cerebellar vermian atrophy. DNA linkage analysis revealed a common marker in all the affected family members on chromosome 19. We suggest that the hemiplegic migraine attacks and the cerebellar degeneration are linked genetically and that the eye movements are not the ischemic sequelae of recurrent migraine. Strikingly similar ocular motility findings and cerebellar degeneration are reported in both FHM and a genetically related disorder, hereditary paroxysmal cerebellar ataxia (HPCA). The significance of these similarities is discussed along with a proposed pathophysiology for FHM.     

A familial disorder with subcortical ischemic strokes, dementia, and leukoencephalopathy.

A family had a disorder characterized by (1) a pattern suggestive of autosomal dominant inheritance, (2) recurrent attacks of focal brain deficits starting in mid adulthood and often leading to severe motor disability with pseudobulbar palsy and dementia of the subcortical type, and (3) neuroimaging evidence of leukoencephalopathy and well-circumscribed lesions consistent with small deep infarcts. Some affected members were clinically asymptomatic but had MRI signs of leukoencephalopathy. Extensive investigations failed to uncover a previously described recognizable genetic disorder.     

A patient with alternating hemiplegia in childhood

Alternating hemiplegia in childhood (Verret, 1971) is a disorder presenting with frequent episodes of alternating hemiplegia from early infancy. We report a patient with this disorder, along with a pathophysiological study and a discussion about the available therapies for this disorder. The patient, an 11-year-old boy, visited our hospital with episodes of alternating hemiplegia from early infancy. His family history showed that many members suffered from migraine. He was born with asphyxia. Mental and motor developmental delays were seen from early infancy. The hemiplegic episodes with ipsilateral facial palsy had occurred frequently from early infancy. The episodes were frequently induced by emotional stress. The duration of hemiplegia varied from 10 minutes to 3 days. From the age of 11 years, he had begun to have migrainous attacks with or without hemiplegic episodes. Neurological examination revealed slight muscle hypotonia, choreoathetosis and dystonic movements induced by locomotion, positive Myerson sign, increased deep tendon reflexes and Babinski reflex. CAG, VAG and CAT revealed normal findings. EEG revealed diffuse generalized slowing during hemiplegic episodes. Measurement of regional cerebral blood flow (CBF) by 133Xe inhalation method revealed a slight decrease of bilateral CBF during a quadriplegic episode. Positron emission tomography using C15O2 revealed a slight decrease of CBF at the insula, putamen and claustrum of the left side during a right sided episode. Increased excretion of urinary 5-HIAA was seen during one episode. From our clinical and laboratory findings, we think this disorder may be a special type of migraine. Therapeutic trials of diazepam and flunarizine were both effective, but the initial effectiveness was decreased after 5 months.     

123I-iodoamphetamine SPECT brain imaging in alternating hemiplegia

Alternating hemiplegia of childhood is an unusual disorder characterized by early onset (occurring before 18 months of age); repeated attacks of hemiplegia involving both sides of the body; other paroxysmal phenomena, such as tonic stiffening, dystonic posturing, choreoathetoid movements, ocular motor abnormalities, and autonomic disturbances, in association with bouts of hemiplegia or occurring independently; and evidence of mental or neurologic deficits. A girl was examined because of left hemiplegia at the age of 16 months. The patient had begun exhibiting episodes of alternating hemiplegia at approximately 4 months of age. They consisted of tonic stiffening and dystonia of the right or left extremities, lasting from 30 min to several hours and followed by residual hemiparesis. They were invariably accompanied by ocular motor abnormalities. Magnetic resonance imaging, computed tomography, and angiography all were normal. Single proton emission computed tomography brain images during an acute episode of right hemiplegia demonstrated hypoperfusion of the left cerebral hemisphere. Following improvement of the hemiplegia, the patient was re-evaluated. The uptake of the radiotracer in the left hemisphere was increased. The scan did not demonstrate significant asymmetry in cerebral perfusion.     

