Hereditary sensory and autonomic neuropathy

Last update: December 10, 2018

Recommended panel testing at Breda Genetics for this condition:

Hereditary sensory and autonomic neuropathy (ATL1, ATL3, DNMT1, DST, ELP1, KIF1A, NGF, NTRK1, PRDM12, RETREG1, SCN11A, SCN9A, SPTLC1, SPTLC2, WNK1)

Summary

The hereditary sensory and autonomic neuropathies (HSAN), which are also referred to as hereditary sensory neuropathies (HSN) in the absence of significant autonomic features, are a genetically and clinically heterogeneous group of disorders associated with sensory dysfunction. These disorders are genetically heterogeneous and may be inherited in an autosomal dominant or recessive fashion.

Detailed clinical description

Hereditary sensory and autonomic neuropathy type 1A (HSAN1A) is an axonal form of hereditary motor and sensory neuropathy charcaterized 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. This form of HSAN is often associated with progressive sensorineural deafness. Motor involvement may be severe and is usually present in advanced stages of the disease. Muscle wasting and weakness first involves distal extremities, but then progresses to proximal involment, so that wheelchair may be necessary in the sixth or seventh decade. Occasional findings may be consistent with drenching sweating of the hands and feet and pupillary abnormalities. Visceral involvement is rare. Disease onset is reportedly between the second and the fourth decade, although particularly severe cases with congenital onset have also been described. HSAN1A is autosomal dominant and is casued by mutations in the SPTLC1 gene. The pheontype may resemble the one of Charcot-Marie-Tooth disease type 2 (CMT2) with prominent sensory loss with foot ulcers and shooting pains (and, in fact, CMT2 is part of differential diagnosis of HSAN1A).

HSAN1B is also known as HSN1 with cough and gastroesophageal reflux (GER). Unexplained chronic cough, which could progress to cough syncope, may be the first symptom. Sensory loss begins in the feet and legs between the third and fifth decades. No gene is known yet for HSAN1B.

HSAN1C is caused by heterozygous mutation in the SPTLC2 gene and is inherited in an autosomal dominant manner. The neuropathy is phenotypically similar to HSAN1A but usually without autonomic signs (although autonomic dysfunction such as anhidrosis has been reported in one case). Nerve conduction velocity studies indicates a mixed axonal and demyelinating sensorimotor neuropathy. Onset may be from 5 to 50 years. Presenting symptoms imay include loss of touch and vibration in the feet, dysesthesia and severe panmodal sensory loss in the upper and lower limbs, and distal lower limb sensory loss with ulceration and osteomyelitis necessitating amputation of the right great toe. Some patients may also show distal muscle weakness. Reported additional features include scoliosis, focal epilepsy, hyperreflexia of the upper limbs, and clenched hands.

HSN1D is caused by heterozygous mutation in the ATL1 gene and is transmitted in an autosomal dominant manner. HSAN1D is characterized by adult onset of a distal axonal sensory neuropathy affecting all modalities, often associated with distal ulceration and amputation as well as hyporeflexia, although some patients may show features suggesting upper neuron involvement.

HSN1E is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia. HSN1E is casued by heterozygous mutations in the DNMT1 gene.

HSN1F is an autosomal dominant sensory neuropathy affecting the lower limbs. Distal sensory impairment becomes apparent during the second or third decade of life, resulting in painless ulceration of the feet with poor healing, which can progress to osteomyelitis, bone destruction, and amputation. There is no autonomic involvement, spasticity, or cognitive impairment. HSN1F is caused by heterozygous mutation in the ATL3 gene (autosomal dominant inheritance).

HSAN2 is distinguished by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit predominantly affects lower limbs. 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 and painless fractures may be a complication. Autonomic dysfunction may include hyperhidrosis, tonic pupils, and urinary incontinence in advanced stages of the disease. HSAN2A is caused by mutation in the WNK1 gene, HSAN2B is caused by mutation in the RETREG1 gene (formerly known as FAM134B or JK1), HSAN2C is caused by KIF1A mutation, and HSAN2D is caused by SCN9A mutation.

HSAN3, also known as familial dysautonomia, is caused by homozygous or compound heterozygous mutation in the ELP1 gene (formerly known as IKBKAP gene) and is inherited in an autosomal recessive fashion. Autonomic disturbances are very prominent in HSAN3. Clinical features may include defective lacrimation, episodic hypertension, hyperhidrosis, cyclic vomiting, skin blotching, absence of lingual fungiform papillae with impaired taste, vasomotor instability, glomerulosclerosis, hypoactive or absent deep tendon reflexes, relative indifference to pain and temperature, incoordination, and emotional instability. Somatic growth is poor, and by 10 years of age, 85% of patients have scoliosis. Seizures with decerebrate posturing can follow breath-holding episodes.

