Felicia B. Axelrod

Normative values of vibratory perception in 530 children, juveniles and adults aged 3–79 years

Impaired vibratory perception is an early and frequent finding in various neuropathies. Quantitative vibratory threshold assessment refines the diagnosis of neuropathies but is based on psychophysical techniques requiring patient cooperation. Large, age and sex matched normative data bases are needed to better identify abnormal vibratory perception. In this study vibratory perception was tested at the second metacarpal bone and above the first metatarsal bone of 530 children, juveniles and adults aged 3.3-79.2 years. Thresholds assessed with a 128 Hz graded Rydel-Seiffer tuning fork, TF, were compared to three Vibrameter values, the vibration perception thresholds, VPT, determined with increasing vibration stimuli, the vibration disappearance threshold, VDT, determined with decreasing supraliminal stimuli, and the vibration threshold VT which equals the mean of VPT and VDT. The influence of gender, age, body height, weight and skin temperature at the tested site on thresholds was studied. Retest reliability was tested in 73 children aged 3.3-6.9 years and in 20 volunteers aged 5.2-66.1 years who were also tested for the influence of pretest skin warming on thresholds and for differences between results of the left and right body side. TF, VPT, VDT, VT were closely correlated with each other (Spearman: -0.67<Rs<-0.47; P<0.01). The skin temperature, body side, weight and height did not influence thresholds. In adults, thresholds increased with age and were higher in men above the age of 50 than in women of the same age. Thresholds at the feet were higher than at the hands (Wilcoxon: P<0.001). Retest reliability was high and did not depend on the retest interval. The study provides important normative data for the widespread use of quantitative vibration testing.

Hereditary sensory and autonomic neuropathies: types II, III, and IV

The hereditary sensory and autonomic neuropathies (HSAN) encompass a number of inherited disorders that are associated with sensory dysfunction (depressed reflexes, altered pain and temperature perception) and varying degrees of autonomic dysfunction (gastroesophageal reflux, postural hypotention, excessive sweating). Subsequent to the numerical classification of four distinct forms of HSAN that was proposed by Dyck and Ohta, additional entities continue to be described, so that identification and classification are ongoing. As a group, the HSAN are rare diseases that affect both sexes. HSAN III is almost exclusive to individuals of Eastern European Jewish extraction, with incidence of 1 per 3600 live births. Several hundred cases with HSAN IV have been reported. The worldwide prevalence of HSAN type II is very low. This review focuses on the description of three of the disorders, HSAN II through IV, that are characterized by autosomal recessive inheritance and onset at birth. These three forms of HSAN have been the most intensively studied, especially familial dysautonomia (Riley-Day syndrome or HSAN III), which is often used as a prototype for comparison to the other HSAN. Each HSAN disorder is likely caused by different genetic errors that affect specific aspects of small fiber neurodevelopment, which result in variable phenotypic expression. As genetic tests are routinely used for diagnostic confirmation of HSAN III only, other means of differentiating between the disorders is necessary. Diagnosis is based on the clinical features, the degree of both sensory and autonomic dysfunction, and biochemical evaluations, with pathologic examinations serving to further confirm differences. Treatments for all these disorders are supportive.

Quantitative studies of dorsal root ganglia and neuropathologic observations on spinal cords in familial dysautonomia

Intrauterine development and postnatal maintenance of dorsal root ganglion neurons are abnormal in familial dysautonomia, an autosomal recessive disorder associated with autonomic, motor and sensory deficits. Normally, dorsal root ganglion weight increases with age. This does not occur in the cervical plexus ganglia of dysautonomic patients. Neurons in dorsal root ganglia are found to be markedly diminished in the youngest patients and slow degeneration causes further depletion with age. Quantitative studies on C8 dorsal root ganglia show the normal neuron content to be between 42,500 and 53,600. In 3 patients with familial dysautonomia the range was 4,090-8,590 with the smallest number being in the oldest patient. Lateral root entry zones and Lissauers tracts are severely depleted of axons. In older patients loss of dorsal column myelinated axons becomes evident and is first seen in lumbar fasciculus gracilis, cervical fasciculus cuneatus and interfascicular fasciculus. Temperature sensation is markedly impaired from infancy in familial dysautonomia. Loss of pain sensation is prominent and worsens with age. Vibration sense diminishes in adolescence and coordination of limb movements becomes poor in older patients. Neuron depletion in dorsal root ganglia and the progressive pattern of cord changes correlate well with these clinical observations.

