Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition.

BACKGROUND: A novel autosomal recessive condition, dilated cardiomyopathy with ataxia (DCMA) syndrome, has been identified in the Canadian Dariusleut Hutterite population, characterised by early onset dilated cardiomyopathy with conduction defects, non-progressive cerebellar ataxia, testicular dysgenesis, growth failure, and 3-methylglutaconic aciduria. OBJECTIVE: To map DCMA syndrome and identify the mutation underlying this condition. METHODS: A genome wide scan was undertaken on consanguineous Hutterite families using a homozygosity mapping approach in order to identify the DCMA associated chromosomal region. Mutation analysis was carried out on positional candidate genes in this region by sequencing. Reverse transcriptase polymerase chain reaction and bioinformatics analyses were then used to characterise the mutation and determine its effect on the protein product. RESULTS: The association of DCMA syndrome with a 2.2 Mb region of chromosome 3q26.33 was found. A disease associated mutation was identified: IVS3-1 G-->C in the DNAJC19 gene, encoding a DNAJ domain containing protein of previously unknown function (Entrez Gene ID 131118). CONCLUSIONS: The DNAJC19 protein was previously localised to the mitochondria in cardiac myocytes, and shares sequence and organisational similarity with proteins from several species including two yeast mitochondrial inner membrane proteins, Mdj2p and Tim14. Tim14 is a component of the yeast inner mitochondrial membrane presequence translocase, suggesting that the unique phenotype of DCMA may be the result of defective mitochondrial protein import. It is only the second human disorder caused by defects in this pathway that has been identified.

Normal physiological emotions but differences in expression of conscious feelings in children with high-functioning autism.

To provide insight into what aspects of the emotional circuit might be affected in high-functioning autism, we measured indices of physiological emotions and of the expression of conscious feelings in 10 children with high-functioning autism or Asperger syndrome and 10 comparison participants. Pleasant, unpleasant, and neutral pictures were presented while skin conductance responses were measured. Self-report ratings of pleasantness and interestingness were taken between pictures. Skin conductance responses did not differ between the groups. Self report ratings were different, with the children with autism giving more similar answers to the two questions than the comparison children. Impairments in socio-emotional expression in autism may be related to deficits in perception and/or expression of conscious feelings; physiological emotions may be relatively preserved.

Is hyperarousal essential to obsessive-compulsive disorder? Diminished physiologic flexibility, but not hyperarousal, characterizes patients with obsessive-compulsive disorder.

OBJECTIVE: To examine the hypothesis that the pathologic features of obsessive-compulsive disorder (OCD) are facilitated by abnormal levels of arousal, we compared patients with OCD with controls on self-reports and psychophysiologic measures. METHODS: Twenty-three patients with OCD were compared with 21 controls on rating scales and on psychophysiologic measures (ie, heart interbeat interval, skin conductance, respiration, blood pressure, and electromyographic activity) during rest and during two psychologically stressful tasks. RESULTS: Patients rated themselves higher on psychic and somatic anxiety scales. Mean physiologic activities were not elevated at rest. During tasks, changes in electrodermal, cardiovascular (except blood pressure), and muscle activities were smaller in patients with OCD, indicating decreased physiologic flexibility. CONCLUSIONS: Hyperarousal, measured peripherally, is not an essential pathologic feature of OCD. Decreased physiologic flexibility indicates an anxiety-related, but not OCD-specific, impairment of psychophysiologic reactivity to one's environment.

Somatic manifestations in women with generalized anxiety disorder. Psychophysiological responses to psychological stress.

Generalized anxiety disorder is associated with symptoms that suggest heightened muscular tension and autonomic arousal. Since self-reports of physiological states in patients with anxiety disorder are frequently unreliable, we compared 20 female patients with generalized anxiety disorder with a matched group of nonanxious controls on a battery of psychophysiological assessments (skin conductance, heart interbeat interval, blood pressure, respiration, and forehead and gastrocnemius electromyographic activity). We found that during baseline patients with generalized anxiety disorder differed from controls on electromyographic, but not on autonomic, measures. During psychological stress tasks, patients with generalized anxiety disorder showed a weaker mean skin conductance response with a narrower range in both skin conductance and heart rate than controls. These findings suggest that sympathetic inhibition, rather than enhancement, occurs in patients with generalized anxiety disorder during performance stress.

Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas.

BACKGROUND: Paragangliomas are rare and highly heritable tumours of neuroectodermal origin that often develop in the head and neck region. Germline mutations in the mitochondrial complex II genes, SDHB, SDHC, and SDHD, cause hereditary paraganglioma (PGL). METHODS: We assessed the frequency of SDHB, SDHC, and SDHD gene mutations by PCR amplification and sequencing in a set of head and neck paraganglioma patients who were previously managed in two otolaryngology clinics in the USA. RESULTS: Fifty-five subjects were grouped into 10 families and 37 non-familial cases. Five of the non-familial cases had multiple tumours. Germline SDHD mutations were identified in five of 10 (50%) familial and two of 37 ( approximately 5%) non-familial cases. R38X, P81L, H102L, Q109X, and L128fsX134 mutations were identified in the familial cases and P81L was identified in the non-familial cases. Both non-familial cases had multiple tumours. P81L and R38X mutations have previously been reported in other PGL families and P81L was suggested as a founder mutation. Allelic analyses of different chromosomes carrying these mutations did not show common disease haplotypes, strongly suggesting that R38X and P81L are potentially recurrent mutations. Germline SDHB mutations were identified in two of 10 (20%) familial and one of 33 ( approximately 3%) non-familial cases. P131R and M71fsX80 were identified in the familial cases and Q59X was identified in the one non-familial case. The non-familial case had a solitary tumour. No mutations could be identified in the SDHC gene in the remaining four families and 20 sporadic cases. CONCLUSIONS: Mutations in SDHD are the leading cause of head and neck paragangliomas in this clinic patient series. SDHD and SDHB mutations account for 70% of familial cases and approximately 8% of non-familial cases. These results also suggest that the commonness of the SDHD P81L mutation in North America is the result of both a founder effect and recurrent mutations.

Somatic symptoms of anxiety: comparison of self-report and physiological measures.

The frequently reported absence of significant correlations between patient rating scales and physiological measures has led to the belief that patients cannot reliably perceive physiological changes that are experienced under conditions of stress. To determine whether or not this conclusion is justified for patients with clinical anxiety, self-reports and psychophysiological recordings were examined and compared in 20 patients suffering from generalized anxiety disorder. No systematic correlations were found between patient ratings and physiological measures of somatic symptomatology during periods of rest or psychological stress (Stroop Test). However, parallel directional changes in the two sets of measures were observed upon exposure to stress, indicating that patients could accurately report the direction, but not the degree, of changes in physical symptoms of anxiety. These results suggest that patient reports of physical symptoms such as sweating and rapid heart rate can be useful in clinical evaluation and research settings that do not require quantitative assessment of physiological activity.

The effects of NMDA receptor blockade on the acquisition of a conditioned emotional response.

Excitatory amino acids, acting at the N-methyl-d-aspartate (NMDA) receptor, have been postulated to play an important role in the acquisition of behavior (learning). Previous studies have shown that some forms of response acquisition can be impaired by drugs that block the NMDA receptor. To determine whether excitatory amino acid blockade could also affect the ability to acquire an emotional response, the effects of the noncompetitive NMDA receptor antagonist MK-801 were studied on the development of response suppression under a conditioned emotional response (CER) procedure in the rat. The CER procedure progressively suppressed responding when saline was given prior to the eight daily sessions over which animals were initially exposed. Daily treatment with MK-801 blocked the development of response suppression. Thus, these data are consistent with the notion that excitatory amino acid blockade prevents or diminishes the development of a learned emotional response. This suggests a potential role for this receptor in the development of anxiety-related disorders in humans.

Treatment effects of alprazolam and imipramine: physiological versus subjective changes in patients with generalized anxiety disorder.

The correspondence between changes in physiological activity and somatic symptom reports was assessed in generalized anxiety disorder patients treated with alprazolam or imipramine. After 6 weeks, the two medications produced comparable reductions in self-reported somatic symptoms. However, patients taking alprazolam showed decreases in systolic blood pressure, epinephrine, and norepinephrine, and patients taking imipramine showed increases in heart rate, blood pressure, electromyographic activity, and norepinephrine. Thus, though the physiological changes associated with alprazolam treatment were consistent with changes in symptom reports, treatment with imipramine produced a desynchrony: patients reported significant decreases in cardiovascular symptoms and muscle tension in spite of the fact that heart rate, blood pressure, and electromyographic activity increased. Possible explanations for this counterintuitive phenomenon are discussed.

