Hereditary Sensory and Autonomic Neuropathies

The hereditary sensory and autonomic neuropathies (HSANs) are conditions in which primary sensory and

autonomic neurons either fail to develop or undergo system atrophy and degeneration. Dyck proposes the comprehensive subdivision seen in T.ab!e...36.-10 . These disorders have been called by a large variety of names because their symptoms were described by various investigators. Types I, II, and III are discussed here. Within this classification there are two large divisions: HSAN I is a progressive disorder with symptom onset usually occurring in the second decade or later with primarily lower extremities affected. HSANs II to V are static congenital disorders that are more generalized. A common thread among all the types is an insensitivity to pain.y

HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE I

HSAN I is a disorder in which sensory disturbances and associated tissue complications outweigh its motor and autonomic manifestations. HSAN I is a rare disorder that is usually autosomal dominantly inherited, although recessive and X-linked pedigrees have been identified. y There is chronic axonal atrophy, myelin remodeling, and axonal degeneration with sparing of the central nervous system and non-neural tissues. Multipoint linkage analysis has mapped a gene for HSAN I to 9q22.1-q22.3, although the different modes of inheritance and phenotypes suggest that there may be other loci. y

Although there are different phenotypes, typically the disorder presents in one of the following ways: (1) foot complications, such as plantar ulcers, recurring paronychia of toes, stress fractures of foot bones, recurrent cellulitis, and resorption of foot bones; (2) spontaneous pain, either burning or aching of the feet that is worsened with weight

TABLE 36-10 -- HEREDITARY SENSORY AND AUTONOMIC NEUROPATHIES (HSANs}

Type

Hallmark

Inheritance Pattern

HSAN I (hereditary sensory radicular neuropathy)

Insensitivity to pain in feet and ensuing tissue complications

Primarily autosomal dominant

HSAN II (congenital sensory neuropathy)

Early onset of loss of sensation in all modalities

Autosomal recessive

HSAN III (familial dysautonomia, Riley-Day syndrome)

Early onset, predominantly autonomic symptoms, absence of fungiform papillae on the tongue

Autosomal recessive, predominantly Jewish (gene on D9S58)

HSAN IV (familial sensory neuropathy with anhydrosis, congenital insensitivity to pain)

Mild mental retardation, episodes of fever related to environment rather than infection

Rare

HSAN V (congenital sensory neuropathy with selective loss of small myelinated fibers)

Congenital insensitivity to pain in extremities normal strength and tendon reflexes, abnormality of nocioception

Fewer than 10 cases reported

bearing and decreased at night, or disabling lancinating pain in deep tissues of the feet, legs, or shoulder; or (3) symptoms of sensory and autonomic neuropathy.

The complications of HSAN I may be of sudden, overwhelming onset, with ulcers first developing over pressure points on the foot. When these ulcers are neglected, they do not heal and are associated with the complications previously described. Phenotypes have been reported in which HSAN is associated with deafness, leg weakness and atrophy, burning feet, restless legs, and neuropathic atrophy. HSAN is a slowly progressive disorder that does not seem to decrease the lifespan. It cannot be emphasized enough that proper foot care can prevent complications that can lead to foot amputation and sepsis.

HSAN I may be distinguished from other varieties of HSAN because it starts later, usually in the second or third decade; is slowly progressive; and preferentially affects lower limbs. It is closest in presentation to HSAN II, although in that condition, the motor and autonomic symptoms outweigh the sensory symptoms and deficits of type I. Spinocerebellar degeneration can be distinguished from HSAN I because of its kinesthetic and mechanoreceptor loss, cerebellar ataxia, and relatively less small fiber sensory and autonomic dysfunction. Familial amyloidosis may include sexual and sphincter dysfunction, which are not found in HSAN I, and porphyria with neuropathy, which has a more acute onset associated with changes in mental status.

Typically, touch-pressure threshold, thermal discrimination, and nocioception are abnormally elevated in the foot and leg, although they may be altered in the arm and hand as well. Paresthesias are not present. Loss of sweating in the distal leg is common. Sural nerve amplitudes are reduced, with small myelinated fibers being primarily affected. A decrease in the Achilles tendon reflex is common, followed most often by a decrease in the quadriceps reflex. [sal

There is no effective treatment. The main goal is the prevention of foot ulcers. The feet should be inspected regularly for signs of pressure points, soaked daily, and treated with petrolatum lotion applied to seal in moisture. Shoes should be chosen carefully to avoid pressure points. Any ulcers should be treated promptly with cleaning and de(c)bridement, if necessary. The appropriate antibiotic should be used for cellulitis or septicemia. Genetic counseling should include information about phenotypic variation and degree of risk.

HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE II

HSAN II is characterized by an early onset of loss of sensation in all modalities. This is a rare disorder, in which cases reported are either sporadic or within a sibship, suggesting an autosomal recessive pattern of inheritance. There is profound loss of myelinated fibers in cutaneous nerves, especially the sural nerve. Dyck proposes that the degenerative process begins in utero or in infancy. y There are fewer nerve fibers at the ankle than the midcalf, marked denervation of the extensor digitorum brevis, evidence of segmental demyelination and remyelination, and

electron microscopic abnormalities within axis cylinders. y As yet, no gene locus has been identified.