Tissue-Specific Reduction in Splicing Efficiency of IKBKAP Due to the Major Mutation Associated with Familial Dysautonomia

We recently identified a mutation in the I-kappa B kinase associated protein (IKBKAP) gene as the major cause of familial dysautonomia (FD), a recessive sensory and autonomic neuropathy. This alteration, located at base pair 6 of the intron 20 donor splice site, is present on >99.5% of FD chromosomes and results in tissue-specific skipping of exon 20. A second FD mutation, a missense change in exon 19 (R696P), was seen in only four patients heterozygous for the major mutation. Here, we have further characterized the consequences of the major mutation by examining the ratio of wild-type to mutant (WT:MU) IKBKAP transcript in EBV-transformed lymphoblast lines, primary fibroblasts, freshly collected blood samples, and postmortem tissues from patients with FD. We consistently found that WT IKBKAP transcripts were present, albeit to varying extents, in all cell lines, blood, and postmortem FD tissues. Further, a corresponding decrease in the level of WT protein is seen in FD cell lines and tissues. The WT:MU ratio in cultured lymphoblasts varied with growth phase but not with serum concentration or inclusion of antibiotics. Using both densitometry and real-time quantitative polymerase chain reaction, we found that relative WT:MU IKBKAP RNA levels were highest in cultured patient lymphoblasts and lowest in postmortem central and peripheral nervous tissues. These observations suggest that the relative inefficiency of WT IKBKAP mRNA production from the mutant alleles in the nervous system underlies the selective degeneration of sensory and autonomic neurons in FD.Therefore, exploration of methods to increase the WT:MU IKBKAP transcript ratio in the nervous system offers a promising approach for developing an effective therapy for patients with FD.

CURRENT CONCEPTS OF DYSAUTONOMIA: NEUROPATHOLOGICAL DEFECTS*

The complexity of the clinical picture in familial dysautonomia (FD)1 makes it difficult to identify any single underlying congenital defect. Corneal anaesthesia, poor taste discrimination, deficient vestibular reflexes, and insensitivity to pain and temperature indicate sensory abnormalities. The absence of a flare in response to intradennal injection of histamine points to absence of function in parts of the peripheral components of sensory axons.2 Some of the anticipated responses to sympathomimetic and parasympathomimetic agents are exaggerated, suggesting denervation supersensitivity or imbalance of autonomic system functions. Thus, the observed exaggerated hypertensive response to infusion of low doses of norepinephrine might suggest denervation hypersensitivity,3 and the absence of reflex bradycardia raises the question of parasympathetic insufficiency. The latter possibility is supported by the meiotic reaction of the pupil to instillation into the conjunctival sac of dilute methacholine’ which would be subthreshold in a normal subject, whereas dilute sympathomimetic agents do not produce dilation. The possibility of cholinergic insufficiency appears strengthened by the observation that intravenous methacholine produces overflow tears, restoration of the knee jerk, and return of the histamine flare, thus reversing temporarily three of the cardinal abnormalities of familial dysautonomia.5 Some of these responses could represent pharmacological effects rather than replacement therapy. The clinical course of the disease includes characteristic crises in which the children become irritable, wirh occasional screaming attacks, lose their power of concentration, and show marked hypersensitivity of their hair, feet, and genitalia which causes them to object vehemently to being touched in these areas. Occasionally, the cranial hair is said to !‘stand on end.” The crises are also marked by vomiting, hypertension, fever, symmetrical blotching of the skin, and puffy, red, cold hands. The hypertension and symmetrical blotching can be reproduced by infusion of norepinephrine.3 Eating often leads to sweating, primarily on the head and occasionally on the back. The soles of the feet and palms of the hand do not sweat. Mature males are capable of penile erection, but ejaculation apparently does not occur. Children with dysautoxiomia characteristically fail to form overflow tears, but there is sufficient function of the lacrimal glands to keep the eyes moist. Orthostatic hypotension and wide fluctuations in body temperature unrelated to environmental temperature also suggest autonomic dysfunction. Excretion of norepinephrine and methoxy-hydroxy-mandelic acid, which is largely derived from the breakdown of norepinephrine, are reduced in FD, but the required catabolic enzymes remain intact.6 Norepinephrine produced by hydroxylation of dopamine, is the immediate precursor of epinephrine. The presence in the urine of normal amounts of Iiomovanillic acid, which is derived from d o p