Symptoms and treatment responses of generalized anxiety disorder patients with high versus low levels of cardiovascular complaints.

Clinical observations suggest that patients with generalized anxiety disorder differ in somatic symptoms. The authors compared 28 patients with generalized anxiety disorder who had high levels of cardiovascular complaints with 32 patients with generalized anxiety disorder who had low levels of cardiovascular complaints on rating instruments, physiological measures, and use of anxiolytic medication. The two groups differed on somatic but not psychic symptoms on rating instruments. Patients with high levels of cardiovascular symptoms had higher levels of cardiac lability and required higher doses of alprazolam. These findings suggest that anxious patients with comparable levels of psychic anxiety may differ in levels of physical symptoms.

Cardiac symptoms and anxiety disorders: contributing factors and pharmacologic treatment.

Anxiety may have deleterious effects on the cardiovascular system in persons who have, or are predisposed to have, cardiovascular disease. Contributing factors consist of the type of anxiety, constitutional characteristics and personality traits. The treatment of anxiety thus has a beneficial effect on patients with cardiovascular disease. However, anxiety reduction through medication, even if it includes subjective improvement in somatic symptoms, should not necessarily be equated with beneficial effects on the cardiovascular system. Three groups of medication used in the treatment of anxiety have different effects. Antidepressants lower psychic anxiety but may have the opposite effect on the cardiovascular system, whereas beta-adrenergic blockers lower sympathetic tone without affecting psychic anxiety. Only benzodiazepines fulfill both functions. Since subjective reports of somatic, including cardiovascular, changes correlate poorly with physiologic changes, assessment of new medications should not rely on self-reported improvement in cardiac symptoms but should include objective measures as well.

Asymmetry quantification utilizing hand radiographs.

Asymmetry can be either directional or fluctuating. Detection of abnormal amounts of asymmetry has important implications for clinical diagnosis, but measurement of subtle levels is very difficult. We describe a method and normative values for asymmetry quantification using hand radiographs.

Multiple malformations and exposure to therapeutic ultrasound during organogenesis.

We present a case of sacral agenesis, microcephaly, and developmental delay. The pregnancy with this child was complicated by left psoas bursitis that was treated by 18 applications of ultrasound between days 6 and 29 of gestation.

VACTERL manifestations in two generations of a family.

Most cases of the VACTERL "association" [Martinez-Frias et al., Am. J. Med. Genet. 76: 291-296, 1998] are sporadic, with an empiric recurrence risk of 1% or less. Rare families with recurrence of VACTERL-H association are described with patterns consistent with single gene inheritance. Also described are occasional single anomalies of the VACTERL association in sibs or parents of affected individuals. We describe a mother and son with typical VACTERL anomalies. The patient was born by cesarean section to a 27-year-old G1 mother following an uncomplicated pregnancy. He was found to have an asymmetric crying face, preaxial polydactyly on the right, a small midmuscular ventricular septal defect with an incomplete right bundle branch block on echocardiogram, a small cleft in T3, and incomplete development of the left half of the sacrum. The kidneys were normal ultrasonographically. The patient's mother was born with an H-type tracheo-esophageal fistula, imperforate anus, rectovaginal fistula, a triphalangeal thumb, hypoplastic left kidney, and vertebral anomalies. There were no other individuals with VACTERL anomalies in the family. No families with VACTERL association in the offspring of an affected individual have been reported previously.

Combination of renal agenesis with respiratory and alimentary tract atresia results in normal lung development.

The VACTERL complex comprises renal agenesis and atresias of the alimentary and respiratory tracts. We report on a case with this combination causing severe oligohydramnios but with normal lung development. The likely protective mechanism for pulmonary development was an increase in alveolar pressure and reduced alveolar fluid loss due to the esophageal-tracheal malformation. This suggests the possible treatment of oligohydramnios by tracheal occlusion.

Autosomal dominant hypoparathyroidism with intracranial calcification outside the basal ganglia.

We describe a family with autosomal dominant hypoparathyroidism. The 3 affected individuals had no detectable serum parathyroid hormone on radioimmunoassay. The propositus presented with seizures and on CT scan had bilateral basal ganglion calcification and calcification in the frontal lobes. His similarly affected mother had even more intracerebral calcification. The latter manifestation has not been described previously in autosomal dominant hypoparathyroidism.