Familial hemiplegic migraine and autosomal dominant arteriopathy with leukoencephalopathy (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently described familial cerebrovascular disorder shown to map to chromosome 19q12. Familial hemiplegic migraine has also been shown in some families to map close to the CADASIL locus. The fully developed CADASIL phenotype consists of recurrent strokes developing in the fourth decade, progressing to a pseudobulbar palsy, spastic quadriparesis, and subcortical dementia. In an Irish family 15 members were fully investigated by magnetic resonance scanning; 10 had typical magnetic resonance features of CADASIL. Five members of this family had familial hemiplegic migraine and 4 of these had magnetic resonance evidence of CADASIL. Two other members had migraine with and without aura as a presenting clinical symptom of CADASIL. This disorder has been shown by linkage analysis to map to the CADASIL locus at chromosome 19. The phenotype at presentation of CADASIL in this family was variable and age related and included familial hemiplegic migraine, migraine with and without aura, transient ischemic attacks, strokes, and spinal cord infarction. This family study increases our understanding of the spectrum of clinical manifestations of this underrecognized familial cerebrovascular disorder.     

Evidence for mitochondrial dysfunction in patients with alternating hemiplegia of childhood

Phosphorus magnetic resonance spectra of resting muscle were obtained from 4 patients with alternating hemiplegia of childhood. All patients had abnormally high resonance intensities from inorganic phosphate and an abnormally law calculared cytosolic phosphorylation potential. Tow of the 4 patients had abnormally law resonance intensities from phosphocreatine and an abnormally high calculated cytosolic free adenosine diphosphare conecntration. These abnormalities are indicative of mitochondrial dysfunction. The combination of a central nervous system disorder and evidence of mitochondrial dysfunction in muscle suggests that alternating hemiplegia of childhood may represent a previously unrecognized phenotype of mitochondrial disease.     

Rapid-onset dystonia-parkinsonism: a fourth family consistent with linkage to chromosome 19q13.

Rapid-onset dystonia-parkinsonism (RDP, DYT12, MIM 128235) is a rare autosomal dominant movement disorder characterized by abrupt onset of slow, dystonic movements and prominent bulbar features. Three families and 1 isolated case have been described in the literature, and linkage to markers on chromosome 19q13 have been reported. Here, we describe the clinical features in a fourth family (the second in Europe) with 4 affected members, suggesting that RDP may be misdiagnosed for years and/or may mimic other dystonic/parkinsonian syndromes. By using haplotype analysis, we show that the family is consistent with linkage to markers on chromosome 19q13.     

Alternating hemiplegia of childhood: New diagnostic options

A syndrome of alternating hemiplegia of childhood (AHC) is a rare disorder first presented in 1971. AHC is characterized by transient episodes of hemiplegia affecting either one or both sides of the body. Age of onset is before 18 months and the common earliest manifestations are dystonic or tonic attacks and nystagmus. Hemiplegic episodes last minutes to days and the frequency and duration tend to decrease with time. Motor and intellectual development is affected, deficits may also develop later. Epileptic seizures occur in some patients. Neuroimaging of the brain usually reveals no abnormalities. The variability of individual clinical presentations and evolution of symptoms have made diagnosis difficult. Therefore the problems of misdiagnosis could account for the low prevalence of this syndrome. This paper hopes to present actual data on AHC, especially of the results of genetic research and new diagnostic tools.     

Single photon emission computed tomography findings in a case of alternating hemiplegia of childhood in relation to migraine

Single photon emission computed tomography (SPECT) was performed 3 times during attacks and performed 4 times during postictal periods on a case of alternating hemiplegia of childhood. Hyperperfusion of the corresponding hemisphere to hemiparesis was suggested by asymmetric increase RI uptake during the ictal scans, whereas interictal scans showed symmetric topography of cerebral blood flow. Manifestations except hemiplegia included loss of consciousness and vomiting. These manifestations and ictal SPECT findings are the same evidence as hemiplegic migraine. It suggests that these two disorders have a similar pathophysiology. There are two interesting findings regarding this patient. The first finding is magnetic resonance imaging showed progressive cerebellar atrophy. Second finding is interictal SPECT showed a progressive decrease of cerebral perfusion, especially in cerebellar hemispheres. These two findings suggest alternating hemiplegia of childhood may be a chronic progressive disorder.     

