Hereditary sensory and autonomic neuropathy type I (HSAN I) or hereditary sensory neuropathy type I (HSN I) is a group of autosomal dominant inherited neurological diseases that affect the peripheral nervous system particularly on the sensory and autonomic functions. The hallmark of the disease is the marked loss of pain and temperature sensation in the distal parts of the lower limbs. The autonomic disturbances, if present, manifest as sweating abnormalities.
The beginning of the disease varies between adolescence and adulthood. Since affected individuals cannot feel pain, minor wounds or blisters in the painless area may not be immediately recognized and can develop into extensive and deep foot ulcerations. Once infection occurs, the complications such as inflammation and progressive destruction of the underlying bones may follow and may require amputation of the surrounding area.
HSAN I is the most common type among the five types of HSAN. As a heterogeneous group of diseases, HSAN I can be divided into five subtypes HSAN IA-E. Most of the genes associated with the diseases have been identified. However, the molecular pathways leading to the manifestation of the diseases are not fully understood. Therefore, the potential targets for therapeutic interventions are not known. Moreover, gene-based therapies for patients with the diseases are not available to date, hence supportive care is the only treatment available for the patients.
Signs and symptoms At the beginning, affected individuals often notice the loss of pain and temperature sensation or all sensory modalities in their feet. As the disease progresses, the sensory abnormalities may extend up to the knees. However, they often do not notice sensory loss for a long time. Many affected individuals only become aware of the disease when they notice painless injuries and burns or when they seek medical advice for slowly healing wounds or foot ulcers. Foot ulcerations may appear due to permanent pressure, such as long walks or badly fitting shoes. Minor wounds or blisters may then lead to deep foot ulcerations. Once infection occurs, complications such as inflammation and destruction of the underlying bones may follow. Affected individuals who do not lose sensation may experience spontaneous pain. In addition, many affected individuals exhibit, to a variable degree, symmetrical distal muscle weakness and wasting.
HSAN I is characterized by marked sensory disturbances mainly as the loss of pain and temperature sensation in the distal parts of the lower limbs. The loss of sensation can also extend to the proximal parts of the lower limbs and the upper limbs as the disease progresses. Some affected individuals do not lose sensation, but instead experience severe shooting, burning, and lancinating pains in the limbs or in the trunk. Autonomic disturbances, if present, manifest as decreased sweating. The degree of motor disturbances is highly variable, even within families, ranging from absent to severe distal muscle weakness and wasting.
The disease progresses slowly, but often disables the affected individuals severely after a long duration. The onset of the disease varies between the 2nd and 5th decade of life, albeit congenital or childhood onset has occasionally been reported. With the progression of the disease, the affected individuals lose the ability to feel pain in their feet and legs. Minor injuries in the painless area can result in slow-healing wounds which, if not immediately recognized, can develop into chronic ulcerations. Once infection occurs, these ulcerations can result in severe complications that lead to foot deformity, such as inflammation of the underlying bones, spontaneous bone fractures, and progressive degeneration of weight-bearing joints. Furthermore, foot deformity promotes skin changes such as hyperkeratosis at pressure points. These complications may necessitate amputation of the affected foot.
Biopsies of severely affected sural nerve (short saphenous nerve) in patients with HSAN I showed evidence of neuronal degeneration. Only a very few myelinated fibers were observed some of which showed a sign of primary (segmental) demyelination. A reasonable number of unmyelinated axons remained, although the presence of stacks of flattened Schwann cell processes suggested unmyelinated axon loss. Electrophysiological testing provides additional evidence that neuronal degeneration underlies the disease. Sensory potentials are usually absent in the lower limbs but are often recordable or even normal in the upper limbs of the patients. In addition, motor conduction is slow, possibly implying a demyelinating process.
Cause Advances in molecular genetics have enabled identification of most genes associated with HSAN I. However, the molecular mechanisms that underlie the disease are not fully understood and are under investigation. One of challenges in the investigation is to elucidate how faulty genes that are ubiquitously expressed and are involved in basic cellular functions, such as sphingolipid metabolism, maintenance of organellar integrity, membrane dynamics, and transcription regulation, affect specific populations of neurons.
HSAN IA HSAN IA is associated with heterozygous missense mutations in the SPTLC1 gene. The gene encodes SPTLC1 protein, which together with SPTLC2 protein, forms serine palmitoyltransferase (SPT) in humans. SPT is a pyridoxal-5'-phosphate-dependent enzyme that catalyzes the first and rate-limiting step in the de novo biosynthesis of sphingolipids. Together with cholesterol, sphingolipids form the main component of lipid rafts, structures in the plasma membrane that facilitate efficient signal transduction. Many intermediate sphingoid bases and their derivatives, as well as complex sphingolipids, are active as extracellular and intracellular regulators of growth, differentiation, migration, survival, and cellular responses to stress.