CAMPS: computer-automated metacarpophalangeal profile system.

The metacarpophalangeal profile (MCP) pattern has been proven useful in describing individuals with genetic and nongenetic syndromes. However, the measurement of the 19 bone lengths is a tedious procedure requiring use of hand vernier calipers, detailed normative data to be looked up in extensive tables, hand calculator, and manual graphing techniques. Presently there are no reports of microcomputer-automated systems for the accurate measurement, recording, analysis, and graphing of MCP profiles. We describe a computer-automated metacarpophalangeal profile system (CAMPS) that will assist in the derivation of the MCP profile. This program allows the user to select different program routines that perform the functions necessary for MCP profile construction. The "data acquisition module" (DAM) assists in bone length measurement from contact prints of hand radiographs and stores the 19 measurements on a floppy disk. The "standardization analysis module" (SAM) then compares the 19 measurements to age- and sex-matched normal data and converts the raw data to z-score values. The "Pearson product-moment correlation module" (PPM) generates a correlation coefficient describing the degree of similarity between the two hands measured and graphically illustrates the resulting scatterplot. The "MCP plotting module" (MCPM) provides a graphic plot of the 19 bones in either transverse rows or phalangeal rays on a dot-matrix printer or X-Y plotter.

Metacarpophalangeal pattern profile analysis in Williams syndrome.

Many patients with Williams syndrome (WS) are not diagnosed until they are old enough to demonstrate the characteristic personality and facial changes. A number of these changes are quite subtle and none of them is present in all affected individuals. The cause of WS remains obscure and consequently, there are no cytogenetic, biochemical, or molecular studies to help in the diagnosis of patients in whom the diagnosis is uncertain. We have generated a mean WS metacarpophalangeal pattern profile (MCPP) on 21 clinically diagnosed individuals with WS. This mean syndrome profile shows that WS hands are smaller than average age-matched control hands and that the distal phalanx of the thumb is disproportionately large with respect to the rest of the hand. A mathematical model, which effectively discriminates WS patients from unaffected control individuals, was developed using discriminant analysis of the MCPP data. Of the 21 WS patients classified by this method, only 2 were misclassified as "normal." Similarly, 2 of the 24 control individuals were misclassified as "WS," yielding an over-all successful classification rate of 91%.

Chromosome 6q deletions: a report of two additional cases and a review of the literature.

Here we report on two additional cases of distal 6q deletions with one case showing a terminal deletion of chromosome 6 (46,XY, del(6)(pter----q26:)) and one case showing an interstitial deletion of chromosome 6 (46,XY, del(6)(pter----q23::q25----qter)). The association of retinal abnormalities in 6q deletions is supported, and the additional manifestations of skin hyperextensibility, sacral abnormality, and imperforate anus are described.

Metacarpophalangeal pattern profile analysis in fragile X syndrome.

We analyzed the metacarpophalangeal pattern profile (MCPP) on 18 male individuals from 16 families with fragile X--fra (X), or Martin-Bell--syndrome and calculated a mean syndrome profile. Fourteen of 18 individuals with fra (X) syndrome had significant positive correlations which indicated clinical homogeneity. Discriminant analysis of individuals with fra (X) syndrome compared with a sample of normal individuals produced a correct classification rate of 88% based on a function of 3 MCPP variables that may provide a useful tool in screening individuals for the fra (X) syndrome. Discriminant and correlation analyses of individuals with Sotos sequence and individuals with fra (X) syndrome did not identify MCPP similarities. Therefore, there was no MCPP evidence in our study of patients with Sotos sequence and fra (X) chromosome expression.

Polytopic anomalies with agenesis of the lower vertebral column.

We describe clinical, pathological and radiological findings in 15 cases of sporadic and familial lower spine agenesis with additional anomalies of the axial skeleton and internal organs and speculate about the cause and pathogenesis of this malformation complex. We show that all of these findings are defects of blastogenesis, originate in the primary developmental field and/or the progenitor fields, thus representing polytopic field defects. This concept appears applicable in our cases and makes such terms such as "caudal regression syndrome" or "axial mesodermal dysplasia spectrum" redundant.