A boy with nystagmus, refractory dystonia and apneic attack due to alternating hemiplegia of childhood

We herein report the findings of a 2-year-6-month-old boy, who had been experiencing monocular pendular nystagmus, strabismus, and episodic eye deviation nystagmus, intractable dystonia and apneic attack which all began when he was 2 days of age. He underwent a complete blood count test, blood chemistry test, analysis of amino acids in the blood and urine, analysis of pyruvate/lactate in blood and cerebrospinal fluid, head computed tomography and magnetic resonance imaging and no abnormal results were identified. His attacks were resistant to multiple antiepileptic and dopaminergic drugs. He showed transient left and/or right hemiplegia after nystagmus, dystonia and/or apneic attacks at 8-months of age with retardation in intelligence. We diagnosed him to have alternating hemiplegia of childhood (AHC). We were unsure how to deal with his attacks after he was discharged from the hospital, however, resuscitation with the ambu bag by his mother at home and the intravenous infusion of diazepam or thiamylal at the hospital together was proven to be an effective method for treating his severe apneic attacks. The effect of diazepam and amantadine on these attacks was transient, however, the administration of flunarizine with amantadine resulted in an improvement in his attacks. We therefore consider the administration of flunarizine to be essential for the effective treatment of AHC in this case.     

Alternating hemiplegia of childhood: clinical manifestations and long-term outcome

We present our analysis of 44 patients with alternating hemiplegia of childhood. The clinical course usually consisted of three phases. The first was dominated by abnormal eye movements and dystonic episodes, the second by hemiplegic spells and psychomotor regression, and the third by persistent developmental delay and fixed neurologic deficits. The age of onset was 0-54 months (mean = 7.9 +/- 13 months). The presenting signs included abnormal ocular movements in 65%, dystonia in 60%, and hemiplegia in 32%. Patients with an early onset of the disorder and an early appearance of hemiplegic spells faired the poorest developmentally. Developmental delay was present in 91%, ataxia in 68%, choreoathetosis in 50%, and seizures in 18%. Laboratory investigations suggested mitochondrial abnormalities and cerebrovascular dysfunction in several patients. Numerous therapies were largely ineffective. Flunarizine reduced the duration, severity, and frequency of the hemiplegic attacks in 78%. Patients who received flunarizine did not differ developmentally from those who did not. Our data suggest that flunarizine does not adversely affect and may favorably influence the outcome in patients with alternating hemiplegia of childhood. Additionally, the occurrence of autosomal-dominant cases of the syndrome, although rare, suggests that, in addition to mitochondrial dysfunction, genetic factors may be important.     

Paroxysmal dystonic choreoathetosis: clinical features and investigation of pathophysiology in a large family.

Paroxysmal dystonic choreoathetosis (PDC) is an unusual hyperkinetic movement disorder characterized by attacks of chorea, dystonia, and ballism with onset in childhood. We report a large British family with dominantly inherited PDC linked to chromosome 2q and describe the clinical features in 20 affected family members. Attacks were precipitated by a variety of factors, including caffeine, alcohol, or emotion, and could be relieved by short periods of sleep in most subjects. The clinical features in the family are compared with those of 11 other PDC families in the literature and a core phenotype for PDC suggested. CSF monoamine metabolites measured at baseline and during an attack in one subject were found to increase during the attack. Magnetic resonance spectroscopy of brain and basal ganglia performed both during and between attacks was normal. Positron emission tomography using the D2 receptor ligand, 11C-raclopride, showed no abnormalities.     

