Sptlc1-Related Hereditary Sensory Neuropathy
Summary
Clinical characteristics.
SPTLC1-related hereditary sensory neuropathy (HSN) is an axonal form of hereditary motor and sensory neuropathy distinguished by prominent early sensory loss and later positive sensory phenomena including dysesthesia and characteristic "lightning" or "shooting" pains. Loss of sensation can lead to painless injuries, which, if unrecognized, result in slow wound healing and subsequent osteomyelitis requiring distal amputations. Motor involvement is present in all advanced cases and can be severe. After age 20 years, the distal wasting and weakness may involve proximal muscles, possibly leading to wheelchair dependency by the seventh or eighth decade. Sensorineural hearing loss is variable.
Diagnosis/testing.
The diagnosis of SPTLC1-related HSN is established in a proband with characteristic clinical features and identification of a heterozygous pathogenic variant in SPTLC1 on molecular genetic testing.
Management.
Treatment of manifestations: Clean and protect wounds on neuropathic limbs; surgical treatment similar to that for leprosy; ankle/foot orthotics for foot drop; arthrodesis for Charcot joints; pregabalin, carbamazepine, gabapentin, or amitryptiline, or a combination of an antiepileptic drug and an antidepressant drug for shooting pains.
Prevention of secondary complications: Routine care by a diabetic foot care specialist to prevent/treat calluses and foot ulcers; education about good skin care and burn prevention (e.g., to hands when cooking).
Surveillance: At least daily inspection of feet for injuries or sources of wear.
Agents/circumstances to avoid: Opiates as SPTLC1-related HSN is a chronic disorder.
Genetic counseling.
SPTLC1-related HSN is inherited in an autosomal dominant manner. Most probands have an affected parent. Offspring of an affected individual have a 50% chance of inheriting the SPTLC1 pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family.
Diagnosis
Suggestive Findings
SPTLC1-related hereditary sensory neuropathy (HSN) should be suspected in individuals with the following clinical findings and family history:
- Initial sensory neuropathy that then becomes a motor and sensory axonal neuropathy
- Painless injuries in the feet and hands with skin ulceration, Charcot joints, sometimes amputations
- Distal muscle weakness that spreads proximally producing limb girdle weakness in advanced stages
- At some stage, occurrence of typical sharp shooting "lightning" pains lasting seconds to minutes
- Sensorineural hearing loss (variably present)
- Family history consistent with autosomal dominant inheritance
Establishing the Diagnosis
The diagnosis of SPTLC1-related HSN is established in a proband with the above Suggestive Findings and a heterozygous pathogenic variant in SPTLC1 identified by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SPTLC1-related HSN is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with sensory neuropathy are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of SPTLC1-related HSN, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
- Single-gene testing. Sequence analysis of SPTLC1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: To date gain-of-function pathogenic variants located in exons 5 and 6 have been reported (see Molecular Genetics). No duplications or deletions have been found or are expected given the disease mechanism.
- A multigene panel that includes SPTLC1 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by sensory neuropathy, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in SPTLC1-Related Hereditary Sensory Neuropathy
| Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by This Method |
|---|---|---|
| SPTLC1 | Sequence analysis 3 | 100% 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Includes pathogenic variants in exon 5 and exon 6 [Bejaoui et al 2001; Dawkins et al 2001; Houlden et al 2006; Author, personal communication]; see Molecular Genetics.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
No duplications or deletions have been found or are expected as the disease mechanism involves a gain-of-function pathogenic variant of the active site of the enzyme (see Molecular Genetics).
Clinical Characteristics
Clinical Description
SPTLC1-related hereditary sensory neuropathy (HSN) is usually first noticed when painless injuries appear. Onset ranges from the teens to the sixth decade. Later, positive sensory phenomena occur (numbness, paresthesia, burning, and shooting pains). Shooting pains may be a distinctive but variable feature of SPTLC1-related HSN.
If the sensory loss is unheeded, chronic ulcerations of the extremities may lead to osteomyelitis and require amputations. Neuropathic joints are common.
Weakness commences in the distal lower limbs, followed by the distal upper limbs and in severe cases, proximal upper- and lower-limb girdle muscles. Distal muscle weakness and wasting are present in all advanced cases. The weakness of ankle flexors produces a floppy, flipper-like foot rather than pes cavus.
A few instances of early severe motor involvement have been reported [Houlden et al 2006].
Older affected individuals may require a wheelchair for mobility.
Retained and even brisk proximal reflexes in some affected individuals may indicate some upper motor neuron involvement. Corticospinal degeneration was not observed on an autopsy of an individual with SPTLC1-related HSN, but data are limited.
Sensorineural hearing loss is variable. When present, its onset is in middle to late adulthood.
Rarely, pupillary abnormalities termed "tonic pupils" or pseudo-Argyll-Robertson pupils (i.e., those not associated with syphilis) are present.
Visceral autonomic features are rare [Nicholson, unpublished data], with abdominal pain, diarrhea, and weight loss reported in some individuals in one family only [Houlden et al 2006].
Electrophysiology is initially normal and is not useful for early detection [Author, personal observation].
- Sensory nerve action potentials are reduced only late in the disease.
- Motor nerve conduction velocities are normal until motor action potential amplitudes become reduced.
- Motor nerve conduction velocities are mildly slowed and motor action potentials are reduced in advanced cases.
Sural nerve biopsy shows axonal degeneration with loss of both small and large fibers. These findings are nonspecific and not diagnostic.
Neuropathology. The disease process affects the axons and cell bodies of dorsal root ganglia neurons and motor neurons in the anterior horns of the spinal cord. Studies show a distal axonal degeneration with loss of unmyelinated, small myelinated, and large myelinated fibers with decreasing severity in that order, proceeding to ganglion cell loss [Houlden et al 2006, Auer-Grumbach 2013]. See review in Thomas [1993].
