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.     

Autosomal dominant episodic ataxia: a heterogeneous syndrome

We describe six kindreds with autosomal dominant episodic ataxia, apparently representing three distinct syndromes. Four kindreds were characterized by episodic ataxia and response to acetazolamide, and in three, interictal nystagmus. One kindred was characterized by paroxysmal ataxia and in one member, paroxysmal choreoathetosis. The last kindred had brief attacks of ataxia and interictal neuromyotonia. The age of onset and severity of the disorder varied within each kindred. These kindreds illustrate the heterogeneity of episodic ataxia as well as the variable expressivity within each kindred.     

Autosomal dominant muscle cramp syndrome in a Japanese family

OBJECTIVES: To identify the clinical, electrophysiological, histological, and genetic characteristics of a Japanese family with a muscle cramp syndrome. METHODS: Fourteen patients (eight men, six women) were studied in four generations of a single family. Electrophysiological examinations were performed in four cases and muscle and nerve biopsies were performed on the propositus. RESULTS: The mode of inheritance seemed to be autosomal dominant. The cramps occurred during both exertion and at rest, and during sleep. Electromyographic examination indicated a neurogenic aetiology. There was a decreased number of large myelinated fibres in the sural nerve, and fibre type grouping in the quadriceps femoris muscle biopsy. CONCLUSIONS: The autosomal dominant muscle cramp syndrome in this family is probably caused by a polyneuropathy.     

Autosomal dominant glut-1 deficiency syndrome and familial epilepsy

Glut-1 deficiency syndrome was first described in 1991 as a sporadic clinical condition, later shown to be the result of haploinsufficiency. We now report a family with Glut-1 deficiency syndrome affecting 5 members over 3 generations. The syndrome behaves as an autosomal dominant condition. Affected family members manifested mild to severe seizures, developmental delay, ataxia, hypoglycorrhachia, and decreased erythrocyte 3-O-methyl-D-glucose uptake. Seizure frequency and severity were aggravated by fasting, and responded to a carbohydrate load. Glut-1 immunoreactivity in erythrocyte membranes was normal. A heterozygous R126H missense mutation was identified in the 3 patients available for testing, 2 brothers (Generation 3) and their mother (Generation 2). The sister and her father were clinically and genotypically normal. In vitro mutagenesis studies in Xenopus laevis oocytes demonstrated significant decreases in the transport of 3-O-methyl-D-glucose and dehydroascorbic acid. Xenopus oocyte membranes expressed high amounts of the R126H mutant Glut-1. Kinetic analysis indicated that replacement of arginine-126 by histidine in the mutant Glut-1 resulted in a lower Vmax. These studies demonstrate the pathogenicity of the R126H missense mutation and transmission of Glut-1 deficiency syndrome as an autosomal dominant trait.     

Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive myoclonus-dystonia syndrome

The authors report a kindred in which GTP-CH deficiency resulted in a myoclonus-dystonia syndrome. The proband, a 17-year-old boy, presented with early-onset myoclonus and later, dystonia and bradykinesia. Blood prolactin was increased and CSF homovanillic acid, 5-hydroxyindoleacetic acid, and biopterin were all reduced. L-Dopa/carbidopa administration resulted in clinical improvement. In the paternal branch, the grandfather and three relatives had myoclonus-dystonia and resting or postural tremor of limbs. The authors found a missense mutation in the exon 6 of GCH-1 gene (K224R).     

Autosomal dominant congenital Horner''s syndrome in a Dutch family.

A Dutch family is reported with congenital Horner's syndrome in five cases spanning five generations, with symptoms of varying degree but mainly ptosis and meiosis. Heterochromia iridium, anhidrosis, and enophthalmos were not present. The site of the lesion may be in the region between Gasser's ganglion and the short vertical segment of the internal carotid artery near the siphon. There are only four previous reports showing autosomal dominant inheritance of congenital Horner's syndrome.     

Autosomal dominant nocturnal frontal lobe epilepsy: the syndrome]

The identification of the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in 1994 was rapidly followed by that of other familial forms of non lesional partial epilepsies (familial temporal lobe epilepsy, autosomal dominant partial epilepsy with variable foci). Since then around forty families with ADNFLE have been described, most of them having only 3 or 4 affected individuals. The epilepsy usually begins during childhood (mean age at onset: 11 years). The seizures mainly consist of motor elements which can be dystonic, tonic or hyperkinetic (bipedal automatisms, pelvic thrashing movements...), often preceded by a non specific aura. They are brief and frequent, taking place at night, in clusters. Some patients also present some diurnal seizures. One third of the patients report the occurrence of rare secondarily generalized tonic-clonic seizures. There is a large intra-familial variability as to age of onset, intensity of the manifestations and the course of the epilepsy. During the period of highest frequency of seizures, some patients may present moderate neuropsychological disturbances concordant with frontal dysfunctioning, or transitory behavioral disorders. The seizures often subside with age and may even disappear at adulthood. The most effective antiepileptic drug is carbamazepine, however pharmacoresistance is seen in 20 to 30 p. 100 of the cases. Interictal EEG shows non specific epileptiform anomalies with a frontal predominance, often seen solely on sleep recording, in more than half of all patients. Ictal EEG does not always give evidence of definite ictal discharges. The clinical heterogeneity of ADNFLE as it is especially observed in very variable types of auras which are non localizing, aside form the EEG's own limits, makes it difficult to localize the primary epileptic focus with certainty in the frontal lobe in all cases. In all, the clinical and electrical spectrum of ADNFLE is large, and the topographical identification of these familial frontal lobe epilepsies sets the same problems as for sporadic, classical cryptogenic frontal lobe epilepsies.     

