The X-linked infantile spasms syndrome (Mim 308350) maps to Xp 11.4–Xpter in two pedigrees

We report 2 families with X-linked infantile spasms syndrome (X-linked West syndrome). Data from clinical examination, biochemical analysis, neuroimaging, and neuropathology are discussed. In these families, genetic linkage analysis was able to locate the disease gene to the distal part of the short arm of the X chromosome, between Xpter and Xp11.4. This is the first report of linkage with genetic markers in this disorder. Although most cases are sporadic, further unraveling of the genetic background of the familial cases might greatly improve our understanding of infantile spasms.     

A novel form of distal hereditary motor neuronopathy maps to chromosome 9p21.1-p12

Distal hereditary motor neuronopathies (dHMNs) form a heterogeneous group of rare disorders characterized by distal weakness and wasting in the limbs with no significant sensory involvement. Harding has classified dHMNs into seven categories based on clinical and genetic criteria. We report a novel form of autosomal recessive dHMN in 7 consanguineous families located in the Jerash region of Jordan. Onset of the disease is between 6 and 10 years of age and is characterized by weakness and atrophy of the lower limbs associated with pyramidal features. Within 2 years, symptoms progress to the upper limbs. Neurophysiological studies typically show normal conduction velocities, reduced compound motor action potential amplitudes, normal sensory nerve action potentials, and chronic neurogenic changes on needle electromyography. No significant abnormalities are seen on sural nerve biopsy. We call this novel form of dHMN Jerash hereditary motor neuronopathy. We studied the families at the molecular genetic level and mapped the Jerash hereditary motor neuronopathy gene to an approximately 0.54-cM region on chromosome 9p21.1-p12, flanked by microsatellite polymorphic marker loci D9S1845 and D9S1791. A maximum LOD score of 19.80 at theta = 0.001 was obtained between the disease and locus D9S1878.     

A Turner syndrome neurocognitive phenotype maps to Xp22.3

Background  

Turner syndrome (TS) is associated with a neurocognitive phenotype that includes selective nonverbal deficits, e.g., impaired visual-spatial abilities. We previously reported evidence that this phenotype results from haploinsufficiency of one or more genes on distal Xp. This inference was based on genotype/phenotype comparisons of individual girls and women with partial Xp deletions, with the neurocognitive phenotype considered a dichotomous trait. We sought to confirm our findings in a large cohort (n = 47) of adult women with partial deletions of Xp or Xq, enriched for subjects with distal Xp deletions.     

Autosomal dominant cerebellar ataxia with retinal degeneration (ADCA II): clinical and neuropathological findings in two pedigrees and genetic linkage to 3p12-p21.1.

OBJECTIVES: To investigate relations between clinical and neuropathological features and age of onset, presence of anticipation, and genetic linkage in autosomal dominant cerebellar ataxia type II (ADCA II). METHODS: The natural history of ADCA II was studied on the basis of clinical and neuropathological findings in two pedigrees and genetic linkage studies were carried out with polymorphic DNA markers in the largest, four generation, pedigree. RESULTS: Ataxia was constant in all age groups. Retinal degeneration with early extinction of the electroretinogram constituted an important component in juvenile and early adult (< 25 years) onset but was variable in late adult presentation. Neuromuscular involvement due to spinal anterior horn disease was an important contributing factor to illness in juvenile cases. Postmortem findings in four patients confirm the general neurodegenerative nature of the disease, which includes prominent spinal anterior horn involvement and widespread involvement of grey and white matter. Genetic linkage was found with markers to chromosome 3p12-p21.1 (maximum pairwise lod score 4.42 at D3S1285). CONCLUSIONS: The sequence of clinical involvement seems related to age at onset. Retinal degeneration is variable in late onset patients and neuromuscular features are important in patients with early onset. Strong anticipation was found in subsequent generations. Linkage of ADCA II to chromosome 3p12-p21.1 is confirmed.     