Genotype-Phenotype Correlations
Individuals with SPTLC1 pathogenic variants at Ser331, including p.Ser331Phe and p.Ser331Tyr, have been reported to have an earlier-onset motor and sensory neuropathy with a distinct phenotype that can include early-onset cataract, growth retardation, hypotonia, and intellectual disability [Auer-Grumbach 2013, Suh et al 2014].
Penetrance
Variable penetrance has been observed [Houlden et al 2006].
Nomenclature
The term "hereditary sensory neuropathy" (HSN) was first used by Hicks [1922] to describe a family with associated spontaneous shooting pains and deafness. The family was later reported as having a form of peroneal muscular atrophy.
Motor involvement was also noted in other families in southern England and described by Ellison in his University of Edinburgh MD thesis, and later by Campbell & Hoffman [1964]. The Australian families with an SPTLC1 pathogenic variant described by Dawkins et al [2001] have no visceral autonomic signs or symptoms and share a common ancestor with the southern English families described by Ellison and reported by Campbell & Hoffman [1964] as having HSN. Therefore, the term "HSN" was used in the review by Thomas [1993], and the disorder is also listed in OMIM as HSN1A. Although individuals with HSN1 rarely have visceral autonomic signs, this disorder is still classified as a hereditary sensory and autonomic neuropathy (HSAN1A).
Even so, the terms "HSN" and "HSAN" are not ideal, as the disorder is both a sensory and a motor neuropathy. Therefore, strictly, it is a form of Charcot-Marie-Tooth neuropathy. The phenotype is that of a slowly progressive length-dependent adult-onset axonal form of Charcot-Marie-Tooth neuropathy (CMT type II, and hereditary motor and sensory neuropathy, HMSN II) but with prominent loss of pain fibers.
The term "HSN1" designates dominantly inherited forms of hereditary sensory neuropathy. HSAN types 2 to 6 are recessively inherited forms of sensory and autonomic neuropathies.
Prevalence
HSN affects 25 of 600 families (4.2%) with CMT studied by the author. Of these families with HSN, 25% have SPTLC1-related HSN (1% of all families with CMT).
If the overall incidence of motor and sensory neuropathies is 30:100,000, the prevalence of HSN is on the order of 2:1,000,000. HSN1A may be underestimated because diagnosis previously depended erroneously on finding pure sensory involvement, shooting pains, and/or skin damage or ulcers.
Differential Diagnosis
Dominant forms of hereditary sensory neuropathy (HSN) are genetically heterogeneous:
- HSAN1B (OMIM 608088), a dominantly inherited sensory neuropathy without foot ulcers but with cough and gastroesophageal reflux disease, maps to chromosome 3p24-p22.
- HSAN1C (OMIM 613640) is caused by pathogenic variants in SPTLC2. The neuropathy is phenotypically similar to SPTLC1-related HSN.
- HSN1D (OMIM 613708) is caused by pathogenic variants in ATL1.
- HSN1E (hereditary sensory neuropathy with dementia and hearing loss), a late-onset mild sensory neuropathy associated with ataxia and deafness, is caused by pathogenic variants in DNMT1.
Disorders with similar phenotypes are two forms of CMT2:
- CMT2B, a motor and sensory neuropathy with severe sensory loss and foot ulcers but no shooting pains. CMT2B is caused by pathogenic variants in RAB7.
- CMT2I/J. The MPZ pathogenic variant p.Thr124Met is associated with a phenotype almost identical to HSAN1A, with severe sensory loss, shooting pains, and occasional pseudo-Argyl-Robertson pupils but no ulcerations.
Painful diabetic neuropathy may have a similar phenotype but usually lacks a family history of neuropathy.
See Hereditary Sensory and Autonomic Neuropathy: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SPTLC1-related hereditary sensory neuropathy (HSN), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
- Examination of the skin of the feet, ankles, and hands
- Examination of joints for evidence of Charcot joints
- Strength assessment
- Examination for loss of sweating and compensatory patchy hyperhidrosis
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Wounds on neuropathic limbs heal if they are clean and protected and the limb is rested. Principles of treatment are the same as for leprosy surgery; see Warren & Nade [1999].
Foot drop can be treated with ankle/foot orthotics, but these need sleeving with stockings or some form of second skin to prevent skin abrasion.
Charcot joints may require arthrodesis.
Shooting pains are difficult to treat and only partial relief can be obtained with carbamazepine, gabapentin, or amitryptiline, or a combination of an antiepileptic and an antidepressant. Opiates are contraindicated as SPTLC1-related HSN is a chronic disorder.
Prevention of Secondary Complications
Foot ulcers are frequently caused by breakdown of callus. Therefore, it is important to prevent callus formation by removing sources of pressure and to treat existing callus by softening the skin. Routine foot care by a diabetic clinic or by a podiatrist instructed to treat as for a diabetic foot is recommended.
Burns can be prevented by using gloves as needed (e.g., during cooking).
A diabetic education clinic is an excellent source of advice regarding skin care.
Surveillance
Feet should be inspected at least daily for injuries or sources of wear.
Agents/Circumstances to Avoid
Opiates are contraindicated as this is a chronic disorder.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Penno et al [2010] found that SPTLC1 pathogenic variants associated with HSN result in decreased specificity of the active site of the enzyme, allowing alanine and glycine into the active site and producing neurotoxic sphingoid bases. The finding suggests that SPTLC1-related HSN is caused by these toxic products and opens an avenue for possible (at present, experimental) therapeutic approaches. Addition of serine to the diet of an HSN1A animal model and to 14 humans with SPTLC1-related HSN was effective in reducing plasma levels of the toxic deoxysphingolipids [Garofalo et al 2011].
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions.