Monday, May 7, 2012

Disorders of the Autonomic Nervous System

By definition, the diagnosis of dysautonomia indicates that a patient has clinically significant orthostatic hypotension. Many patients experience syncope or near-syncope, "gray-outs" that place them at risk of falls due to impairment of the autonomic nervous system (ANS).

Many patients with dysautonomia, or postural orthostatic tachycardia syndrome (POTS) are bed-bound because of an inability to stand up and/or walk due to cardiac instability, "head rush" severity, and a host of other symptoms that may include chronic dehydration, salt wasting, chronic urinary tract infections, brain fog, sweats, deconditioning, muscle atrophy, traumatic brain injury (TBI), and/or imbalance. Some patients are able to get out of bed for doctor visits, but may find themselves at the end of a one-way trip to the store or social event, only to leave the facility by EMT assistance (1).

Confounding variables may affect a person with dysautonomia such that there is a need for a wheelchair. This includes the following subtype diagnoses of dysautonomia or POTS: Ehlers-Danlos Syndrome (EDS), pure autonomic failure (PAF), hyperadrenergic POTS, Multiple System Atrophy (MSA or Shy-Drager Syndrome), familial dysautonomia, Parkinson's Syndrome, Mastocytosis, and Neurally-Mediated Syncope (NMS).

Inherited autonomic neuropathies include the following: Fabry Disease, Familial Amyloid Polyneuropathy, the porphyrias, and the Hereditary Sensory and Autonomic Neuropathies (HSAN) (2). The HSANs include specific genetic disorders that all carry denervation sensory components, in addition to autonomic dysfunction. There are five major classifications of these genetic disorders (3); each one is described herein as to genetic mutation (i.e., genotype), onset, clinical syndrome (i.e., phenotype), and nerve fiber pathology, if applicable.

Type I HSAN:
Genotype: Autosomal Dominant; SPTLC1 Gene. Point mutations in serine palmitoyltransferase (SPT), chromosome 9q22.1-q22.3 (4) SPT is the enzyme necessary for sphingolipid synthesis of sphingomyelin and ceramide. Ceramide programs neuronal cell death.
Onset: Juvenile or Adult.
Phenotype: Charcot-Marie Tooth Type 2B Syndrome; Thevenard Syndrome; Familial Syringomyelia; Mal Perforant du Pied; Hereditary Sensory Radicular Neuropathy; Familial Trophoneurosis; Ulcero-mutilating Neuropathy.
Characteristics: Severe loss of sensation in the lower limbs, resulting in injury. Ulcers of the feet, especially the soles.
Nerve fibers: Sensory action potential is low.

Type II HSAN: 
Genotype: Autosomal Recessive; HSNII Gene.
Onset: Before the age of 20 years.
Phenotype: Morvan's Disease; Congenital Sensory Neuropathy.
Characteristics:  More clinically severe than Type I.  Early ulcers. Loss of sensation in upper and lower limbs, trunk, forehead.
Nerve fibers: Nerves show a marked loss in both myelinated and unmyelinated nerves.

Genotype: Autosomal Recessive; IKBKAP Gene. The defect is in the B cell inhibitor of k-light polypeptide gene enhancer, kinase complex-associated protein at chromosome 9q31.
Onset: At birth (5) or early childhood (2).
Phenotype: Familial dysautonomia,  Riley-Day Syndrome.
Characteristics: Found in Ashkenazi Jews.
Nerve fibers: myelinated nerve fibers are normal and there is an absence of unmyelinated fibers (6).

Genotype: Autosomal Recessive; NTRK1 Gene. The defect is in tyrosine kinase receptor A, or nerve growth factor receptor at chromosome 1q21-q22. In 2004, two missense mutations in  tyrosine kinase were described in a pediatric patient (7).
Onset: At infancy.
Phenotype: Anhidrosis, congenital insensitivity to pain.
Nerve fibers: Loss of myelinated and small, unmyelinated nerve fibers.

Type V HSAN:
Genotype: Autosomal Recessive; NGFB/NTRK1 Gene. A mutation in the nerve growth factor Beta gene (NGFB) has been implicated as causing loss of pain perception.
Onset: Early.
Phenotype: Anhidrosis, congenital insensitivity to pain in the extremeties; no mental retardation.
Nerve fibers: Not applicable. It is a Growth Factor mutation.

Autonomic nervous system pathologies may present with nomenclature confusion given that the presenting symptoms may evolve into a more discrete syndrome. The POTS diagnosis should be reserved to those manifesting primarily the sympathetic vs. the parasympathetic nerve dysfunctions. For patients presenting with orthostatic hypotension (e.g., sympathetic dysfunction) and gastroparesis (e.g., parasympathetic dysfunction), the more broad classification of 'dysautonomia' may be used. Given that our understanding of the pathology of the disease is improving, it is likely that the terminology will continue to evolve.

(4) Bejaoui K, Wu C, Scheffler MD, et al. SPTLC1 is mutated in hereditary sensory neuropathy,
      type 1. Nat Genet. Mar 2001;27(3):261-2. [Medline].
(6) Low PA, Vernino S, Suarez G. Autonomic dysfunction in peripheral nerve disease.
               Muscle Nerve. Jun 2003;27(6):646-61. [Medline].
(7) Ohto T, Iwasaki N, Fujiwara J, et al. The evaluation of autonomic nervous function in a patient with hereditary sensory and autonomic neuropathy type IV with novel mutations of the TRKA gene. Neuropediatrics. Oct 2004;35(5):274-8. [Medline].


No comments:

Post a Comment

We Are Amazed at Your Comments and Ideas!
Thank you for your input!
LET'S SHARE is the Theme Concept!

If you are posting to a Male:Female Matter,
please envision yourself walking into a group of both women and men. For group comfort, all comments are Moderated.
Relax! Enjoy!


Note: Only a member of this blog may post a comment.