Keywords
Alacrima, anhidrosis, autonomic dysfunction, baroreflex failure, congenital insensitivity to pain, familial dysautonomia (FD), hereditary sensory and autonomic neuropathies (HSAN), insensitivity to pain, orthostatic hypotension
Introduction
The hereditary sensory and autonomic neuropathies (HSANs) are a group of rare disorders caused by different genetic mutations, each affecting specific aspects of development, function, or survival of small myelinated and unmyelinated neurons resulting in variable phenotypic expression. Affected patients have impaired pain and temperature perception of different severity and varying autonomic abnormalities. These sensory deficits frequently lead to unnoticed acral ulcerations that can become infected, resulting in osteomyelitis and autoamputations, which are perhaps the most dramatic feature of patients with HSANs. The sensory and autonomic neurons have common embryonic origin in the multipotent neural crest cells. Their differentiation and commitment to function in the mature nervous system require exposure to growth factors along the migratory route and then within the target tissue. Differentiation will determine the neuron’s ability to produce specific neurotransmitters. HSANs causing mutations affect these processes at different steps.
The HSANs have been classified by Dyck and Ohta as types I to V on the basis of age at onset, mode of inheritance, and the predominant clinical features. More recently, the identification of a number of disease-causing mutations in ten HSAN disease-causing genes, a number that will likely continue to increase, has allowed a genotype-based classification that is still evolving ( Table 18.1 ). Many published cases lacked genetic confirmation, and there is still controversy over terminology and classification. HSAN-causing mutations affect key proteins involved in the development of nerves such as the nerve growth factor receptor in HSAN 4 or other proteins, such as IKBKAP in HSAN 3, whose functions are less well understood. For each HSAN type, penetrance is complete but there can be marked variability in phenotypic expression.
| Type | Other Names | Inheritance | Genes | OMIM |
|---|---|---|---|---|
| I | Hereditary sensory radicular neuropathy | Autosomal dominant | SPTLC1, SPLTC2 ATL1 RAB7 DNMT1 | 162400 613640 613708 600882 126375 |
| IIAIIBIIC | Congenital insensitivity to pain | Autosomal recessive | WNK1 FAM134B KIF1A | 201300 613115 614213 |
| III | Familial dysautonomia (FD)/Riley Day | Autosomal recessive | IKBKAP | 223900 |
| IV | Congenital insensitivity to pain with anhidrosis (CIPA) | Autosomal recessive | TrK A/NGF R | 256800 |
| V | Congenital insensitivity to pain | Autosomal recessive | NGF B | 608654 |
Hsan Type I
Molecular Genetics
HSAN I, also known as hereditary sensory radicular neuropathy, is an autosomal dominant disorder that usually presents between the second and fifth decades, but congenital or childhood onset has been reported. Several causative mutations have been identified in five genes: SPTLC1 , SPLTC2 , ATL1 , RAB7 , and DNMT1 .
SPTLC1 and SPTLC2 encode subunits 1 and 2 of serine palmitoyltransferase (SPT), an enzyme that catalyzes the biosynthesis of serine and palmitoyl CoA. Upregulation of SPT is suggested to play a role in apoptosis. Gain of function mutations in the SPTLC1 and SPTLC2 genes lead to the formation of atypical deoxysphingoid bases that cannot be converted to complex sphingolipids or degraded, resulting in their intracellular accumulation with pronounced neurotoxic effects on neurite formation and neurofilament structure. The single patient reported with congenital presentation and very severe phenotype had a de novo missense mutation in SPTLC1 (c.992C>T; p.Ser331Phe) that was not present in either parent.
Four missense mutations in RAB7 have been identified that are associated with the phenotype of profound sensory loss and motor weakness, now termed Charcot-Marie-Tooth type 2B (CMT2B) disease. RAB7 mutants impair epidermal growth factor (EGF) receptor trafficking. The resulting downregulation of EGF receptor dependent nuclear transcription impedes normal axon outgrowth and peripheral innervation and results in neurodegeneration.
Pathophysiology
Neurophysiology studies show a sensory axonal neuropathy, but in many individuals there is also electrical evidence of demyelination. The disease process affects the axons and cell bodies of primary sensory neurons in the dorsal root ganglia and motor neurons in the anterior horns of the spinal cord. Sural nerve biopsies and post-mortem findings showed distal axonal degeneration. Although there is loss of unmyelinated, small myelinated, and large myelinated fibers, the small fibers are affected to a greater degree and there is subsequent dorsal root ganglion cell loss. Dorsal columns in the spinal cord are diminished in size. Dorsal roots are small, but motor roots are normal. Primary sensory neurons show degenerative changes, and residual nodules are prominent, especially in sacral and lumbar sensory ganglia.
Clinical Features
Hick’s original clinical description in 1922 was of an autosomal dominant progressive disease in an English family. The features described included perforating ulcers of the feet, shooting pains on the body, and deafness, with clinical signs of dissociated sensory loss and areflexia in the feet. The same family was later reported by Denny-Brown in 1951, when he termed the disorder as hereditary sensory radicular neuropathy. With increased awareness of the disorder and discovery of various mutations, it was appreciated that there can be great variability in both penetrance and age of onset. Patients with SPTLC1 and SPTLC2 are phenotypically indistinguishable. The usual sensory findings include prominent loss of pain and temperature sensation that is particularly marked in the lower limbs, causing ulcerations, infected calluses, and bony deformities of the feet. Intermittent lancinating pains occur in some kinships. Touch and pressure sensations are lost to a lesser extent. Distal tendon reflexes are lost, and there is moderate weakness. The autonomic disturbances are usually limited to hypohidrosis, which roughly matches the distribution of sensory deficits. Blood pressure control, and sphincter and sexual functions are normal. Intelligence may be mildly impaired. A study by Houlden et al. showed that there is clinical heterogeneity both within and between families, suggesting the influence of other genetic and acquired factors. There is also a report of congenital onset in a French Gypsy patient with a de novo missense mutation in SPTLC1 resulting in an unusually severe phenotype associated with severe growth and mental retardation, hypotonia, gastroesophageal reflux, and vocal cord paralysis. Nerve conduction studies showed absent sensory and motor responses in the upper and lower limbs in this patient.
ATL1
Patients with HSAN type I caused by atlastin-GTPase 1 ( ATL1 ) mutations may have additional symptoms that include trophic skin and nail changes. Patients with mutations in DNA (cytosine-5-)-methyltransferase 1 ( DNMT1 ), have dementia and hearing loss.
RAB7
Because mutations in RAB7 also cause distal weakness, the disease is also called CMT2B. Affected patients are indistinguishable from those with HSAN. In addition, the sensory loss is more generalized, affecting vibration, touch, and proprioception, as well as pain and temperature. Patients with RAB7 mutations are also more likely to present in adolescence.
Hsan Type II
Molecular Genetics
HSAN type II is also termed congenital insensitivity to pain. There are at least three causative gene mutations resulting in subtype designations 2A, 2B, and 2C. Although mutations in different genes are involved, the clinical features of HSAN type II are similar.
HSAN 2A
The affected WNK1 gene encodes the serine-threonine protein kinase WNK1, an osmotic sensor that regulates sodium, chloride, and potassium homeostasis and can change membrane excitability. It is normally expressed in the central and peripheral nervous systems, with particularly high levels in dorsal root ganglia and sciatic nerves as well as increased expression in sensory axons as compared to motor. All mutations in WNK1 are presumed to result in loss of function as they cause truncations in the transcript. WNK1 is known to decrease the cell-surface expression of TRpV4, a nonselective cation channel that is involved in thermal and mechanical nociception. It has been suggested that a loss of function mutation could increase expression of this receptor, raising the threshold for sensitivity to pain as well as cold and heat detection.
HSAN 2B
The function of the affected FAM134B is poorly understood. It is known to be a component of the Golgi matrix and as such has a role in cellular structure. It has been suggested that the FAM134B protein is involved in neuronal survival, particularly nociceptive neurons, and that nonfunctional FAM134B protein would result in apoptosis of neuronal cells. As FAM134B is predominantly expressed in sensory and autonomic ganglia, it would explain the clinical phenotype seen in HSAN type II patients.
There may be genes other than the WNK1 or FAM134B genes that also cause the HSAN type II phenotype since there are some individuals who have all clinical features of HSAN type II but fail to demonstrate mutations in either gene. Many of these individuals also manifest sensorineural hearing loss.
HSAN 2C
Recently, a third mutation has been found to cause the HSAN2 phenotype. Erlich et al. described three brothers from an inbred Palestinian family with ulcero-mutilating sensory neuropathy and distal sensory loss along with distal motor involvement resulting in spastic paraplegia. Loss of function mutations in the KIF1A gene were identified via exome sequencing. KIF1A encodes KIF1A, a member of the kinesin superfamily that transports membranous organelles and macromolecules along microtubules. In axons, precursors of synaptic vesicles are transported anterogradely by KIF1A.
