Hereditary Sensory and Autonomic Neuropathies (HSAN): Overview

See Table H-5.

At a Glance

Genetic neurodegenerative disorder characterized by a loss of sensations, especially in the lower extremities, leading to perforating skin ulceration and bone destruction as a result of abnormal functioning of the autonomic nervous system.

Synonyms

Acrodystrophic Neuropathy; Burning Feet Syndrome; Denny-Brown Syndrome I; Hereditary Sensory Neuropathy type I (HSN I); Hereditary Sensory Radicular Neuropathy; Hick Syndrome; Lumbosacral Syringomyelia; Mutilating Acropathy; Sensory Radicular Neuropathy, type I; Smith-Thévenard Syndrome; Thévenard Disease II; Thévenard Syndrome; Ulcerative and Mutilating Acropathy.

History

First reported by Auguste Nélaton, a French physician and surgeon, in 1852.

Genetic Inheritance

Autosomal dominant, chromosome 9q22.

Pathophysiology

Shorter lifespan of ganglion cells in sacral and lumbar dorsal root ganglia.

Diagnosis

Ganglia biopsy showing loss of neuronal cells with sometimes amyloid deposits, mainly around the capillaries. At the beginning, Meissner corpuscles count in skin biopsies are normal. With disease progression, loss of these sensory corpuscles occurs. Sometimes associated with brain atrophy.

Clinical Aspects

Onset is between 15 and 40 years of age. Loss of sensitivity in the feet, with painless ulcers, occurs first, followed by shooting pain and lightning pain in the lower legs. Ulcers require years to heal. There is thermal sensory loss of the lower extremities, often extending to the thigh, sometimes thermal loss in the hands, and restless legs and burning sensations in the feet. Shortly thereafter, the patient complains of bilateral neurosensory deafness. Normal sweating. The other cranial nerves are not involved. Normal ocular motility, normal pupils and pupillary reactions, no nystagmus. Disappearance of ankle jerks and knee jerks. Secondary Charcot-type neurotrophic arthropathy and mutilating acropathy. Upper extremities seldom affected. No motor involvement. Deafness is a common feature of the syndrome.

Precautions before Anesthesia

Usually patients present with painless cutaneous ulcers for orthopedic procedures. For medicolegal reasons, it is advisable to obtain a neurologic evaluation before and after the procedure. Search for signs of autonomic dysfunction before induction.

Anesthetic Considerations

General anesthesia is often preferred, even though regional anesthesia cannot be contraindicated on scientific grounds. However, the undetected preoperative presence of nerve dysfunction may be a source of confusion after the use of regional anesthesia. Proper positioning on the operating table and after the procedure. No particular airway involvement. Check blood pressure carefully during procedure. Usually uneventful recovery.

Pharmacological Implications

No specific implications with this condition.

References

At a Glance

Genetic neurodegenerative disorder characterized by inflammation of the fingers and/or toes with paronychia and whitlows, multiple ulcers (fingers, soles of the feet), and sensory loss in both arms and legs.

Synonyms

Giaccai (often misspelled Giacci) Familial Neurogenic Acroosteolysis; Giaccai Syndrome; Hereditary Sensory Radicular Neuropathy, Recessive form; Hereditary Sensory Neuropathy Type II (HSN II); Neurogenic Acroosteolysis.

Incidence

Very rare (fewer than 50 cases reported).

Genetic Inheritance

Autosomal recessive.

Pathophysiology

Peripheral nerve degeneration of unknown cause. A high urinary excretion of sphingomyelin and lecithin in three sibs of a Turkish family suggested that the pathogenetic mechanism was a disorder of phospholipid metabolism. Several authors believe the disease is nonprogressive.

Diagnosis

Nerve biopsy shows wallerian degeneration of the axons, with reduction of the number of myelinated fibers. Unmyelinated fibers also were involved but to a lesser degree.

Clinical Aspects

Age of onset usually is between 5 and 15 years, which is earlier than the dominant type. There is a loss of all modalities of cutaneous sensation in the lower extremities. It is associated with joint and leg swelling that leads to cylinder-shaped limbs. Proximal sensation is preserved and tendon reflexes are lost. There is no deafness or other cranial nerve involvement. No nystagmus or ocular involvement. There is generalized neurogenic osteoporosis, with acroosteolysis and collapse of the distal phalanges, leading to digital clubbing.

