Hereditary Sensory And Autonomic Neuropathy Type Ii
Summary
Clinical characteristics.
Hereditary sensory and autonomic neuropathy type II (HSAN2) is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease.
Diagnosis/testing.
Diagnosis is based on clinical findings and molecular genetic testing of WNK1 (previously HSN2) (type HSAN2A), RETREG1 (previously FAM134B, JK1) (type HSAN2B), KIF1A (type HSAN2C), and SCN9A (type HSAN2D), the only genes in which mutation is known to cause HSAN2.
Management.
Treatment of manifestations: Treatment is symptomatic and often involves a team including neurologists, orthopedic surgeons, and physiotherapists. Training in the care of the sensory-impaired limb, often in a diabetic clinic, is important and includes self-examination especially of the feet for any signs of trauma. To prevent osteomyelitis, and hence amputations, wounds require cleaning and protection along with antiseptic treatment. To prevent callous formation the skin of neuropathic limbs requires hydration and lipid-based unguents. Appropriate shoes and socks are recommended.
Surveillance: The feet should be inspected daily for injuries or sources of wear. Annual follow up in centers with comprehensive care of diabetics and/or persons with Charcot-Marie-Tooth neuropathy is recommended.
Agents/circumstances to avoid: Ill-fitting shoes or other sources of trauma to the feet or hands (e.g., use protective gloves when handling hot items when cooking).
Genetic counseling.
HSAN2, which includes HSAN2A, HSAN2B, HSAN2C, and HSAN2D, is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing of at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.
Diagnosis
Clinical Diagnosis
The clinical diagnosis of hereditary sensory and autonomic neuropathy type II (HSAN2) is based on the presence of the following:
- Congenital or early-onset (1st-2nd decade) sensory deficit
- Sensory loss affecting all modalities
- Ulcerations of hands/feet often requiring amputations
- Acral mutilations
- Painless fractures and neuropathic arthropathy in some
- Varying degree of autonomic involvement: hyperhidrosis, urinary incontinence, and slow pupillary reaction to light.Note: Autonomic disturbances appear to be less prominent in HSAN2 than in the other autosomal recessive sensory neuropathies (HSAN3, HSAN4, HSAN5, HSAN6).
- Family history consistent with autosomal recessive inheritance
Testing
Electrophysiology reveals the following:
- Reduced/absent sensory nerve action potentials
- Preserved or reduced motor nerve conduction velocities (NCV)
- Variably reduced compound muscle action potentials (CMAP)
Histopathology. Sural nerve biopsy shows signs of an axonal sensory neuropathy, pronounced absence of (small) myelinated fibers, and decreased unmyelinated fibers. Additionally, loss of large myelinated fibers may be seen in those with HSAN2D.
Molecular Genetic Testing
Genes. The four types of hereditary sensory and autonomic neuropathy type II (HSAN2) and associated genes:
- HSAN2A. WNK1 (previously named HSN2, a gene symbol that is now retired). The previously designated HSN2 was first reported as a single-exon gene located in intron 8 of WNK1, with both genes transcribed from the same strand [Lafreniere et al 2004]. Subsequently, HSN2 was found to be an alternatively spliced exon present in a nervous system-specific isoform of WNK1 [Shekarabi et al 2008]. This exon, the so-called ‘HSN2’ exon, is exon 10 in the reference sequence of the nervous system-specific WNK1 isoform variant 4 (see Molecular Genetics for details).
- HSAN2B. RETREG1 (previously FAM134B, JK1)
- HSAN2C. KIF1A
- HSAN2D. SCN9A
Table 1.
Molecular Genetic Testing Used in Hereditary Sensory and Autonomic Neuropathy Type II
| HSAN2 Type | Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant Detectable by This Method |
|---|---|---|---|
| HSAN2A | WNK1 2 | Sequence analysis 3, 4 | Unknown |
| HSAN2B | RETREG1 5 | ||
| HSAN2C | KIF1A | ||
| HSAN2D | SCN9A |
- 1.
See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.
- 2.
The pathogenic variants reported are (except for one) located in an alternatively-spliced nervous system-specific WNK1 transcript that is expressed in the cell body of sensory ganglia neurons and particularly in neuronal projections. Pathogenic variants in this nervous system-specific transcript, which includes the ‘HSN2’ exon, cause HSAN2A disease. This should be taken into account when performing molecular genetic testing. Because pathogenic variants in other exons of WNK1 may also contribute to the HSAN2A phenotype, sequence analysis of all known exons from genomic DNA may be necessary if only one pathogenic variant is found in the ‘HSN2’ exon. Note: Homozygous or compound heterozygous null alleles affecting all WNK1 isoforms are speculated to be embryonically lethal.