Pathophysiology
No cutaneous sensory receptors or nerve fibers are seen. Within the sural nerve there is severe depletion of myelinated axons and a lesser loss of nonmyelinated fibers. Neurophysiological evaluation reveals elevated vibratory and thermal thresholds at the hands and feet. Typically, nerve conduction velocities cannot be recorded as there is absence of the sensory nerve action potentials. Motor nerve conduction velocities are at or slightly below the normal limit and compound motor action potentials show slightly reduced amplitudes. EEG and electromyographic (EMG) studies are normal, but rate-dependent changes in brainstem auditory evoked potentials are increased indicating immature pathways.
Catecholaminergic sympathetic fibers were demonstrated by aldehyde-induced fluorescence.
Clinical Features
HSAN type II manifests in infancy or early childhood. Affected patients have profound sensory loss and frequent gastrointestinal and respiratory problems. The neonatal course is characterized by severe feeding problems and frequent apnea. Gastroesophageal reflux and vomiting occur commonly. Other autonomic disturbances such as erythematous blotching of the skin and episodic hyperhidrosis have been observed, especially in the FAM134B -related HSAN (HSAN 2B), but not postural hypotension. Tearing is frequently delayed but is eventually normal.
All sensory modalities are affected, including pain, temperature, and position senses. Unintentional self-injury is common and may begin with eruption of primary teeth. Taste sensation is diminished and lingual fungiform papillae are hypotrophic. Corneal and gag reflexes are diminished. Deep tendon reflexes are decreased. Painless fractures and acral ulcers can develop and repeated injury can lead to Charcot joints ( Figure 18.1 ). Generalized hypotonia can delay attainment of developmental milestones. The severe hypotonia may contribute to scoliosis. Growth is normal. Cognitive function varies greatly. Some patients are mildly retarded with expressive aphasia, whereas the subset with sensorineural hearing loss has normal intelligence.
Hsan Type III
Molecular Genetics
HSAN type III was originally described by Conrad Riley and Richard Day and was renamed by Riley himself as familial dysautonomia (FD). HSAN III is an autosomal recessive disease that appears to almost exclusively affect children with Eastern European Jewish parents. Three causative mutations have been reported in the IKBKAP gene, but 99.5% of HSAN III patients are homozygous for a splice-site mutation, a T to C change at base pair 6 of intron 20. The other two mutations, R696P and P914L, are missense mutations and thus far are always paired with the common mutation. The carrier frequency of the most common HSAN III mutation among the Ashkenazi Jews of North America has been reported to be between 1 in 27 and 1 in 32.
The missplice mutation, IVS20+6T_C, causes a tissue-specific decrease in splicing efficiency with variable skipping of exon 20 in the IKBKAP message resulting in a truncated protein product, IKAP or ELP1. ELP1 is a scaffold protein that is required to assemble the RNA polymerase II elongator complex, a key mediator of transcriptional elongation. Many of its target genes are required for migration and maturation of the nervous system. The IVS20+6T_C mutation does not cause complete loss of function, but neuronal tissues seem most severely affected as they primarily express mutant mRNA, somatic tissues express roughly equal levels of normal and mutant mRNA, and lymphoblast cell lines primarily express the normal product.
Pathophysiology
The mutation responsible for HSAN III results in an abnormal IKAP protein, now known as ELP1. How abnormal ELP1 results in the phenotype is unknown. As ELP1 is part of normal elongator transcription function, most studies have focused on identifying genes that are downregulated in the absence of a functional elongator complex, especially those that might regulate cell motility, development, differentiation, and survival. Because elongator may also facilitate acetylation of α-tubulin in the cytoplasm, decreased ELP1 might result in defective cytoskeletal organization.
Sensory Nervous System
Consistent with the theory of incomplete development or early cell death, pathologic studies have shown decreased numbers of unmyelinated and small myelinated neurons in the peripheral nervous system. Dorsal root ganglia are small and have markedly reduced numbers of neurons. The sural nerve is hypoplastic with markedly reduced numbers of nonmyelinated and small myelinated fibers, but there is also depletion of large-myelinated axons. Lissauer’s tracts and dorsal columns are diminished in size. Lingual sensory axons and submucosal neurons are diminished in number. Circumvallate papillae are hypoplastic and bear few taste buds. Fungiform papillae are absent and filiform papillae are rudimentary.