Precautions before Anesthesia

Patients are often scheduled for amputations secondary to osteomyelitis. Usually no specific cardiovascular or respiratory involvement. No central nervous system problem. No airway problems related to the syndrome.

Anesthetic Considerations

Difficult venous access as a result of pachydermoperiostosis and soft tissue swelling. Enhanced body temperature loss caused by hyperhydrosis. Airways usually are not involved by soft tissue swelling, but special attention must be given to this possibility. Proper positioning on the operation table and in the postoperative period to prevent pressure sores. Use of regional anesthesia is controversial.

Pharmacological Implications

Effect of local anesthetics remains unclear. Normal response to neuromuscular blockers.

Other Conditions to Be Considered

Hereditary Sensory and Autonomic Neuropathy Type I: Characterized by a loss of sensation usually affecting the feet and legs more severely than the hands and forearms. Other clinical features include open sores on the feet and anomalies of pain and temperature sensations that are affected more than touch-pressure sensation.

Charcot-Marie-Tooth Disease: Neurologic disorder characterized by muscle atrophy and weakness most prominent in the legs and the small muscles of the hands. A decrease in vibration, pain, and thermal sensation in the hand, foot, and lower part of the leg may occur. Stretch reflexes are usually absent.

Peripheral Neuropathy: Produced by disease of a single nerve (mononeuropathy, mononeuritis), several nerves in asymmetrical areas of the body (mononeuritis multiplex), or many nerves simultaneously (polyneuropathy, polyneuritis, multiple peripheral neuritis). These symptoms may involve sensory, motor, reflex, or blood vessel (vasomotor) function.

Syringomyelia: Caused by the development of a syrinx within the spinal cord destroying the fascicle of Lissauer. Clinically, it is characterized by loss of pain and temperature sensations first noticed in the fingers, hands, arms, and upper chest. In the early stages, a sense of touch is still present. As the disease evolves, a loss of feeling may spread over the shoulders and back. Chronic progressive degeneration of the stress-bearing part of a bone joint (Charcot joint) is another symptom. Other clinical features include loss of tendon reflexes in the upper extremities, spasticity, muscle weakness, muscular incoordination in the lower extremities, and paralysis of the bladder.

Roussy-Levy Syndrome: Motor sensory disorder characterized by a foot deformity in the shape of a claw (clawfoot), muscle weakness, atrophy of the leg muscles, and tremor in the hands.

References

At a Glance

Genetically transmitted neurodegenerative disorder characterized by the absence of overflow tears with emotional crying in infants, hypotonia, difficult feeding, inappropriate reactions to stress, speech, and motor incoordination, progressive loss of thermal and pain perceptions, and absence of fungiform papillae on the tongue.

Synonyms

Familial Dysautonomia; Riley-Day Syndrome; Hereditary Sensory Neuropathy Type III (HSN III).

History

Peripheral nerve degeneration involving unmyelinated fibers. First reported in 1949 by Conrad Milton Riley and Richard Lawrence Day, American pediatricians.

Incidence

Incidence is 1:3800 in Eastern European Jews. Only reported in individuals of Ashkenazi Jewish descent (classified as one of the Jewish genetic diseases). The familial dysautonomia gene is carried by 1:30 individuals of Eastern European Jewish ancestry.

Genetic Inheritance

Autosomal recessive with complete penetrance. Chromosome 9 (9q31). Two mutations of the familial dysautonomia gene (IKBKAP) can cause the disease: (1) a mutation in intron 20 (99% of cases) in which the gene product IKAP is not expressed in the brain (but is in lymphoblasts), and (2) a missense mutation in exon 19 that causes a disruption of a phosphorylation site of IKAP, which decreases its activity.

Pathophysiology

Loss of small unmyelinated nerve fibers carrying pain, temperature, and central autonomic nervous control.