Initially, mutations in the SPTLC1 gene were associated with increased activity of SPT. Subsequent studies rather suggested that the mutations reduce the activity of the enzyme. However, it cannot account for the aberrant sphingolipid-related cellular features in heterozygous patient-derived cells or the HSAN IA clinical features in heterozygous mice. These results suggest that the activity of non-mutant SPTLC1 protein may be sufficient for maintaining normal sphingolipid biosynthesis and cell viability. Therefore, the neuronal degeneration in HSAN IA is likely due to subtler and rather long-term effects of the mutations or perhaps accumulation of toxic lipids produced by mutant enzymes.
Further studies supported the latter notion. The mutations have been shown in vitro to facilitate substrate promiscuity of SPT. Mutant SPT mediates the condensation not only of its normal substrate serine, but also of alanine or glycine, with palmitoyl-coenzyme A. The reactions lead to the formation of two aberrant sphingolipid metabolites 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine, respectively. As the metabolites lack a hydroxyl group that is required for their further conversion and degradation, they accumulate inside the cell. The metabolites have been shown to be more toxic to sensory neurons than to motor neurons. They accumulate in the peripheral nervous system where HSAN manifest, but not in the central nervous system in mice bearing a HSAN IA-associated mutation. Furthermore, serine-enriched diet reduced the levels of the metabolites and improved sensory and motor performance of the mice. A small-scale clinical trial also showed similar results. These studies demonstrated that an altered substrate selectivity of the mutant SPT is the key to the pathophysiology of HSAN IA.
HSAN IB HSAN IB is linked to a 3.42 cM interval on chromosome 3p22–p24. This finding was confirmed in another family with similar clinical features. However, mutation analysis of genes in the candidate region has not revealed any disease-causing gene. Since then, this rare form of HSAN I has not been reported in other families. The gene associated with the disease still remains to be identified.
HSAN IC HSAN IC is associated with heterozygous missense mutations in the SPTLC2 gene. The gene encodes SPTLC2 protein which is one of two subunits of SPT. As mutations in the gene affect the same enzyme as those in the SPTLC1 gene, the molecular basis of the disease is suggested to be the same as that of HSAN IA.
HSAN ID HSAN ID is caused by heterozygous missense mutations in the ATL1 gene which encodes atlastin-1. Atlastin-1 is a member of the dynamin/Mx/guanylate-binding protein superfamily of large GTPases. The enzyme contains an endoplasmic reticulum (ER) retention moiety, indicating that it functions predominantly in the organelle. It is highly expressed in the mammalian central nervous system and is enriched in the hippocampus and pyramidal neurons. However, information on the expression of the gene in the peripheral nervous system is still lacking.
In fruit fly (Drosophila melanogaster), atlastin-1 has been shown to induce tethering and fusion of membranes adjacent to the ER to help maintain the integrity of the ER. The function of atlastin-1 is crucially dependent on its GTPase activity. In humans, a HSAN ID-associated mutation caused significant loss of the GTPase activity of the enzyme, leading to prominent disruption of ER network. In addition to maintaining the integrity of the ER, atlastin-1 also has neuron-related functions. The enzyme is implicated in the trafficking and signaling of type I bone morphogenetic protein (BMP) receptors in zebra fish (Danio rerio). BMP signaling is involved in axon guidance and synapse formation, as well as axonal transport and the organization of the microtubule network in developing neurons. The signaling is disturbed in several neurodegenerative disorders. It also regulates membrane dynamics in the neuronal growth cone in rat.
Mutations in the ATL1 gene are also a common cause of early-onset hereditary spastic paraplegia (HSP) in humans. The disease is characterized by progressive stiffness and contraction (spasticity) in the lower limbs due to damage to or dysfunction of the nerves. The vast majority of HSP-associated mutations are missense mutations that are scattered throughout the affected protein. Some of these mutations have been shown to reduce the GTPase activity of atlastin-1 in vitro. However, the unique molecular signature of the mutations or the functional domains of the ATL1 gene that are affected in patients with HSAN ID and HSP that could explain the differences in clinical features between these two diseases are not clear. This finding indicates that additional genetic and/or environmental factors may modulate the clinical manifestation of the main causative mutation.
HSAN IE HSAN IE is associated with heterozygous missense mutations in the DNMT1 gene which encodes DNA methyltransferase 1 (Dnmt1). Dnmt1 belongs to a family of enzymes that catalyze the transfer of a methyl group from S-adenosyl methionine to DNA. Dnmt1 has a high preference for hemimethylated DNA, hence it is called maintenance methyltransferase. The protein also has de novo DNA methyltransferase activity which is responsible for establishing methylation patterns during embryonic development. Dnmt1 is highly expressed in post-mitotic neurons in the adult central nervous system, with peak expression during the S-phase of the cell cycle.