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 amitriptyline, or a combination of anti-seizure medication 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.

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).

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

SPTLC1 pathogenic variants at Ser331, including p.Ser331Phe [Suh et al 2014] and p.Ser331Tyr [Rotthier et al 2009, Auer-Grumbach 2013], are associated with severe childhood-onset motor and sensory neuropathy (generally without skin ulceration as in classic HSAN1A). Affected individuals have muscle atrophy (which may include atrophy of the tongue), hypotonia, growth deficiency, intellectual disability (in some individuals), cataracts, and laryngeal involvement. Disease is caused by accumulation of toxic sphingolipids [Auer-Grumbach 2013]. The general absence of skin ulceration in these severe childhood-onset neuropathies may be explained by slow accumulation of toxic sphingolipids. (One individual, described by Suh et al [2014], was reported to have skin ulceration.)

An individual with pathogenic variant p.Ser331Tyr was included in a description of SPTLC1-related juvenile ALS by Johnson et al [2021]. The described syndrome was caused by toxic sphingolipids and sensory involvement was demonstrated; thus, it was most likely a severe early-onset form of HSN.

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.

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 amitriptyline, or a combination of anti-seizure and antidepressant medication. 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 EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

SPTLC1-related hereditary sensory neuropathy (HSN) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with SPTLC1-related HSN have an affected parent.
• Some individuals diagnosed with SPTLC1-related HSN may have the disorder as the result of a de novo SPTLC1 pathogenic variant. One apparently de novo variant, reported as pathogenic [Verhoeven et al 2004], is now thought to be non-pathogenic [Hornemann et al 2009]; the proportion of SPTLC1-related HSN caused by a de novo pathogenic variant is unknown.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Although no instances of germline mosaicism have been reported, it remains a possibility.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant. Note: Recommendations for evaluation of the parents also include clinical examination and electrophysiologic testing; however, diagnostic clinical and electrophysiologic findings have not been reported to emerge after age 30 years.
• The family history of some individuals diagnosed with SPTLC1-related HSN may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to each sib of inheriting the pathogenic variant is 50%; sibs who inherit the pathogenic variant may or may not be affected as reduced penetrance has been observed.
• If the SPTLC1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the SPTLC1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SPTLC1-related HSN because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
• Note: Because diagnostic clinical and electrophysiologic findings have not been reported to emerge after age 30 years, sibs who are asymptomatic at age 30 years are no longer considered to be at increased risk for SPTLC1-related HSN.

Offspring of a proband. Each child of an individual with HSN1A has a 50% chance of inheriting the SPTLC1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the SPTLC1 pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of HSN1A it is appropriate to consider testing of symptomatic individuals regardless of age.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the SPTLC1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Revision History

• 2 December 2021 (aa) Revision: additions to Genetically Related Disorders and Genotype-Phenotype Correlations [Johnson et al 2021, Mohassel et al 2021]
• 21 November 2018 (sw) Comprehensive update posted live
• 10 September 2015 (me) Comprehensive update posted live
• 7 March 2013 (me) Comprehensive update posted live
• 3 May 2012 (gn) Revision: edits to Therapies Under Investigation
• 15 March 2012 (cd) Revision: targeted mutation analysis no longer listed as available clinically in the GeneTests™ Laboratory Directory
• 22 September 2011 (cd) Revision: addition to Differential Diagnosis; change in disease nomenclature (HSN1 → HSN1A)
• 20 July 2010 (me) Comprehensive update posted live
• 2 October 2007 (me) Comprehensive update posted live
• 11 March 2005 (me) Comprehensive update posted live
• 28 September 2004 (me) Comprehensive update posted live
• 21 May 2004 (gn) Revision: prenatal testing available
• 23 September 2002 (me) Review posted live
• 21 March 2002 (gn) Original submission

Published Guidelines / Consensus Statements

• Committee on Bioethics; Committee on Genetics, and American College of Medical Genetics and Genomics: Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 11-30-21.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 11-30-21.

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