Diagnosis

Nerve biopsy shows a loss of unmyelinated fibers. Muscle biopsies shows loss of Golgi tendon organs. Tongue has few or no papillae. Urinary catecholamines and metabolites excretion are decreased. Definitive diagnosis established by molecular biology (DNA analysis by genetic linkage testing). Prenatal diagnosis and carrier genetic testing (when there is a family history) is available.

Clinical Aspects

In early infancy, there is poor swallowing with pharyngeal dyscoordination and aspiration. Poor sucking. Swallowing difficulties remain the main problem, leading to significant failure to thrive. Sweating during meals. Delayed and ataxic walking. Ataxia is secondary to loss of feedback by muscle spindles. Progressively, pain and thermal sensation are lost. When children are 2 to 6 years old, painless corneal ulcerations and numerous painless traumatic injuries occur frequently. Tendon stretch reflexes are absent. Skeletal deformity and scoliosis are often present. Generalized convulsions can be observed in 40% of these patients. Autonomic crises begin between 3 and 6 years. They include cyclic vomiting every 20 minutes, with hypertension, sweating, mottled skin, and irritability. Prognosis is poor, with patients dying of aspiration or respiratory failure, unopposed vagal stimulation, or sleep abnormality. Prior to 1960, 50% of patients died before 5 years of age; currently, approximately 50% of patients reach 30 years of age.

Precautions before Anesthesia

An anesthesia consultation is highly recommended for elective surgery. Patients often require anesthesia care for trauma, burns, or eye surgery. Spinal correction procedure is frequent. Nissen fundoplication is indicated to prevent chronic pulmonary aspiration. There are no airway problems directly related to the syndrome. Check for scoliosis and respiratory restrictive syndrome. Check and correct electrolyte imbalances and intravascular volemia before induction. Invasive arterial pressure monitoring is recommended.

Anesthetic Considerations

In the absence of cardiovascular hemodynamic stability and poor thermoregulatory control, the anesthetic management must specifically account for these potential complications. All measures to prevent hypothermia must be implemented. In the absence of corneal protection reflexes, use artificial tears and careful eye closure during anesthesia to prevent corneal desiccation. Regional anesthesia has been safely used in several reported cases. Postoperative nausea and vomiting frequently occur. Protection from injuries is important in the postoperative period because of irritability and loss of pain sensation. Depending on pulmonary status, patients may require postoperative mechanical ventilation.

Pharmacological Implications

Because of the possibility of an excessive response to vasopressors, doses should be titrated to effect. Normal response to neuromuscular blockers, opiates, and local anesthetics. Increased cardiovascular depression (bradycardia and hypotension) following hypnotics.

References

At a Glance

Genetic neurodegenerative disorder (peripheral nerve degeneration involving small fibers) characterized by congenital insensitivity to pain (resulting in painless injuries), episodic fever (hot weather) as a consequence of anhidrosis, autonomic disorders, mental retardation, short stature, self-mutilation, and joint deformities.

Synonyms

Congenital Sensory Neuropathy with Anhidrosis; Familial Dysautonomia Type II; Congenital Insensitivity to Pain with Anhydrosis (CIPA) of Swanson; Swanson Syndrome.

Incidence

Very rare disease. High prevalence in Israeli-Bedouin Arabs.

Genetic Inheritance

Autosomal recessive. Gene map location is chromosome 1q21-q22. Mutations in the same gene are associated with familial medullary thyroid carcinoma. The protein has a single extracellular domain (nerve growth factor binding) that acts as a signal peptide and a single intracellular domain (tyrosine kinase).

Pathophysiology

Nociceptive neurons in the dorsal root ganglia derive from the neural crest, and they can survive only if they are stimulated by the nerve growth factor through the TrkA receptor. Mutations in the TrkA gene have shown a correlation with the defective development of the nociceptive neurons. It results in the loss of small “C" nerve fibers responsible for carrying pain, temperature and autonomic control. HSAN IV is a result of a defect of the high-affinity tyrosine kinase (TrkA) receptor (neurotrophin signal transduction system) for nerve growth factor. Consequently, there is a defect in neural crest differentiation and the system responsible for pain and temperature sensation, the first-order afferent system, is lost. The Lissauer spinothalamic tract is absent. Temperature regulation and sensation are inexistent, which may represent a life-threatening condition. Nerve growth factor modulates synaptic plasticity and nervous transmission and plays a modulating role among the nervous, immune, and endocrine systems. It may interfere with the skeletal cell metabolism.