- 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.
To date, all WNK1, RETREG1, KIF1A, and SCN9A variants that cause HSAN2 are nonsense, frameshift, or splice site variants. Copy number variants in the genes have not been addressed in the current literature.
- 5.
HSAN2B has been confirmed in six families by RETREG1 sequence analysis.
Testing Strategy
To confirm/establish the diagnosis in a proband. The diagnosis of HSAN2 is established in individuals who meet clinical diagnostic criteria and who have biallelic pathogenic variants in either WNK1, RETREG1, KIF1A, or SCN9A.
Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.
Serial single-gene testing is based on phenotype:
- Sequence analysis of WNK1 and KIF1A may be considered first in individuals who do not have clinical autonomic dysfunction.Note: Due to the small number of affected individuals reported with HSAN2, presence or absence of autonomic dysfunction may not be a sufficient criterion to distinguish between HSAN2 subtypes.
- Sequence analysis of RETREG1 may be considered first in affected individuals who have autonomic dysfunction with or without distal motor involvement.
- Sequence analysis of SCN9A should be performed in those who have no pathogenic variant (or only one pathogenic variant) identified by sequence analysis of RETREG1, WNK1, and KIF1A.
A multigene panel that includes WNK1, RETREG1, KIF1A, SCN9A, and other genes of interest (see Differential Diagnosis) may also be considered. 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; thus, clinicians need to determine which multigene panel is most likely 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. (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.
More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of HSAN2.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Clinical Characteristics
Clinical Description
The hereditary sensory and autonomic neuropathies present a genetically and clinically heterogeneous group of neurodegenerative disorders of the peripheral nervous system. The published clinical descriptions of hereditary sensory and autonomic neuropathy type II (HSAN2) are inconsistent, possibly in part as a result of reports that lack molecular genetic confirmation of the diagnosis. Clinically, WNK1-related HSAN (HSAN2A), RETREG1-related HSAN (HSAN2B) and KIF1A-related HSAN (HSAN2C) appear to be very similar but may actually be distinguishable as additional cases are described in the future. Autonomic dysfunction may be more pronounced in RETREG1-related neuropathy, and individuals with KIF1A-related HSAN also showed distal muscle weakness. SCN9A-related HSAN (HSAN2D) was reported only recently in two families [Yuan et al 2013].
Typically in molecularly confirmed HSAN2, the onset is in the first two decades (often before puberty). It is characterized by progressive numbness of the hands and feet, together with reduced sensation to pain, temperature, and touch. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced.
Neuropathic skin tends to produce excessive keratin and hyperkeratosis that may be forced down into the deeper layers of soft tissue and/or may crack, promoting ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Secondary muscle atrophy and Charcot joints may occur. Painless fractures can complicate the disease.
Intellectual development is usually normal.
Autonomic disturbances appear to be less pronounced than in the other autosomal recessive sensory neuropathies. Sweating and tearing are usually normal but hyperhidrosis is present in some cases. Tonic pupils are observed. With progression of the disease urinary incontinence is reported.
Genotype-Phenotype Correlations
No genotype-phenotype correlations are known. Inter- and intrafamilial phenotypic variability is reported.
Nomenclature
HSAN2 has also been reported as the following:
- Morvan’s disease
- Congenital sensory neuropathy
- Neurogenic acroosteolysis
- Hereditary sensory radicular neuropathy
Dyck originally proposed five different HSAN types on the basis of clinical symptoms and nerve biopsy specimens [Dyck 1993]. This classification still stands after the molecular characterization of the subtypes, but additional genetic and phenotypic heterogeneity has been included [Verhoeven et al 2006], suggesting a need for a detailed classification based on the underlying gene defects [Rotthier et al 2012]
Prevalence
The worldwide prevalence of HSAN2 is unknown. For comparison, the overall prevalence of the closely related hereditary motor and sensory neuropathies (HMSN or Charcot-Marie-Tooth disease) is on the order of 30:100,000, and hereditary sensory and autonomic neuropathies (HSAN) occur with markedly lower frequency.
Clustering of cases of HSAN2A in eastern Canada is the result of relatively common founder variants [Roddier et al 2005].
Differential Diagnosis
Disorders accompanied by self-mutilating behavior resemble some aspects of the congenital forms of HSAN including Lesch-Nyhan syndrome or untreated phenylketonuria. Diabetic neuropathy shares some aspects of adult-onset HSAN. Confusion of HSAN with leprosy is reported in some cases.
