Hereditary Sensory and Autonomic Neuropathies

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.

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.

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.

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.