Diagnosis

Clinically evocated by progressive insensitivity to pain, associated with anhydrosis. Nerve biopsy shows a loss of unmyelinated fibers. Small myelinated and unmyelinated axons are almost absent (0-5% of normal); large myelinated axons are mildly reduced (45-65% of normal). Absence of innervation of sweat glands. Provocative sweating tests are negative. Normal sweat glands in the skin, with absence of sweating.

Clinical Aspects

Symptoms present from birth. There is a progressive insensitivity to pain, associated with anhydrosis. HSAN IV shares some clinical similarities with HSAN III, but instead of profuse sweating there is complete anhydrosis. Children present with unexplained fever up to 43°C (109.4°F) because of loss of thermal regulation. Self-mutilating behavior, with numerous trauma, tongue bites, and burns. Mental retardation with IQ in the 60s is often observed. Other features include fingernail dystrophy and various neurogenic joint disorders. Prognosis is poor; 30% of children die before 3 years of age uncontrolled fever and/or massive infection.

Precautions before Anesthesia

Patients often require anesthesia care for trauma, burn, or eye surgery. No airway problems should be expected directly related to the syndrome. The absence of central autonomic response must be evaluated, especially for the cardiovascular hemodynamic stability.

Anesthetic Considerations

Poor cardiovascular stability, poor temperature control, no corneal protection reflexes. Perioperatively, it is mainly a temperature-control problem. The presence of self-mutilating behavior and severe mental retardation make be a challenge during induction of anesthesia. The use of preoperative sedation must be evaluated. Protection from injuries is important in the postoperative period because of irritability and loss of pain sensation. All measures must be taken preoperatively to prevent hypothermia or hyperthermia responses.

Pharmacological Implications

Because of an excessive response to vasopressors, doses must be titrated to effect. Normal response to neuromuscular blockers, opiates, and local anesthetics is expected.

Other Condition to Be Considered

Familial Generalized Anhidrosis: Familial disorder characterized by anhidrosis already present at birth and resulting in heat intolerance. Muscarinic stimulation results in significantly reduced sweat production (10-50% of normal).

References

At a Glance

Group of genetically inherited disorders that share the primary feature of progressive, generally severe, lower extremity spasticity. Also termed congenital absence of pain without anhidrosis.

Synonyms

Diplegia Spinalis Progressive; Familial Spastic Paraplegia (or Paraparesis) (FSP); French Settlement Disease (FSD); Hereditary Charcot Disease; Hereditary Progressive Spastic Paraplegia; Hereditary Sensory Neuropathies type V; Spastic Paraplegia (SPG); Spastic Spinal Paralysis (SSP); Strümpell-Lorrain Syndrome; Strümpell Disease.

History

First described by Ernst Adolf Gustav Gottfried von Strümpell, a German neurologist, in 1880. Subclassified into pure (or uncomplicated) and complicated forms based on the presence of additional neurologic or nonneurologic features.

Incidence

Pure hereditary spastic paraplegia is the most common form of hereditary spastic paraplegia, with a prevalence of 9.6:100,000 in the general population of Spain.

Genetic Inheritance

Autosomal dominant inheritance accounts for 70 to 80% of cases, with autosomal recessive inheritance responsible for most of the remainder. X-linked recessive inheritance is very rare. Three autosomal dominant genes causing pure hereditary spastic paraplegia have been mapped on chromosomes 2p, 14q, and 15q. A new locus for HSP gene has been mapped to chromosome 13q12.3 (encoding spartin); it is responsible for a recessive form of complicated HSP (Troyer syndrome) that is found mainly in patients of Old Order Amish descent.

Pathophysiology

Axonal degeneration involving the terminal ends of the longest fibers of the corticospinal tracts and dorsal columns. The spinocerebellar tracts are less affected. The cell bodies of the involved fibers are normal.