Clinical overlap is also observed between adult-onset HSAN and Charcot-Marie-Tooth Neuropathy (CMT). For example, CMT2J, caused by the p.Thr124Met pathogenic variant in MPZ, encoding myelin protein zero, is characterized by severe sensory loss, but no ulcerations [De Jonghe et al 1999].
CMT2B, caused by pathogenic variants in RAB7A, is characterized by distal muscle weakness and wasting as often the first and most prominent sign of the disease [Verhoeven et al 2003]. The disease is accompanied by sensory loss of all modalities with a high frequency of foot ulcers necessitating amputations. Nerve conduction velocity studies indicate a primarily axonal neuropathy. (See Charcot-Marie-Tooth Neuropathy Overview.)
Hereditary sensory and autonomic neuropathy type I (HSAN1) is an autosomal dominant genetically heterogeneous disorder:
- HSAN1A and HSAN1C (OMIM 613640) are caused by pathogenic variants in SPTLC1 (HSAN1A) [Bejaoui et al 2001, Dawkins et al 2001] and SPTLC2 (HSAN1C) [Rotthier et al 2010]. The SPT enzymes, encoded by these genes catalyze the de novo synthesis of sphingolipids. Sensory loss in these conditions usually starts in the adult. In rare cases early onset of symptoms is also reported. Dysesthesia with characteristic lancinating pain helps in clinical diagnosis but can be absent. Painless injuries and osteomyelitis requiring amputations are reported as well. The disease can be associated with sensorineural deafness. Motor involvement is mild to severe (including wheelchair requirement). Visceral autonomic features appear to be absent.
- HSAN1B (OMIM 608088) with autosomal dominant inheritance is an adult-onset sensory neuropathy with cough and gastroesophageal reflux. This entity has been mapped to 3p24-p22 and was described in two independent families, but to date no causative pathogenic variant has been identified.
- HSN1D (OMIM 613708). Pathogenic variants in ATL1, known to be associated with spastic paraplegia 3A (SPG3A), have also been identified in individuals with HSAN [Guelly et al 2011].
- HSN1E. Hereditary sensory neuropathy with dementia and hearing loss is an adult-onset autosomal dominant condition caused by pathogenic missense variants in DNMT1, encoding DNA methyltransferase 1 [Klein et al 2011]. Affected persons typically have early mortality and often require total care because of dementia, hearing loss, and loss of ambulation from predominant sensory ataxia.
- HSN1F (OMIM 615632) is caused by pathogenic missense variants in ATL3 and is similar to HSN1D [Fischer et al 2014, Kornak et al 2014]
Hereditary sensory and autonomic neuropathy type III (HSAN3, familial dysautonomia, or Riley-Day syndrome) is caused by pathogenic variants in ELP1 (IKBKAP) and is inherited in an autosomal recessive manner. Prevalence of HSAN3 is high in individuals of Ashkenazi Jewish descent as a result of two founder variants that account for more than 99% of mutated alleles. HSAN3 is a sensory neuropathy characterized by prominent autonomic manifestation. Absence of tears (alacrima) with emotional crying is one of the cardinal features. Lingual fungiform papillae are also absent. Hypotonia and feeding difficulties contribute to delay in acquisition of motor milestones. Affected individuals have gastrointestinal dysfunction, nausea and vomiting crises, recurrent pneumonia, and cardiovascular instability culminating in autonomic crisis. Sensitivity to pain and temperature perception is reduced but usually not as profoundly as with the other HSAN disorders.
Hereditary sensory and autonomic neuropathy type IV (HSAN4, congenital insensitivity to pain with anhidrosis [CIPA]) results from the presence of two NTRK1 pathogenic variants. HSAN4 is characterized by profound sensory loss predominantly affecting perception of pain and temperature. As a consequence of the early onset of reduced pain perception, self-mutilating behavior (biting of tongue, lips, and fingertips) is common. Repeated fractures are secondary consequences. Anhidrosis caused by lack of sweat gland innervation results in poor thermoregulation and can cause recurrent febrile episodes which can be fatal. Intellectual disability is variable.
Hereditary sensory and autonomic neuropathy type V (HSAN5) (OMIM 608654) shows marked clinical overlap to HSAN4 and has been reported to be caused by pathogenic variants in NGF [Einarsdottir et al 2004, Carvalho et al 2011]. However, some cases of clinically diagnosed HSAN5 appear to be caused by NTRK1 pathogenic variants as well. HSAN5 is inherited in an autosomal recessive manner. In HSAN5 anhidrosis is less prominent than in HSAN4. Selective loss of deep pain perception, painless fractures, and joint deformities have been described for this entity.