Familial paroxysmal dystonic choreoathetosis and its differentiation from related syndromes

Four generations of a family are described in which 7 of 8 affected members suffered from prolonged dystonic seizures; the eighth member's attacks were those of paroxysmal choreoathetosis. The attacks lasted up to 4 hours, were precipitated by alcohol, emotion, or fatigue, and responded poorly to phenytoin and barbiturates but were controlled by clonazepam. Autopsy on an affected child who died a "crib death" at the age of 2 years disclosed no major abnormality of the brain. This family appears to have the same condition as that described by Mount and Reback in 1940, Forssman in 1961, and Richards and Barnett in 1968, which the last authors termed paroxysmal dystonic choreoathetosis to distinguish it from the more common movement-induced (kinesigenic) form of the disorder. Analysis of reports of 100 cases of paroxysmal kinesigenic choreoathetosis shows that the attacks last less than 5 minutes, are precipitated by sudden movement or startle, and usually respond well to phenytoin or barbiturates. A clinical classification is presented in which the kinesigenic form is divided into a familial group (72% of cases) and a sporadic group (28% of cases) and contrasted with paroxysmal dystonic choreoathetosis. One family with an intermediate form, in which dystonic choreoathetosis was provoked by continued exertion and lasted for up to 30 minutes, is also reported.     

Benign nocturnal alternating hemiplegia of childhood: A new case with unusual findings

It has been described a neuro developmental disorder labelled “Benign nocturnal alternating hemiplegia of childhood” (BNAHC) characterized by recurrent attacks of nocturnal hemiplegia without progression to neurological or intellectual impairment. We report a female patient who at 11 months revealed a motionless left arm, unusual crying without impairment of consciousness and obvious precipitating factors. The attacks occur during sleep in the early morning with lack of ictal and interictal electroencephalographic abnormalities, progressive neurological deficit, and cognitive impairment. Unlike previous reports of BNAHC our patient come from a family with a history of both migraine, hemiplegic migraine, and sleep disorders. Our study remarks on the typical features described in previous studies and stresses the uncommon aspects that could help to identify the disorder which is likely to have been underestimated. Despite some clinical similarities between BNAHC and familiar hemiplegic migraine and alternating hemiplegia of childhood, the genetic analyses of our patient did not reveal genetic mutations found in both disorders.     

Discordance of T-cell receptor beta-chain genes in familial multiple sclerosis.

Restriction fragment length polymorphisms of the T-cell receptor beta-chain gene were studied in DNA obtained from 96 individuals from 14 multiplex families with multiple sclerosis (MS). Thirty-four family members had definite MS and two had probable MS. Five normal family members had abnormal findings on cranial magnetic resonance imaging (MRI) scans. Linkage analysis was performed using the BglII and the KpnI polymorphisms. With penetrance values from 0.1 to 0.7, and altering the scoring of the normal individuals with abnormal findings on MRI scans from "unknown" to "affected," log of the odds scores between -4.59 to -12.76 were found for the autosomal dominant model. For the autosomal recessive model with a penetrance range from 0.1 to 1.0, the LOD scores ranged from -8.20 to -32.98. These findings do not support a direct role of T-cell receptor beta-chain gene in the inheritance of MS.     

Familial paroxysmal dystonic choreoathetosis: clinical findings in a large Japanese family and genetic linkage to 2q.

BACKGROUND: Paroxysmal dystonic choreoathetosis (PDC) is a rare familial movement disorder that has been mapped to chromosome 2q31-36. OBJECTIVE: To study the first Japanese family with PDC clinically and genetically. PATIENTS AND METHODS: We studied a large Japanese family in which at least 17 members in 6 generations have been affected by PDC. We interviewed and examined 26 family members, 8 of whom revealed choreoathetosis-like and dystonialike involuntary movement and 1 of whom revealed no involuntary movement but only muscle stiffness such as the aura of paroxysmal dystonic choreoathetosis (PDC). Genetic linkage studies of this family were carried out with polymorphic DNA markers. RESULTS: The attacks of involuntary movement or muscle stiffness were precipitated by ovulation, menstruation, emotional stress, or caffeine or alcohol ingestion. Magnetic resonance imaging of the brain revealed no abnormalities. Clonazepam therapy was effective for reducing the attacks, and ingestion of garlic was believed by patients to be effective for softening the attacks. An affected woman with only muscle stiffness showed remission after hysterectomy for hysteromyoma. This woman also had the disease haplotype and transferred it to her typical PDC-affected daughter. Maximal pairwise logarithm of odds scores exceeding 2.00 were obtained at D2S2250, D2S1242, D2S377, D2S2148, and D2S126. The PDC gene was demonstrated by linkage analyses to be located in a 15.3-centimorgan interval lying between D2S371 and D2S339 based on pairwise and multipoint logarithm of odds scores and obligate recombination events in affected individuals. CONCLUSIONS: Linkage of PDC to chromosome 2q32-36 was confirmed in a Japanese family. The clinical characterizations of this family with PDC include that ovulation seems also to be a precipitating factor of the attacks and that hysterectomy seems to be effective for softening the attacks. Although low-dose clonazepam treatment was most effective, garlic use was believed by affected members to be effective for softening the attacks. Furthermore, based on the results of clinical and genetic analyses, we suggest that muscle stiffness without involuntary movement may represent a forme fruste of PDC.     