HSAN4, also known as congenital insensitivity to pain with anhidrosis (CIPA), is caused by homozygous or compound heterozygous mutation in the NTRK1 gene (autosomal recessive inhertiance). The onset is in early infancy with episodic fevers, extreme hyperpyrexia and recurrent febrile convulsions (due to anhidrosis) as well as self-mutilation. The cardinal feature of HSAN4 is absence of or markedly decreased sweating. Pain and temperature perception are absent. Sensory insensitivity leads to self-mutilation, auto-amputation, and corneal scarring. Hypotonia and delayed developmental milestones are frequent in the early years, but normalize with age. Scoliosis may be present (20%).

HSAN5 is caused by homozygous mutation in the NGF gene (autosomal recessive inheritance). Only a small number of cases have been described in the literature. HSAN5 is characterized by loss of pain perception and impaired temperature sensitivity, in the absence of any other major neurological anomalies. Additional features include ulcers, self-mutilation and damaged joints.

HSAN6 is thought to be cause by mutations in the DST gene with autosomal recessive inheritance. However, just one family has been reported, so additional evidence should be warranted to confirm the disease-gene association. HSAN6 is a severe autosomal recessive disorder distinguished by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities including labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, areflexia, and absent axonal flare response after intradermal histamine injection.

HSAN7 is caused by heterozygous mutation in the SCN11A gene (autosomal dominant inheritance). The clinical history may be variably characterized by congenital inability to experience pain since birth resulting in self-mutilations, slow-healing wounds, multiple painless fractures, failure to thrive secondary to intestinal dysmotility, ongoing abdominal and urinary discomfort with chronic constipation. Mild muscle weakness and delayed motor development is also seen. The autonomic involvement is suggested by hyperhidrosis and gastrointestinal dysfunction necessitating temporary parenteral nutrition.

HSAN8 is caused by homozygous mutation in the PRDM12 gene (autosomal recessive inheritance) and is characterized by congenital insensitivity to pain resulting in ulceration to the fingers, tongue, lips, and other distal appendages. Affected individuals may also have decreased sweating and tear production.

Molecular genetics

HSAN and HSN are genetically quite heterogenous. Both autosomal dominant and recessive inheritance have been reported. So far, pathogenic mutations have been reported in the following genes: ATL1, ATL3, DNMT1, DST, ELP1, KIF1A, NGF, NTRK1, PRDM12, RETREG1, SCN11A, SCN9A, SPTLC1, SPTLC2, WNK1.

Differential diagnosis

The clinical differential diagnosis of HSAN and HSN include different subtypes of Charcot-Marie-Tooth disease type 2, Lesch-Nyhan syndrome (progressive self-injurious behavior), untreated phenylketonuria, diabetic neuropathy and leprosy. In particular for familial dysautonomia (HSAN3), the differential diagnosis includes Stüve-Wiedemann syndrome (LIFR gene mutations). When thinking in particular to congenital insensitivity to pain, one should also consider hypohidrotic/anhidrotic ectodermal dysplasia (EDA, EDAR, EDARADD gene mutations; lack of sweating and risk of hyperthermia), COL1A1- or COL1A2-related osteogenesis imperfecta (multiple fractures), and MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (absent pain responses from birth and developmental delay)

Testing strategy

Because of its genetic heterogeneity, it is recommended to test for HSAN and HSN by means of a next generation sequencing panel of genes. Breda Genetics offer HSAN and HSN genes in panels based on either Mendeliome, exome or full genome sequencing. As both point mutations and large deletions/duplications have been reported, both standard sequence analysis and copy number variation (CNV) analysis are recommended. Both studies are possible when doing next generation sequencing, thanks to the use of two differnt bioinformatics algorithms. The confirmation of one large deletion or duplication might require a second method in some cases (e.g. MLPA or qPCR). If the panel is negative, one may proceed to an add-on panel to test the genes included in the differential diagnosis or to the upgrade of the analysis of all data from exome or genome sequencing.

Recommended panel testing at Breda Genetics for this condition:

Hereditary sensory and autonomic neuropathy (ATL1, ATL3, DNMT1, DST, ELP1, KIF1A, NGF, NTRK1, PRDM12, RETREG1, SCN11A, SCN9A, SPTLC1, SPTLC2, WNK1)

References:

Hereditary Sensory and Autonomic Neuropathy Type II. Kurth I In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2010 Nov 23 [updated 2015 Feb 19]. PMID: 21089229

Congenital Insensitivity to Pain Overview. Schon K, Parker A, Woods CG. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2018 Feb 8. PMID: 29419974

OMIM: 162400608654256800614213608088615548613115614653223900616488615632201300613708613640614116

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