Hereditary sensory and autonomic neuropathy type VI (HSAN6) (OMIM 614653) is characterized by dysautonomic symptoms, absent tearing, feeding difficulties, absent deep tendon reflexes, abnormal histamine test with no axon flare, distal contractures, motionless open-mouthed facies, severe psychomotor retardation, and early death [Edvardson et al 2012]. Only one affected family has been reported to date.
Congenital insensitivity to pain (CIP) may be caused by pathogenic variants in either SCN9A or SCN11A:
- Biallelic pathogenic loss-of-function variants in SCN9A [Cox et al 2006] cause the autosomal recessive channelopathy CIP. Individuals with CIP have painless injuries beginning in infancy but otherwise normal sensory responses. The complications of the disease follow the inability to feel pain, and most individuals have injuries to the lips or tongue caused by biting themselves in early childhood. Affected individuals usually have a history of unnoticed fractures. The insensitivity to pain appears to result from a defect in nociceptive transmission and not from axonal degeneration, as the nerves appear to be largely normal on examination. Individuals with SCN9A-related CIP have anosmia. See Congenital Insensitivity to Pain Overview.
- Heterozygous de novo pathogenic gain-of-function variants in SCN11A, encoding the voltage-gated sodium channel NaV1.9 (OMIM 615548) [Leipold et al 2013, Woods et al 2015], can also lead to CIP. Hyperhidrosis, muscular weakness, severe gastrointestinal motility disturbances, and intolerance to moderate heat have also been described in affected individuals.
Table 2.
Comparison of HSAN/Sensory Neuropathy Subtypes
| Subtype | Typical Onset Age | MOI | OMIM | Genes | Clinical Signs | Sural Nerve Biopsy 1 |
|---|---|---|---|---|---|---|
| HSAN1 | Adult | AD | 162400 613640 613708 615632 614116 | SPTLC1 SPTLC2 ATL1 DNMT1 ATL3 |
| Distal loss of unmyelinated & myelinated fibers |
| CMT2B | Adult | AD | 600882 | RAB7A |
| Reduced density of myelinated fibers; larger ones more affected |
| HSAN2 | Childhood | AR | 201300 613115 614213 | WNK1 RETREG1 KIF1A SCN9A |
|
|
| HSAN3 | Congenital | AR | 223900 | ELP1 (IKBKAP) |
|
|
| HSAN4 | Congenital | AR | 256800 | NTRK1 |
|
|
| HSAN5 | Congenital | AR | 608654 | NGF NTRK1 |
| Selective decrease of small myelinated & unmyelinated fibers |
| HSAN6 | Congenital | AR | 614653 | DST | Dysautonomic symptoms
| Not known |
MOI = mode of inheritance
ID = intellectual disability
- 1.
According to Schenone [2005]
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with hereditary sensory and autonomic neuropathy type II (HSAN2) the following evaluations are recommended:
- Neurologic examination to determine extent of sensory loss and involvement of autonomic and motor nervous system
- Nerve conduction velocity (NCV)
- Detailed family history
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Treatment is symptomatic and often involves a team including neurologists, orthopedic surgeons, and physiotherapists.
Training in the care of the sensory-impaired limb is important and includes self-examination especially of the feet for any signs of trauma. A diabetic clinic is a good source of advice. Appropriate shoes and socks are recommended.
It is best to prevent callous formation in neuropathic skin; once present, calluses should be treated with hydration and lipid-based unguents to prevent cracking and may require medical consultation.
Cleaning and protection of wounds on neuropathic limbs in combination with antiseptic treatment to eradicate infections help prevent osteomyelitis and amputations.
Surveillance
The feet in particular should be inspected daily for injuries and sources of wear.
Patients should be followed annually by centers with comprehensive care for diabetes and/or CMT.
Agents/Circumstances to Avoid
Avoid ill-fitting shoes or other sources of trauma to the feet or hands (e.g., use protective gloves when handling hot items when cooking).
Evaluation of Relatives at Risk
It is appropriate to evaluate at-risk sibs in early childhood in order to identify those who will develop sensory loss and would benefit from measures to prevent injury to limbs and/or self-mutilation. Molecular genetic testing can be used to clarify the genetic status of at-risk sibs if the pathogenic variants in the family are known.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.