X-chromosome-linked ichthyosis associated to epilepsy, hyperactivity, autism and mental retardation, due to the Xp22.31 microdeletion

X-chromosome-linked ichthyosis is caused by mutation or deletion of the STS gene associated with a deficiency of the enzyme steroid sulphatase, located in the distal part of the short arm of the X chromosome (Xp22.3-pter), close to the pseudo-autosomal region. Depending on its size, it can present as an isolated entity or combined with a syndrome caused by neighbouring genes, thus associating itself with other monogenic diseases as well as other mental disorders. The most relevant findings from the literature review are the importance of the Xp22.3-pter region and the higher incidence of neurological disorders among males (attention deficit hyperactivity disorder, autism and X-linked mental retardation). The role and implication of these genes in the disease are discussed and the authors suggest a possible contribution of the gene PNPLA4, which was originally described as GS2 and codes for calcium-independent phospholipase A2 beta, involved in lipoprotein metabolism, as one of the causes of autism. Improvements have been observed following treatment with citicoline, thanks to the role this nootropic plays in the biosynthesis of structural phospholipids involved in the formation and repair of the neuronal membrane.     

Urodynamic evaluation of patients with autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24

OBJECTIVES—There are at least threeclinically indistinguishable but genetically different types ofautosomal dominant pure spastic paraplegia (ADPSP). Lower urinary tractsymptoms are often present but have not been described in a homogeneouspatient population. In this study lower urinary tract symptoms,cystometrical, and neurophysiological characteristics are described inpatients with ADPSP linked to chromosome 2p21-p24.
METHODS—Lower urinary tract symptoms were recordedat an interview and according to a formalised questionnaire. Elevenpatients were clinically evaluated and cystometry, measurements of thecutaneous perception threshold, bulbocavernosus reflex latency, andsomatosensory evoked potentials (SSEPs) of the pudendal nerve were performed.
RESULTS—All patients experienced urinaryurgency or urge incontinence. Rectal urgency and sexual dysfunctionwere reported by most patients. The cystometrical findings showed amixed pattern of bladder dysfunction. The SSEPs were normal in all butthe bulbocavernosus reflex latency was significantlyprolonged in seven patients and the cutaneous perception threshold wasraised in five patients.
CONCLUSIONS—Lower urinary tract symptoms andprobably also bowel and sexual dysfunction in patients with ADPSPlinked to chromosome 2p21-p24 are due to a combination of somatic andautonomic nervous system involvement which support the proposedmultisystem affection in ADPSP linked to chromosome 2p21-p24.

     

Ramsay Hunt syndrome with mental disorder.

This is a case of Ramsay Hunt syndrome with mental disorder. The patient had action myoclonus, grand mal seizure and severe cerebellar ataxia. Schizophrenia-like symptoms including delusion of persecution and self-reference, auditory hallucination and incoherence were characteristically observed before the neurological disturbance became manifest. Subsequently, euphoria, disinhibition, moria and mild dementia appeared with neurological symptoms. The possibility of Ramsay Hunt syndrome to accompany organic mental syndromes and the relationship between cerebellar dysfunction and psychiatric symptoms are discussed.     

Sleep patterns in mental retardation: Down's syndrome.

EEG and eye movements during two consecutive nights were recorded in 21 "normal" and 21 Down's subjects of both sexes in the 14-24-year age range. Records of most Down's subjects were characterized by longer total sleep time, lack of waking alpha, frequent awakening and movement epochs and fewer spindle bursts. Significantly longer "awake" and stage 4 percentages, but less stage 2, were found in the Down's group. They also had longer REM latency, and lower eye movement density based on number of eye movements. Density based on integrated eye activity correlated positively with IQ in the Down's subjects. Spectrum analysis for EEG frequencies from 1 to 20 c/sec showed significantly greater power in the Down's group below 9 and above 12 c/sec, but no difference in the alpha range. The greater power at low frequencies was more pronounced in "awake", stage 1 and REM.     

Aggressive behavior linked to corticotropin-reactive autoantibodies.