Symptoms first appear in infancy or early childhood and may be widespread. Paronychia, whitlows, ulcers of the fingers and feet, and previously undetected fractures of the foot and hand are common and result directly from underlying sensory disturbance ( .Fig, 36-9 ). There have been pedigrees reported with HSAN II and other dysautonomic features, as well as retinitis pigmentosa or tonic pupils. There is sensory loss affecting all modalities in the lower and upper limbs and sometimes in the trunk. Tendon reflexes are generally absent or diminished in all limbs. There is loss of sweating over acral parts. However, there is no prominent muscle weakness, postural hypotension, or sphincter disturbance.

Generally, there are no sensory nerve action potentials elicitable in the ulnar, median, or sural nerves, while the conduction velocities of motor fibers of the same nerves are at or just below the lower end of normal. Minimal fibrillation may be found in the extensor digitorum brevis, which has a decreased number of motor unit potentials, a large number of which are polyphasic. y

Complications are much more difficult to prevent in HSAN II owing to its early onset at an age when patients cannot understand the problem or cooperate with preventive regimens. In addition, complications are frequent because the hands are so seriously affected. Preventive care, which is similar to that of HSAN I, needs to be as aggressive as possible because complications may be life threatening. Special attention should be given so that these children have adequate educational opportunities to develop their intellectual potential in spite of severe physical handicaps. Genetic counseling should be provided.

Figure 36-9 Child with hereditary sensory neuropathy type II showing destruction of tongue tissue due to insensitivity to p(Courtesy of Dr. J. Sarlangue, Hopital Pelligrin Enfants, Bordeaux, France.)

HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE III (RILEY-DAY SYNDROME)

HSAN III is present almost exclusively in Ashkenazi Jews. Some investigators argue that those who are not Jewish in fact have a different type of neuropathy. The gene frequency has been estimated at 0.01 per 100,000 Jews in the United States. y Decreased levels of dopamine-beta-hydroxylase, the enzyme that converts dopamine to norepinephrine, and increased levels of antigen of the beta unit of nerve growth factor (NGF) have been identified. However, the structural gene for beta-nerve growth factor and the gene for the receptor for nerve growth factor were both excluded as the site of mutation in HSAN III. Rather, it has been linked to D9S58, which has an unknown gene product.y Postmortem studies have varied widely; some have shown no nervous system lesions at all, whereas others show extensive damage, particularly in the brain stem reticular formation, the cortex, and the long tracts of the cord. There is a marked decrease in the number of unmyelinated fibers of the cutaneous nerves. y

Usually, HSAN III presents at birth. Axelrod proposes that it should be suspected in a child of Eastern European Jewish extraction with breech delivery, meconium staining, poor suck, hypotonia, or hypothermia. There is difficulty feeding and a failure to thrive, along with unexplained fevers, lack of tearing, paroxysmal hypertension, increased sweating, cold hands and feet, erythematous blotching of the skin, and drooling. There is also a lack of fungiform papillae on the tongue, a feature that is highly distinctive of this disorder. Although there is overlap between symptoms and signs of this and other types of HSAN, examination of the tongue leads to the exclusion or inclusion of this diagnosis. If the disorder presents later, it may be observed as delayed development or stunted growth with decreased pain sensation and ataxia. Abnormalities in cutaneous temperature discrimination and nocioception are present in most patients, whereas fewer have abnormalities in joint position and vibratory sensation.

Recurrent vomiting is common in the early years. Several gastrointestinal abnormalities have been identified: megaesophagus, pylorospasm, gastric ulcer, jejunal distention, and megacolon. Corneal abrasions may occur secondary to corneal insensitivity, whereas neuropathic or Charcot's joints may occur secondary to pain insensitivity. About half of the patients develop kyphosis, scoliosis, or both. Pulmonary complications, profound hypotension, and prolonged respiratory depression from the administration of anesthesia have been reported. y

Clinical and laboratory diagnosis may be based on the presence of five signs: (1) lack of the normal flare after intradermal injection of histamine, (2) absence of fungiform papillae on the tongue, (3) miosis of the pupil after conjunctival instillation of 2.5 percent methacholine chloride, (4) absent deep tendon reflexes, and (5) diminished tear flow. Sural nerve biopsy shows markedly decreased unmyelinated fibers, no active fiber degeneration, and fewer Schwann cell cytoplasmic clusters than other types of neuropathy. Nerve conduction velocity studies have mixed nerve velocities within the normal range. y

Treatment remains supportive and is best provided by

an interdisciplinary team that includes a genetic counselor. Prenatal diagnosis is available for informative families. y Most patients do not survive to adulthood, succumbing to either recurrent infections or hyperpyrexia. The oldest surviving patient in one series was 38 years old, with one third of the patients in that series being 20 years or older. y

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