Autosomal dominant Parkinson's disease

Over the past two decades the understanding and classification of Parkinson's disease (PD) has been revolutionized by genetic research. Currently, sixteen PARK loci have been identified with autosomal dominant genes such as SNCA, and LRRK2, and autosomal recessive genes such as PRKN, DJ-1, and PINK1. Among these genes, LRRK2 is the most prevalent. Additionally, susceptibility variants located on some of these genes are widely recognized as risk factors for PD in certain ethnic populations. Alpha synuclein Lewy body (LB) pathology, the hallmark of sporadic PD, is predominantly seen in carriers of SNCA and LRRK2. Recently two new autosomal dominant PD genes have been discovered, eukaryotic translation initiation factor 4-gamma (EIF4G1) and vacuolar protein sorting 35 (VPS35). EIF4G1 is associated with LB pathology; however, only limited data currently exists on pathology of the VPS35. Thus, it remains to be seen if LB pathology can be identified on autopsy examination of carriers of VPS35 gene. The mechanism behind the cause of PD has yet to be elucidated; however, genetic studies on autosomal dominant PD have provided novel insights into the potential etiology of PD. Thus, paving the way for future targeted therapies aimed at disease prevention and cure.     

Autosomal dominant holocalvarial craniosynostosis

Isolated holocalvarial synostosis with normal intelligence is described in two pairs of sibs from one kindred. Diagnosis was delayed until the age of 5 years in the proband. The gene carriers were asymptomatic and had no head deformity. The genetic pattern is consistent with autosomal dominant inheritance.     

Autosomal dominant cerebellar ataxias

Cerebellar ataxias with autosomal dominant transmission (ADCA) are far rarer than sporadic cases of cerebellar ataxia. The identification of genes involved in dominant forms has confirmed the genetic heterogeneity of these conditions and of the underlying mechanisms and pathways. To date, at least 28 genetic loci and, among them, 20 genes have been identified. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes more complex multisystemic neurological deficits. Seven ADCA (SCA1, 2, 3, 6, 7, 17, and dentatorubro-pallido-luysian atrophy) are caused by repeat expansions in the corresponding proteins; phenotype-genotype correlations have shown that repeat size influences the progression of the disease, its severity and clinical differences among patients, including the phenomenon of anticipation between generations. All other ADCA are caused either by non-coding repeat expansions, conventional mutations or large rearrangements in genes with different functions. This review will focus on the genetic features of ADCA and on the clinical differences among the different forms.     

Autosomal dominant cramping disease

A family was studied in which four generations (16 of 41 members) suffered from painful recurrent muscle cramping. A clear pattern of autosomal dominant inheritance was noted. The cramping first developed during adolescence or early adulthood. Electromyographic analysis indicated a neurogenic origin. The cramps seemed to be due to dysfunction of the motor neurons. The mechanisms underlying this alteration are unclear and require further investigation.     

Autosomal dominant humeroperoneal myopathy

Emery-Dreifuss muscular dystrophy is a syndrome with five salient features: early and unusual contractures; humeroperoneal muscle wasting; the slow progression of weakness, beginning in childhood; cardiac conduction defects; and X-linked inheritance. We present two cases and detail other reports with a similar constellation of findings with apparent autosomal dominant inheritance. We postulate separate genetic disorders with similar phenotypic expression.     

Autosomal dominant occipital cephalocele

The authors report the clinical and radiographic characteristics of a non-consanguineous Vietnamese kindred with an autosomal dominant form of occipital cephalocele. Affected family members all presented with occipital subscalp bulges at birth. Except for the proband, all individuals were developmentally normal with otherwise normal neurologic examinations. Unaffected family members, including obligate carriers, share no clinical characteristics, demonstrating incomplete penetrance.     

Autosomal dominant centronuclear myopathy]

In a family 6 members in 3 generations were affected by centronuclear myopathy (CNM) of autosomal dominant inheritance. The apparent onset was in the early forties and the disease progressed slowly. Limb weakness was predominant. Strabismus was present in 5 cases and calves hypertrophy in 3. Serum creatinine kinase was always within the normal range. In one case myotonic bursts were found at electromyography. In 2 cases brain stem auditory evoked potential studies demonstrated abnormal prolongation of interpeak latencies I-III and favoured subclinical nervous system involvement. Muscular biopsies showed typical features of centronuclear myopathy with 50 to 80% central nuclei. In two cases immunocytochemical labelling of dystrophin showed staining in the sarcoplasm in favour of an arrest in the morphogenesis of developing myofiber. Others families with autosomal dominant CNM in the literature and also some sporadic adult cases had similar clinical features.     

Autosomal dominant multicore disease.

Two girls and their mother with multicore myopathy are described. The cores consisted of Z band disorganisation and decreased or absent enzyme activity. Only one case has clinical signs of myopathy. Muscle enzyme activity was elevated in the two children. The mode of inheritance was autosomal dominant.     

Autosomal dominant spinocerebellar ataxia]

The modern classification is presented based on genetic criteria of the group of degenerative nervous system diseases inherited as autosomal dominant trait and called collectively spinocerebellar ataxia (SCA). They belong mostly to the class of diseases of similar mutation mechanism in which amplification is present of the trinucleotide sequence (CAG)n. Clinical picture and neuropathological changes in various SCA types are compared.