BACKGROUND: Altered stress response is characteristic for subjects with abnormal aggressive and antisocial behavior, but the underlying biological mechanisms are unclear. We hypothesized that autoantibodies (autoAbs) directed against several stress-related neurohormones may exist in aggressive subjects. METHODS: Using enzyme-linked immunosorbent assay, we studied whether autoAbs directed against corticotropin (ACTH), alpha-melanocyte-stimulating hormone (alpha-MSH), oxytocin, and vasopressin are present in serum of male subjects with conduct disorder and prisoners with history of violence. Healthy blood donors served as control subjects. RESULTS: Both conduct disorder and prisoners groups displayed strongly increased levels of ACTH-reactive immunoglobulin G (IgG) and immunoglobulin M (IgM) autoAbs compared with control subjects. Levels of oxytocin-reactive IgM autoAbs were slightly increased in both groups of aggressive subjects, whereas levels of vasopressin-reactive IgG and IgM autoAbs were lower only in conduct disorder. No differences in the levels of alpha-MSH-reactive autoAbs were found between aggressive and control subjects. CONCLUSIONS: High levels of ACTH-reactive autoAbs as well as altered levels of oxytocin- and vasopressin-reactive autoAbs found in aggressive subjects may interfere with the neuroendocrine mechanisms of stress and motivated behavior. Our data suggest a new biological mechanism of human aggressive behavior that involves autoAbs directed against several stress-related neurohormones.     

Cortically evoked motor responses in patients with Xp22.3-linked Kallmann's syndrome and in female gene carriers.

Patients with Kallmann's syndrome show hypothalamic hypogonadism, hyposmia, and congenital mirror movements. As a correlate, a defect of gonadotropic neuron migration into the brain was recently detected. Considering abnormal outgrowth of neurons also as a possible substrate underlying mirror movements, we studied 3 patients and 2 asymptomatic female gene carriers from a kindred with proven linkage to Xp22.3, using focal transcranial magnetic stimulation of motor cortex hand areas with a figure-eight coil. In all 3 affected brothers, bilateral responses could be evoked almost simultaneously in their thenar muscles (slight latency differences were statistically insignificant). In contrast, the mother and the maternal aunt showed only unilateral, normal thenar responses, even with maximum tolerable stimulator output and high signal amplification. Correspondingly, mirror movements were present in the patients, but not in the gene carriers. Bilaterality of cortically evoked hand muscle responses and mirror movements, therefore, behaved as X-chromosomal recessive traits. A likely cause might be a disorder of neuronal outgrowth in the motor system, particularly of inhibitory callosal fibers. For normal anatomical development of the motor system, one intact Xp22.3 gene seems necessary.     

Autopsy case of acute encephalopathy linked to familial hemiplegic migraine with cerebellar atrophy and mental retardation

A 19‐year‐old female patient, who had exhibited esotropia, mild cerebellar ataxia, mild mental retardation, and cerebellar atrophy on magnetic resonance images at the age of 15, developed signs of acute encephalopathy, and thereafter died of disseminated intravascular coagulation on the day of her admission. Both her mother and sister suffered from attacks of hemiplegic migraine, mild mental retardation, and cerebellar ataxia. Neuropathological examinations revealed acute changes in the widespread cerebral cortex, chronic degenerative changes in the anterior lobe of the cerebellar vermis, axonal spheroids in the Goll's nucleus, pseudo‐calcinosis in the globus pallidus, and glial bundles in the cranial nerves. The most fascinating features were changes of Purkinje cells, such as cactuses (asteroid bodies, dendritic expansions), somatic sprouts, and torpedoes. These changes may be characteristic of familial hemiplegic migraine with cerebellar atrophy, as well as the other metabolic diseases, such as Menkes’ kinky hair disease, infantile (Tay–Sachs type) amaurotic idiocy, organic mercury intoxication, and mitochondrial encephalopathy, of which cases often exhibit such pathological changes of Purkinje cells. Therefore, familial hemiplegic migraine may share some metabolic abnormalities with the diseases mentioned above.     