Autonomic Nervous System
Recent work from our laboratory indicates that the main autonomic defect in patients with HSAN III is in the afferent (sensory) neurons that relay incoming information from the arterial baroreceptors. Despite the sympathetic ganglia being one third normal size with about one tenth the normal neuronal population, efferent sympathetic function is intact and can be activated to raise blood pressure dramatically. Preganglionic sympathetic neurons in the spinal cord are reduced to about half the normal population. Surviving neurons tend to be slightly larger and have markedly increased tyrosine hydroxylase levels. Despite fewer remaining sympathetic terminals on vessels of skin, and kidney, the plasma concentration of norepinephrine, the sympathetic neurotransmitter, is normal.
Parasympathetic ganglia are variably affected. The ciliary ganglion is normal or marginally depleted of neurons, but the sphenopalatine ganglion has less than one tenth the normal population.
Patients are hypersensitive to sympathomimetics and parasympathomimetics. Small doses of clonidine can cause profound falls in blood pressure. Doses of norepinephrine that would be below threshold in normal subjects cause hypertension. The pupil is supersensitive to constriction by methacholine but not to dilation by epinephrine.
Excretion of breakdown products of epinephrine and norepinephrine is decreased, but those of dopamine are eliminated in increased amounts. During emotional arousal, sympathetic activity is unrestrained and dopamine and norepinephrine rise markedly. Blood pressure falls when upright because of a failure to activate sympathetic neurons and increase norepinephrine and vascular resistance when needed.
Clinical Features
There is considerable variation in some of the clinical features of HSAN III. Signs of the disorder are present from birth and some neurological features like gait and vision slowly deteriorate with age.
Somatic Sensory and Motor Systems
In HSAN III, the peripheral sensory abnormalities involve primarily the nociceptive functions, pain and temperature perceptions which are transmitted by Aδ (smaller myelinated) and C (unmyelinated) fibers. Thermal discrimination is more profoundly affected than pain and there are varying degrees of insensitivity. Typically, bone and skin pain are diminished but not absent, and sensitivity to visceral pain is present. Patients have decreased pain perception in the distribution of the trigeminal nerve, diminished corneal reflexes, and deficient taste, especially for sweet, which is due to the absence of fungiform papillae on the tip of the tongue. Defects in taste correlate with a decreased number of neurons in the geniculate ganglion.
Tendon reflexes are decreased or absent and the gait is ataxic, at least partly explained by loss of functional muscle spindles and impaired proprioception.
Autonomic System
There is widespread involvement of afferent autonomic neurons resulting in dysfunction of multiple organ system.
Gastrointestinal
Feeding difficulties manifesting as poor suck, uncoordinated swallowing, aerophagia, and frequent misdirection of food or liquid into the trachea are frequently the earliest clinical signs in a baby with FD (see Case Example 18.1 ). Recurrent misdirection, especially of liquids, and frequent gastroesophageal reflux put the patient at risk for aspiration and chronic lung disease. Severe cases are usually managed with a combined fundoplication and gastrostomy. Protracted episodes of nausea and vomiting, termed dysautonomic or hyperadrenergic crisis, are characteristic for patients with HSAN III. Circulating catecholamines, including dopamine, rise during these crises. Nausea and retching are likely caused by activation of dopamine receptors in the chemoreceptor trigger zone. Other physical signs associated with a crisis include agitation, tachycardia, hypertension, blotchy erythema, and diaphoresis, all signs of exagerated sympathetic activation. In some patients, these crises are daily morning events whereas in others, they occur only with extreme physical or emotional stress.
A 5-year-old girl presented for evaluation with short stature and failure to thrive. Her parents were Ashkenazi Jewish. She was breech presentation and delivered by C-section at 37 weeks. After delivery, she had bilateral pneumothoraces. She was also hypotonic and had absent myotatic reflexes. She failed to breastfeed and had gastroesophageal reflux and recurrent pneumonia. She had nocturnal choking episodes. Poor oral coordination with aspiration was confirmed on swallow study. She was not able to meet caloric or fluid needs and was diagnosed with failure to thrive at age 2. She breath-held and the mother described decerebrate posturing. Developmental milestones were delayed. Words were noted at 18 months. Physical therapy and occupational therapy were added. By age 5, she was verbal and had a history of tongue ulcers and pneumonias. Her parents could not recall her crying with tears. She had just been toilet trained.