Epileptic encephalopathy with features of rapid‐onset dystonia Parkinsonism and alternating hemiplegia of childhood: a novel combination phenotype associated with ATP1A3 mutation

Mutations in ATP1A3 have been found to cause rapid‐onset dystonia Parkinsonism, alternating hemiplegia of childhood, epileptic encephalopathy and other syndromes. We report a four‐year, nine‐month‐old boy with episodes of frequent and recurrent status epilepticus, who first began having generalized tonic‐clonic seizures at four months of age. Development was normal until the age of four months, and markedly slowed down after the onset of seizures. Between the age of seven months and two and a half years, the patient had recurrent attacks of unilateral and bilateral hemiplegia. At the age of 21 months, after a febrile illness with status epilepticus, he regressed and developed continuous severe dystonia and bradykinesia with superimposed intermittent painful dystonic spasms. Extensive neurological and genetic workup revealed a de novo p.V589F ATP1A3 mutation (NM_152296.5:c.1765G>T, NC_000019.9:g.42482344C>A). This is a novel mutation associated with a novel phenotype that shares features with epileptic encephalopathy, alternating hemiplegia of childhood, and rapid‐onset dystonia Parkinsonism.     

Autosomal dominant syndrome with strokelike episodes and leukoencephalopathy

BACKGROUND AND PURPOSE: We conducted a prospective survey of a family presenting a new syndrome characterized mainly by recurrent strokelike episodes and neuroimaging evidence of leukoencephalopathy. SUMMARY OF REPORT: Forty-five members of a single family were studied clinically and with magnetic resonance imaging. Nine had strokelike episodes, including transient ischemic attacks, and minor or major strokes starting between the fourth and sixth decades, with neuroimaging evidence of small, deep infarcts and a widespread white matter disorder. Other symptoms included migraine (three), dementia (two), epilepsy (one), and hearing loss (one). In some patients, we found various immunologic anomalies and muscular lipidosis without ragged-red fibers. Eight other family members were clinically normal, but had identical neuroimaging signs of leukoencephalopathy. No abnormality was detected in the 28 other members of the family examined. Extensive investigations failed to reveal any known cause of cerebral ischemia. CONCLUSIONS: There appears to be a new syndrome in this family that is characterized by recurrent subcortical strokelike episodes, leukoencephalopathy, immunologic anomalies, muscular lipidosis, and an autosomal dominant pattern of transmission.     

Alternating hemiplegia of childhood: Studies of regional cerebral blood flow using 99mTc-hexamethylpropylene amine oxime single-photon emission computed tomography

Alternating hemiplegia of childhood is a rare disorder of unknown cause associated with progressive neurological deterioration. We report the results of regional cerebral blood flow studies using ^99mTc-hexamethylpropylene amine oxime single-photon emission computed tomography in 3 patients. These studies were performed during the hemiplegic attacks (n = 6) and during the symptom-free periods (n = 2). Six single-photon emission computed tomographic studies performed during hemiplegic attacks consistently showed relative hyperperfusion of the contralateral cerebral hemisphere. Two single-photon emission computed tomographic studies performed during the asymptomatic phase showed normal and symmetrical cerebral perfusion. This is the first definite demonstration of unilateral increase of cerebral blood flow in alternating hemiplegia. These findings support the possibility of a relationship between the cause of alternating hemiplegia and migraine.