Pediatric Autonomic Disorders

The scope of pediatric autonomic disorders is not well recognized. The goal of this review is to increase awareness of the expanding spectrum of pediatric autonomic disorders by providing an overview of the autonomic nervous system, including the roles of its various components and its pervasive influence, as well as its intimate relationship with sensory function. To illustrate further the breadth and complexities of autonomic dysfunction, some pediatric disorders are described, concentrating on those that present at birth or appear in early childhood.

Hereditary sensory autonomic neuropathy caused by a mutation in dystonin

In 4 infants with a new lethal autonomic sensory neuropathy with clinical features similar to familial dysautonomia as well as contractures, we identified a deleterious mutation in the DST gene, using homozygosity mapping followed by exome sequencing. DST encodes dystonin, a cytoskeleton linker protein, and the mutation results in an unstable transcript. Interestingly, dystonin is significantly more abundant in cells of familial dysautonomia patients with IKBKAP (I‐κ‐B kinase complex‐associated protein) mutation compared to fibroblasts of controls, suggesting that upregulation of dystonin is responsible for the milder course in familial dysautonomia. Homozygosity mapping followed by exome sequencing is a successful approach to identify mutated genes in rare monogenic disorders. Ann Neurol 2012;71:569–572

Increased Nerve-Growth-Stimulating Activity in Disseminated Neurofibromatosis

NERVE-GROWTH factors have been isolated from a variety of substances such as sarcoma, snake venoms and the spinal-axial region of the chick embryo. The best source has been the submandibular saliva...

Hereditary sensory and autonomic neuropathies

The hereditary sensory and autonomic neuropathies (HSAN) are a group of rare, clinically and genetically heterogeneous disorders. A numerical classification (type I to V) based on clinical phenotype and pattern of inheritance is widely used but additional entities have been described. With the exception of HSAN type I, which has a dominant pattern of inheritance, all other HSANs are autosomal recessive traits. Diagnosis of the HSANs depends on clinical examinations and detailed sensory and autonomic assessments. In recent years, identification of specific genetic mutations for some of the HSANs has allowed confirmation of the diagnosis and a more genotype-based disease classification. There is still no cure for any of the HSANs but clinical trials of potential disease modifying therapies are under way in HSAN I and III. In the meantime, treatment is supportive and directed toward specific symptoms.

Familial dysautonomia: A prospective study of survival

FAMILIAL DYSAUTONOMIA can no longer be considered solely a disease of childhood; increasing numbers of patients are reaching adulthood. At the Dysautonomia Center at New York University Medical Center, 59 patients are 20 years or older and account for 33% of the living patient population; the oldest patient at time of writing is 38 years of age. Previously the only analysis of survival probability was a retrospective study compiled by Brunt and MeKusick ~ in 1970. With the establishment of a center for evaluation and treatment in 1969, a large number of patients could be followed and receive more consistent treatment. We have reanalyzed mortality figures to determine current survival and the general prognosis for patients with familial dysautonomia.