Gilles de la Tourette syndrome is not linked to D2-dopamine receptor

Gilles de la Tourette syndrome has an important genetic component; the pathophysiology of this disorder may involve the dopamine system. We tested a D2-dopamine receptor (locus DRD2, recognized by probe hD2G1) for genetic linkage with Gilles de la Tourette syndrome. Using a genetic linkage map of the region of DRD2 on the long arm of chromosome 11 and restriction fragment length polymorphism data from a total of four markers (DRD2 itself, D11S84, D11S29, and PBGD), we were able to exclude linkage of this candidate gene and Gilles de la Tourette syndrome in two extended kindreds segregating for Gilles de la Tourette syndrome. This rules out causation of Gilles de la Tourette syndrome by mutation in DRD2 in the kindreds studied under the genetic assumptions we employed; use of the map and multipoint linkage analyses also allowed us to exclude a Gilles de la Tourette syndrome susceptibility locus from a larger genetic region.     

Dropped head syndrome in severe intractable epilepsies with mental retardation.

PURPOSE: Dropped head syndrome is characterized by a gradual forward sagging of the head due to the isolated weakness of the neck extensor muscles. The syndrome has a relatively benign clinical course. To date, there have been no reports of dropped head syndrome in epileptic patients. METHODS: Nine patients with intractable epilepsy (mean age, 33.6+/-9.91 years), each presenting with apparent dropped head, were evaluated. The duration of the drooping head symptom varied from 3 to 15 years (mean, 7.4+/-4.06 years), with a slowly progressing weakness in most of the patients. In all of the patients, extensive clinical, laboratory, electrophysiological, histopathological, and neuroimaging examinations were performed. RESULTS: The weakness in all of the subjects was strictly limited to the cervical paraspinal muscles. Laboratory studies produced normal results from all subjects. EMG and muscle biopsy were normal or revealed subtle nonspecific myopathic changes without inflammation in the cervical paraspinal muscles. Polymyographic investigation revealed that none of the patients had convincing dystonic spasms of the anterior neck muscles. No atrophy or fatty changes of the neck extensor muscles were observed on CT or MRI. In most of the patients (7/9), altered L-carnitine concentrations were observed (four patients displayed a marked decrease in plasma carnitine concentrations, and three other patients showed abnormalities in urinary excretion of carnitine). CONCLUSIONS: These findings seem to suggest that a secondary carnitine deficiency, induced by antiepileptic drugs (principally valproic acid), represents a plausible pathogenetic mechanism for the development of dropped head in some epileptic patients.     

Partial epilepsy syndrome in a Gypsy family linked to 5q31.3-q32

Purpose:   The restricted genetic diversity and homogeneous molecular basis of Mendelian disorders in isolated founder populations have rarely been explored in epilepsy research. Our long-term goal is to explore the genetic basis of epilepsies in one such population, the Gypsies. The aim of this report is the clinical and genetic characterization of a Gypsy family with a partial epilepsy syndrome.
Methods:   Clinical information was collected using semistructured interviews with affected subjects and informants. At least one interictal electroencephalography (EEG) recording was performed for each patient and previous data obtained from records. Neuroimaging included structural magnetic resonance imaging (MRI). Linkage and haplotype analysis was performed using the Illumina IVb Linkage Panel, supplemented with highly informative microsatellites in linked regions and Affymetrix SNP 5.0 array data.
Results:   We observed an early-onset partial epilepsy syndrome with seizure semiology strongly suggestive of temporal lobe epilepsy (TLE), with mild intellectual deficit co-occurring in a large proportion of the patients. Psychiatric morbidity was common in the extended pedigree but did not cosegregate with epilepsy. Linkage analysis definitively excluded previously reported loci, and identified a novel locus on 5q31.3-q32 with an logarithm of the odds (LOD) score of 3 corresponding to the expected maximum in this family.
Discussion:   The syndrome can be classified as familial temporal lobe epilepsy (FTLE) or possibly a new syndrome with mild intellectual deficit. The linked 5q region does not contain any ion channel–encoding genes and is thus likely to contribute new knowledge about epilepsy pathogenesis. Identification of the mutation in this family and in additional patients will define the full phenotypic spectrum.