On examination, she was fair, very thin, and small for age. Facial features were normal. She made good eye contact. Her tongue appeared smooth. Neurological exam revealed mild hypotonia with absent deep tendon and corneal reflexes. Gait was clumsy. Skin blotching, hyperhidrosis, and hypertension were observed when she was upset and subsided when relaxed. The gene mutation was found on testing.
Comment
As this child’s case illustrates, feeding problems that are due to uncoordinated swallow occur early, compromise nutrition, and produce respiratory infections. The neurological examination showed hypotonia, depressed tendon reflexes, and gait ataxia. Erythematous skin blotching and sweating when upset are signs of sympathetic arousal and occur because of catecholamine release. Breath-holding spells show lack of hypoxic ventilatory drive. Although prenatal diagnosis is available, testing is not always done and children with this disorder are still being born.
Respiratory
Repeated aspiration pneumonias and abnormal ventilatory drive to hypoxia and hypercapnea result in a particular type of chronic lung disease. Additional cases may be further complicated by a component of restrictive lung disease and neuromuscular weakness.
Minute ventilation fails to increase in response to hypoxia (at high altitude, during air travel, or during a pneumonia). Severe hypoxemia can cause hypotension, bradyarrhythmia, and syncope. Agitated patients are able to hold their breath without the drive to breathe producing cyanosis, syncope, decerebrate posturing, and seizures. Diving or underwater swimming can be hazardous. Tachypnea does not accompany respiratory infections. Frequently, abnormal spinal curvature further compromises respiratory function decreasing chest compliance, and it is unclear if corrective spine surgery adds to the restrictive component of the lung disease.
Cardiovascular
Cardiovascular lability as a result of afferent baroreflex failure is characteristic for this disorder. Patients with FD are unable to modulate sympathetic activity and to release vasopressin by baroreflex-mediated stimuli, and they exhibit marked sympathetic activation during cognitive arousal. Thus, patients can exhibit both profound and rapid postural hypotension without compensatory tachycardia with change of position as well as extreme hypertension and tachycardia when emotionally and physically stressed. Although postural hypotension can be pronounced, patients appear to tolerate extremely low blood pressures well. Symptoms are exaggerated and syncope is more apt to appear with cutaneous vasodilatation (hot weather), reductions in venous return (straining), or intravascular volume depletion (dehydration or anemia). Hypertension frequently occurs when the individual is supine, is responding to emotional stress or visceral pain, or is experiencing a dysautonomic crisis. Hypertension may contribute to target organ damage, particularly left ventricular hypertrophy and chronic renal failure.
Blotchy erythema occurring during eating or emotional excitement is further evidence of abnormal vasomotor control. The extremities may intermittently become cold, red, and mottled. Inappropriate temperature response to infection or environmental changes can result in either hypothermia or hyperthermia.
The Eye
Absence of tearing (alacrima) with emotional crying is a cardinal feature of this disorder. Baseline eye moisture varies among affected individuals and is further compromised by hypoesthesia resulting in a decreased blink frequency with rapid evaporation of baseline moisture. Corneal de-epithelialization, ulceration, and scarring with opacity often occur. The pupil responds appropriately to light and accommodation, suggesting intact parasympathetic pathways. Supersensitivity to infused methacholine may be caused by reduced tears resulting in higher local concentration of pharmacologic agents. Recently FD patients have been shown to have a specific type of optic neuropathy with predominant loss of papillomacular nerve fibers.
Cognition and Development
Developmental milestones are commonly delayed. Intelligence is usually within low normal ranges and learning disabilities are common. There is a general tendency for better verbal than motor performance. Memory is usually intact but executive planning skills are frequently impaired and there is a tendency to concrete thinking with problems in extrapolation. Anxiety and obsessive-compulsive repetitive and oppositional behavior disorders appear to occur more frequently. Puberty is usually delayed in both sexes. Average age at menarche is 15 years (normal 12.8 years). Nevertheless, primary and secondary sexual characteristics do develop, and males and females have demonstrated reproductive capability. Offspring of affected individuals and their nonaffected partners have been healthy obligatory carriers of the mutation.
Musculoskeletal
Individuals with FD tend to have similarities in facial characteristics that may be related to poor oromotor coordination as these characteristics are not noted at birth but become more distinguishable with age. Small jaws, mild dental crowding, and malocclusions are frequent. In addition, the upper lip tends to be thin and straight especially with smiling. Somatic growth is poor, the average adult height being about 5 feet. Growth hormone levels are usually normal. The high incidence of juvenile scoliosis further compromises eventual height. By 10 years of age, 85% of patients have scoliosis ( Figure 18.2 ).
