Hereditary sensory and autonomic neuropathy type 1 (ORPHA:36386)
A rare slowly progressive neurological disorder characterized by prominent predominantly distal sensory loss, autonomic disturbances in some patients, autosomal dominant inheritance, and juvenile or adulthood disease onset.
Epidemiology
The exact prevalence is unknown, but is estimated as very low.
Clinical description
Disease onset varies between the 2nd and 5th decade of life. Early onset is occasionally reported. The main clinical feature of hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a reduction of sensation sense, mainly distributed around the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Spastic paraparesis, or cough and gastroesophageal reflux have been observed in rare cases.
Etiology
HSAN1 is a genetically heterogenous condition with several loci and mutations in four genes (SPTLC1, SPTLC2, ATL1, ATL3) identified so far. DNMT1 gene variants also lead to a specific form of the disease, HSAN1E, clinically distinct due to the presentation of dementia and hearing loss.
Diagnostic methods
Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when complications such as bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the above mentioned genes. DNMT1-associated disease is clinically distinct from the other HSAN1 subtypes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counseling and prognosis.
Differential diagnosis
Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin tumors like amelanotic melanoma.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. However, availability depends on country-specific regulations.
Genetic counseling
Transmission is autosomal dominant; whilst several cases occur sporadically, genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Management of HSAN1 largely follows the guidelines given for diabetic foot care (removal of pressure to the ulcer and eradication of infection, followed by the use of specific protective footwear) and starts with early and accurate counselling of patients about risk factors for developing foot ulcerations. Preclinical and clinical trials are ongoing for SPTLC-associated disorders (L-Serine therapy).
Prognosis
The disorder is slowly progressive and may not influence life expectancy in many cases but is often severely disabling after a long duration of the disease. Early-onset severe cases are reported.

                            Last update: 
                            April 2024


                            - Expert reviewer(s): 
                            Pr Ingo KURTH