A number sign (#) is used with this entry because of evidence that hereditary sensory and autonomic neuropathy type VI (HSAN6) is caused by homozygous or compound heterozygous mutation in the DST gene (113810) on chromosome 6p12.

Hereditary sensory and autonomic neuropathy type VI (HSAN6) is a severe autosomal recessive disorder characterized 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 (summary by Edvardson et al., 2012).

For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).

Edvardson et al. (2012) reported a large consanguineous family of Ashkenazi Jewish descent in which 3 infants and 1 fetus had a severe form of sensory and autonomic neuropathy with joint contractures. All had neonatal hypotonia with poor feeding and poor respiratory effort with apneic spells necessitating artificial ventilation. Features consistent with HSAN included alacrima and absent corneal reflexes with subsequent corneal scarring, decreased fungiform papillae, absent deep tendon reflexes, absence of an axon flare with intradermal histamine, recurrent hyperpyrexia, and episodic bradycardia or tachycardia with labile blood pressure. Two had episodic erythematous blotching of the skin. One was noted to have decreased pain response. Flexion contractions of the hands were present; 1 also had limited hip extension and 2 had clubfeet. Two had paucity of facial expression with persistently open mouth. Mild dysmorphic features, including low-set ears, high-arched palate, and small chin were noted in 1 infant. Brain MRI was normal in all 3 patients, and none had seizures. However, there was essentially no neurologic development, and all died by age 2 years. Edvardson et al. (2012) noted the phenotypic similarities to HSAN3 (223900).

Fortugno et al. (2019) reported 3 adult sibs, born to nonconsanguineous parents of Italian ancestry, with HSAN6. The female proband was first seen at age 56 years with poorly healing ulcerations of the feet and painless fractures since the age of 26 years that resulted in persistent osteomyelitis, disarticulations and amputations of the toes, and joint deformities. She also had autonomic disturbances and severe pain insensitivity. One of her brothers was first evaluated at age 63 years and presented with bilateral ulcerations of the feet associated with painless fractures since age 37 years with recurrent septic osteoarthritis, disarticulations and amputations of toes, and joint deformities. He also had autonomic disturbances, sensorineural hearing loss, pupillary abnormalities, urinary incontinence, and severe pain insensitivity. Another brother was examined at age 70 years with distal bilateral ulcerations of the feet with painless fractures since a young age that resulted in recurrence septic osteoarthritis, toe amputations, and joint deformities. All 3 patients were also diagnosed with type 2 diabetes.

Manganelli et al. (2017) identified 3 adult brothers affected with HSAN-VI who were born to healthy nonconsanguineous Italian parents. The brothers had onset in infancy of severely impaired pain sensitivity resulting in poor healing of distal ulcerations, finger or toe amputations, and joint deformities. Development was normal. Sensations to pain, touch, and vibration were reduced, and deep tendon reflexes were absent. The patients also had autonomic disturbances, including reduced sweating with heat intolerance in all 3, absent pupillary light reflexes in 2, chronic diarrhea in all 3, and erectile dysfunction in 1. Nerve conduction studies showed a severe axonal sensory neuropathy. A lack of sensory and autonomic nerve fibers was seen on skin biopsy.

The transmission pattern of hereditary sensory and autonomic neuropathy in the kindred reported by Edvardson et al. (2012) was consistent with autosomal recessive inheritance.

By homozygosity mapping followed by whole-exome sequencing in an Ashkenazi Jewish family with hereditary sensory and autonomic neuropathy type VI (HSAN6), Edvardson et al. (2012) identified a homozygous truncating mutation in the DST gene (113810.0001).

In 3 members of an Italian family with an adult form of HSAN6, Fortugno et al. (2019) identified novel compound heterozygous mutations in the DST gene: a nonsense mutation (K4330X; 113810.0004) and a missense mutation (A203E; 113810.0005) affecting a highly conserved residue in an isoform-specific N-terminal region of the dystonin protein. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Patient fibroblasts had defects in actin cytoskeleton organization and delayed cell adhesion, spreading, and migration, and the A203E mutation was shown to disrupt the binding of dystonin to actin. Affected individuals were seen in their fifties to seventies with ulcerations of the feet, painless fractures, amputations of the toes, and joint deformities. The authors proposed that homozygous truncating mutations result in a severe disorder with congenital defects and early lethality, whereas compound heterozygosity for a truncating and a missense mutation partially maintains dystonin protein expression and function and thus results in neuropathy that is compatible with an adult lifespan.

In 3 adult brothers, born to healthy nonconsanguineous Italian parents, with HSAN-VI, Manganelli et al. (2017) identified compound heterozygosity for 2 mutations in the DST gene (113810.0008-113810.0009) affecting only the neuronal isoform-a2. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family. Levels of the DST protein were absent or very low in neurons derived from induced pluripotent stem cells of the patients.