Diagnosis

Magnetic resonance imaging (MRI) scans may show spinal cord atrophy, especially in the cervical region. Sensory polyneuropathy on electrophysiologic studies. Normal motor nerve conduction velocities. Severe loss of large diameter fibers and relative preservation of small myelinated and nonmyelinated fibers on sural nerve biopsy. Prenatal testing is possible in families with SPG2 with an identified PLP gene (chromosomal locus Xq28) mutation only.

Clinical Aspects

Progressive spastic paraplegia manifests as insidious onset of an abnormal gait. The age of onset ranges from childhood (as delayed motor milestones) to adulthood. Considerable variation with regard to onset of symptoms and severity of disease. Affected subjects range from entirely asymptomatic (10-20% of cases) to chair bound (10-15% of cases). Urinary symptoms (frequency, urgency, or hesitancy) are common (50% of cases). Hypertonicity of the lower limbs is often disproportionate to weakness and is the most disabling feature. Mild upper limb incoordination may occur. Subclinical sensory abnormalities are present in most cases. No therapy that slows the disease process is available. Treatment is aimed at maximizing functional ability and preventing contractures.

Precautions before Anesthesia

Document all existing neurologic involvement, with emphasis on the level of cord involvement. The presence of autonomic hyperreflexia should be excluded. The suitability of a regional anesthetic technique should be discussed, taking into account the presence of any existing anticoagulation therapy. Investigations include urinalysis, complete blood count, electrolytes, urea and creatinine levels, chest radiography, and electrocardiogram.

Anesthetic Considerations

Although there is no reported anesthetic experience in these patients, the considerations should be similar to those involving patients with chronic spinal cord injury. However, because the involvement in these patients is limited mainly to the lower limbs, the degree of cardiopulmonary involvement is minimal. Chair-bound patients are prone to thromboembolic disease, and appropriate perioperative measures should be taken (stockings, anticoagulation, or pneumatic compressive devices for long operations). Osteoporosis and hypercalcemia may be present in these non-weight-bearing patients, and careful positioning is required to prevent fractures and pressure areas. Although a regional anesthetic technique may be useful, difficulty in testing sensory levels after a spinal or epidural block and use of anticoagulation often preclude the use of these routes.

Pharmacological Implications

Thromboembolic prophylaxis should be continued into the perioperative period.

Other Conditions to Be Considered

Amyotrophic Lateral Sclerosis: Adult-onset idiopathic, progressive degeneration of anterior horn cells involving both upper and lower motor neurons characterized by progressive muscle weakness with fasciculations and atrophy; sporadic in most cases, but autosomal dominant transmission has been reported.

Multiple Sclerosis: Most common disease of the central nervous system (brain and spinal cord), which presents as a progressive immune-mediated inflammatory neurodegenerative disease resulting in myelin loss, destruction of oligodendrocytes, and astrogliosis affecting multiple body systems.

Hereditary Sensory and Autonomic Neuropathy Type IV: Characterized by congenital pain insensitivity and severe temperature sensation defect and anhidrosis. Patients present with severe mental retardation and self-mutilating behavior. Other clinical features include absent corneal sensation, corneal opacities, and ulceration because of very poor corneal healing. Unexplained high fever is often associated with episodic hyperpnea. Most individuals affected with HSAN type IV present with repeated traumatic and thermal injuries. Laboratory investigation confirms the presence of normal-appearing sweat glands on skin biopsy, absent afferent system for pain and temperature, absent small myelinated and unmyelinated fibers, and no sweat response to thermal, painful, emotional, or chemical stimuli. There are no histamine-evoked axonflare and no tearing with methacholine (Mecholyl) or neostigmine. The inheritance mode is believed to be autosomal recessive.

Troyer Syndrome (Autosomal Recessive Spastic Paraplegia; Childhood-Onset Spastic Paraplegia with Distal Muscle Wasting; designated Troyer Syndrome for the surname of many of the affected persons in the Amish population): Clinical presentation includes onset in early childhood with dysarthria and distal muscle wasting. Lower limb spasticity and contractures usually make walking impossible by the third or fourth decade. Drooling and mild cerebellar signs may occur. All have weakness and atrophy of thenar, hypothenar, and dorsal interosseous muscles.

References